Long-term contraceptive efficacy of vaccine of ovine follicle-stimulating hormone in male bonnet monkeys (Macaca radiata). A group of ten healthy fertile adult male bonnet monkeys were actively immunized using procedures acceptable for human use with pure follicle-stimulating hormone (oFSH) isolated from sheep pituitaries. The vaccine elicited an immunogenic response in all ten monkeys; the antibody-binding capacity, determined by Scatchard analysis, varied from 3 to 18 micrograms oFSH ml-1, the binding affinity ranging from 0.13 to 2.0 x 10(10) mol-1. A substantial population of antibodies against oFSH crossreacted with 125I-labelled human (h) FSH, used here as a representative ligand of primate FSH. The bioneutralization activity of the antisera assessed by a specific bioassay in vitro, when the antibody titre was high, was 6.9 +/- 0.18 micrograms hFSH ml-1. Immunization for 4.7-5.7 years did not affect the health and libido of the animals. Concentration of testosterone in serum remained normal throughout the study, but, within 150 days of immunization, there was a marked decrease (75-100%) in the number of spermatozoa in seminal ejaculates. Oligospermic status interspersed with azoospermia was maintained by periodic boosting. The fertility of these animals was monitored between 6 months and 2 years after primary immunization. All the ten animals proved infertile in repeated mating experiments with females of proven fertility. After stopping booster injections, nine of ten animals regained fertility, but the time taken for this depended upon the rate of decline of antibody titres. Re-boosting these monkeys with 100 micrograms oFSH after confirming that recovery had occurred revealed prompt increases in antibody titres followed once again by onset of oligo-azoospermia and infertility, underscoring the specificity of immunization effect. The immunized monkeys, apart from being acutely oligospermic, ejaculated spermatozoa that were markedly deficient in key acrosomal enzymes, such as acrosin and hyaluronidase, and motility as well as in their ability to penetrate a gel in vitro, suggesting that the infertility observed was due to gross reductions in the numbers of spermatozoa that could effectively interact with the oocyte and cause successful fertilization.


The contribution of singletons, twins and triplets to low birth weight, infant mortality and handicap in the United States. Among multiple gestations the magnitude of neonatal mortality, morbidity and postneonatal handicap is unknown. Although the proportion of multiple births has risen dramatically during the past decade, the proportion of total births in the United States is relatively small. The vast majority of multiples are low birth weight (LBW) or very low birth weight (VLBW), conditions that magnify both short-term and long-term risks. In this study, the risks for infant mortality and for postneonatal morbidity and handicap have been calculated from race-, plurality- and birth weight-specific mortality rates from the National Infant Mortality Surveillance (NIMS) Project and birth weight-specific postneonatal handicap rates from the Office of Technology Assessment report Healthy Children in proportion to the 1988 U.S. birth cohort. U.S. health objectives for the year 2000 for race-specific birth weight and infant mortality rates were used for comparison. Compared with that of singletons, twins' and triplets' relative risks for LBW are 10.3 and 18.8, respectively. Their relative risks for VLBW are 9.6 and 32.7. Compared with singletons, twins and triplets have relative risks for infant mortality of 6.6 and 19.4, respectively. For twins and triplets, postneonatal survivors' relative risks for severe handicap are 1.7 and 2.9 while those for overall handicap are 1.4 and 2.0, respectively. Recommendations for optimizing pregnancy outcomes in multiple gestations include liberalized weight gains, reduced physical effort and early, comprehensive prenatal care.


Uterine surface temperature changes caused by electrosurgical endometrial coagulation. To assess the risk for transmural thermal injury to abdominal viscera during electrosurgical ablation of the endometrium, thermocouples were laparoscopically directed to the surface of the uterus at the time of endometrial ablation. A 2- or 5-mm ball, or a barrel electrode directed through a urologic resectoscope was placed in the cornual area, and current varying from 50 to 150 W of unmodulated ("cutting") or modulated ("coag") current was applied for five seconds without moving the electrode. The resultant temperature rise of the uterine serosa did not exceed 6 degrees C.


Pelviscopy/laparoscopy and its complications in Germany, 1949-1988. The fourth German pelviscopy/laparoscopy statistical report includes survey data on a total of 219,314 laparoscopies from 354 clinics and 40,892 laparoscopies from 161 private practices. Clinics' response rate was 44.7%; 98.9% of them reported performing laparoscopies; and the number of serious complications requiring laparotomy or control laparoscopy was 492 (2.2/1,000). For private practices, the comparable figures were 66%, 90.8% and 123 (3/1,000), respectively. Compared with data from the third laparoscopy statistical survey, the data show a slight increase in serious complications, most of which were mechanical lesions of blood vessels in the abdominal wall or in the mesosalpinx, followed by mechanical lesions of the intestine. As shown by the previous survey, 16.5% of the complications were burns. For tubal sterilization, bipolar techniques were still predominant; approximately equal numbers of departments used this method, with or without subsequent transsection of the tubes. Endocoagulation by the method of Semm was the second most popular procedure; the use of clips and rings was of little significance. Monopolar high-frequency (HF) current was still used with transsection by 4.1% of clinics (4.7% of private practices) and without transsection by 2.5% (5.3%). Sterilization failure rates remained the same as those previously reported (4.6/1,000 in clinics, 5.3/1,000 in private practices); the highest rates were observed after the use of monopolar HF techniques. Sixty-six percent of the clinics and 41% of the private practices reported their intention to increase the use of endoscopic operational methods.


Preoperative therapy in preparation for endometrial ablation. In order to improve the success of endometrial ablation for uncontrolled uterine bleeding, a variety of preoperative agents were utilized. Patients were given either no preparation, progestins, danazol or leuprolide acetate depot as preoperative therapy to determine the best way to increase the incidence of amenorrhea and to decrease the failure rates. The lowest rates were achieved with danazol or no preparation, with amenorrhea rates of 41 and 43%, respectively. The highest rates were obtained with the use of either progestins or leuprolide acetate depot, 61 and 67%, respectively. Progestin use was discontinued early in the study because of side effects, resulting in numbers too low for accurate comparison. We concluded that the use of leuprolide acetate depot in a single-dose regimen resulted in the highest amenorrhea rates, with minimal or no side effects.


Endometrial ablation in women with abnormal uterine bleeding aged fifty and over. Endometrial ablation, rapidly becoming a standard operation for the management of abnormal uterine bleeding, is usually performed for patients between ages 35 and 45. This study reports on the results of resectoscopic endometrial ablation for 26 patients aged 50 and older, followed from 7 to 43 months (average follow-up period, 21 months). Seventeen of the patients were menopausal at the time of the procedure or became menopausal during the follow-up period, with 13 on combined estrogen and progestin therapy and 4 on unopposed estrogen (because of progestin intolerance). Twenty-three of the 26 patients (88%) are amenorrheic, one premenopausal patient has normal periods and none have failed. The fear of hiding glandular tissue that subsequently becomes malignant is discussed and believed to be highly unlikely to occur.


Sonographic assessment of late proliferative phase endometrium during ovulation induction. Late proliferative phase endometrium was assessed sonographically in 400 patients undergoing ovulation monitoring or stimulation. Endometrial evaluation was classified in relation to its widest diameter (quantity) and by the presence or absence of a double-layered (outer echogenic/inner hypoechoic) pattern (quality). No patient conceived if the endometrium was totally echogenic and less than 8 mm in diameter. All patients who conceived had an endometrium that was double-layered or greater than 9 mm in diameter. Positive, double-layered patterns correlated with correction of hormonal aberrations such as hypoestrogenism, hyperprolactinemia or hyperandrogenism. Such a positive pattern was also accomplished after discontinuation of clomiphene citrate in certain low-body weight/low-body fat women and administration of human menopausal gonadotropins to those patients. Application of the principles described to ensure the development of an adequate, double-layered (follicular phase) endometrium at midcycle were found to coincide with a higher incidence of pregnancy and viable gestation.


Mechanical preparation of the endometrium prior to endometrial ablation. Of 143 women who underwent endometrial ablation between May 1986 and August 1991, 16 also had repeat procedures. Medical preparation of the endometrial lining (danazol, leuprolide acetate, or nafarelin acetate) was used in 109 patients; mechanical preparation in the form of suction curettage, in 28 patients; and no preparation, in 6 postmenopausal patients. Evaluation of the results following endometrial ablation showed that the results in mechanically prepared patients were comparable to those in patients receiving traditional medical preparation; thus mechanical preparation can make the procedure simpler, enhance patient compliance, and reduce side effects considerably.


Laparoscopic en bloc resection for treatment of the obliterated cul-de-sac in endometriosis. In endometriosis patients with obliteration of the cul-de-sac, laparoscopic en block resection of the uterosacral ligaments, posterior cervix, cul-de-sac, and bowel wall efficiently removes invasive disease.


Myomectomy after selective preoperative treatment with a gonadotropin releasing hormone analog. In 1988 and 1989, 67 women (mean age, 36.7 years) underwent myomectomy to remove uterine fibroids; selection of the procedure was based on the presence of symptoms and the patient's desire to avoid hysterectomy. For 8 weeks before myomectomy, 48 patients with a uterine size greater than or equal to 16 weeks' gestation received the gonadotropin releasing hormone (GnRH) analog leuprolide acetate, 0.5 mg self-administered daily by subcutaneous injection or 3.75 mg as the depot form every 28 days by intramuscular injection; the remaining 19 patients were used for a comparison. In the leuprolide-treated patients, the mean uterine size and mean number of fibroids removed per patient were significantly higher, and the mean postoperative hemoglobin concentration was significantly lower than in the non-leuprolide-treated group. The mean estimated blood loss and mean length of hospital stay were equivalent for the two groups. Eight patients (12%), all but one in the leuprolide-treated group, developed postoperative complications, primarily infections that were treated successfully with antibiotics; one patient, the only one undergoing a repeat myomectomy, experienced pelvic hematoma, infection and pelvic thrombophlebitis. There were no significant adverse reactions attributable to leuprolide administration.


Calcium requirements and the diets of women and children. A review of dairy resources. This review concerns the role of calcium in nutrition and health and its relation to the changing American diet. The ideal dietary calcium intakes for women and children represent the United States Department of Agriculture's most recent recommended dietary allowances. Both calcium and total nutrient composition of cow, goat and human milk differ. Goat milk has special utility in the treatment of childhood allergy.


