A review of the nature and activity of a general surgical service in Ireland. The steady increase in hospital costs has led to demands for closer scrutiny of activity levels, workloads and outcomes. This study sought to examine these parameters in a typical district general surgical unit in this country. In the five year period 1985-89, 11,227 inpatient and 3,354 outpatient procedures were performed; 83% of the inpatient procedures were elective and 17% were emergency surgical operations. All inpatient procedures were categorized: minor (41%), intermediate (42%) and major (17%). A prospective one year review in 1990/1991 confirmed the accuracy of the retrospective data. During that year 2,335 inpatient operations and 765 outpatient operations were performed, of which 80.5% of the inpatient operations were elective and 19.5% were emergency procedures. Of these 16.6% were major, 34.4% intermediate and 49% were minor operations. 60% of the operations were performed by consultants. The in-hospital surgical mortality for the 1 year prospective review was 1.35% and the perioperative mortality was 0.64%. The overall operation morbidity rate was 9% and the procedure-related morbidity was 4.7%. The wound infection rate was 2%. Of the common operations performed throughout the six year study period appendicectomies and external hernia operations accounted for 20% of the caseload; 14% were urological, 7% were breast and 6% were biliary operations. The average waiting time for elective admissions was less than 4 weeks. The average length of hospital stay and the bed occupancy rates did not change.


Contemporary risk factors for sudden infant death in an Irish population--a case control study. This case-controlled study examines some recently implicated risk factors for Sudden Infant Death Syndrome (S.I.D.S.) in Irish infants. Irish S.I.D.S. infants are lighter at birth than controls (3463g) compared to (3542g) and boys out-number girls by a ratio of 1.3:1. S.I.D.S. infants are more frequently: breast-fed (42% vs 25%) and sleep in a location other than the parent's bedroom (54% vs 21%), but start solids at a similar age and appear not to be sicker prior to death than the control group. This study highlights the frequency of symptoms of possible ill-health (i.e. snuffles and being "chesty") in well infants during the first months of life with 32% of the control group having snuffles and 35% described as "chesty". In addition these symptoms are frequently treated with antibiotics with 31% of the control group having already received antibiotics by 2 months of age. A majority of S.I.D.S. infants were described as cold when found (52%) with 39% described as warm and 15% as sweaty. Obviously the recently implicated role of overheating may be relevant in the latter 15% of S.I.D.S. cases. In this series, 88% of infants had died by 6 months of age. Of the 97 parents of S.I.D.S. infants questioned, 78 had subsequently become pregnant by the time the study was conducted at an average time of 5 months post the S.I.D.S. event.


The correlation between clinical diagnosis of knee pathology and findings at arthroscopy. 175 patients referred for arthroscopy were studied prospectively to assess the accuracy of clinical examination supplemented by standard radiology in the evaluation of knee symptoms. Clinical diagnosis of medial meniscal tears was inaccurate while greater confidence could be placed in the diagnosis of anterior cruciate ligament and lateral meniscus tears. Clinical accuracy rates could be improved if patients with minimal symptoms were excluded from arthroscopy examination.


Hyperthyroidism associated with acute suppurative thyroiditis. Acute suppurative thyroiditis is a rare condition with potentially serious complications. It has been suggested that hyperthyroidism may be a feature in occasional cases but this has been poorly documented. We describe a patient in whom acute suppurative thyroiditis caused transient hyperthyroidism.


Colo-rectal carcinoma 1975 and 1990: no improvement in the stage of disease at resection. There is no overall consensus as to what screening patterns should be adopted for individuals of average risk for colo-rectal carcinoma. The single most important prognostic factor in survival is the stage of the colo-rectal neoplasm at the time of resection. Consequently significant resources have been directed to early detection while the disease is at a curative stage. To assess the impact of widespread availability of faecal occult blood testing and large bowel endoscopy we prospectively examined all large intestine specimens resected for carcinoma in 1990 and compared them with specimens resected for colonic carcinoma in 1975. We excluded adenomatous polyps with malignant change which had been treated by snaring at colonoscopy, without subsequent colectomy, as their precise Duke's staging was so difficult. In any event, their numbers were small (> 5 in 1990). Our study shows that despite the resources targeted at early diagnosis of colo-rectal carcinoma resection of tumours at a prognostically favourable stage has not been improved in the 25 years since 1975.


The role of designated driver programs in the prevention of alcohol-impaired driving: a critical reassessment. We review the "designated driver" concept and the current debate over its role in preventing alcohol-impaired driving. In our view, the focus on this strategy by broadcasters, the alcohol industry, and various public service groups has deflected attention from other alcohol-related problems that account for the vast majority of deaths and injuries associated with alcohol use. This focus has also distracted many public health advocates and policymakers from the bigger and more important jobs of increasing public awareness of the social, environmental, and economic factors that influence alcohol consumption and promoting debate on legislation and other public policy solutions to alcohol-impaired driving. As part of a comprehensive strategy, we strongly encourage a renewed focus on "sobriety checkpoints," strict enforcement of laws against alcohol sales to minors, alcohol advertising reform, increased excise taxes, and other public policy initiatives supported by the Surgeon General. These measures will curb underage and heavy alcohol consumption and will create a legal and social environment in which individuals are motivated to avoid impaired driving through several alternative strategies, including but not limited to the use of designated drivers.


Mammography usage and the health belief model. Regular screening mammograms for asymptomatic women are the most effective method for early detection of breast cancer. This study assessed the relative influence of Health Belief Model (HBM) constructs on prior mammography usage and the intention to obtain mammograms with data from a sample of 1,057 women over the age of 35 years residing in an urban community in the United States. Covariance structure analysis with latent variables was used initially to perform a confirmatory factor analysis of indicators of Socioeconomic Status (SES), Perceived Susceptibility, Perceived Barriers, Perceived Benefits, Cues to Action, Prior Mammography, and Future Intentions. Once a plausible factor structure was confirmed, a predictive path model was tested with Future Intentions and Prior Mammography as the outcome variables. Cues to Action, operationalized as a physician influence variable, particularly impacted Prior Mammography, and Perceived Susceptibility was the most powerful predictor of Future Intentions. SES only related significantly to Perceived Barriers, and Cues to Action, and did not directly influence Prior Mammography and Future Intentions. HBM predictor variables alone accounted for the relationship between previous mammography experience and intentions to obtain mammograms in the future. Health education implications and an applied outreach program are discussed.


A three-year evaluation of the know your body program in inner-city schoolchildren. The impact of the Know Your Body (KYB) comprehensive school health education program was evaluated in a sample of first through sixth-grade students from New York City, using two analytic strategies: a longitudinal cohort and a "posttest only" cohort. In both cohorts, program impact was examined between condition (i.e., KYB vs. no-treatment comparison group) as well as within condition (i.e., low, moderate, and high student exposure). Students in the longitudinal cohort (n = 1,209) who were exposed to high implementation teachers had significantly (p < .05) lower total plasma cholesterol and systolic blood pressure at 3-year posttest than comparison students. Students in the posttest only cohort (n = 3,066) who had high implementation teachers showed significantly (p < .05) lower total plasma cholesterol, systolic blood pressure, self-reported intake of meat and desserts, as well as higher health knowledge and self-reported intake of "heart healthy" foods and vegetables than comparison students. In both cohorts, program effects for several outcome variables were linearly related to level of student exposure to the curriculum, suggesting a dose-response effect. While several methodologic limitations may have influenced study outcomes, these data nonetheless appear to confirm that the KYB program can have a significant positive impact on the knowledge, behavior, and selected risk factors of students in primary grades and that efforts to disseminate and evaluate school health education programs should include strategies to monitor and enhance teacher implementation.


Patient attitudes concerning health behaviors during pregnancy: initial development of a questionnaire. The major determinant of infant mortality in the United States is low birthweight (LBW). Health behaviors related to LBW are inadequate prenatal care, poor nutrition, smoking, and moderate to heavy alcohol use. Before interventions can be designed to assist women in modifying these health behaviors, more must be understood about their causes. The Health Belief Model (HBM) is a framework for analyzing beliefs that motivate health behaviors and is well established as a model for understanding health behavior decisions. The chief aim of this study was to develop an instrument to assess women's health beliefs during pregnancy. Questions for the instrument were generated around the four major constructs of the HBM: perceived susceptibility, seriousness, benefits, and barriers. Four focus group interviews, a literature review, and consultation with an HBM expert provided content for questions. The questionnaire was administered to a convenience sample of 127 women. The measurement models were tested using confirmatory factor analysis. Parsimony was achieved by reducing the original 106-item scale to 64 items. The final instrument provides support for the HBM but not for all of its discrete constructs.


The impact of tailored self-help smoking cessation guides on young mothers. It has been suggested that tailoring self-help materials for specific target populations will increase their effectiveness. This study tested the value of a self-help guide tailored specifically for women with young children. These women were recruited through a media campaign that encouraged smokers to call the Cancer Information Service (CIS) for assistance in stopping smoking. Women smokers with young children (under the age of 6) who called the CIS were given telephone counseling on quitting and were mailed one of three stop smoking guides. One third of callers received Quitting Times, a guide written specifically for women with young children; one third received the American Lung Association guide, Freedom from Smoking for You and Your Family; and one third received Clearing the Air, a guide developed by the National Cancer Institute. Six months after calling the CIS, these women were contacted by telephone to assess changes in smoking behavior. Overall, 12.5% of the women reported not smoking for at least 1 week at the time of the 6-month follow-up interview. There were no significant differences between subjects in the three groups in use of the self-help guides, methods used to attempt quitting, and quitting behavior. Findings from this study do not support the hypothesis that using a tailored stop smoking guide increases the targeted audience's cessation rate or affects quitting-related behavior. However, it should be noted that the smokers who called were predominantly in the contemplation or action stages.


Mitogenic activities of heteroglycan and heteroglycan-protein fractions from culture medium of Lentinus edodes mycelia. The water soluble material (LEM) was prepared from the solid culture medium in which Lentinus edodes mycelia were growing actively. An alcohol insoluble material was prepared from LEM and subjected to Sepharose 6B gel filtration. The void fraction (LAP1) was composed mainly of xylose-rich heteroglycan and protein. From LAP1, a heteroglycan fraction (LAF1) was prepared by DEAE-Sepharose CL-6B column chromatography. LAP1 and LAF1 enhanced the incorporation of [3H]thymidine into mouse splenic cells (SPs). At each of the optimum doses, the rate of the incorporation was about 10 times as high with LAF1 as with LAP1. Such mitogenic responses were not induced in nylon-column effluent SPs and thymocytes. sIg-expressed cells were responsive to LAF1, but not to LAP1. Moreover, with each fraction, the incorporation was enhanced more in plastic adherent splenic cells (ADs) than in SPs. The flow cytometric assay revealed that the number of Mac-1+ cells is about 13 times as many in ADs as in SPs and that the number of Ly-5+ or Thy-1.2+ cells is considerably reduced in ADs compared with that in SPs. Thus, the present studies suggest that LAP1 and LAF1 act as mitogens predominantly for mouse splenic macrophages and/or monocytes.


