Substitution of aspartate for glycine 1018 in the type III procollagen (COL3A1) gene causes type IV Ehlers-Danlos syndrome: the mutated allele is present in most blood leukocytes of the asymptomatic and mosaic mother. A proband with arterial ruptures and skin changes characteristic of the type IV variant of Ehlers-Danlos syndrome was found to have a single-base mutation in the type III procollagen gene, which converted the codon for glycine at amino acid position 1018 to a codon for aspartate. (Amino acid positions are numbered by the standard convention in which the first glycine of the triple-helical domain of an alpha chain is number 1. The numbers of positions in the alpha 1(III) chains can be converted to positions in the human pro alpha(III) chain by adding 167.) Nucleotide sequencing of overlapping PCR products in which the two alleles were distinguished demonstrated that the mutation of glycine 1018 was the only mutation that changed the primary structure of type III procollagen. The glycine substitution markedly decreased the amount of type III procollagen secreted into the medium by cultured skin fibroblasts from the proband. It is surprising that the same mutation was found in about 94% of the peripheral blood leukocytes from the proband's asymptomatic 72-year-old mother. Other tissues from the mother contained the mutated allele; it was present in 0%-100% of different samples of hair cells and in about 40% of cells from the oral epithelium. Therefore, the mother was a mosaic for the mutation. Since the mutated allele was present in cells derived from all three germ layers, the results indicated that the mutation arose by the late blastocyst stage of development. The results also indicate that assays of blood leukocytes do not always reveal mosaicism or predict phenotypic involvement of tissues, such as blood vessels, that are derived from the same embryonic cells as are leukocytes.


Role of the pseudoautosomal region in sex-chromosome pairing during male meiosis: meiotic studies in a man with a deletion of distal Xp. Meiotic studies were undertaken in a 24-year-old male patient with short stature, chondrodysplasia punctata, ichthyosis, steroid sulfatase deficiency, and mild mental retardation with an inherited cytologically visible deletion of distal Xp. Molecular investigations showed that the pseudoautosomal region as well as the steroid sulfatase gene were deleted, but telomeric sequences were present at the pter on the deleted X chromosome. A complete failure of sex-chromosome pairing was observed in the primary spermatocytes of the patient. Telomeric approaches between the sex chromosomes were made at zygotene in some cells, but no XY synaptonemal complex was formed. The sex chromosomes were present as univalents at metaphase I, and germ-cell development was arrested between metaphase I and metaphase II in the vast majority of cells, consistent with the azoospermia observed in the patient. The failure of XY pairing in this individual indicates that the pseudoautosomal sequences play an important role in initiating XY pairing and formation of synaptonemal complex at meiosis.


Ethnic differentiation at VNTR loci, with special reference to forensic applications. Allele-rich VNTR loci provide valuable information for forensic inference. Interpretation of this information is complicated by measurement error, which renders discrete alleles difficult to distinguish. Two methods have been used to circumvent this difficulty--i.e., binning methods and direct evaluation of allele frequencies, the latter achieved by modeling the data as a mixture distribution. We use this modeling approach to estimate the allele frequency distributions for two loci--D17S79 and D2S44--for black, Caucasian, and Hispanic samples from the Lifecodes and FBI data bases. The data bases are differentiated by the restriction enzyme used: PstI (Lifecodes) and HaeIII (FBI). Our results show that alleles common in one ethnic group are almost always common in all ethnic groups, and likewise for rare alleles; this pattern holds for both loci. Gene diversity, or heterozygosity, measured as one minus the sum of the squared allele frequencies, is greater for D2S44 than for D17S79, in both data bases. The average gene diversity across ethnic groups when PstI (HaeIII) is used is .918 (.918) for D17S79 and is .985 (.983) for D2S44. The variance in gene diversity among ethnic groups is greater for D17S79 than for D2S44. The number of alleles, like the gene diversity, is greater for D2S44 than for D17S79. The mean numbers of alleles across ethnic groups, estimated from the PstI (HaeIII) data, are 40.25 (41.5) for D17S79 and 104 (103) for D2S44. The number of alleles is correlated with sample size. We use the estimated allele frequency distributions for each ethnic group to explore the effects of unwittingly mixing populations and thereby violating independence assumptions. We show that, even in extreme cases of mixture, the estimated genotype probabilities are good estimates of the true probabilities, contradicting recent claims. Because the binning methods currently used for forensic inference show even less differentiation among ethnic groups, we conclude that mixture has little or no impact on the use of VNTR loci for forensics.