Intracervical prostaglandin E2 gel. Safety for outpatient cervical ripening before induction of labor. Cervical ripening prior to induction of labor is often necessary for medical complications of pregnancy. We proposed to prospectively determine the safety of administering prostaglandin E2 (PGE2) gel intracervically in an outpatient setting. Four hundred forty-six patients underwent 515 gel procedures as outpatients. Trained perinatal nurses placed 0.5 mg of PGE2, prepared in a standard methylcellulose base, in the intracervical canal. The PGE2 dose was administered every two hours for a total of three doses if labor did not start. The patient was sent home two hours after the last dose if she was not in active labor. Labor started in 90 patients (20%) during the gel procedure; they were admitted to the labor-and-delivery unit. The remaining patients were discharged. Eighty-eight patients (20%) were later admitted in active labor prior to scheduled induction. One patient (0.02%) was found to have occasional prolonged decelerations on admission and underwent a cesarean section two hours after admission; the Apgar scores were 8 and 9 and the arterial pH, 7.21. Hyperstimulation with excessive intrauterine activity caused significant deceleration of the fetal heart rate in four patients (0.8%), two of whom required transfer to the labor-and-delivery unit but none of whom needed a cesarean section for fetal distress. PGE2 gel can be administered safely intracervically as an outpatient procedure by trained perinatal nurses.


Significance of intrapartum amniotic fluid volume in the presence of nuchal cords. Among 70 women delivering infants with nuchal cords, there was a significantly higher incidence of meconium passage and severe variable fetal heart rate decelerations/fetal bradycardia in those who had intrapartum oligohydramnios, as defined by an amniotic fluid index less than or equal to 5.0 cm. Oligohydramnios in the presence of nuchal cord entanglement might represent an increased risk of ominous intrapartum fetal heart rate patterns.


3 alpha-Androstanediol and 3 alpha-androstanediol glucuronide. Maternal and umbilical cord plasma concentrations in normal pregnancy. Concentrations of 3 alpha-androstanediol (A) and 3 alpha-androstanediol glucuronide (AG) were measured with a radioimmunoassay in pregnancy plasma samples collected from the mother in the first trimester (first, n = 18) and second trimester (second, n = 20) and at term (n = 14). At term, along with the maternal samples, matching cord plasma samples were also obtained (n = 14). Throughout pregnancy the levels of A and AG were significantly higher than in normally menstruating women. Although the total concentration of A and AG did not change significantly throughout pregnancy, the levels of A in the second and at term were significantly higher than in the first. In contrast, AG concentrations in the second were significantly lower than in the first and at term. As compared to the maternal concentrations at term, the cord levels of AG and A plus AG were not significantly different. However, the levels of A in the cord were significantly lower than those in the maternal circulation at term. Significant correlations were observed between the term maternal and cord levels of AG and A plus AG. No sex-related differences in the plasma levels of A and AG were noted. The results show that levels of A and AG increase significantly in the first trimester and remain elevated throughout pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)


Influence of triphasic oral contraceptives on blood rheology and hemostatic and metabolic patterns in young women. Results of a three-year study. Long-term (three-year) variations in clinical, hemorheologic, hemostatic and blood lipid parameters were evaluated in 20 young healthy women taking a triphasic oral contraceptive. Body weight, arterial blood pressure, whole blood, plasma and serum viscosity, erythrocyte deformability, fibrinogen, fibronectin, alpha-2 macroglobulin, Von Willebrand factor antigen, triglycerides, nonesterified fatty acids, total and low density lipoprotein cholesterol, very low density lipoprotein, low density lipoprotein and apolipoprotein B levels remained unchanged throughout the study. However, high density lipoprotein cholesterol, high density lipoprotein and apolipoprotein A1 serum concentrations increased significantly during treatment. Long-term use of the triphasic oral contraceptive does not seem to adversely affect the blood rheology pattern or vascular endothelium function, which are the main factors responsible for the development of thromboembolic complications.


Maternal coagulation inhibitors and the effects of cesarean delivery. Maternal hypercoagulability in normal pregnancy results from significant increases in blood factors that promote thrombosis or decreases in factors that inhibit thrombosis, such as antithrombin III (AT-III) and proteins C and S. The precise role of these factors in puerperal hemostasis is not clear. In 10 normal, pregnant women at term undergoing scheduled repeat cesarean section, the percent activities of AT-III, proteins C and S, and C4b-binding protein were determined in peripheral venous blood preoperatively and in samples of uterine venous blood before the uterine incision was made and 5 and 15 minutes after placental delivery using the Laurell Rocket electroimmunodiffusion technique. The mean percent activities of AT-III (73%), protein S (81%) and C4b-binding protein (85%) were lower than those in nonpregnant controls, were similar in peripheral and uterine venous blood and were unchanged after placental delivery. These data suggest that such factors may not play an important role in acute uteroplacental hemostasis during normal pregnancy.


Characteristics of indigent women with ruptured and unruptured tubal pregnancies. The diagnosis of tubal pregnancy, whether ruptured or unruptured, often requires a surgical procedure, such as laparoscopy or laparotomy, for confirmation. We compared women with ruptured and unruptured tubal pregnancies to determine whether the clinical presentations, morbidity and surgical complications in the two groups were significantly different. We compared the demographic characteristics, clinical presentations, laboratory findings, morbidity and complications from surgical management in the two groups. Women with ruptured tubal pregnancies had a higher incidence of abdominal pain lasting less than 24 hours, adnexal tenderness and positive culdocentesis from hemoperitoneum as compared to women with unruptured tubal gestations. Abnormal uterine bleeding was observed less frequently in women with ruptured tubal pregnancies as compared to women with unruptured ones despite similar gestational ages at presentation. All the patients with a tubal pregnancy were managed surgically. The morbidity and surgical complication rates in the two groups were not significantly different.


Persistence of a normal pregnancy after an early luteectomy. A report of two cases. Two cases occurred of early luteectomy/left cystectomy. In one case it resulted from a hemorrhagic corpus luteum at four weeks' gestation. In the second case it resulted from a left adnexectomy at five weeks from torsion of the adnexa. Histologic analysis defined the lesions as a hemorrhagic corpus luteum and necrotic ovary, respectively. Despite the lack of a corpus luteum and the absence of hormonal replacement therapy, both pregnancies developed normally, in the first case for 7 weeks, until it was terminated on the patient's request, and in the second case until 38 weeks, when a normal infant was delivered by cesarean section.


Type II congenital cystic adenomatoid malformation of the lung with a mediastinal shift. A case report. We report a case of an early (22-week) prenatal diagnosis of type II congenital cystic adenomatoid malformation of the lung complicated by a mediastinal shift. Detailed ultrasound examination of the fetus, including fetal Doppler velocimetry and echocardiography, and diagnostic amniocentesis were normal. There was a gradual, spontaneous resolution of the mediastinal shift and improvement in the lung lesions. The intrapartum and early neonatal clinical courses were uneventful.


Pristane induced arthritis in mice. IV. Immunotherapy with monoclonal antibodies directed against lymphocyte subsets. Pristane induced arthritis (PIA), a seropositive experimental disease model in mice, was used to investigate the influence of immunotherapy with monoclonal antibodies against lymphocyte subsets. Treatment with L3T4, a monoclonal antibody specific for murine CD4+ T cells, significantly reduced the incidence of pristane arthritis, and delayed the disease onset. Monoclonal antibody to Lyt2, the murine CD8+ T cell marker, significantly reduced the levels of rheumatoid factor in pristane injected animals compared with controls, but did not influence the clinical course of PIA. Our experiments demonstrate the ability of anti-CD4 antibodies to modify the course of PIA, and provide support for the hypothesis that CD4+ T lymphocytes have an important role in the pathogenesis of this experimental autoimmune arthritis.


Cyclosporine and chloroquine synergistically inhibit the interferon-gamma production by CD4 positive and CD8 positive synovial T cell clones derived from a patient with rheumatoid arthritis. To investigate synergistic interaction between cyclosporine (Cy) and chloroquine (Chl) in an in vitro system, with regard to interferon-gamma (IFN) production by OKT3 activated T cell clones. CD4+ and CD8+ T cell clones, derived from synovial tissue of a patient with rheumatoid arthritis (RA) were activated with plastic coated OKT3 monoclonal antibody in the presence or absence of various concentrations of Cy, Chl and their combinations. After 24 h of incubation the supernatants were assayed for IFN by ELISA: Cy as well as Chl were able to completely inhibit in a concentration dependent fashion the IFN production by CD4+ and CD8+ T cell clones. Combinations of Cy and Chl, which in themselves give minor inhibition of IFN production, were able to inhibit in a synergistically enhanced fashion the production of IFN by these clones. The synergy was formally proven by the construction of isoboles. This synergy was most pronounced when drug concentrations were used which individually gave minor inhibition of IFN production. We conclude that the results of our in vitro experiments may give rise to further investigation of the promising combination of Cy and Chl in the treatment of RA.


Cyclosporine A for the treatment of necrotizing scleritis and corneal melting in patients with rheumatoid arthritis. Two of the ocular complications of rheumatoid arthritis (RA), necrotizing scleritis and keratolysis, have been associated with poor response to standard ocular therapy, and thus poor ocular outcome. We describe 6 patients with active ocular disease and active RA who failed to respond to disease modifying agents or immunosuppressive therapy and whose ocular and arthritic disease subsequently responded to cyclosporine A. Drug related complications were consistent with those reported for patients receiving similar doses for RA.


Interleukin 2 receptor membrane bound and in soluble form in the aqueous humor and peripheral blood of patients with acute untreated uveitis. Uveitis is a manifestation of various chronic inflammatory arthritic conditions. There are considerable data implicating abnormalities of immune function in the etiopathogenesis of uveitis. We evaluated the percentage of cells expressing interleukin 2 (IL-2) receptor (membrane bound) and the levels of soluble IL-2 in the blood and aqueous humor of patients in various rheumatic diseases and acute untreated uveitis. Our findings showed increased IL-2 receptors (IL-2R) and soluble IL-2 receptors on the aqueous humor of patients with uveitis when compared to healthy controls. These results suggest an immunoregulatory role of IL-2R in acute uveitis and raises the possibility that its detection may be useful in management.