Cd-metallothionein in liver and kidney of goldfish (Carassius auratus): effects of temperature and salinity. Treatment of goldfish with Cd, by intraperitoneal injection, resulted in Cd-metallothionein (Cd-MT) synthesis mainly in liver and kidney. The relative amount of Cd sequestered by liver metallothionein was always greater in fish maintained at 20 degrees C compared to those reared at 10 degrees C, indicating a temperature dependence of metallothionein biosynthesis; in the kidney this dependence was not so clearly evident. Changes in MT levels induced by adapting fish to different salinities did not correlate with the salinity change.


Morphological heterogeneity of secretory granules of rat Clara cells: an immunocytochemical study. The secretory granules of rat bronchiolar Clara cells were classified into different types by their ultrastructural appearances followed by immunocytochemistry using anti-rat 10 kDa Clara cell-specific protein (10 kDa CCSP) antibody. One predominant type was the oval to round granule (type A granule), of which the matrix was composed of a map-like mixture of electron-dense and less electron-dense material. Another predominant type was the rod-shaped granule (type B granule). The content of type B granules varied from a finely fibrillar (type B1 granule) to an electron-dense, rod-like (type B3 granule) structure. Various intermediate types (type B2 granule) between type B1 and B3 granules were also found. Small cytoplasmic vesicles were found occasionally in close proximity to type B2 or B3 granule. Another type of granule (type C granule) was large, up to 8 microns in diameter, and contained a moderately electron-dense amorphous matrix. Both type A and C granules stained at a similar density with the antibody. The nascent form of type A granules, which was found in the vicinity to the trans face of the Golgi apparatus, was also labeled. On the other hand, the labeling density of type B granules varied: type B1 granules were almost devoid of immunolabeling, whereas type B3 granules were intensely labeled. Type B2 granules stained with the antibody; however, the labeling density was less than that of type B3 granules. The small cytoplasmic vesicles of type B2 granules were labeled.(ABSTRACT TRUNCATED AT 250 WORDS)


In vivo treatment with a monoclonal antibody to interferon-gamma neither affects the survival nor the incidence of lupus-nephritis in the MRL/lpr-lpr mouse. The effects of the in vitro treatment with a mAb (DB-1) that neutralizes mouse IFN-gamma on the development of the SLE-like syndrome in MRL/lpr-lpr (MRL-lpr) mice were studied. The results show that the i.p. administration of 2.6 mg/week of DB-1 from the 12th to the 20th week of age neither affected the survival nor the incidence and severity of lupus nephritis in MRL-lpr mice. This study argues against the pathogenic relevance of IFN-gamma in this experimental model of human SLE.


Comparative lectin histochemistry on taste buds in foliate, circumvallate and fungiform papillae of the rabbit tongue. Taste buds (TB) in the foliate, circumvallate and fungiform papillae of the rabbit tongue were examined with lectin histochemistry by means of light (LM) and electron (EM) microscopy. Biotin- and gold-labeled lectins were used for the detection of carbohydrate residues in TB cells and subcutaneous salivary glands. At the LM level, the lectins of soybean (SBA) and peanut (PNA) react with material of the foliate and circumvallate taste pores only after pretreatment of the section with neuraminidase. This indicates that the terminal trisaccharide sequences are as follows: Sialic acid-Gal-GalNAc in O-glycosylated glycoproteins or Sialic acid-Gal-GlcNAc in N-glycosylated glycoproteins. In fungi-form taste buds the lectins of Dolichos biflorus (DBA) and Helix pomatia (HPA), also specific to GalNAc residues, are reactive without preincubation with neuraminidase. Wheat germ agglutinin (WGA), specific to GlcNAc, reacts with TBs of all papillae; and the lectin from Ulex europaeus (UEA I), specific to fucose, binds to individual TB cells. The presence of sialic acid may protect mucus or other glycoproteins in TB cells and inside the taste pore from premature enzymatic degradation. In a post-embedding EM procedure on LR-White-embedded tissue sections, only gold-labeled HPA was found to bind especially on membrane surfaces of the microvilli which protrude into the taste pore; however HPA did not bind to the electron-dense mucus inside the taste pore. The mucus situated in the trough and at the top of the adjacent epithelial cells also is strongly HPA-positive, but is of different origin and composition than that found in the taste pore. These results demonstrate distinct carbohydrate histochemical differences between fungiform and circumvallate/foliate taste buds. The different configuration of galactosyl residues and the occurrence of mannose in circumvallate and foliate TBs leads to the suggestion that the lectin reactivities of TBs are not only due to the presence of mucins, but also to N-linked glycoproteins, possibly with a hormone-like paraneuronal function. A possible relationship to v. Ebner glands in these papillae is discussed.


Bromodeoxyuridine (BrdU) immunocytochemistry by exonuclease III (Exo III) digestion. A new procedure is described to generate single-stranded DNA by exonuclease III (Exo III) digestion for bromodeoxyuridine (BrdU) immunocytochemistry on tissue sections. We compared this procedure with the most widely used procedure of DNA denaturation with 2 N HCl. In vivo and in vitro pulse and continuous labelling of tissues and cells were used. The specimens were fixed in formalin, ethanol, glutaraldehyde, Carnoy's, Bouin's or Zamboni's fixative and embedded in paraffin or used unfixed as cryostat sections or cytospin preparations. After Exo III digestion, BrdU substituted DNA was detected irrespective of the fixation procedure applied. The optimal protocol for nuclease digestion appeared to be simultaneous incubation, of 10 Units Exo III per ml EcoRI buffer and anti-BrdU monoclonal antibody at 37 degrees C. The advantages of Exo III digestion for BrdU immunocytochemistry compared to acid denaturation were: less non-specific nuclear background reactivity, no DNA renaturation, less DNA loss, optimal nuclear morphology, increase in antibody efficiency and the possibility for simultaneous detection of acid-sensitive tissue constituents. Disadvantages of the Exo III digestion are decreased sensitivity and the need for more rigorous pepsin pretreatment. We conclude that Exo III digestion of DNA is an appropriate alternative for acid denaturation for BrdU immunocytochemistry on sections of pulse-labelled specimens.


Subtractive antibody to a human immunosuppressive lymphokine affinity isolates a suppressive factor and blocks its function. Hybridoma suppressor factor(s) (HSF), secreted by a human thymus hybridoma (8E-24) established in this laboratory, suppresses Ig as well as IL-2 synthesis by peripheral blood mononuclear cells (PBMC). To aid in the characterization of this lymphokine, we prepared a subtractive antibody to HSF using the products of the hybridoma parent cell line to generate antibodies to irrelevant proteins. The concentrated supernatant fluid of the hybridoma parent cell line (CEM) was used to generate rabbit antibodies and titers of anti-CEM were monitored by enzyme immunoassay (EIA). Next, to remove factors shared by both the parent cell line and hybridoma, the concentrated supernatant fluid of 8E-24 (crude HSF) was passed over an immunoaffinity column, composed of protein A beads coupled to anti-CEM. The 'subtracted' HSF, termed partially purified HSF, was shown to be suppressive in vitro and was then used to prepare a second rabbit antisera. Using partially purified HSF as antigen, the presence of specific antibody was monitored by EIA. This antibody (anti-HSF) was used to prepare another immunoaffinity column by covalently coupling this antibody to protein A beads. Factors bound and then eluted from this affinity column were shown to inhibit IL-2 production by PBMC in a manner similar to HSF. Specific activity of the affinity purified HSF was 50 times that of partially purified HSF. Furthermore, the suppressive activity of affinity purified HSF was abrogated in the presence of anti-HSF. Western blot analysis performed on the concentrated crude HSF, using both the anti-HSF and anti-CEM antibodies, revealed the presence of several bands that selectively reacted with anti-HSF and not anti-CEM. Each of these bands were present in the affinity purified HSF. Of particular interest due to their similar size to the suppressive agent are a band at 12 kDa that reacts selectively with anti-HSF and is detected in crude and affinity purified HSF and a band at 10 kDa. In summary, this protocol resulted in the detection and separation of hybridoma specific proteins within the predicted size range of the suppressive lymphokine.


Adduct formation at C-8 of guanine on in vitro reaction of the ultimate form of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine with 2'-deoxyguanosine and its phosphate esters. We examined the reactivity of the N-hydroxyamino derivative of a carcinogenic heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), after its O-acetylation with four 2'-deoxyribonucleoside 3'-monophosphates. 32P-Postlabeling analysis demonstrated that the levels of adducts with 2'-deoxyguanosine 3'-monophosphate were much higher than those with the other three nucleotides. 1H-NMR, mass spectral and UV absorption spectral analyses of the major adducts formed by N-acetyoxy-PhIP with 2'-deoxyguanosine and with its phosphate esters indicated that PhIP bound at the C-8 position of guanine, as previously demonstrated with other heterocyclic amines.


Atrophic gastritis and stomach cancer risk: cross-sectional analyses. The relationship between atrophic gastritis and stomach cancer risk was investigated in case-control analyses involving 387 cases with stomach cancer and 5,422 control subjects who received gastroscopic examination at Aichi Cancer Center Hospital from April, 1985 to March, 1989. The presence of atrophic gastritis, the degree and extension of the atrophy and the presence of granularity and erosion were diagnosed endoscopically by six gastroenterologists. The prevalence of atrophic gastritis increased with age and was higher in males than in females. The relative risk (RR) of stomach cancer was 5.13 (95% confidence interval (CI): 2.79-9.42) if a subject had any type of atrophic gastritis. The risk further increased with advancing degree of atrophy and increasing extension on the greater and lesser curvatures. The RR associated with severe atrophy was 7.73 (95% CI: 3.95-15.12). These associations remained significant when analyzed by sex and age. The presence of granularity and erosion did not much affect the estimated risks. A clear difference in risk appeared in the analyses by histological type of cancer. The RR associated with atrophic gastritis was 24.71 (95% CI: 3.46-176.68) for the intestinal type and 3.49 (95% CI: 1.77-6.87) for the diffuse type. These findings may suggest a need for intensive follow-up of patients with severe atrophic gastritis.