A note on Hardy-Weinberg equilibrium of VNTR data by using the Federal Bureau of Investigation's fixed-bin method. To fully utilize the information of VNTR data for forensic inference, the probability of observing the matching suspect and evidentiary profile in a reference population is estimated, usually by assuming independence of alleles within and between loci. This assumption has been challenged on the basis of the observation that there is frequently an excess of single-band phenotypes (SBP) in forensic data bases, which could indicate lack of independence. Nevertheless, another explanation is that the excess SBP are artifacts of laboratory methods. In this report we examine the excess of SBP for three VNTR loci studied by the FBI (D17S79 and D2S44, for blacks, and D14S13, for Caucasians). The FBI claims that the excess is due to the effect of null alleles; the null alleles are suspected to be too small to be detected. We estimate the frequency of null alleles for two loci (D17S79 and D14S13) by comparing, for these loci, the data from the FBI data base and the data from the Lifecodes data base. These comparisons yield information on small fragments because Lifecodes uses the restriction enzyme PstI, which yields larger fragments than does HaeIII, which the FBI uses. For D17S79 in blacks, we estimate a null allele frequency of 4.4%, and, for D14S13 in Caucasians, we estimate a frequency of 3.0%. The null-allele frequency for D2S44 in blacks is derived similarly, again being based on analyses of DNA cut with HaeIII and PstI; our estimate of the null-allele frequency for this locus is 1.5%.(ABSTRACT TRUNCATED AT 250 WORDS)


Likelihoods of multilocus DNA fingerprints in extended families. A concept for the application of complex pedigree analysis to multilocus DNA fingerprinting is described. By following this approach, the extent to which the DNA fingerprints of grandparents influence the phenotype likelihoods of their offspring was determined. It was demonstrated by simulation that approximately 90% of paternity disputes can be solved if mother, child, and paternal grandparents, instead of the putative father, are tested. If only phenotype information on a single paternal sib is allowed for, true paternity will be detected with reasonable persuasive power in up to 64% of cases. Exclusion of false paternity remains possible for 40% of cases. Finally, the analysis concept is modified by reducing the number of genotype variations considered in likelihood computations. This time-saving procedure is shown to yield sufficiently accurate likelihoods in the analysis of both simulation data and multilocus DNA fingerprints obtained in two large families.


Dystrophin in frameshift deletion patients with Becker muscular dystrophy. In a previous study we identified 14 cases with Duchenne muscular dystrophy (DMD) or its milder variant, Becker muscular dystrophy (BMD), with a deletion of exons 3-7, a deletion that would be expected to shift the translational reading frame of the mRNA and give a severe phenotype. We have examined dystrophin and its mRNA from muscle biopsies of seven cases with either mild or intermediate phenotypes. In all cases we detected slightly lower-molecular-weight dystrophin in 12%-15% abudance relative to the normal. By sequencing amplified mRNA we have found that exon 2 is spliced to exon 8, a splice that produces a frameshifted mRNA, and have found no evidence for alternative splicing that might be involved in restoration of dystrophin mRNA reading frame in the patients with a mild phenotype. Other transcriptional and posttranscriptional mechanisms such as cryptic promoter, ribosomal frameshifting, and reinitiation are suggested that might play some role in restoring the reading frame.


HLA heterozygosity contributes to susceptibility to rheumatoid arthritis. We have investigated the role of HLA-DR genotypes in 184 patients with severe rheumatoid arthritis (RA) and in 46 patients with Felty syndrome, to establish the relative contribution of the RA-associated subtypes of DR4 (Dw4, Dw14, and Dw15). There was an excess of DR4 homozygotes, particularly Dw4/Dw14 compound heterozygotes (relative risk [RR] 49). The risk associated with Dw4 depended on the other allele present--Dw4/DR1 (RR 21), Dw4/Dw4 (RR 15), and Dw4/DRX (RR 6). There was a significant risk from Dw4/Dw14 compared with Dw4/Dw4, both in those with severe RA (RR 2.9; P less than .02) and in those with Felty syndrome (RR 4.2; P less than .02). In contrast, in a further 63 known DR4 homozygotes with RA, not selected for severe disease, the excess of Dw4/Dw14 was much less striking (RR 1.4; not significant), suggesting that this genotype may be particularly associated with more severe disease. We also found four cases with the rare Dw4/Dw15 genotype (expected less than or equal to 0.5; P less than or equal to .02). Since the Dw4, Dw14, Dw15, and DR1 molecules have similar antigen-binding sites and since combinations of these alleles particularly predispose to severe RA, we suggest that synergistic mechanisms are involved. These could include an effect on T-cell repertoire selection.