Recurrence of cervical spine instability in rheumatoid arthritis following previous fusion: can disease progression be prevented by early surgery? In a retrospective study, 110 patients with rheumatoid arthritis who had cervical spine fusion were evaluated for recurrence of cervical spine instability and resultant need for further surgery. Recurrence of cervical instability was correlated with initial radiographic abnormality, primary surgical procedure and interval between the 2 surgeries. There were 55 patients who had atlantoaxial subluxation (AAS) and required C1-C2 fusion as primary surgery. Three of these patients (5.5%) developed subaxial subluxation (SAS) and had a second procedure after a mean interval of 9 years. Twenty-two patients had AAS with superior migration of the odontoid (AAS-SMO) and had initial surgery of occiput-C3 fusion. Eight of these patients (36%) developed SAS and had a second surgery after a mean interval of 2.6 years. Of the 19 patients with primary radiographic deformity of SAS, one required further surgery for subluxation of an adjacent superior vertebra after a period of 6 years. Fourteen patients had combined deformity of AAS-SMO-SAS, and one required further surgery for SAS after an interval of 22 months. Recurrence of cervical instability following a previous fusion occurred in 15% of these 110 patients. It was seen in 5.5% of patients with initial deformity of AAS vs 36% of patients with AAS-SMO. No patients with C1-C2 fusion for AAS progressed to develop superior migration of the odontoid. We conclude that early C1-C2 fusion for AAS before development of SMO decreases the risk of further progression of cervical spine instability. The pattern of progression of cervical spine involvement, as discussed in the literature, is reviewed.


99mTc human immunoglobulin scintigraphy--a reliable method to detect joint activity in rheumatoid arthritis. The ability of 99mtechnetium labelled nonspecific, polyclonal human immunoglobulin G (99mTc-IgG) scintigraphy to depict and quantify synovial inflammation was studied in 30 patients with rheumatoid arthritis (RA). All patients were injected with 350 MBq 99mTc-IgG and imaging was performed 4 h later. This resulted in excellent images of inflamed synovium. Scores for 99mTc-IgG joint scintigraphy correlated highly with scores for joint swelling and C-reactive protein levels, weakly with pain scores and not with radiographic scores of joint destruction. These results suggest that 99mTc-IgG joint scintigraphy may provide an objective test to detect synovitis and measure the activity of the disease.


Antinuclear antibodies heralding the onset of systemic lupus erythematosus. On the basis of record linkage with the Social Security Institution's population register, 16 specimens from healthy subjects who subsequently developed systemic lupus erythematosus or mixed connective tissue disease could be traced from stored sera collected in connection with nationwide maternity welfare program in Finland. The sera were tested for antinuclear antibodies (ANA) using an immunofluorescence technique. Ten of the 16 specimens were positive. Eight of 11 cases were positive when the interval from taking the blood specimen to the onset of the first symptoms of disease was 2 years or less and 2 of 5 cases were positive when the interval was over 3 years. Eighteen of 21 sera with established disease and 5 of 85 control sera from the same serum collection were positive. Thus, ANA as detected by a sensitive technique frequently precede the onset of disease indicating that they are not a secondary manifestation of inflammation or tissue destruction.


Anti-dsDNA antibodies in laboratory workers handling blood from patients with systemic lupus erythematosus. The presence of antinuclear antibodies was determined in female laboratory workers with varying degrees of exposure to blood from patients with systemic lupus erythematosus (SLE). Subjects recruited from SLE research laboratories and a membership roster provided by the American Society for Medical Technology were classified according to self-reported frequency of handling blood from patients with SLE into high and low exposure groups. Employment and medical history were obtained by questionnaire from each study subject and their sera were tested for antibodies to double stranded DNA, single stranded DNA, and synthetic polynucleotide poly(dA-dC).poly(dG-dT) by ELISA. Analysis of the results using an independent t test showed the mean optical density for anti-dsDNA was higher in the high exposure group (mean = 0.010) than in the low exposure group (mean = 0.005, p = 0.016). There were no significant differences found between the 2 groups for anti-ssDNA or anti-poly(dA-dC).poly(dG-dT), but the means for both anti-dsDNA and anti-poly(dA-dC).poly(dG-dT) were higher in the laboratory workers than in an unexposed nonlaboratory group of women (p less than 0.001). Our results are provocative for they lend support to the hypothesis that a transmissible agent capable of causing autoantibody formation may exist in blood from patients with SLE.


Light microscopy of dried saliva in the evaluation of xerostomia of the sicca syndrome. A preliminary report. Dried, freshly produced saliva from 21 patients with xerostomia related to the sicca syndrome [15 with primary Sjögren's syndrome (pSS), 3 with rheumatoid arthritis (RA) and secondary Sjögren's syndrome (sSS), and 3 with Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE)] and 21 age and sex matched controls, was examined by light microscopy. A typical fern-like pattern was demonstrated by the crystallized mucus of the healthy individuals. In contrast, much thicker, shorter, irregular and densely arranged branches of crystallized mucus, sometimes giving a reindeer horn appearance, were observed in the patients' saliva. Given the lack of a reliable clinical measure for the objective evaluation of xerostomia, light salivary microscopy, simple and easy as it is, may fill this deficit, if its sensitivity and specificity are documented.


A family study of the antiphospholipid syndrome associated with other autoimmune diseases. Antiphospholipid syndrome (APS) is an entity characterized by recurrent thrombotic events and may occur spontaneously or in the context of systemic lupus erythematosus (SLE). We describe an English Canadian family in whom the propositus, a woman with Graves' disease and SLE, was found to have a lupus anticoagulant and anticardiolipin antibody (aCL). A brother with deep vein thrombosis, pulmonary emboli, bilateral adrenal hemorrhage and thrombocytopenia, circulating anticoagulant and aCL had a positive antinuclear antibody and Coombs' test, but no other features of SLE. Fourteen members of 3 generations of this family underwent clinical assessments, serological testing and HLA typing. The propositus' mother had a family history of autoimmune thyroid disease and the father had aCL, but was asymptomatic. The thyroid disease and the SLE were associated with HLA-B8, DR3 haplotype. The aCL and the anticoagulant were associated with HLA-B60, DR4 haplotype. Both these haplotypes were present in the propositus. Among the other 4 carriers of the haplotype B60, DR4, 3 demonstrated significant titers of aCL. Our findings support the reported association between APS and the HLA haplotype DR4 in patients of English descent with SLE.


Antiphospholipid antibodies require beta 2-glycoprotein I (apolipoprotein H) as cofactor. IgG was isolated from 9 patients with high levels of anticardiolipin antibodies (aCL). The standard ELISA was modified, using gelatin to postcoat ELISA plates and as diluent. Under these conditions, 8/9 samples of IgG bound to cardiolipin only in the presence of a cofactor, found in fetal calf serum and normal human serum (NHS). beta 2-glycoprotein I (apolipoprotein H) was at least as effective as NHS as a cofactor for 7/9 IgG samples. Our studies confirm that for some aCL detected in conventional assays, the antibody will react with cardiolipin only if beta 2-glycoprotein I is present.


Color chart assisted diagnosis of Raynaud's phenomenon in an unselected hospital employee population. The prevalence of Raynaud's phenomenon (RP) in 750 subjects was assessed by questionnaire, clinical interview, and use of a chart of color photographs taken of hands during attacks of RP. Eighty-three of 600 women (13.8%) and 7 of 150 men (4.7%) reported cold induced digital color changes on the questionnaire, 76 women (12.7%) and 6 men (4%) were diagnosed as having RP at an independent clinical interview, and 3 women could not be assessed using the color chart because of defective color perception. Fifty-four of the remaining 597 women (9%) and 6 of 150 men (4%) were diagnosed as having RP when a positive response to both chart and questionnaire was required. The color chart should be useful in lessening the frequency of false-positive responses and in standardizing the diagnosis for epidemiological surveys.


Tuberculous arthritis in the course of connective tissue disease: report of 4 cases. We describe 4 female patients with diverse connective tissue diseases who developed tuberculous arthritis concurrently with their underlying disease, in the absence of lung involvement. Throughout, diagnosis was delayed but later confirmed by detection of Mycobacterium tuberculosis in synovial membrane culture. Two patients died of unrelated causes, while the other 2 recovered with chronic joint sequelae. Despite the rarity of this association, M. tuberculosis infection should be considered in the differential diagnosis of chronic mono or oligoarthritis in patients with connective tissue diseases.


Hyperferritinemia in adult onset Still's disease and the hemophagocytic syndrome. Increments in serum ferritin levels in adult onset Still's disease (AOSD) were reported to be higher than one could expect for a simple inflammatory state. When we analyzed the scores of 40 patients with various severe inflammatory diseases aside from AOSD, we recorded no serum ferritin values higher than 3,300 ng/ml (N less than 200 ng/ml). In 3 of 10 consecutive patients with AOSD, the ferritin levels were higher than 3,500. Among these 3 patients, one case had a ferritin value of 3,600 ng/ml and bone marrow aspirate showed a marked hyperplasia of mature appearing histiocytes, and the 2 other patients (serum ferritin levels of 65,000 ng/ml and 250,000 ng/ml) displayed the features of a hemophagocytic syndrome. In 2 patients with normal or mildly increased levels of ferritin, the bone marrow examination was normal. We suggest that very high serum ferritin levels encountered in AOSD reflect the presence of histiocytic hyperactivity that sometimes leads to a hemophagocytic syndrome.


Biochemical clues to a fibromyalgia-depression link: imipramine binding in patients with fibromyalgia or depression and in healthy controls. Both fibromyalgia and depression may be related to disturbed serotonin metabolism, and an association between the 2 disorders has been postulated. We measured 3H-imipramine binding (IB), a biochemical indicator of serotonin uptake, pretreatment, in 10 nondepressed women with fibromyalgia, 14 subjects with major depression, and 10 volunteer controls. Our objective was to determine if IB in the 2 patient groups differed and in the same direction from the control values. Compared with depressed women, IB was significantly lower both in the women with fibromyalgia and in the men with depression. However, no women with fibromyalgia or men with depression had IB levels that were significantly different from control women and men. There was a trend for higher IB levels in depressed compared to control women.