Species difference among experimental rodents in induction of P450IA family enzymes by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Rats, mice, hamsters and guinea pigs were given an i.p. injection of 2-amino-1-methyl-6-phenyl-imidazo[4,5-b]pyridine (PhIP), a protein-derived pyrolysate component present in cooked foods, and inductions of cytochrome P450 (P450) in the liver and kidney of these animals were examined. The activity and amount of P450s corresponding to the rat P450IA1 and P450IA2 were assessed by means of a bacterial mutation test using 3 carcinogenic heterocyclic aromatic amines including PhIP as substrates and by Western blotting with a monoclonal antibody reactive with both P450IA1 and P450IA2. In rats, PhIP induced P450IA1, P450IA2 and a new but unspecified P450 isozyme in the liver, and induced P450IA1 in the kidney. However, PhIP induced none of these P450 isozymes in mice, hamsters and guinea pigs.


Significance of strain and sex differences in the development of 252Cf neutron-induced liver tumors in mice. Mouse liver tumors occurring in C3H/HeN, C57BL/6N and C3B6F1 hybrid (C3H x C57BL) were studied following 252Cf fission neutron irradiation. Three strains of mice of both sexes (about 30 mice/group) were irradiated once with 252Cf at doses of 0, 12.5, 50 and 200 cGy. The groups were observed for 13 months after irradiation. The incidence of liver tumors in the non-irradiated controls was 0% in both sexes of C57BL/6N, 11.7% in males and 0% in females of C3B6F1 and 39.5% in males and 11.4% in females of C3H/HeN mice. In the four strains of mice thus far studied, including B6C3F1 hybrid (C57BL x C3H) which was previously studied, 252Cf irradiation has increased the tumor incidence dose-dependently in males and in females, but less effectively in females. The mean number and size of liver tumors were clearly correlated with tumor incidence. The incidence was always highest in C3H/HeN mice of both sexes, followed by B6C3F1, C3B6F1 and C57BL/6N mice. The influence of sex hormones was studied in B6C3F1 mice of both sexes after 200 cGy of 252Cf irradiation. In males, the incidence of liver tumors was significantly decreased from 55.2% to 23.3% and 25.9% after orchidectomy, and in females it was slightly decreased from 27.6% to 14.8% and 18.8% after ovariectomy. Supplementation of testosterone in orchidectomized mice did not restore the occurrence of liver tumors.


ras mutations in endocrine tumors: mutation detection by polymerase chain reaction-single strand conformation polymorphism. To elucidate the molecular basis for endocrine tumorigenesis, ras mutations in human endocrine tumors were analyzed using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. Mutations of the H-, K-, N-ras genes were examined in genomic DNAs from 169 successfully amplified primary endocrine tumors out of 189 samples. Four out of 24 thyroid follicular adenomas analyzed contained mutated N-ras codon 61, and one contained the mutated H-ras codon 61. One of the 19 pheochromocytomas revealed mutation of the H-ras codon 13. No mutations of the ras gene were detected in pituitary adenomas, parathyroid tumors, thyroid cancers, endocrine pancreatic tumors, and adrenocortical tumors. Based on these findings we conclude that activation of the ras gene may play a role in the tumorigenesis of a limited number of thyroid follicular adenomas and pheochromocytomas, and that mutation of the ras gene is not frequent in other human endocrine tumors.


DT-5461, a new synthetic lipid A analogue, inhibits lung and liver metastasis of tumor in mice. We have investigated the antimetastatic effect of a new synthetic lipid A analogue, of low endotoxicity, DT-5461, against two highly metastatic tumor cell lines, L5178Y-ML25 T-lymphoma and B16-BL6 melanoma cells in mice. Four intermittent i.v. administrations of DT-5461 at intervals of 4 days resulted in a significant inhibition of liver metastasis caused by i.v. injection of L5178Y-ML25 cells and lung metastasis of B16-BL6 cells in the experimental metastasis models. Intraperitoneal and intranasal administrations as well as i.v. administration of DT-5461 were also effective in preventing lung metastasis of the melanoma cells. Multiple administrations of DT-5461 before the surgical excision of primary tumors significantly reduced the number of lung colonies of melanoma cells and primary tumor size. Similarly, this treatment modality after the surgical excision of primary tumors showed a greater reduction of lung tumor colonies as compared with lipopolysaccharide, a synthetic lipid A (No. 506) and its analogue as well as untreated control in the spontaneous lung metastasis model. Furthermore, the group that received DT-5461 after the inoculation of lymphoma or melanoma cells showed significantly enhanced survival rate compared with the untreated control. These results suggested that DT-5461 may be therapeutically useful for the inhibition of tumor metastasis.


Altered glycosylation of membrane glycoproteins associated with human mammary carcinoma. N-Linked sugar chains of normal mammary gland, mammary carcinomas (primary lesion), and axillary lymph node metastases of mammary carcinomas were released from their membrane preparations by hydrazinolysis and their structures were analyzed. Fractionation using a Datura stramonium agglutinin (DSA)-Sepharose column revealed that the metastasized carcinomas contain more than twice as much DSA-binding oligosaccharides as the normal gland, and the primary carcinomas contain an intermediate amount. These oligosaccharides were elucidated to have tri- and tetraantennary structures containing the GlcNAc beta 1-->6(GlcNAc beta 1-->2)Man group with and without N-acetyllactosamine repeating units. Lectin blot analysis of membrane glycoproteins and histochemical staining of tissues using biotinylated DSA indicated that these glycosylation changes predominantly occur in a limited number of glycoproteins with apparent molecular weights of 90, 160, and 210 kilodaltons, and mammary carcinomas are distinguishable from normal gland by their intense intracytoplasmic staining.


Inhibition by fibrin coagulation of lung cancer cell destruction by human interleukin-2-activated killer cells. We examined the effect of fibrin coagulation on tumor cytotoxicity mediated by human lymphokine (IL-2)-activated killer (LAK) cells. LAK cells were induced from peripheral blood mononuclear cells (MNC) by culture with recombinant IL-2 for 4 or 5 days, and LAK cell-mediated cytotoxicity against tumor cells was assessed by 51Cr release assay in the presence or absence of plasma from normal subjects and lung cancer patients. Plasma did not affect the phase of induction of LAK activity by IL-2, but dose-dependently inhibited the effector phase of LAK cell-mediated cytotoxicity against Daudi cells. Similar inhibition of LAK cell-mediated cytotoxicity was observed on pretreatment of Daudi cells and human lung cancer cell lines with human fibrinogen plus thrombin. A parallel relationship was found between the amount of fibrinogen in plasma of lung cancer patients and inhibition of LAK cytotoxicity. This inhibition was reduced by addition of anticoagulants (heparin or argatroban). These findings suggest that fibrin coagulation on tumor cells protects them from LAK cell-mediated tumor cytotoxicity in malignant lesions and that a combination of an anticoagulant drug and IL-2/LAK therapy may be effective for treatment of lung cancer patients.


Fluorouracil catabolism in the combination treatment of cyclophosphamide, methotrexate and fluorouracil. The CMF-regimen is amongst the most effective chemotherapeutic approaches in the treatment of breast cancer. It is generally accepted that the efficacy of the combination of the three agents used in the regimen, i.e., cyclophosphamide (CY), methotrexate (MTX) and fluorouracil (FUra), is based on interactions between the drugs at the intratumoral level. In WAG/Rij rats we previously demonstrated that change of FUra clearance at the first day of the CMF-regimen occurs owing to concomitant CY + MTX. In the present study clearance of FUra and the first product of FUra catabolism, FUraH2, were monitored at day 1 and day 8 of the regimen upon treatment with single agent FUra (F), MTX + FUra (MF), CY + FUra (CF), and CY + MTX + FUra (CMF). At the first day of treatment, FUra and FUraH2 systemic exposure was demonstrated to be increased in CMF-treated rats owing to concomitant CY+MTX. At the eighth day of treatment it was found that repeated CY administration during the previous seven days in CF-treated rats resulted in increased FUra and FUraH2 systemic exposure and therefore increased the dose of FUra artificially. It is concluded that altered FUra clearance owing to extratumoral interactions by concomitant CY and MTX contributes to the efficacy of the CMF-regimen.


The orbital glands of the chelonians Pseudemys scripta and Testudo graeca: comparative histological, histochemical and ultrastructural investigations. The orbital glands of the chelonians Pseudemys scripta and Testudo graeca were investigated at the histological, histochemical and ultrastructural levels. Four acinar cell types were seen in the harderian gland of P. scripta on the basis of histochemical reactions and ultrastructure. Secretory granules were of 2 types, one showing moderate electron density with an electronlucent core, the other being smaller and more osmiophilic with an electron-dense core. In the harderian gland of T. graeca only 2 glandular cell types were found; one type contained secretory granules with a dense core surrounded by a wide zone of lower density. Acinar cells of the anterior lacrimal gland in both species were of 2 types, one being of mucous type. In the harderian gland and in the lacrimal gland of both species, one cell type appeared not to be involved in the secretion of organic material. These cells contained numerous tightly packed mitochondria among which were abundant clumps of glycogen; the cell membrane was specialised at both edges. This cell type was similar ultrastructurally to the 'salt cells' described in the salt-secreting glands of various marine vertebrates, i.e. of the cells involved in transport processes. These combined histological, histochemical and ultrastructural studies have allowed us to distinguish orbital glands. In the past, the harderian and lacrimal glands in chelonians have often been mistaken for one another.


The cutaneous branches of the superior gluteal nerve with special reference to the nerve to tensor fascia lata. Cutaneous branches from the superior gluteal nerve were studied in 39 half pelves (18 right, 21 left) of 23 adult Japanese cadavers. A detailed description of the branches is not currently available in the literature. Most of these branches perforated tensor fascia lata and were distributed to the centre of the lateral gluteal region.


Characterisation of ramified microglial cells: detailed morphology, morphological plasticity and proliferative capability. Several cellular properties of brain microglia in the rat were investigated using both whole tissue and cultures of dissociated cerebral cortical cells. As revealed by thiamine pyrophosphatase histochemistry, tissue microglia possessed a highly distinctive cellular morphology. Stained microglia showed similar overall features of morphology and distribution in both preparations; however, the cells in culture displayed some slight differences from those of the tissue, including larger somata and less developed processes. Through studying living ramified cells in culture, both morphological plasticity as evidenced by patterned variations in soma size and mitotic activity were directly confirmed. It was concluded that ramified microglia definitely possess proliferative capability, and this may reduce the need for blood cell recruitment in brain immune responses. In addition, cultured microglia exist in a somewhat more activated state than those in normal tissue, and in some instances undergo further activation as macrophages. This cortical tissue culture system should provide an amenable preparation for investigating the regulation of microglial function.