Effects of tiaprofenic acid and acetylsalicylic acid on human articular chondrocytes in 3-dimensional culture. Two nonsteroidal antiinflammatory drugs (NSAID: acetylsalicylic acid, ASA, and tiaprofenic acid, TA) were tested on differentiated human chondrocytes cultivated in clusters. DNA synthesis was depressed by ASA at therapeutic concentrations. The amount of proteoglycans in culture medium was decreased by ASA, whereas type II collagen was not modified. By contrast, TA did not affect chondroformative processes in chondrocytes. Both NSAID were potent inhibitors of prostaglandin E2 (PGE2) synthesis, TA being more efficient than ASA. From these experiments, we conclude that TA and ASA inhibit PGE2 synthesis; TA did not depress chondroformative variables in human cartilage in vitro, while ASA induced a decrease of DNA and proteoglycan syntheses.


Fibronectin fragments in osteoarthritic synovial fluid. Fibronectin is an adhesive multifunctional glycoprotein found in the extracellular matrix of most types of cells and that exerts growth factor, differentiative and chemotactic activities toward many types of cells, including those cells found in knee joint tissue. Since fibronectin levels in the synovial fluid (SF) and on the cartilage surface of patients with osteoarthritis (OA) have been shown to be greatly increased over normal levels and since protease levels are also enhanced in diseased cartilage, we have investigated the presence of fibronectin fragments in the SF of patients with OA. We report that concentrations of at least 1 microM of 100 to 200 kDa fragments were found in all OA fluids examined. Since we have recently shown that fibronectin fragments can cause cartilage to release metalloproteinases, resulting in severe proteoglycan depletion, and others have shown that fragments also enhance metalloproteinase expression in synovial fibroblasts, the presence of these fragments suggests pathologic consequences in arthritis.


Comparison of the acute inflammation induced by calcium pyrophosphate dihydrate, apatite and mixed crystals in the rat air pouch model of a synovial space. Pure monoclinic or triclinic calcium pyrophosphate dihydrate (CPPD) crystals, apatite crystals or mixtures of these crystals were injected into the synovial-like space created by the rat air pouch to compare the acute inflammation induced by these crystals. Fluids were withdrawn 6 h after injection and examined for leukocyte counts, protease, prostaglandin E2 (PGE2) and tumor necrosis factor (TNF) levels. CPPD crystals (especially monoclinic CPPD) induced higher numbers of leukocytes, and more protease, PGE2 and TNF than apatite. CPPD seemed to play a predominant role in the acute inflammation induced by mixed crystals.


The philatelic rheumatologist.

The philatelic rheumatologist. Many postage stamps illustrate themes, persons, or topics with rheumatologic connections. Examples include scientists from related disciplines, victims of rheumatic diseases, drugs used for arthritis, and stamps commemorating events such as World Rheumatism Year. A brief orientation to postage stamps and philately is given, and a small collection of rheumatologically related stamps is illustrated.


Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review. We describe 2 Caucasian men with rheumatoid arthritis (RA) who developed non-Hodgkin's lymphoma of identical histological type during treatment with low dose oral weekly methotrexate (MTX). Both patients had longstanding RA and had been treated with MTX for over 2 years at time of tumor diagnosis; neither had secondary Sjögren's syndrome. The oncogenic potential of MTX and RA arthritis is reviewed.


Massive intrahepatic hemorrhage following routine liver biopsy in a patient with rheumatoid arthritis treated with methotrexate. Massive intrahepatic hemorrhage occurred in a patient with rheumatoid arthritis (RA) after a routine liver biopsy done to assess possible methotrexate (MTX) hepatotoxicity. Major complications of liver biopsy occur about once in every 600 biopsies, and mortality from liver biopsy has been reported. Life threatening hepatic toxicity occurs rarely during low dose MTX administration, and it is unclear whether routine liver biopsies identify patients at high risk for these complications. Until the relative risks of liver biopsy and serious MTX liver toxicity are better defined, the use of routine liver biopsies should be recommended only after careful consideration of potential procedural complications in patients with RA treated with MTX.


Thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus. Case report and literature review from the plasmapheresis era. Although thrombotic thrombocytopenic purpura (TTP) has been described in patients with systemic lupus erythematosus (SLE), the relationship between these 2 diseases is controversial. We recently treated a patient with longstanding SLE who developed TTP. The patient responded to therapy with aggressive plasmapheresis. Review of the literature revealed that TTP may occur in the setting of either active or inactive SLE. Survival in SLE associated TTP correlated with the use of plasma therapy (plasma infusion or plasmapheresis) rather than with the activity of the underlying autoimmune disease. We conclude that TTP and SLE represent distinct clinical entities that may occur together in an immunologically predisposed host. The use of plasma therapy appears to have had a significant impact on survival in these patients.


Thrombotic thrombocytopenic purpura in systemic lupus erythematosus and antiphospholipid antibodies: effective treatment with plasma exchange and immunosuppression. We describe 2 patients with systemic lupus erythematosus (SLE) with neurological complications and thrombocytopenia, who, upon further investigation, were found to have thrombotic thrombocytopenic purpura. While neither patient responded to treatment with corticosteroids, both responded to plasma exchange and intravenous cyclophosphamide. This highlights the need to carefully consider this diagnosis in patients with SLE presenting with neurological complications and thrombocytopenia.


Seven Achilles tendinitis including 3 complicated by rupture during fluoroquinolone therapy. We describe 7 Achilles tendinitis occurring during fluoroquinolone treatment. Antibiotic agents used were pefloxacin and ofloxacin. In 3 cases the course was complicated by rupture of the tendon, one of which is histologically documented. The toxic effects of quinolones on tendon is discussed.


Cerebral aneurysm in relapsing polychondritis. A 51-year-old woman with relapsing polychondritis involving auricular and nasal cartilage, hearing loss, vasculitic skin lesions and a cerebral aneurysm of the posterior cerebral artery is described. Cerebral aneurysm is a rare manifestation of relapsing polychondritis which to our knowledge has not yet been described.


Endotracheal intubation skills of medical students. The ability and confidence of clinical medical students to insert endotracheal tubes correctly and quickly and to recognize oesophageal misplacement was evaluated. Ten (33%) of the medical students intubated the trachea correctly at their first attempt but 14 (47%) incorrectly identified the position of the endotracheal tube. However, recognition improved by their second and third attempts (70% and 80% respectively). Ninety-three percent of students intubated correctly on their third attempt. Although medical students can obtain better results at correct tube placement with repeated attempts under optimum conditions--a practice effect--and do better at recognizing correct tube placement there is still a persistent failure to recognize endotracheal tube misplacement, ie oesophageal intubation. It is the ability to recognize oesophageal intubation promptly that is a life-saving skill. This essential skill should be taught during the introductory anaesthesia programme through the use of clinical patients.


Emotional distress in doctors: sources, effects and help sought. All doctors in a London Teaching Hospital were sent a self-administered, anonymous questionnaire, to study past episodes of emotional distress. We inquired about frequency of past and current emotional distress, sources of distress, effects on work and home life, type of help sought and perceived outcome of that help. Of 320 doctors, 210 (66%) responded. One hundred and forty-one (68%) reported previous episodes of moderate or severe emotional distress. Logistic regression revealed that distress was significantly more common in younger doctors and in women. Many respondents reported work problems as causing their distress and work was frequently adversely affected by episodes of distress. Professional help was rarely sought; non-professional help was from family and friends. Current emotional distress was related to a history of past distress, especially among the most junior doctors. We conclude that past emotional distress is reported by most doctors, with work pressures an important contributing factor. Doctors do not appear to use available sources of professional help. Our findings confirm that doctors have difficulty disclosing psychological problems. Specific programmes aimed at prevention and management of distress in doctors need to be initiated and evaluated.


Sudden death in epilepsy: an avoidable outcome? In a retrospective survey of mortality among the first 1000 unselected patients referred to the Epilepsy Research Unit at the Western Infirmary in Glasgow between 1985 and 1990, a total of 18 deaths were identified. Three patients had committed suicide and one each had died of status epilepticus in hospital, a subdural haematoma and a myocardial infarction. The remaining 12 deaths (67%) were sudden (median age 32 years; range 22-68 years). Poor seizure control and poor compliance with antiepileptic drug therapy were recorded in only three (25%) of these patients. There was a change in antiepileptic drug regimen in five (28%) in the month before death. Only two (17%) underwent postmortem examination. In nine of the 12 patients dying suddenly, the primary cause of death was not listed as epilepsy but as asphyxia (3), aspiration (2) and one each of ischaemic heart disease, myocardial infarction, asystole and drowning (in the bath). 'Status epilepticus' was assumed to have been responsible for the other three deaths, two of which were unwitnessed. Sudden death in people with epilepsy is an entity of great concern. Appropriate death certification and mandatory postmortem examination are essential to provide a truer picture of this neglected phenomenon.


A pilot study of the effect upon multiple sclerosis of the menopause, hormone replacement therapy and the menstrual cycle. A questionnaire enquiring about changes in severity of symptoms of multiple sclerosis with the menstrual cycle, menopause and use of hormone replacement therapy was answered retrospectively by 11 premenopausal and 19 postmenopausal women. Eighty-two per cent of menopausal women reported an increase in severity premenstrually. Of the postmenopausal women 54% reported a worsening of symptoms with the menopause, and 75% of those who had tried hormone replacement therapy reported an improvement. The results of this pilot study indicate the need for further research to clarify the effects of the menopause and hormone replacement therapy upon multiple sclerosis.


Eye tests in the elderly: factors associated with attendance and diagnostic yield in non-attenders. Patients aged 60-75 years registered with one inner city general practice were sent a questionnaire asking when they last received an eye check by an optometrist. Of the 193 (77%) who responded, 110 (59%) had attended in the last 2 years, and 138 (74%) in the last 3 years. Males and those with mobility problems were less likely to have had their eyes checked. Seventy-seven previous non-attenders were offered an appointment with an optometrist and this was accepted by 34 (44%). These individuals showed a high level of ophthalmic morbidity. Discussion of optometric checks should be included in general practice health checks and the elderly surveillance programme.


Beyond music: auditory temporary threshold shift in rock musicians after a heavy metal concert. Audiometry was undertaken before and within half an hour following a heavy metal concert to assess evidence of noise damage. Of the four members tested, one member wore an ear defender in his right ear during the period of noise exposure. All unprotected ears showed a temporary threshold shift which was maximum in the lower frequencies. There was some evidence that early noise damage had occurred with a dip at 6 kHz. The role of music as noise and its potential to damage the cochlea are discussed.


Hypnoanalgesia for chronic pain: the response to multiple inductions at one session and to separate single inductions. Serial hypnotic inductions conveying the same analgesic message produce a progressively longer response in an increasing number of patients. The resulting analgesia appears to be independent of the spacing of inductions--whether given at a single session or on separate occasions--and to depend upon their number. However, multiple inductions at a single session save time. Elimination of pain can be achieved, by either approach, for a year or more in up to 70% of patients.


Diagnosis and management of renal angioma. Five patients with symptomatic renal angiomata are described. All presented with heavy haematuria and unilateral ureteric obstruction without evidence of a mass distorting the renal architecture. Renal angiomata are most easily diagnosed by selective renal angiography. They may be treated by intraarterial embolization, avoiding the need for major ablative surgery.


Diurnal changes in perceptions of energy and mood. Data from five separate groups of volunteers show that diurnal variation in perceptions of physical and mental energy ('vigour') can be simply measured by the use of visual analogue scales. In all five groups, perceptions of vigour were significantly higher in the morning than at other times of day. In three groups where energy levels were measured six times daily the values achieved between 10.00 h and 12.00 h were significantly higher (P < 0.05) than those recorded on rising or retiring. Some evidence was also found for the existence of high energy levels in the evening (particularly among the undergraduates) and for an 'afternoon dip' in energy in about 20% of subjects. Higher levels of positive affect were also found in the morning and levels recorded between 10.00 h and 12.00 h were significantly greater than those on rising or retiring, (P < 0.01). However, no similar diurnal variation was observed for negative affect. The difference may be due to the fact that positive affect has a distinct 'biological' component contributing to perceptions of energy, whilst negative affect depends more on features in the individual's environment, which show no consistent diurnal pattern.


Dementia and driving.

Dementia and driving. Many European countries test cars, but not their drivers, as they age. There is evidence to suggest that human factors are more important than vehicular factors as causes of motor crashes. The elderly also are involved in more accidents per distance travelled than middle-aged drivers. As the UK relies on self-certification of health by drivers over the age of 70 years, we examined the driving practices of patients with dementia attending a Memory Clinic. Nearly one-fifth of 329 patients with documented dementia continued to drive after the onset of dementia, and impaired driving ability was noted in two-thirds of these. Their families experienced great difficulty in persuading patients to stop driving, and had to invoke outside help in many cases. Neuropsychological tests did not help to identify those who drove badly while activity of daily living scores were related to driving ability. These findings suggest that many patients with dementia drive in an unsafe fashion after the onset of the illness. The present system of self-certification of health by the elderly for driver-licensing purposes needs to be reassessed.


Laxative induced diarrhoea--a neglected diagnosis. A laxative screening service was established and offered to gastroenterologists in hospitals covering the West and Central belt of Scotland. The prevalence of laxative induced diarrhoea was assessed in two populations and was found to be 4% in new patients presenting to a gastroenterology clinic with diarrhoea and 20% in patients already under investigation of chronic idiopathic diarrhoea. A high rate of missed diagnosis of laxative induced diarrhoea (71%) and a low request rate (eight per annum) confirm the low clinical awareness of this diagnosis. We found potential savings of 80% of the cost of investigations subsequently ordered which could have been avoided by performing laxative screens on all patients presenting with diarrhoea. The introduction of such a screening policy is recommended as a cost-effective measure.


'I thought it would go away': patient denial in breast cancer. A significant proportion of patients with cancer present late to the doctor. The characteristics of these patients and the reasons behind their delaying behaviour is poorly understood. In this study a group of 30 women with breast cancer who delayed their presentation were compared with a randomly selected group with the same disease. The women who presented late did not appear to fit into any particular socio-demographic category, but examination of their histories revealed widespread denial of illness and a diversity of beliefs and behaviour.


The Ring total knee replacement--a comparison of survivorship. Long term results of joint replacement are frequently expressed as survivorship; it therefore becomes increasingly important to have the ability to make valid comparisons between survivorship tables in order to determine accurately the statistical significance of published differences. We present a statistical method for direct comparison of survivorship tables. We have applied this technique to evaluate the survivorship of the unconstrained, uncemented Ring total knee replacement first implanted in 1975 and compare this to contemporaneous constrained prostheses. There is a significant improvement in survival, which suggests a beneficial long-term effect on the bone/implant interface of this changing design concept.


An audit of university education in trauma and orthopaedic surgery in Great Britain. An audit of undergraduate trauma and orthopaedic surgery teaching was carried out in 24 of the 27 medical schools in Great Britain and major differences were found between the medical schools. The range of time spent in teaching trauma and orthopaedic surgery for undergraduates varied from 3 weeks to 12 weeks and in five out of 27 medical schools trauma and orthopaedic surgery tuition was split between various years of the clinical curriculum. In some schools there were 30 students on a firm and in others only one. The opportunity for undergraduates to give feedback to their teachers, the use of objective assessment at the end of such an appointment by the teachers, varied between medical schools. To avoid some of these very basic differences between our medical schools, the teaching of clinical subjects to undergraduates in medicine should be reviewed nationally and minimum standards set.


Cerebral blood flow and mental processes in schizophrenia. The patterns of cerebral blood flow associated with three syndromes of schizophrenic symptoms are compared with the loci of cerebral activation in normal subjects during the performance of mental processes implicated in the three syndromes. The psychomotor poverty syndrome, which has been shown to involve a diminished ability to generate words, is associated with decreased perfusion of the dorsolateral prefrontal cortex at a locus which is activated in normal subjects during the internal generation of words. The disorganization syndrome, which has been shown to involve impaired suppression of inappropriate responses (eg in the Stroop test), is associated with increased perfusion of the right anterior cingulate gyrus at a location activated in normal subjects performing the Stroop test. The reality distortion syndrome, which evidence suggests arises from disordered internal monitoring of activity, is associated with increased perfusion in the medial temporal lobe at a locus activated in normal subjects during the internal monitoring of eye movements.


Abnormalities of cerebral structure in schizophrenia on magnetic resonance imaging: interpretation in relation to the neurodevelopmental hypothesis. The nature of abnormalities of cerebral structure evident in schizophrenia on magnetic resonance imaging is considered in relation to the neurodevelopmental hypothesis of the disorder. While schizophrenic patients showed increased ventricular volume, the extent of increase with age was comparable with that evident in controls and was unrelated to duration of illness. Conversely, cortical atrophy was evident only in patients, and this increased markedly with age and duration of illness. Such findings could be suggestive of two distinct pathophysiological processes in schizophrenia, but a schema for their reconciliation with the neurodevelopmental hypothesis is elaborated.


Vesico-vaginal and recto-vaginal fistulae. A personal series of 716 patients with vesico-vaginal and/or recto-vaginal fistulae is presented. Five hundred and seventy-eight patients were managed in Africa, mainly at the Addis Ababa Fistula Hospital, while 138 were kindly referred to me from various parts of Britain. The main cause of such fistulae in the developing world is pressure necrosis from obstructed labour. In the developed world the aetiology is surgery, malignancy, radiotherapy or a combination of these. Other causes include neglected foreign bodies, coital injury and local treatment by an unqualified practitioner. A vesico-vaginal fistula alone was present in 78.8%, a recto-vaginal fistula alone in 4.3%, while 16.9% of patients had both a vesico-vaginal and a recto-vaginal fistula. Six hundred and six (84.6%) patients were cured at the first attempt at repair, 45 (6.3%) failed and 65 (9.1%) had stress incontinence.


The spectrum of brittle diabetes.

The spectrum of brittle diabetes. A group of 42 severely brittle insulin dependent diabetic patients were studied, and compared with a similar number of 'stable' diabetic patients. Brittle diabetics were predominantly female (86% v 45%, P < 0.01), were of younger age (mean +/- SD 27.9 +/- 12.8 years v 40.1 +/- 13.6 years, P < 0.001), and of shorter duration of diabetes (13.7 +/- 9.4 years v 19.6 +/- 11.2 years, P < 0.01). Control as measured by glycosylated haemoglobin (HbA1) was poorer (13.7 +/- 3.1% v 10.1 +/- 1.5%, P < 0.001), and daily insulin dose higher (98 +/- 81 u v 47 +/- 14 u, P << 0.001). There was no difference in diabetic complication rates, but psychosocial disturbances (74% v 17%) and factitious instability (40% v 2%) were highly significantly more common amongst brittle patients. Examination of patterns of admission revealed most brittle diabetics to have hyperglycaemic problems (70%), mainly due to recurrent ketoacidosis (52%). Recurrent hypoglycaemia accounted for 12% of the group, and only 5/42 patients (12%) had mixed forms of instability. Brittle diabetes is thus characterized by young age and female sex, and usually manifests itself as recurrent ketoacidosis or other forms of hyperglycaemic instability. Psychosocial problems and factitious metabolic decompensation are common.