The foramen meningo-orbitale and its relationship to the development of the ophthalmic artery. The incidence of the foramen meningo-orbitale is reported from a sample of 50 adult dried skulls. The foramen meningo-orbitale is not an inconsistent finding, being identifiable in half of the samples studied. Multiple foramina may exist. Although the location of the foramen meningo-orbitale is not fixed, it lies along or near the suture leading superolaterally from the superior orbital fissure. The foramen represents the remnant of an embryonic conduit for the supraorbital division of the stapedial artery en route to the orbit and the developing ophthalmic artery. An alternative, more medial, pathway exists through the superior orbital fissure. The embryonic anastomosis that occurs between the internal and external carotid systems does not occur at the level of this foramen, but closer to the optic nerve as a portion of the primitive 'ring' artery. The term 'stapedial-ophthalmo-lacrimal' foramen is proposed to proclaim the embryonic significance of this foramen.


The hamster harderian gland: a combined scanning and transmission electron microscopic investigation. Scanning electron microscopy of the epithelial cells of the female hamster harderian gland reveals a range of surface features. Some cells exhibit a uniform covering of microvilli while others, often with swollen apices, are relatively devoid of microvilli. Surface pitting is frequent for all cells; pits represent regions of exocytotic lipid vacuole release. A similar range of surface appearances occurs in the male gland but here cells with uniform microvilli represent type I cells (characterised by small lipid vacuoles) while swollen cells with sparse microvilli are type II cells (characterised by large lipid vacuoles). It is suggested that different cell forms represent a single cell type in varying activity states. Luminal debris is often marked, consisting chiefly of lipids. Solid porphyrin accretions, sometimes surrounded by neutrophils, are numerous in female (but not male) glands. Interstitial mast cells are also numerous in the female gland. The gland contains fenestrated capillaries and extensive lymphatics. The duct of the gland, which has received little attention, possesses ciliated cells, nonciliated cells and basal cells. Ciliated cells possess kinocilia and relatively tall thin microvilli, as well as some lipid vacuoles. Nonciliated cells bear shorter microvilli, apically located mucoid granules, and lamellar formations of smooth endoplasmic reticulum. The basal cells are squat and pyramidal; their lateral walls, which interdigitate with the main duct cell types, show pronounced folding.


Human intervertebral disc acid glycosaminoglycans. Alcian blue critical electrolyte concentration (CEC) staining of intervertebral discs (annulus and nucleus of cervical, thoracic and lumbar discs) distinguished 3 groups where CEC staining correlated with age (less than 3 months; from 3 months to 5 years; over 10 years). The CEC increased markedly (implying increased sulphation of the glycosaminoglycans) in the period of maturation (fetal life to 10 years) and then remained constant throughout adult life. This is at variance with accepted views which attribute such changes to degenerative changes in old age. The major part of the CEC increase occurred after the disappearance of blood vessels from the disc, which is almost complete by 4 years. Our results are compatible with the hypothesis that keratan sulphate replaces chondroitin sulphate, functionally, in conditions of oxygen lack.


Delamination of neuroepithelium and nonneural ectoderm and its relation to the convergence step in chick neurulation. We have analysed the characteristics of the neuroectoderm-nonneural ectoderm meeting point at several axial levels in relation to the mechanics of neurulation in each level. The results show wide differences at cephalic and somitic levels. At cephalic levels, where convergence plays an important role, the delamination process appears at the beginning of the convergence step. This phenomenon produces a major isolation of the basal lamina, forming a space between this structure and the epithelial sheet in whose basal surface a new basal lamina begins to form. This cavity contains abundant extracellular matrix stained with ruthenium red (RR) and tannic acid (TA), and its increase in volume correlates with the progressive convergence of neural folds. At somitic levels, where the convergence is not important, delamination involves the progressive formation of a half-moon-shaped cavity. This structure appears between a dorsal attachment point, in the tip of neuroectodermal wall, and a ventral attachment point which coincides with the point of bending that determines the bilateral furrow, if it exists. In this small cavity, delamination is not related to an isolation of basal lamina. The RR-staining of the extracellular matrix in this cavity is scarce and the volume increase is smaller than in the cephalic region. These results are discussed in terms of neural fold convergence and neural tube closure.


RT97- and calcitonin gene-related peptide-like immunoreactivity in lumbar intervertebral discs and adjacent tissue from the rat. The innervation of rat intervertebral disc and adjacent ligamentous tissue has been investigated using 2 antibodies, RT97 and anti-calcitonin gene-related peptide. Immunoreactivity to the peptide was found in many fibres throughout the long ligaments around the intervertebral discs and in the periosteum, especially associated with vascular channels entering the vertebral bodies. Few of the immunoreactive fibres entered the annular lamellae of the disc tissue. Most of those which terminated did so as fine fibres which lay close to, or in, the interlamellar spaces of the outer annulus fibrosus. Calcitonin gene-related peptide-like immunoreactivity was also found in more complex endings in the longitudinal ligaments and rarely within the annulus fibrosus. RT97-immunoreactivity was also present in the complex endings and associated fibres. Conversely, RT97-immunoreactivity was apparent only in a few fine filamentous fibre endings. This suggested that the majority of fine filamentous, or free, nerve endings were of an unmyelinated sensory origin. Alternatively, those endings of a more complex nature, which were RT97-immunoreactive, were of a myelinated sensory origin. No immunoreactivity to either antibody was seen in the inner annular or nuclear tissue. It was therefore concluded that the sensory innervation of the rat intervertebral disc has both myelinated and unmyelinated components, the latter being more extensive. Both types of innervation appear to be restricted to the outermost rings of the annulus fibrosus.


Morphometry of cupromeronic blue-stained proteoglycan molecules in animal corneas, versus that of purified proteoglycans stained in vitro, implies that tertiary structures contribute to corneal ultrastructure. Isolated, purified small chondroitin (dermatan) sulphate proteoglycans from corneas of cow and rabbit and cow sclera were stained with Cupromeronic blue in 'model' experiments. The lengths and thicknesses of the images were compared with those of the same proteoglycans stained in the tissue, using the critical electrolyte concentration principle to give specificity for sulphated proteoglycans, and keratanase 1 or chondroitinase ABC digestion to distinguish between chondroitin and keratan sulphate. Corrections for orientation of the stained glycan filaments within the section plane were made to convert the observed lengths to true average lengths. Observed lengths of stained chondroitin (dermatan) sulphate were greater than those of keratan sulphate, both in models and tissues, in agreement with published data from biochemical and rotary-shadowing studies, in both species. Corrected (true) average lengths of stained isolated chondroitin (dermatan) sulphate proteoglycans were slightly, but not significantly, longer than expected from rotary shadowing or biochemical measurements. Keratan sulphate lengths were similarly somewhat longer. The data support the idea that Cupromeronic blue acts as a scaffold that helps maintain polyanion shape against distortion on staining. Stained filaments in tissues were sometimes over twice the length of isolated stained proteoglycans, suggesting that 2 glycan chains were aligned end-to-end. Thicknesses of proteoglycan filaments suggested that at least 2 glycan chains were aligned side-by-side, both in models and in tissues. A scheme for proteoglycan tertiary structure in cornea is proposed, in which glycan chains may bridge collagen fibrils in duplexed forms similar to those observed in rotary shadowed preparations.


Parvalbumin and calbindin immunoreactivity in the cerebral cortex of the hedgehog (Erinaceus europaeus). To investigate the morphology and distribution of nonpyramidal neurons in the brain of insectivores, parvalbumin and calbindin 28 kDa immunoreactivity was examined in the cerebral cortex of the hedgehog (Erinaceus europaeus). Parvalbumin-immunoreactive cells were found in all layers of the isocortex, but in contrast to other mammals, a laminar organisation or specific regional distribution was not seen. Characteristic parvalbumin-immunoreactive neurons were multipolar cells with large ascending and descending dendrites extending throughout several layers. Calbindin-immunoreactive neurons were similar to those found in other species, although appearing in smaller numbers than in the cerebral cortex of more advanced mammals. The morphology and distribution of parvalbumin- and calbindin-immunoreactive cells in the piriform and entorhinal cortices were similar in hedgehogs and rodents. Parvalbumin-immunoreactive cells in the hippocampal complex were pyramidal-like and bitufted neurons, which were mainly found in the stratum oriens and stratum pyramidale of the hippocampus, and in the stratum moleculare and hilus of the fascia dentata. Heavily stained cells were found in the deep part of the stratum granulare. Intense calbindin immunoreactivity occurred mainly in the granule cell and molecular layers of the dentate gyrus and in the mossy fibre layer. The most outstanding feature in the hippocampal complex of the hedgehog was the extension of calbindin immunoreactivity to CA1 field of the hippocampus, suggesting, in agreement with other reports, that mossy fibres can establish synaptic contacts throughout the pyramidal cell layer.


Quantitative study of the development and maturation of human oesophageal innervation. By 8 wk gestation, the human fetal oesophagus is identifiable as a hollow epithelium-lined tube with primitive nerve and muscle precursors present. From 8-16 wk gestation, the muscle layers and innervation mature until fetal swallowing commences at 16 wk. This study examines quantitatively the development and maturation of nerve fibres and cell bodies within the oesophagus using histochemistry. Oesophageal samples (n = 35) from 8 wk gestation to 28 months of age and adults (n = 3) were immunostained using antisera for the general nerve marker, protein gene product (PGP 9.5), the glial tissue marker S100, and the synaptic vesicle protein synaptophysin (p38). Histochemical staining for NADH diaphorase enzyme activity was also used to identify neurons. Computer-assisted image analysis of the muscularis externa permitted detailed quantification of cell size, nerve density and myenteric (plexus) fraction. At 8 wk gestation, PGP and synaptophysin were present in immature neurons throughout the cytoplasm, but from 10 wk synaptophysin was localised solely at nerve synapses. S100 immunoreactivity was also detected from 8 wk gestation onwards and was confined to glial tissue. Nerve cell size increased with maturation from 6 microns at 8 wk gestation to 20 microns at term and 21 microns at 28 months. The numbers of cells, nerve density (% area occupied by nerves throughout section) and myenteric fraction (% area occupied by ganglion cells and nerve fibres within the myenteric plexus) all peaked at 16-20 wk gestation and, whereas the number and density then fell towards adult levels, the myenteric fraction fell during the late second trimester and became constant from 30 wk gestation.(ABSTRACT TRUNCATED AT 250 WORDS)


High incidence of the median artery of the forearm in a sample of recent southern African cadavers. Observations of the presence of the median artery, providing substantial blood supply to the hand, were conducted on 96 dissected forearms of 15 adult African females and 49 adult males. The artery has a much higher incidence (27.1%) than previously reported by any author. There is no significant difference in its occurrence between sexes, nor between right and left limbs. The artery seems to occur more often bilaterally than unilaterally. The presence of the artery is not related to age. From a theoretical standpoint it is difficult to accept that a structure present in more than 1 in 4 of individuals should be considered an 'anomaly' or a 'variant'. A different approach to description of normal human anatomy is therefore necessary--that of presenting alternative anatomical patterns of equal standing rather than a single 'normal' pattern.