Infective endocarditis in a district general hospital. Thirty-three cases of infective endocarditis presenting during a 6.5 year period to a district general hospital were analysed retrospectively. The annual incidence was 22 cases per million population. Twenty-two cases had pre-existing cardiac disease, mainly valvular disease-usually rheumatic (nine cases) and prosthetic valves (10 cases). Recognizable precipitants such as recent surgery were uncommon. Two cases presented after deliberate drug overdose possibly due to depression exacerbated by systemic disease. Symptoms were usually non-specific. All but two cases had murmurs and most were pyrexial. Splinter haemorrhages and clubbing were seen in about 20% of cases. Viridans-type streptococci were the commonest infecting organisms (14 cases). Staphylococcal infection (six cases) was confined to intravenous drug abusers and patients with prosthetic valves. Five cases were culture negative. Cardiac failure was present in 13 cases at presentation and developed in seven others during treatment. Acute valve replacement was necessary in eight cases, and late replacement in three. Renal impairment (plasma urea > 8 mmol/l and/or plasma creatinine > 120 mumol/l) occurred in 19 cases during the course of their illness. Embolic phenomena occurred in 12 patients and mostly involved the central nervous system. In the 8 fatal cases, the cause of death was cardiac failure in six, cerebrovascular accident in one, and myocardial infarction in one. Four of the six patients who subsequently died of cardiac failure had been referred for surgery. Both those who were not referred had coexisting medical problems. Factors associated with increased mortality were age, male sex, cardiac failure (P < 0.01), renal impairment (P < 0.05), and embolic phenomena (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Long term use of transcutaneous electrical nerve stimulation at Newcastle Pain Relief Clinic. This retrospective study of long-term use of transcutaneous electrical nerve stimulation (TENS) at Newcastle Pain Relief Clinic indicates that TENS has been a successful analgesic treatment for 58.6% of 1582 patients attending the clinic over a period of 10 years. A wide range of pain conditions were found to respond to TENS and many patients continued to use the treatment for several years. Most patients not responding to TENS (during a home trial) returned stimulators at the first follow-up appointment. Thus TENS should be considered as a simple, safe and reusable first line treatment for many pain conditions.


Critical ischaemia of the upper limb.

Critical ischaemia of the upper limb. Fifty-seven patients who presented to the Royal Surrey County Hospital, Guildford, with critical upper limb ischaemia between 1980 and 1989 were studied. Only 13 patients had emboli, while 23 presented with arteritis, seven involving large vessels and 16 with small vessel disease. Other causes included nine patients with trauma, six with atherosclerosis (of whom five were women), and four with vascular complications of thoracic outlet obstruction. Single examples of ischaemia due to radiation fibrosis and disseminated intravascular coagulation were also seen. Critical ischaemia of the upper limb remains an uncommon yet challenging problem. The review demonstrates that total limb arteriography should be performed in all patients, except the minority who present with direct arterial trauma or classical emboli.


Renal conservation in the management of bilateral renal tumours. We report five patients with bilateral tumours and review their management which include many of the therapeutic options that are available.


Why 100 patients failed to keep an outpatient appointment-audit in a dermatology department. Failure to keep outpatient appointments is common at all clinics and various explanations may be offered. One hundred attending patients who had failed to keep their previous dermatology clinic appointment were asked the reason for their non-attendance. Many and varied reasons were given but illness (28%), and problems related to appointments (33%) were prominent. They were also asked how they had obtained a further appointment. Stricter follow-up of non-attenders by the hospital including informing the GP, and subsequent GP action if necessary, may improve attendance figures.


Bringing about change: the introduction of secure units. The introduction of regional secure units into the NHS was studied as one example of the diffusion of patient care innovations. As well as the general history of secure units events in four Regions were studied in detail for the period from 1974 up to mid-1983. It is concluded that secure units became gradually more acceptable over time as (i) the need for such units was recognized, (ii) the climate of opinion changed in psychiatric hospitals from seeing secure units as a retrograde step, following the acceptance of more open door policies, to seeing secure units as a prestige development which might safeguard the future of a particular hospital, (iii) government loosened the definitions of what secure units should be and how they should operate so that there was more room for different regions to assess their own needs. Regions which were able to move relatively fast on secure unit development were those where there was already a 'product champion' present to promote the ideas, usually a forensic psychiatrist, and where there was also managerial support and designated responsibility for secure unit development at local and regional level. It is concluded that while public reaction was a hindrance it did not slow down secure unit development as much as might have been expected.


Botulinum toxin treatment of spasmodic torticollis. We reviewed the efficacy and adverse effects of repeated botulinum toxin injections into hyperactive neck muscles of 107 successive patients with spasmodic torticollis. They received 510 injection treatments over a median period of 15 months (range 3-42 months). One patient failed to benefit at all, but 101 (95%) patients reported considerable (moderate or excellent) benefit from at least one treatment. On a global subjective response rating, 93% of 429 treatments resulted in some improvement and 76% in moderate or excellent improvement. Pain reduction followed 89% of 190 treatments with moderate or excellent reduction after 66%. Median duration of benefit was 9 weeks. All torticollis types responded equally well and injections into two (or more) involved neck muscles were more effective than injection into a single muscle. The most frequent adverse effect was dysphagia, occurring after 44% of all treatments, but this was severe after only 2%. Antibodies to botulinum toxin were detected in the serum of three out of the five patients in whom loss of treatment efficacy occurred. We conclude that botulinum toxin treatment is the most effective available therapy for spasmodic torticollis and practical advice is provided for anyone wishing to set up the technique.


Ceftazidime versus aminoglycoside and (ureido)penicillin combination in the empirical treatment of serious infection. Urgent treatment of serious infections with broad spectrum antibiotics usually starts before bacteriological evidence of the infective organism(s) becomes available. In this study 471 patients with a clinical diagnosis of sepsis were treated empirically with ceftazidime (CAZ) monotherapy (249 patients), or with an aminoglycoside+(ureido)penicillin combination (AG+PEN) (222 patients) to establish clinical outcome and bacteriological response. Up to 72 h post-treatment 94.5% of patients in the CAZ group and 93.8% in the AG+PEN group were treated successfully (treatment difference 0.7%, P < 0.01, 95% confidence interval -3.8%, 5.2%); 2-4 weeks after treatment neither regimen proved clinically superior. The differences in bacteriological response up to 72 h, and at 2-4 weeks after treatment, were 5.6% and 12.4% in favour of CAZ, however, these were not statistically significant. Overall, 56 patients reported 72 adverse events in the CAZ group, compared with 33 patients reporting 41 adverse events in the AG+PEN group. Deaths, 40 on CAZ and 21 on AG+PEN, were mainly related to their underlying condition. The two regimens were shown to be clinically equivalent in seriously ill patients treated empirically.


Nitrous oxide-oxygen analgesia: the performance of the MC mask delivery system. Nitrous oxide administration via an oxygen facemask such as the Mary Catterall (MC) is an accepted technique for supplementing regional anaesthesia. This study assessed the range of nitrous oxide and oxygen concentrations delivered to the trachea using a mechanical lung model. The inspired concentrations of these two gases were determined by the total fresh gas inflow rates, their concentrations in the fresh gas mixture and the peak inspiratory flow rate of the analogue lung. A 1:1 nitrous oxide-oxygen mixture in the fresh gas with an inflow rate of 4-6 l/min is recommended to ensure adequate oxygen delivery into the trachea as well as achieving the therapeutic concentrations of nitrous oxide (20-30%).


Monospot and VP1 tests in chronic fatigue syndrome and major depression. Thirty-four patients with chronic fatigue syndrome (CFS) were compared with controls with DSM-III-R major depression on the Monospot and VP1 antigen tests. There was no significant difference in the numbers initially VP1 positive in the groups (11/34 and 7/34 positive in the chronic fatigue and major depression group respectively). Four CFS but no depressed patients were Monospot positive initially. No patient was both Monospot and VP1 positive. Patients positive on the tests were offered a repeat 6 months later. Eight of the 11 VP1 positive patients in the CFS group were retested and four remained positive, but none of the four depressed patients retested remained positive. No patient retested remained Monospot positive. The Monospot and VP1 tests appear to have little discriminating ability between these groups as screening tests and their predictive validity is unclear.


Aerobic exercise in the adjunctive treatment of depression: a randomized controlled trial. Two clinical trials have been conducted in a sample of depressed patients to determine whether the addition of an aerobic exercise programme to their usual treatment improved outcome after 12 weeks. In the first trial, an aerobic exercise group had a superior outcome compared with a control group in terms of trait anxiety and a standard psychiatric interview. A second trial was then conducted to compare an aerobic exercise programme with low intensity exercise. Both groups showed improvement but there were no significant differences between the groups. In neither trial was there any correlation between the extent of change in the subjects' physical fitness due to aerobic exercise and the extent of the improvement of psychiatric scores.


Management of hypopharyngeal carcinoma: a 6-year review. A retrospective review of 16 consecutive cases of squamous carcinoma of the hypopharynx treated by pharyngo-laryngo-oesophagectomy (PLO) and gastric transposition with a thoracotomy as part of the surgical technique is presented. An operative mortality of 6% and a hospital mortality of 12% occurred. Other complications are discussed. No significant morbidity or mortality occurred as a result of the thoracotomy. A comparison is made with the extra-thoracic technique of gastric transposition.


Acrokeratosis paraneoplastica of Bazex.

Acrokeratosis paraneoplastica of Bazex. Bazex disease is one of the rarer cutaneous paraneoplastic syndromes. It is characterized by psoriasiform changes on the digits, and in some patients spread to the ears, nose and in later stages to the limbs and trunk. The associated malignancy is typically a squamous cell carcinoma of the upper aerodigestive tract. We review the literature regarding acrokeratosis paraneoplastica of Bazex and report three cases which illustrate both the typical and some of the less common changes that are seen in the condition.


Food allergy--fact or fiction: a review. Food sensitivity is a common condition presenting with various clinical syndromes including migraine, urticaria, gluten enteropathy, Crohn's disease and irritable bowel syndrome. It is a heterogeneous condition affecting different organ systems and is also aetiologically diverse with subgroups due to allergy, pharmacological reactions, enzyme deficiencies and psychological causes. Clinical acceptance of food sensitivity has been delayed by the use of dubious diagnostic techniques by a minority of practitioners and the lack of laboratory diagnostic tests, but several double blind studies have now fully validated the existence of food sensitivity syndromes. More widespread recognition of food sensitivity would be cost effective for the National Health Service.


Dietary habits of school-children in Bahrain. A multistage stratified sampling procedure was used to select 1673 Bahraini school children (871 boys and 802 girls) to study their food habits. The results revealed that breakfast was more often skipped than lunch and supper by both sexes. Significant differences in the food consumption between boys and girls were noticed at morning snack; beef burgers, liver and egg sandwiches were more consumed by boys, while girls preferred carbonated beverages, cheese, uncarbonated canned drinks and broad beans. The foods consumed at lunch were very similar to those of the adult population in Bahrain. However, the percentage of fresh fruits consumed at lunch was almost double by girls (31.9%) than boys (17.1%). Corn-puffs, carbonated beverages, chocolates, uncarbonated canned drinks and fruits were the main foods consumed at afternoon snack. Boys were more likely to consume tea, meat, eggs, cheese and rice at supper, while girls preferred cheese, corn-puffs and carbonated beverages. Age has also a significant influence on dietary habits. The consumption of bread at breakfast decreased with age while the consumption of carbonated beverages at morning snack increased remarkably with age. In general the meal and snack patterns of school children vary considerably with age and sex.


Fish mongers and public awareness on fish-food hygiene in Nigeria. Sale of fish is a thriving business in Nigeria because of the high demand for fish. However, there is lack of public awareness on the need for fish hygiene by fish mongers and consumers. This paper discusses the issue of hygiene as it affects a fish shop environment, insects and pests of fish, preservation, handling, transportation, packaging, fish marketing and distribution. Suggestions on improving fish food hygiene and strategies for establishing fish guidelines and inspections are highlighted.


Suspected synergism between consanguinity and familial aggregation in type 2 diabetes mellitus in Saudi Arabia. A retrospective study of 210 cases of diabetes was carried out at King Khalid University Hospital diabetes clinic to delineate etiologic factors in non-insulin dependent diabetes mellitus (NIDDM). Standardised detailed questionnaires were administered to both cases and controls and the information sought included general demographics, dietary patterns, anthropometric values, family history, consanguinity and familial aggregation of Diabetes Mellitus (DM). Familial aggregation yielded an odds ratio of 6:2 which suggests a causal association with DM. A synergistic effect of familial aggregation was observed which needs to be further explored in future studies.


Sampling in epidemiological research: a case study of the prevalence of brucellosis in Saudi Arabia. The superficial description in biomedical journals of sampling methods used in epidemiological studies of the prevalence of some diseases can be attributed to shallow knowledge of basic sampling techniques. The population of interest in most community surveys is usually very large and resources and time available limited, so that researchers have little or no choice but to study a sample of the population. One of the basic principles of sampling is the avoidance of bias, guaranteed by taking a random sample. But the term 'random sample' has often been misinterpreted as synonymous with 'haphazard sample', taking a sample without a definite pattern. It is re-emphasised that a random sample is a probability sample that gives every unit in the population a known probability of being selected in the sample. The procedures for taking a random sample for a nationwide study in the Kingdom of Saudi Arabia are not easy because of the structure of the population, and therefore require more complex sampling methods like the stratified cluster sampling. It is also necessary in a stratified sample to calculate estimated persons affected by a condition for each selected subgroup of the population before obtaining the overall prevalence rate. A proper understanding and use of appropriate sampling techniques is most likely to result in the most desired representative sample, and guarantees that some underlying assumptions for inferential statistics will be satisfied.


Assessment and evaluation of the International Water Decade. The International Drinking Water Supply and Sanitation Decade (1981-90) has ended without reaching its declared goal of providing all people with safe drinking water and proper sanitation. The effect of drinking water and sanitation on health has been established, and the 2 components have been included in the World Health Organization (WHO) global campaign for Health For All by the year 2000, and in the global Primary Health Care programme. The assessment of the achievements has been based on coverage rates expressed in percentage. The findings were computerised. High population growth rates in the developing countries hampered and reduced the coverage. Other hindering factors included the lack of appropriate technology, the preference of the small privileged urban areas over the vast rural areas, the lack of the simultaneous approach in the development of water and sanitation and poor involvement of health education in the activities of the Water Decade. The water and sanitation development activities of the last decade have to be carried forward and continued during the present decade, in a different approach and alternative methods.


Equal blood pressure levels carry different risks in different risk factor combinations. It is well known that combinations of risk factors result in higher risk than their mere sum. The present paper describes, in quantitative terms, the differences between risks pertaining to equal blood pressure elevations at different constellations with other risk factors (smoking and hypercholesterolaemia). From the practical point of view, this concept of 'constellation risk' convincingly underscores the need for controlling, in hypertensive patients, coexisting hypercholesterolaemia and smoking. Also, at equal blood pressure elevations, smoking and hypercholesterolaemic patients are in greater need of antihypertensive medication. This applies in particular to the range of mild hypertension, where individual decisions have to be taken whether to initiate drug treatment.


Haemodynamic contributions to post-exercise hypotension in young adults with hypertension and rapid resting heart rates. The haemodynamic effects of 45 min of treadmill exercise (at 70% of resting heart rate reserve) were determined in 5 young adults with hypertension and rapid resting heart rates (greater than 90 beats/min in clinic) and were compared with those of 5 age-matched normotensive subjects. Blood pressure was lower after exercise in the hypertensive, but not the normotensive subjects. Mean cardiac output before exercise was similar in the two groups, and fell from 6.8 +/- 0.6 before to 5.4 +/- 0.6 l/min 60 min after exercise in the hypertensive group (P less than 0.01). Total peripheral resistance tended to be higher at this time. Neither variable was affected by prior exercise in the normotensive group. The depressor effects of prior exercise on mean arterial pressure (-8.6 +/- 1.0 vs. -1.4 +/- 2.5 mmHg; P less than 0.04) and cardiac output (-1.4 +/- 0.3 vs. -0.1 +/- 0.1 l/min; P less than 0.005) and the increase in total peripheral resistance (+3.0 +/- 1.2 vs. 0.0 +/- 1.0 Units; P less than 0.05) were greater in the hypertensive group. Thus, the post-exercise hypotension in this selected group of young hypertensive subjects with rapid resting heart rates was mediated by a decrease in cardiac output and stroke volume disproportionate to the fall in blood pressure, suggesting sustained compromise of their cardiac performance after acute exercise.


Reproducibility of measurements of blood pressure in a tropical environment. The reproducibility of measurements of the blood pressure of 65 adult male Gambians was investigated to assess the role that replication of measurements may have in epidemiological studies in a tropical environment. Observations were made at approximately seven week intervals over a period of 15 months and measurements were repeated three times on each occasion a subject was seen. The magnitude of the variation of an individual subject's BP between occasions, and between readings on the same occasion, was comparable with those which have been observed in studies in developed countries in temperate climates. The variation between occasions was greater than that between readings on the same occasion. There was a significant fall in systolic pressure between the first and third occasions, and a more gradual fall in diastolic pressure. The observations suggest that an individual subject's BP level would be better characterized by making a second reading on another occasion than by making three or more readings on the same occasion. These results have implications for the design of epidemiological studies and for the diagnosis of hypertension in the tropics.


Demographic, life style and anthropometric correlates of blood pressure of Nigerian urban civil servants, factory and plantation workers. Demographic, life style and anthropometric correlates of blood pressure were analysed in 5,200 civil servants, factory and plantation workers living in an urban setting in the South Eastern part of Nigeria. The subjects were 4,382 men (84.2%) and 818 (15.8%) women. The prevalence of hypertension, using the WHO criteria among the workers was 8.1%, and was lower in women than men, 3.5% and 8.9% respectively. Only 19.6% of the hypertensive population knew that they had hypertension, whilst 29.4% of the total population under study gave a positive family history of hypertension. The blood pressure and the prevalence of hypertension rose with age, number of children in the family, salary scale and with the number of cigarettes smoked per day. The prevalence of hypertension was higher in medium and heavy drinkers than the non-drinkers and light drinkers. The prevalence was also higher in medium and heavy smokers. Multiple regression analysis showed a significant positive relation between the systolic blood pressure and sex, age, marital status, number of children in the family, salary scale, tobacco consumption and weight (P less than 001). On the other hand, occupation (P less than 01) educational qualification (P less than 001), support system (P less than 03) and height (P less than 001) had significant negative relationships with systolic blood pressure. There was also a significant positive relation between the diastolic blood pressure and number of children in the family (P less than 002) and salary scale (P less than 001). It is suggested that hypertension screening and treatment should be incorporated in the primary health care programmes of African communities.


Feasibility of a long-term low-sodium diet in mild hypertension. The present study set out to assess the feasibility of long-term moderate dietary sodium restriction in patients with mild hypertension in general practice. After screening and a run-in phase of 6-8 weeks, a total of 77 previously undiagnosed mildly hypertensive patients were identified. Half of them were randomized to receive a few simple dietary instructions from their general practitioners in order to reduce salt usage; the others were randomized to receive no advice. The patients were followed up for 12 months with quarterly visits. A total of 56 patients (72.7%) completed the study, 26 on a low-sodium diet (LD) and 30 on their usual diet (UD). At each visit in the diet phase, patients provided 24h urine, which was analysed for volume and sodium concentration in order to assess their sodium intake. Blood pressure, heart the rate and body weight were recorded. The mean urinary sodium excretion for all diet phase visits overlapped in the two groups (177.0 +/- 32.9 vs. 169.3 +/- 49.4 mEq/24h respectively in the LD and UD groups). Nevertheless the mean systolic and diastolic blood pressures for all diet phase visits were significantly lower in the LD than in UD group (144.2 +/- 11.1/91.6 +/- 6.4 and 148.0 +/- 13.7/95.6 +/- 4.7 mmHg respectively, P less than 0.01). Our data suggest that it is not feasible at present to reduce sodium intake in mild hypertensives with simple and inexpensive dietary instructions, the only ones suitable for widespread application in general practice.


Urinary salt titrator stick: a useful and quick estimate of dietary sodium intake? Repeated measures of urinary salt excretion are the best compromise between reliability and convenience for estimating dietary salt intake. In order to assess the accuracy of the Uropaper urinary salt titrator stick (giving discrete readings of 4, 6, 8, 10, 12 or 14 g/l of NaCl), 312 urine samples were analysed both with the stick and with an ion-selective electrode. There was a good stick-electrode correlation in all the 312 samples (r = 0.84). With a tolerance of +/- 1 g/l, the percentages of correct estimations dropped from 82% to 33% with increasing concentrations of NaCl in the urinary sample. For NaCl concentrations greater than 8 g/l (137 mmol/l) the error in the stick measurement consisted almost exclusively of overestimation of the electrode readings. These results were unaffected by the concentration of urinary potassium. No discrepancies were found among three different readers. This stick is easy to use and measures, with reasonable accuracy, low urinary NaCl concentrations. It could be useful for self-monitoring during low NaCl diets.