A variant of flexor carpi ulnaris causing ulnar nerve compression. Anatomical variations of the muscles and nerves around the wrist are common. Knowledge of such variations is derived from 2 sources: anatomical dissections and clinically reported cases. We present a case of duplication of the tendon of flexor carpi ulnaris with splitting of the ulnar nerve. The ulnar slip of the tendon was inserted into the pisiform bone and the radial slip into the proximal phalanx of the ring finger. The anatomical literature and the clinically reported cases of variations of the flexor carpi ulnaris are reviewed.


Structural variations in the jugular foramen of the human skull. The jugular foramen was examined in 300 Anatolian skulls from the 17th and 18th centuries. In 61.6% the foramen was larger on the right and in 26% on the left, with the remainder being of almost equal size. An obvious dome caused by a superior jugular bulb was present bilaterally in 49%, on the right only in 36%, on the left only in 6%; it was absent bilaterally in 10.3%. Complete bony septation occurred in 5.6% on the right and in 4.3% on the left, partial septation was observed in 2.6% on the right and in 19.6% on the left. Another foramen which is completely separated by a spicule of bone and which transmits the inferior petrosal sinus was present in 5.6% of skulls on the right and in 4.6% on the left.


Interference with interparietal growth in the human skull by the tectum synoticum posterior. The tectum synoticum posterior, which is one of the 3 skull roof elements of the chondrocranium, interferes with the growth of the human interparietal bone, thus giving rise to lateral incisures in the bone. Our observations on the developmental fate of the incisures strongly suggest that the sutura mendosa is the remnant of these incisures.


A rare anomaly of 5 ossicles in the pre-interparietal part of the squamous occipital bone in north Indians. Examination of 125 adult north Indian skulls revealed a rare anomaly of 5 large ossicles in the upper central part of the squamous occipital bone. Their location and possible derivation are briefly discussed.


Intracellular axonemes within ciliated cells in the tracheal epithelium of domestic pigs. Extended aggregates of intracellular axonemal derivatives can be seen within the apical cytoplasm of ciliated cells of apparently healthy domestic pigs. Such alterations were observed in 15 out of 20 animals. Complete (9 + 2) or incomplete (8 + 2 - 5 + 2) intracellular axonemes were found which sometimes arose from mature, irregularly arranged kinetosomes. In addition, bundles of single microtubules and microtubular pairs were found. In previous investigations on the ciliated epithelium of different mammals, intracellular axonemes were investigated only under pathological or experimental conditions. Our findings indicate that these alterations also occur in healthy animals. The extended aggregates of intracellular axonemal derivatives are more likely to be due to a failure of ciliary maturation than to a degradation of incorporated mature cilia.


Cytoarchitectonic and quantitative Golgi study of the hedgehog supraoptic nucleus. A cytoarchitectural study was made of the supraoptic nucleus (SON) of the hedgehog with special attention to the quantitative comparison of its main neuronal types. The main purposes were (1) to relate the characteristics of this nucleus in the hedgehog (a primitive mammalian insectivorous brain) with those in the SONs of more evolutionarily advanced species; (2) to identify quantitatively the dendritic fields of the main neuronal types in the hedgehog SON and to study their synaptic connectivity. From a descriptive standpoint, 3 neuronal types were found with respect to the number of dendritic stems arising from the neuronal soma: bipolar neurons (48%), multipolar neurons (45.5%) and monopolar neurons (6.5%). Within the multipolar type 2 subtypes could be distinguished, taking into account the number of dendritic spines: (a) with few spines (93%) and (b) very spiny (7%). These results indicate that the hedgehog SON is similar to that in other species except for the very spiny neurons, the significance of which is discussed. In order to characterise the main types more satisfactorily (bipolar and multipolars with few spines) we undertook a quantitative Golgi study of their dendritic fields. Although the patterns of the dendritic field are similar in both neuronal types, the differences in the location of their connectivity can reflect functional changes and alterations in relation to the synaptic afferences.


The effects of clenbuterol on satellite cell activation and the regeneration of skeletal muscle: an autoradiographic and morphometric study of whole muscle transplants in mice. The beta-2 agonist clenbuterol was tested for its effect on the proliferation of satellite cells in transplanted skeletal muscles. Using autoradiographic techniques it was found that satellite cells in clenbuterol treated transplants began proliferating earlier than in control animals. The effect of clenbuterol on the growth of regenerating muscle fibres was also examined using morphometric techniques, which manifested itself as hypertrophy of the fibres when compared with the controls.


The effects of pre- and posttransplantation exercise on satellite cell activation and the regeneration of skeletal muscle transplants: a morphometric and autoradiographic study in mice. The effects of pre- and posttransplantation exercise on satellite cell activation, and the eventual regeneration of skeletal muscle transplants, were studied histologically, morphometrically and autoradiographically. It was found that satellite cells in these transplants were synthesising DNA 30 h after transplantation, and the transplants appeared to be revascularising at 60 h after surgery. Respectively, this was 18 and 12 h earlier than found in previous studies on nonexercising muscle using the same techniques. The morphometric analysis showed hypertrophy of the muscle fibres of the exercised transplants when compared with controls, and also an increase in the capillarity of the exercised transplants.


Anatomical aspects of the lacrimal gland of the tufted capuchin (Cebus apella). In the tufted capuchin (Cebus apella) the main lacrimal gland is composed of 2 distinct portions with an intraorbital and extraorbital localisation, interconnected by a bridge of glandular tissue which crosses the lateral orbital wall through the lateral orbital fissure located in the sphenozygomatic suture. The intraorbital lacrimal gland is flattened and extremely thin, with a variable outline. It lies on the upper and outer third of the globe of the eye, and the aponeurosis and the belly of the lateral rectus muscle, extending antero-posteriorly from the upper lateral angle of the orbit midway along the orbital cavity. The extraorbital lacrimal gland is compact, halfmoon-shaped, with 3 surfaces, 3 borders and 2 extremities. It lies in the temporal fossa between the temporalis muscle and the temporal surface of the zygomatic bone, fitting into a depression in this bone, and totally surrounded by adipose tissue. The secretory cells have a flocculent appearance and either low or high density. They possess a basal region containing the nucleus and rich in granular endoplasmic reticulum, and an apical region filled with secretory granules varying in size, form and density.


Characterisation of secondary spermatocytes in the marbled newt (Triturus marmoratus). Secondary spermatocytes in the marbled newt (Triturus marmoratus) were identified by means of cytophotometric quantification of nuclear DNA in the testicular lobules containing primary spermatocytes in advanced stages of the first meiotic division (from pachytene onwards) and newly formed spermatids. The nucleus of secondary spermatocytes has an intermediate size between that of primary spermatocytes and round spermatids and was characterised by the presence of abundant masses of dense chromatin and the absence of a nucleolus. At the prophase the chromatin masses were located at the periphery of the nucleus. The ultrastructural study revealed that the nuclear envelope displayed blebs and that the cytoplasm was very similar to that of primary spermatocytes including the presence of smooth endoplasmic reticulum whorls, multiple small dictyosomes, and a proacrosomal-like granule near the nucleus. This granule stained weakly with aqueous PTA and was observed in about 6% of secondary spermatocytes. Many of the mitochondria were grouped beneath the plasma membrane. Approximately 2% of these cells presented an axoneme which was not associated with other flagellar components.


Microvessel and astroglial cell densities in the mouse hippocampus. In order to study the factors responsible for glucose uptake in the mouse hippocampus, microvessel and astroglial cell densities were measured and compared in each laminal region. Microvessel density was examined on histologically prepared sections after injection of Indian ink and measured by means of an image analyser. Astroglial cell density was determined after the cells were stained immunohistochemically. Microvessel and astroglial cell densities were determined in 10 different hippocampal structures. Microvessel and astroglial cell densities were strongly correlated in all layers except the pyramidal cell layers. The highest density of perfused microvessels was found in the stratum lacunosum-moleculare, compared with other regions, and the lowest values were found in the stratum lucidum and dentate granular cell layer. Among pyramidal cell layers, microvessel density in sector CA3a was significantly higher than that in CA1.


The ampulla of the ductus deferens in man: morphological and ultrastructural aspects. In order to compare the histology of the ampulla of the ductus deferens with that of the other segments of the duct in man, the seminal vesicle and the adjacent 13-15 cm of the ductus deferens were obtained during cystectomy from 15 adult men, and were processed for light and electron microscopy. Each ductus deferens specimen was divided into 3 segments: segment A or initial segment (the most proximal to the testis) showing a smooth outer surface and, on section, a uniform lumen and absence of mucosal invaginations; segment B (1.5-4 cm) showing a smooth outer surface and, on section, small cavities in the mucosa; and segment C or ampulla (3-4 cm), which was easily recognisable because of the cerebriform pattern on its outer surface. Segment A showed the usual histological pattern reported in studies of the human ductus deferens. Segment B consisted of mucosa, muscularis mucosae, submucosa, muscular coat and adventitia. The epithelial lining formed multiple branched invaginations in the lamina propria and submucosa giving rise to glandular structures. The lumen of the duct and the glands were lined by the same cell types: (1) basal cells; (2) mitochondrion-rich cells; and (3) columnar cells with the ultrastructural features of glycoprotein-secreting cells. The latter cells could be classified into 3 subtypes suggesting different stages of development: (a) with abundant mitochondria; (b) with abundant rough endoplasmic reticulum; and (c) with abundant secretory granules. Segment C or the ampulla showed the same histology as segment B except for the presence of many diverticula in the ampulla.(ABSTRACT TRUNCATED AT 250 WORDS)


Antibacterial profile of flurithromycin, a new macrolide. The in-vitro activity of flurithromycin against common respiratory tract Gram-positive (85 strains) and Gram-negative (44 strains) pathogens, and a collection of anaerobes (125 strains) was compared with that of erythromycin, cefixime, amoxycillin, co-amoxiclav, ciprofloxacin, netilmicin and clindamycin. Flurithromycin possessed the same spectrum and potency of antimicrobial activity as erythromycin. The presence of 50% human serum in the test media enhanced the activity of flurithromycin against all isolates, with the exception of Streptococcus pyogenes. Flurithromycin induced a post-antibiotic effect (PAE) that ranged from 0.25 h (Haemophilus influenzae) to 3.5 h (Streptococcus pneumoniae) for all strains tested. The presence of serum increased or diminished the duration of the PAE, depending on the strain being analysed. No interaction between flurithromycin and the other drugs tested was observed by the checkerboard technique, but when the time-kill system was used, 35 cases of synergy were noted out of 120 tests performed (29%), of which 15 (43%) were with Moraxella catarrhalis, 12 (34%) with Staphylococcus aureus, four (11%) with H. influenzae and the remainder with S. pneumoniae and S. pyogenes. Netilmicin produced most synergic interactions. Antagonism was not detected by either methods.


The combined effect of iron chelators and classical antimalarials on the in-vitro growth of Plasmodium falciparum. The emergence of drug resistant malaria has prompted an intensified search for new antimalarials or combinations of such drugs. Iron chelating agents may represent a new approach to antimalarial treatment and could possibly be used in combination with classical antimalarials. Plasmodium falciparum (FCR-3) strain used at a 1% haematocrit, was subjected to various combinations of the classic antimalarials (chloroquine, pyrimethamine and quinine) and iron chelating agents (desferrioxamine and 2,2'-bipyridyl) in vitro. Tritiated hypoxanthine incorporation was used to determine the growth of the malarial parasites. The iron chelating agents and classic antimalarials when tested alone were found to inhibit the growth of the late stages of the parasite. The combination of the classic antimalarials and iron chelating agents resulted in additive effects on the in-vitro growth of P. falciparum.


Decreased susceptibility of penicillin-resistant pneumococci to twenty-four beta-lactam antibiotics. The in-vitro activity of 24 beta-lactam antibiotics was compared using three groups of pneumococci and an agar dilution method comprising 100 penicillin-susceptible, 100 intermediately penicillin-resistant, and 100 highly penicillin-resistant pneumococcal strains. Our results show that intermediately penicillin-resistant and highly penicillin-resistant pneumococci had decreased sensitivity to other beta-lactam agents. According to their relative in-vitro activity, the antimicrobials were classified into three groups. The first group included drugs more active than penicillin (imipenem, meropenem, cefotaxime, ceftriaxone, and cefpirome), which could be useful for the treatment of infections due to penicillin-resistant strains. The second group showed slightly lesser activity than did penicillin, and included: ampicillin, cefdinir, cefuroxime, cefoperazone, azlocillin, mezlocillin, piperacillin, cephalothin, and cefamandole. The remaining antibiotics (oxacillin, cefixime, ceftizoxime, cefetamet, cefaclor, ceftazidime, cefoxitin, cefonicid, and latamoxef) showed poor activity against penicillin-resistant strains, precluding their use for empirical treatment in areas with a high prevalence of penicillin-resistant strains.


Rapid increase in the prevalence of high-level aminoglycoside resistance among enterococci isolated from blood cultures during 1989-1991. At St Elizabeth Hospital Medical Center in Youngstown, Ohio, USA, the first blood culture isolate of Enterococcus faecalis with high-level gentamicin resistance (MIC > 2000 mg/L) was seen in 1985, and the prevalence of high-level gentamicin resistance among enterococci isolated from blood cultures during 1985-8 was 9%. During the period 1989-91, the prevalence of high-level gentamicin resistance among enterococci isolated from blood cultures increased to 35% (44 of 126 strains). Increases in the prevalence of high-level resistance to amikacin, tobramycin, netilmicin, kanamycin and streptomycin were also demonstrated. Ten of 44 strains (23%) with high-level gentamicin resistance did not exhibit high-level resistance to streptomycin. Of the 126 strains of enterococci, 52% had high-level resistance to at least one aminoglycoside.


Antibiotic sensitivity of ribosomes from wild-type and clindamycin resistant Bacteroides vulgatus strains. The sensitivity to different antibiotics of in-vitro polyuridylic acid-dependent polypeptide synthesizing system from Bacteroides vulgatus RYC18F6 and two clindamycin-resistant derivatives was studied. The ribosomes from the resistant strains were not affected by concentrations of up to 0.1 mM clindamycin and lincomycin. In contrast, streptogramin B was found to cause strong stimulation of the clindamycin-resistant polymerizing systems. The modified ribosomes from the resistant strains were more sensitive to other antibiotics like sparsomycin and chloramphenicol. The data indicate that resistance in these B. vulgatus mutant strains is due to alteration of the ribosome structure.


Inhibition of Chlamydia trachomatis growth in mouse fibroblasts by liposome-encapsulated tetracycline. The in-vitro susceptibility of Chlamydia trachomatis to liposome-encapsulated tetracycline was determined and compared with free tetracycline. Anionic, cationic and neutral small unilamellar liposomes were used in this study. Chlamydia-infected mouse fibroblast monolayers were continuously exposed to varying concentrations of antibiotic, incubated for 48 h and Giemsa stained. The minimum inhibitory concentration (MIC) for anionic, cationic and neutral liposomes containing tetracycline were 0.38, 0.08 and 0.04 mg/L, respectively. This was approximately 2, 10, and 20 times more efficient than free tetracycline (MIC, 0.79 mg/L). Neutral liposomes displayed no visible toxic side-effects on the host cells. When compared with free tetracycline, neutral liposomes were the most efficient for the delivery of inhibitory concentrations of tetracycline to chlamydia-infected mouse fibroblast L cell cultures.


In-vitro effects of liposome-encapsulated amphotericin B (AmBisome) and amphotericin B-deoxycholate (Fungizone) on the phagocytic and candidacidal function of human polymorphonuclear leucocytes. Liposomal amphotericin B (AmBisome), at concentrations > or = 20 mg/L, and amphotericin B-deoxycholate (DC) (Fungizone), at concentrations > or = 1 mg/L, both caused a significant reduction in neutrophil uptake of Candida albicans blastospores following simultaneous addition of the drug with the blastospores. The reduction in uptake was seen also in tests in which blastospores were pre-treated with the drugs for 60 min, but was not detected in tests in which neutrophils were pre-treated for 60 min. Neither formulation affected neutrophil killing of C. albicans blastospores following simultaneous addition of the drug with the blastospores. However, previous treatment of the neutrophils with either formulation at a concentration of 20 mg/L led to enhanced killing of ingested blastospores. The results suggest that much higher concentrations of liposomal amphotericin B (AmBisome) are required to produce deleterious effects on neutrophil phagocytic function than with the conventional formulation of the drug.


Comparative activity of glycopeptide antibiotics against coagulase-negative staphylococci embedded in fibrin clots. The susceptibilities of 16 strains of coagulase-negative staphylococci to vancomycin and teicoplanin were determined by three microdilution methods run in parallel; (i) a reference method in which the medium was Iso-Sensitest broth, (ii) a method in which the organisms were suspended in plasma and (iii) one in which the bacteria were incorporated into a fibrin clot. In comparison with the reference method there was a less than two-fold change in the geometric mean MICs of both antibiotics in plasma, while in clot the increase was 12-fold for vancomycin and 28-fold for teicoplanin. MBCs showed a similar trend although the increase was greater for teicoplanin. These results suggest that protein binding may have a much greater impact on antimicrobial activity when the mobility of the protein is reduced within a clot.


In-vitro and in-vivo evaluation of the antistaphylococcal activity of S-5556, a new 16-membered macrolide. During recent years, a resurgence of interest in the macrolides had led to the discovery of new derivatives of erythromycin with improved antibacterial activity and pharmacokinetic properties. In this study the in-vitro and in-vivo antistaphylococcal activity of S-5556, a 16-membered macrolide, was evaluated. In vitro, S-5556 was slightly less active than erythromycin against methicillin-susceptible Staphylococcus aureus. In contrast, it had superior activity for methicillin-resistant S. aureus (MRSA); several of these strains with inducible resistance to the macrolides-lincosamides-streptogramins group were susceptible to S-5556 whereas erythromycin was inactive. The combination of S-5556 with oxacillin was synergic for most MRSA strains tested. In vivo, a single prophylactic dose of S-5556 prevented 75%-100% of the cases of acute staphylococcal subcutaneous foreign body infection in a guinea pig-model. In a rat-model of chronic implant infection due to a methicillin- and erythromycin-resistant S. aureus strain, S-5556 significantly decreased the bacterial concentration around the foreign material, however resistant mutants emerged.


The anti-inflammatory effect of erythromycin in zymosan-induced peritonitis of mice. The anti-inflammatory effect of erythromycin was investigated using zymosan-induced peritonitis in mice. When mice were given erythromycin 10 mg/kg/day po for 28 days, a marked suppression of inflammatory responses, including the reduced influx of leucocytes, plasma exudation and prostaglandin E2 synthesis, was observed. However, neither a 7-day treatment with erythromycin nor a 28-day treatment with clindamycin suppressed the response. The anti-inflammatory activity induced after a 28-day treatment with erythromycin was comparable to the anti-inflammatory effect conferred by a 2-day treatment with dexamethasone 40 microgram/mouse/day. Thus, these data confirm previous studies which show that erythromycin can exert an anti-inflammatory effect when used over long periods of time.


Amoxycillin-resistant oral streptococci and experimental infective endocarditis in the rabbit. The ability of three amoxycillin-resistant strains of Streptococcus sanguis 254, 24 and 297 (MIC 40 mg/L) to cause infective endocarditis (IE) in the rabbit was investigated. These strains all produced infection in the rabbit, as did an antibiotic sensitive control strain NCTC 7864. Prophylactic amoxycillin (400 mg/kg body weight) administered one hour before bacterial challenge prevented 80% of the animals developing IE irrespective of the challenging strain. It is concluded that amoxycillin-resistant strains of S. sanguis can cause IE and that amoxycillin prophylaxis can still be effective against these bacteria.