Blood pressure and urinary cations in a Chinese population. The prevalence of hypertension and the relationship between blood pressure, age, body mass index (BMI) and urinary cations from casual urine specimens were examined in 1,513 Chinese employees of a public utility company and non-medical personnel of a district hospital. The prevalence of hypertension, defined as systolic blood pressure greater than or equal to 140 or a diastolic blood pressure greater than or equal to 90 mmHg, or a past history of hypertension, was 17% in men and 5% in women. After excluding subjects who were on antihypertensive medication, age, body mass index, and urinary sodium/potassium ratio were independently and positively associated with blood pressure, while urinary potassium/creatinine ratio was inversely related to blood pressure. No association with urinary sodium or sodium/creatinine ratio was found. Higher mean blood pressure in men was accompanied by lower urinary potassium/creatinine and potassium concentration and higher sodium/potassium ratio, even though men had the same mean BMI when compared with women. A difference in potassium intake between the sexes may partly account for this finding. We conclude that in this Chinese population, whose dietary intake is more influenced by the West compared with Chinese in the Peoples' Republic of China, age and BMI are important determinants of blood pressure, together with potassium intake as reflected by urinary potassium excretion. No association of blood pressure with sodium excretion was demonstrated.


Blood pressure and 40 month mortality in elderly Chinese subjects aged 70 years and over. The association between blood pressure and 4 year mortality was examined in a cohort of 970 Chinese subjects aged 70 years and above. After adjusting for age, sex, body mass index, smoking habit, place of residence, and the presence of heart or chronic lung diseases, a U-shaped association between blood pressure and mortality was observed, the risks of mortality among subjects in the extreme quartiles being twice as high as those in the middle quartiles. Subjects with the lowest systolic blood pressure quartile also had a higher risk of developing functional limitations.


ACE inhibition in diabetic patients: effect on pressor responsiveness to noradrenaline. The pressor responsiveness to noradrenaline was assessed before and after four weeks of treatment with enalapril (20 mg/day) in eight mild-to-moderate essential hypertensives, in eight normotensive type II diabetics and in eight mild-to-moderate hypertensive type II diabetic patients. The ACE inhibitor interfered to the same extent with the renin-angiotensin system and did not alter noradrenaline kinetics in the three groups of patients, but significantly reduced the arterial responsiveness only in non-diabetic subjects. It is suggested that factors, such as an exaggerated sodium retention, might determine the lack of effect of enalapril in diabetic patients.


Complete spontaneous remission of cough induced by ACE inhibitors during chronic therapy in hypertensive patients. The files of 172 consecutive hypertensive patients who received captopril or enalapril have been reviewed and the patients questioned on the development of chronic dry cough, persisting for at least two months. Forty patients had cough that was attributed to the drugs. Thirteen of them discontinued the drugs because of this adverse effect. In 15 of the 27 patients (55%) who continued receiving ACE inhibitors (7 males, 8 females, aged 65.4 +/- 9.9 years) the cough had spontaneously disappeared after 3.9 +/- 1.9 months of continued unaltered administration of these drugs and without any treatment aimed against this symptom. All patients were followed for at least four months after disappearance of cough, without recurrences. This finding may discourage withdrawal of ACE inhibitors from many patients who develop cough. Continuation of ACE inhibitors for at least several months, despite cough, (if the cough is not too severe) is probably justifiable.


Hypocholesterolemic activity of synthetic and natural tocotrienols. Tocotrienols are farnesylated benzopyran natural products that exhibit hypocholesterolemic activity in vitro and in vivo. The mechanism of their hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase by a process distinct from other known inhibitors of cholesterol biosynthesis. An efficient synthetic route to tocotrienols and their isolation from palm oil distillate using an improved procedure is presented. gamma-Tocotrienol exhibits a 30-fold greater activity toward cholesterol biosynthesis inhibition compared to alpha-tocotrienol in HepG2 cells in vitro. The synthetic (racemic) and natural (chiral) tocotrienols exhibit nearly identical cholesterol biosynthesis inhibition and HMG-CoA reductase suppression properties as demonstrated in vitro and in vivo.


Synthesis and biological activity of trans(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamide 1-oxide (RP 49356) and analogues: a new class of potassium channel opener. The synthesis and biological activity of trans-(+-)-N-methyl-2-(3-pyridyl)-2-tetrahydrothiopyrancarbothioamid+ ++ e 1-oxide (8a, RP 49356) and analogues is reported. These compounds constitute a new structural class of K(+)-channel opener. The effects of changes in pyridyl group, thioamide, and thiane ring on in vitro K(+)-channel opening reactivity are discussed. A 3-pyridyl or 3-quinolyl group, a small N-alkyl thioamide function, and a thiane oxide ring, in which the sulfoxide is in a trans relationship to the thioamide, are preferred for activity. Selected compounds were tested intravenously in the normotensive anaesthetized rat for hypotensive effects, and the activities reflect their in vitro K(+)-channel opening activity. This led to further evaluation of compound 8a and the selection of the (-)-enantiomer 8b (RP 52891) for development as an antihypertensive and antianginal agent.


1-(2-Aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-e]indole: a rotationally restricted phenolic analog of the neurotransmitter serotonin and agonist selective for serotonin (5-HT2-type) receptors. A series of rotationally restricted phenolic analogs of the neurotransmitter serotonin has been synthesized with the 5-hydroxyindole portion of serotonin replaced by a dihydropyrano[3,2-e]-indole (1, 3, 4, and 5) and a dihydropyrano[2,3-f]indole (2). The receptor binding profile of these compounds has been studied and compared to the natural substrate serotonin. The dihydropyrano[3,2-e]indole derivatives (1, 3, 4, and 5) possess lower affinity for 5-HT1 receptors but equal or greater affinity for 5-HT2 receptors. Like serotonin, these compounds dose-dependently stimulated phosphatidylinositol turnover in rat brain slices. Moreover, the response to 1-(2-aminoethyl)-3-methyl-8,9-dihydropyrano[3,2-]indole (5, CP-132,484) and 1-(2-aminoethyl)-8,9-dihydropyrano[3,2-e]indole (4) is selectively antagonized by 5-HT2 receptor antagonists establishing these tryptamines as selective 5-HT2 receptor agonists. The high affinity and potency of 5 for 5-HT2 receptors suggests that the C5-hydroxy group in serotonin can function as a hydrogen bond acceptor in a 5-HT2 receptor with a directionality of interaction which is down and away from C6 in serotonin (Figure 5). Furthermore, the potent affinity of these compounds for 5-HT2 receptors coupled with their poor affinity for 5-HT1 receptors indicates that the aminoethyl side chain of serotonin adopts significantly different conformations in 5-HT1 versus 5-HT2 receptors.


Antiallergic and cytoprotective activity of new N-phenylbenzamido acid derivatives. A series of new N-phenylbenzamido acid derivatives was synthesized and evaluated for their ability to inhibit the IgE-mediated passive cutaneous anaphylaxis in the rat (PCA), as well as for their capacity to inhibit gastric mucosal damage induced by the oral administration of absolute alcohol in the rat. Some of these new derivatives exhibit potent antiallergic and cytoprotective activity, 20-80 times higher than that of the reference, disodium cromoglycate (DSCG). Structure-activity relationships are discussed. The antiallergic activity of one of the more potent compounds of this series, i.e. 4-(1H-tetrazol-5-yl)-N-[4-(1H-tetrazol-5-yl)phenyl]benzamide (compound 44, CR 2039) was further evaluated in vivo. This compound antagonizes the bronchoconstriction induced by aerosolized ovalbumin in both anesthetized and conscious IgE sensitized guinea pigs with ID50 of 3.7 mg/animal (tracheal insufflation) and 20 mg/kg (im). Further cytoprotective effects were evaluated in gastric ulcer models induced by the acute oral administration of hypertonic sodium chloride solution or by acetic acid and by the subchronic administration of glucose in fasted animals. In the models used experimentally CR 2039 is effective, whereas DSCG seems to be devoid of any protective activity. Such a potent antiallergic and mucosal protectant could provide a new potential agent in the therapy of atopic allergic diseases.


N1-hydroxylated derivatives of chlorpropamide and its analogs as inhibitors of aldehyde dehydrogenase in vivo. Certain (arylsulfonyl)urea hypoglycemic drugs exemplified by chlorpropamide (CP) are known to interact pharmacologically with alcohol (ethanol) to elicit a chlorpropamide-alcohol flushing (CPAF) reaction that is reminiscent of the disulfiram-ethanol reaction (DER). In the present structure-activity study, designed to elucidate the mechanism of inhibition of aldehyde dehydrogenase (AlDH) by CP, we discovered that the N1-methoxy derivative of CP 2a was a potent inhibitor of AlDH in vivo similar in activity to that of the N1-ethyl derivative 2b. Both 2a and 2b can release n-propyl isocyanate, a known inhibitor of AlDH, nonenzymatically. However, (arylsulfonyl)carbamates that are structurally analogous to 2a were also active inhibitors of AlDH, whereas the corresponding (arylsulfonyl)carbamate analogs of 2b were uniformly without activity. We propose a mechanism of bioactivation of 2a and its analogs that involves initial O-demethylation followed by disproportionation and solvolysis of the intermediate formed to release nitroxyl, the putative inhibitor of AlDH.


Prodrugs of nitroxyl as inhibitors of aldehyde dehydrogenase. In the preceding paper, analogs of chlorpropamide with an OMe substituent on the sulfonamide nitrogen were shown to inhibit aldehyde dehydrogenase (AlDH), and it was postulated that these compounds were bioactivated by O-demethylation to release nitroxyl (HN = O, nitrosyl hydride), which is an inhibitor of AlDH. Further evidence for the production of nitroxyl from compounds with O-acyl instead of OMe on the sulfonamide nitrogen is now presented. Thus, nitrous oxide (N2O), the end product of nitroxyl dimerization and disproportionation, was found to be generated on alkaline or enzymatic hydrolysis of N,O-diacylated N-hydroxyarylsulfonamides. Since the latter compounds strongly inhibit yeast AlDH in vitro after bioactivation by an esterase intrinsic to this enzyme, nitroxyl generated from these compounds must be the common intermediate that inhibits AlDH.