Efficacies of amphotericin B lipid complex (ABLC) and conventional amphotericin B against murine coccidioidomycosis. The comparative activities of two preparations of amphotericin B against Coccidioides immitis were investigated. These preparations were a deoxycholate suspension (conventional amphotericin B) and a lipid-based formulation, amphotericin B lipid complex (ABLC). In-vitro susceptibility testing demonstrated that the MICs of ABLC were < or = 0.25 mg/L and of conventional amphotericin B were 0.5 mg/L for C. immitis. However, conventional amphotericin B was at least four-fold more fungicidal, with a minimum fungicidal concentration of 4.0 vs > 16 mg/L for ABLC. The therapeutic efficacies were tested in murine models of acute systemic coccidioidomycosis. Female CD-1 mice were infected iv with C. immitis arthroconidia to establish high (> 50%) or low (< 50%) mortality models. Therapy with conventional amphotericin B or ABLC was given three times per week for two weeks starting three days post-infection. Controls received no therapy or drug-free diluent only. Survival was tallied up to 49 days post-infection and the fungal cfu counts in spleen, liver, and lungs of all survivors were determined. In the low mortality study all treated mice survived and all therapy regimens reduced infection in all organs. All mice given ABLC 6.6 or 13.2 mg/kg/dose and 80% given ABLC 16.5 mg/kg/dose, as well as 90% given conventional amphotericin B 0.66 mg/kg/dose were free of infection; all controls remained infected. In two high mortality studies, all mice given ABLC 0.66-20 mg/kg/dose or conventional amphotericin B 0.22 or 0.66 mg/kg/dose survived compared with 0-20% of controls. Thirty per cent of uninfected mice given ABLC 20 mg/kg/dose and 40% given conventional amphotericin B 2.0 mg/kg/dose died due to drug toxicity. Mice given ABLC or conventional amphotericin B had lower residual cfu counts of C. immitis in all organs than did controls. Sixty to one hundred per cent of mice given ABLC regimens > or = 6.6 mg/kg/dose were cured, whereas all controls and 50-60% of mice receiving the highest non-toxic conventional amphotericin B regimen (0.66 mg/kg/dose) remained infected. At equal non-toxic amphotericin B doses, conventional amphotericin B was more effective than ABLC in reducing cfu in infected organs.(ABSTRACT TRUNCATED AT 400 WORDS)


Multiple dose pharmacokinetics, safety, and effects on faecal microflora, of cefepime in healthy volunteers. In a randomized, double-blind, placebo-controlled study in 12 healthy volunteers pharmacokinetics, safety and impact on the faecal microflora of cefepime were determined. For eight days eight volunteers received cefepime 1000 mg bd by constant infusion over 30 min, four volunteers received placebo. Concentrations of cefepime in serum and urine were measured by bioassay and HPLC. The correlation between the two methods was good and the bioassay results were used for pharmacokinetic calculations. The faecal flora was analysed twice before the study, twice during the study and four times after cefepime administration. There were no significant differences in the pharmacokinetic parameters between days 1 and 8. The following values (mean +/- S.D.) represent day 1. The maximum concentration of 72.69 +/- 12.2 mg/L immediately after infusion decreased to 0.56 +/- 0.17 mg/L after 12 h. The mean 12 h recovery in urine was 93.69 +/- 2.14%. Pharmacokinetic parameters based on an open two-compartment model were as follows (mean +/- S.D.): area under the curve, 142.65 +/- 18.35 mg.h/L; elimination half-life 110.3 +/- 8.3 min; steady state volume of distribution 16.0 +/- 1.9 L/70 kg; total clearance, 107.0 +/- 16.0 mL/min; renal clearance 103.0 +/- 15.2 mL/min. No accumulation was observed during the eight day study period with cefepime at this dosage; trough levels on days 2-7 ranged from 0.52 +/- 0.26 mg/L to 0.90 +/- 0.33 mg/L. In the cefepime treated group the following side-effects were noted: headache (5), fatigue (4), nausea/stomach ache (2), soft stool (2), transient scotoma (1). Side-effects in the placebo group were: headache (2) fatigue (3), nausea/stomach-ache (1), soft stool (2) and photophobia (1). During cefepime administration a decrease in the number of Escherichia coli and bifidobacteria in faeces was observed, whereas Bacteroides spp. and clostridia showed a slight increase. The numbers of faecal bacteria returned to normal 20 to 48 days after the study was completed.


Bronchoalveolar distribution of cefuroxime axetil and in-vitro efficacy of observed concentrations against respiratory pathogens. The concentrations of cefuroxime in human alveolar macrophages (AM), epithelial lining fluid (ELF), bronchial mucosal biopsies and serum were measured after a single dose, equivalent to 500 mg of cefuroxime base, given in the form of the orally-administered pro-drug, cefuroxime axetil. Fourteen patients undergoing fibreoptic bronchoscopy with bronchoalveolar lavage were studied. The mean ELF concentration was 0.7 mg/L, that of bronchial biopsies was 1.8 mg/kg and that of serum 3.5 mg/L. AM-associated cefuroxime was detected in nine patients. To assess the in-vitro activity of the concentrations achieved at the potential sites of infection, clinical isolates of common respiratory pathogens were exposed to two concentrations of cefuroxime, based on the observed concentrations in ELF and bronchial mucosa. ELF and mucosal site concentrations were effective against Streptococcus pneumoniae (except one strain with reduced susceptibility to benzyl penicillin) and Haemophilus influenzae. The ELF concentration was less effective against Moraxella catarrhalis.


Pharmacokinetics of aztreonam in patients with liver cirrhosis and ascites. The pharmacokinetics of aztreonam were studied in six healthy male subjects (group I) and 12 male patients with post-hepatitis liver cirrhosis and ascites. Patients were allocated into two groups according to serum creatinine; group II included nine patients with serum creatinine. < or = 15 mg/L while group III included three patients with serum creatinine > 15 mg/L. Aztreonam 1 g was given as iv bolus injection. Aztreonam reached a peak concentration in the ascitic fluid (AF) of 6.2 +/- 2.3 mg/L at 4 h, and of 8.7 +/- 4.4 mg/L at 6 h in groups II and III respectively. The level of the drug in AF 24 h post-dosing was still higher than MIC90 for Enterobacteriaceae in most patients. The half-life of elimination from serum increased significantly (P > 0.001) from 1.82 +/- 0.14 h in group I to 6.6 +/- 2.1 h and to 8.87 +/- 0.2 h in groups II and III, respectively. Both the central and the terminal volumes of distribution were higher in cirrhotic patients than in healthy volunteers. Liver cirrhosis and ascites resulted in a significant increase (P < 0.001) of the total body clearance (Cl) of aztreonam from 84 +/- 8 mL/h/kg in group I to 209 +/- 87 mL/h/kg in group II. However, the concomitant association of mild renal impairment in group III abolished this increase; Cl in group III was 122 +/- 50 mL/h/kg. The AUC0-infinity serum was 137.5 +/- 12.2, 78.5 +/- 24.9 and 151 +/- 42 mg.h/L in groups I, II and II, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Acquired platelet function defects.

Acquired platelet function defects. Platelet dysfunctions, especially acquired forms, are common causes of hemorrhage, especially when associated with trauma or surgery. Although the hereditary platelet function defects are generally quite rare, hereditary storage-pool disease is common enough to be suspected in an individual, usually a child, with characteristic historical and clinical findings. The acquired platelet function defects, especially those resulting from drugs, are very common and should promptly be suspected in patients developing easy and spontaneous bruising, mild to moderate mucosal membrane hemorrhage, or unexplained bleeding associated with trauma or surgery. The template bleeding time is generally useful as a screening test of platelet function, but a normal template bleeding time, in the face of a suggestive history, suggestive clinical findings, or in the patient frankly bleeding, is not reliable, and platelet aggregation or lumi-aggregation should be done in appropriate clinical situations. Also, prolongation of the template bleeding time is an unreliable predictor of clinical bleeding propensity. The mainstay of therapy for essentially all these defects, if bleeding is significant, is the liberal infusion of appropriate numbers of platelet concentrates. The acquired platelet function defects should also be managed by attempts to treat or control the underlying disease, if possible, and offending drugs or potentially offending drugs should immediately be stopped.


Drug-induced alterations of hemostasis and fibrinolysis. The hemostatic and fibrinolytic systems contribute significantly to the overall pathophysiologic status of a patient in a given clinical setting. Drug modulation of these systems plays a crucial role in the facilitation of the therapeutic effects but may also produce bleeding or thrombotic disorders. Many drugs appear inert; they can, however, modulate both the hemostatic and fibrinolytic systems. Such effects depend on several factors, however, but are significant enough to be recognized for the optimal care of patients. Therefore, it is recommended that the hemostatic and fibrinolytic systems should be routinely monitored during drug delivery.


Disseminated intravascular coagulation.

Disseminated intravascular coagulation. Current concepts of the etiology, pathophysiology, clinical and laboratory diagnosis, and management of fulminant and low-grade DIC have been presented. Considerable attention has been devoted to interrelationships within the hemostasis system. Only by clearly understanding these pathophysiologic interrelationships can the clinician and laboratory scientist appreciate the divergent and wide spectrum of often confusing clinical and laboratory findings in patients with DIC. Many therapeutic decisions to be made are controversial and will remain so until more is published about specific therapeutic modalities and survival patterns. Also, therapy must be highly individualized depending on the nature of DIC, age, etiology of DIC, site and severity of hemorrhage or thrombosis, and hemodynamic and other clinical parameters. Many syndromes that are organ-specific share common pathophysiology with DIC but are typically identified as an independent disease entity, such as hemolytic uremic syndrome, adult shock-lung syndrome, eclampsia, and many other isolated "organ-specific" disorders.


Anticardiolipin antibodies and thrombosis. Anticardiolipin antibodies (ACLAs) are strongly associated with thrombosis and appear to be the most common of the acquired blood protein defects causing thrombosis. Although the precise mechanism(s) whereby ACLAs alter hemostasis to induce a hypercoagulable state remain unclear, several theories, as previously discussed, have been advanced. The most common thrombotic events associated with ACLAs are deep vein thrombosis and pulmonary embolus (type I syndrome), coronary or peripheral artery thrombosis (type II syndrome), or cerebrovascular/retinal vessel thrombosis (type III syndrome), and occasionally patients present with mixtures (type IV syndrome). The relative frequency of ACLAs in association with arterial and venous thrombosis strongly suggests that these should be looked for in any individual with unexplained thrombosis; all three idiotypes (IgG, IgA, and IgM) should be assessed. Also, the type of syndrome (I through IV) should be defined if possible, because this may dictate both type and duration of both immediate and long-term anticoagulant therapy.


Hemostatic abnormalities in multiple myeloma and related disorders. Patients with multiple myeloma, Waldenström's macroglobulinemia, benign monoclonal gammopathy, and other B-cell disorders associated with high titer serum paraproteins can manifest unique hemostatic disorders. Most of these disorders predispose the patient to hemorrhage, especially following surgical procedures. Mechanisms can include: acquired von Willebrand syndrome, paraprotein-induced platelet function defects, factor X deficiency, and local tissue fragility associated with amyloidosis, abnormalities of the function of fibrin, circulating anticoagulants, and thrombocytopenia. The mainstay of therapy is the treatment of the underlying disease. Depending on clinical circumstances, additional therapies might include: plasmapheresis with appropriate factor replacement, arginine vasopressin, fibrinolysis inhibitors, and splenectomy. Less commonly, the paraprotein disorders are associated with thrombotic complications, especially in those cases in which the lupus anticoagulant is present.


Bleeding problems in the cancer patient. Bleeding problems in the cancer patient may result from the effects of the tumor on hemostatic mechanisms or from the treatment of the tumor by cytotoxic and other agents. Among the tumor-related bleeding problems are disseminated intravascular coagulation, primary fibrinolysis, thrombocytopenia, acquired platelet dysfunction, and circulating inhibitors or anticoagulants. Disseminated intravascular coagulation in most solid tumors is associated with hypercoagulability, whereas in acute promyelocytic leukemia bleeding is the most common presentation. Treatment-related bleeding disorders include the common problem of thrombocytopenia secondary to myelosuppressive chemotherapy as well as the interesting microangiopathic hemolytic anemia syndrome associated with mitomycin C and other agents.


Diagnosis and treatment of cancer-related thrombosis. Thrombotic events are common causes of morbidity and mortality in patients with neoplastic diseases. Standard diagnostic tests may give misleading results, and the effects of treatment may not be as expected. This article discusses the pathophysiology, diagnosis, and treatment of thrombosis in this difficult setting.


Acquired circulating anticoagulants.

Acquired circulating anticoagulants. Acquired inhibitors of blood coagulation, which are pathologic circulating substances that directly inhibit clotting factors or their reactions, most commonly occur in patients with hereditary bleeding disorders. This article contains a discussion of acquired circulating anticoagulants that arise de novo in patients with previously normal hemostatic mechanisms. Pathogenesis and management are also discussed. Treatment of these patients poses a challenge for the hematologist because, unlike hereditary hemophiliacs who have learned to adjust their lifestyle, the acquired hemophiliac is unprepared for hemorrhagic episodes.


Cancer cell procoagulants and their implications. Cancer cells induce abnormal blood coagulation through a process that probably involves a combination of increased activators and deficiencies of anticoagulants. The probable participating factors (including tissue factor-factor VII and cancer procoagulant) and their role in this process are discussed. The current theory on the role of coagulation in malignant disease is also discussed.


Use of blood components in cancer patients with bleeding. The need for blood components for oncology patients is small compared with the need for patients with hematologic malignancies. The subject is important because use of these valuable components is dependent on a limited supply and availability. Agreement on when to use components is extremely important. In fact, at the time of this writing, the Transfusion Practices Committee of the American Association of Blood Banks is conducting an extensive survey on the use of platelets in oncology and hematology cancer patients (Questionnaire on Institutional Policy on Platelet Transfusion Practice for Hematology/Oncology Patients). The results will, we hope, provide a consensus on the proper times and counts that require prophylactic use of components for these patients. Because these patients use the vast majority of components (see Table 15), their proper use is imperative to maintaining an adequate platelet and frozen plasma supply. Transfusion support in cancer patients is vital for their survival. Platelets, in particular, are necessary to prevent serious bleeding. The risks from transfusion must always be considered. Fortunately, with increased monitoring of the blood supply, they have been reduced. As with any therapeutic regimen, these risks must be weighed against the benefit the patient may gain. Transfusion should always be used prudently.


Structure and mechanism of action of serpins. Serpins have a central role in regulating proteolysis in blood coagulation, fibrinolysis, and inflammation. Congenital serpin deficiencies cause specific clinical syndromes such as thrombosis with antithrombin III deficiency or emphysema with alpha 1-antitrypsin deficiency. Acquired serpin abnormalities have also been reported, for example, increased PAI-1, which is believed to represent a major risk factor for the development of thromboembolic complications. This article has reviewed the structure/function relationships of serpins and have presented ideas concerning their mechanism of action. The implications of this information for designing drugs that could interfere with serpin function has also been described, and mention has been made of the therapeutic potential of such compounds.


Acquired von Willebrand's disease.

Acquired von Willebrand's disease. avWD is a rare entity that is primarily associated with lymphoproliferative disorders, most commonly with multiple myeloma, lymphoma, and the myeloproliferative diseases. Various pathogenetic mechanisms have been postulated. The most commonly seen is antibodies directed against the FVIII complex, resulting in either its accelerated destruction or its accelerated clearance by the reticuloendothelial system. There may be immunoadsorption of the FVIII complexes onto the clones of malignant cells, as has been reported in several cases, or proteolysis may be causing the peripheral destruction of the FVIII complex. Lastly, as seen in hypothyroidism, global decrease in production of the multimers also results in avWD. The treatment, in general, should be aimed at controlling the underlying disorder and at stopping any life-threatening hemorrhage. The treatment includes any or all of the following: DDAVP, cryoprecipitate, FVIII concentrates, extracorporeal immunoadsorption, and chemotherapy as needed to control the underlying disorders. The screening tests that will allow for the detection of the avWD include measurement of the bleeding time, the FVIII:C, FVIII:vWF, and the FVIII:RCoF. FVIII:C inhibitors can be demonstrated by mixing the patient plasma with normal plasma. A normal prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin time (TT) are expected. Clinically, these patients present with mucosal bleeding, and in avWD tend to have an association with lymphoproliferative malignancies. They tend to be elderly patients with no prior history of bleeding diathesis and to have negative family histories for coagulopathies. Further study of these patients is warranted, because this disorder appears to have a multifactorial etiology. Increasing our understanding of avWD may increase our understanding of congenital vWD, thus allowing us to more effectively treat all patients with von Willebrand's disease.


Hypercoagulability and thrombosis.

Hypercoagulability and thrombosis. This article has summarized known congenital and acquired alterations of hemostasis leading to thrombosis. Decreases in coagulation inhibitors, including antithrombin III, heparin cofactor II, and protein C and protein S, are of major importance in assessing patients with hypercoagulable states or patients with unexplained thrombosis. Newer assays for components of the fibrinolytic system, plasminogen, t-PA and t-PA inhibitor are also now readily available and are important for defining congenital or acquired fibrinolytic defects leading to hypercoagulability and thrombosis. By judicious use of these assays, combined with clinical evaluation, many patients with thrombosis will have an underlying etiologic blood protein defect defined. Delineating reasons for a thrombotic event is of obvious importance for planning long-term prophylactic therapy and for diagnosing and counseling afflicted family members. In this manner, newly found patients can be treated prophylactically before unalterable morbidity or mortality occurs.


Solitary rectal ulcer syndrome.

Solitary rectal ulcer syndrome. Solitary rectal ulcer syndrome (SRUS) clinically presents with rectal bleed. Twenty three cases of SRUS are described highlighting that it is a distinct clinicopathological entity which can be diagnosed in the presence of typical clinical features, sigmoidoscopic findings and histopathological appearance of mucosal biopsy.


Effect of vasodilator and surface active drugs on the efficacy of peritoneal dialysis. The effect of sodium nitroprusside (SNP), a vasodilator drug, and chlorpromazine (CPZ), a surface active drug, on the efficacy of peritoneal dialysis was studied in 25 patients with acute or acute on chronic renal failure in a double blind fashion. Each drug was added to the dialysate during different sets of cycles. In each patient, six clearance periods of 3 cycles each were studied and peritoneal clearances of creatinine and urea and ultrafiltration rates were measured during each clearance period. SNP increased the peritoneal clearance of creatinine and urea by 28.8 percent each (p < 0.001) while CPZ increased the peritoneal creatinine and urea clearance by 17.7 and 26.0 percent respectively (p < 0.001 each). Both drugs significantly increased the ultrafiltration rates (p < 0.001). SNP was found to be superior to CPZ and had prolonged effect even after cessation of administration.


Prevalence of spontaneous bacterial peritonitis. To assess the prevalence of spontaneous bacterial peritonitis (SBP), ascitic fluid cell count, and ascitic fluid culture by conventional method and by bedside inoculation in blood culture bottles were performed in 31 consecutive patients of liver cirrhosis. Seven (22.58%) patients had ascitic fluid polymorphonuclear count (PMN) more than 500/mm. Ascitic fluid culture by conventional method was negative in all the patients, while in 4 patients culture was positive by bedside inoculation method. Six of 7 patients with SBP or its variant were in Child class C. Clinical features in these patients were abdominal pain (5 patients), fever (4) and encephalopathy (2); serum bilirubin level was 6.8 +/- 5.5 mg/dl, serum albumin 1.98 +/- 0.2 g/dl, prothrombin index 59.8 +/- 12.2%, ascitic fluid protein 0.78 +/- 0.24 g/dl. Three of 7 patients with SBP or its variant expired during hospital stay; the other 4 patients recovered after appropriate antibiotic therapy. We conclude that SBP is a serious complication in patients of liver cirrhosis with ascites. Ascitic fluid PMN count and bedside inoculation of blood culture bottles with ascitic fluid are sensitive indicators of SBP. Hence they should be performed routinely for early detection of SBP.


Acquired toxic methaemoglobinaemia.

Acquired toxic methaemoglobinaemia. Eighty Six adult males presented with central cyanosis and constitutional symptoms 2 to 4 hours following ingestion of meal from a common kitchen. On spectrometry methaemoglobin was detected. All recovered fully in 12 to 36 hours on symptomatic treatment. Epidemiological study and toxicological examination revealed that metanil yellow used for colouring the rice was responsible.


Insulin responses to varying hyperglycaemia in newly diagnosed non-insulin dependent diabetic patients. The effect of varying degrees of hyperglycaemia on insulin secretion was studied in newly diagnosed non-insulin dependent diabetic patients, stratified according to the fasting plasma glucose values. Of the 116 patients studied, 62 were non-obese and 54 obese. Insulin response patterns during 2h oral glucose tolerance test were analysed in comparison with the values in weight matched control subjects and also with respect to the degree of hyperglycaemia. The effect of hyperglycaemia on beta cell secretion differed in obese and non-obese patients. In the non-obese, fasting insulin levels were within normal range even in those with severe hyperglycaemia while the corresponding values in response to glucose stimulation showed a decreasing pattern. In obese patients, even fasting immunoreactive insulin (IRI) value was decreased and with increasing hyperglycaemia the reduction in IRI response to glucose stimulation was of greater magnitude compared to non-obese patients. Thus the modulating effect of obesity on insulin secretion appears to disappear with development of hyperglycaemia. The insulinogenic index was low in all the diabetic patients.


Adverse effects of oral amiodarone therapy. Oral amiodarone was administered to 38 patients (25 males, 13 females) with mean age of 43.6 years. Ventricular and supraventricular arrhythmias were present in 30 and 8 patients respectively. Amiodarone was given as 400-1200 mg/day for 1-2 weeks as loading dose and then it was maintained as 100-600 mg/day. The mean duration of therapy was 12.4 months. Adverse effects were noted in 21 (55.3%) cases. The commonest adverse effects observed were asymptomatic corneal microdeposits followed by gastrointestinal, cardiac, neurological and cutaneous disturbances. The drug was withdrawn in 2 (5.3%) patients because of nausea and vomiting. One patient died of pulmonary infiltrations. It is concluded that adverse effects are common with amiodarone but are tolerated well, making this drug an excellent choice for treatment of cardiac arrhythmias.