HLA-DR polymorphism in a Senegalese Mandenka population: DNA oligotyping and population genetics of DRB1 specificities. HLA class II loci are useful markers in human population genetics, because they are extremely variable and because new molecular techniques allow large-scale analysis of DNA allele frequencies. Direct DNA typing by hybridization with sequence-specific oligonucleotide probes (HLA oligotyping) after enzymatic in vitro PCR amplification detects HLA allelic polymorphisms for all class II loci. A detailed HLA-DR oligotyping analysis of 191 individuals from a geographically, culturally, and genetically well-defined western African population, the Mandenkalu, reveals a high degree of polymorphism, with at least 24 alleles and a heterozygosity level of .884 for the DRB1 locus. The allele DRB1*1304, defined by DNA sequencing of the DRB1 first-domain exon, is the most frequent allele (27.1%). It accounts for an unusually high DR13 frequency, which is nevertheless within the neutral frequency range. The next most frequent specificities are DR11, DR3, and DR8. Among DRB3-encoded alleles, DR52b (DRB3*02) represents as much as 80.7% of all DR52 haplotypes. A survey of HLA-DR specificities in populations from different continents shows a significant positive correlation between genetic and geographic differentiation patterns. A homozygosity test for selective neutrality of DR specificities is not significant for the Mandenka population but is rejected for 20 of 24 populations. Observed high heterozygosity levels in tested populations are compatible with an overdominant model with a small selective advantage for heterozygotes.


Microevolution of the Chibcha-speaking peoples of lower Central America: rare genes in an Amerindian complex. Models are developed for the survival, history, and spread of variant alleles, in order to consider what can, and what cannot, be inferred from this type of data. The high variances of the processes involved, and questions of sampling, place severe limitations on inferences. Nonetheless, by combining information on a number of rare variants observed in a group of interrelated populations, reliable qualitative inferences are possible. These ideas and models are developed in the context of data on five rare variants and six private polymorphisms observed in eight Chibcha-speaking tribes of Costa Rica and Panama. The decline and fragmentation of the Amerindian populations of Central America over the last 300 years create considerable difficulties in attempting inference of past genetic events. However, these tribes have been well studied genetically, anthropologically, and linguistically and thus provide an excellent framework for the study of rare-variant spread.


State legislative efforts to regulate use and potential misuse of genetic information. The purpose of this study was to review existing and proposed legislation specifically intended to regulate the collection, use, and potential misuse of genetic data. The study encompasses laws relating to confidentiality, informed consent, discrimination, and related issues. It excludes from consideration legislation relating to medical records generally that may bear indirectly on genetic information. It also excludes both legislation relating to the regulation of DNA data collection for law enforcement purposes and state laws relating to the confidentiality of data collected by newborn-screening programs. While relatively few laws that explicitly regulate the treatment of genetic information have been enacted to date, a considerable amount of activity is currently underway in the nation's legislatures. Although most of the bills under consideration are not comprehensive in scope, they reflect a growing societal awareness that the uncontrolled dissemination and use of genetic data entails significant risks.


Selection bias in genetic-epidemiological studies of cleft lip and palate. The possible impact of selection bias in genetic and epidemiological studies of cleft lip and palate was studied, using three nationwide ascertainment sources and an autopsy study in a 10% sample of the Danish population. A total of 670 cases were identified. Two national record systems, when used together, were found suitable for ascertaining facial cleft in live births. More than 95% ascertainment was obtained by means of surgical files for cleft lip (with or without cleft palate) without associated malformations/syndromes. However, surgical files could be a poor source for studying isolated cleft palate (CP) (only a 60% and biased ascertainment), and they cannot be used to study the prevalence of associated malformations or syndromes in facial cleft cases. The male:female ratio was 0.88 in surgically treated cases of CP and was 1.5 in nonoperated CP cases, making the overall sex ratio for CP 1.1 (95% confidence limits 0.86-1.4) The sex ratio for CP without associated malformation was 1.1 (95% confidence limits 0.84-1.6). One of the major test criteria in CP multifactorial threshold models (higher CP liability among male CP relatives) must be reconsidered, if other investigations confirm that a CP sex-ratio reversal to male predominance occurs when high ascertainment is achieved.


High frequency of mutations in exon 10 of the porphobilinogen deaminase gene in patients with a CRIM-positive subtype of acute intermittent porphyria. Acute intermittent porphyria (AIP) is an autosomal dominant disease characterized by a partial deficiency of porphobilinogen (PBG) deaminase. Different subtypes of the disease have been defined, and more than 10 different mutations have been described. We focused our study on exon 10, since we previously found that three different mutations were located in this exon and that two of them seemed to be relatively common. We used denaturing gradient gel electrophoresis (DGGE) after in vitro amplification to detect all possible mutations in exon 10 in 41 unrelated AIP patients. In about one-fourth of these patients we could distinguish three abnormal migration patterns, indicating the presence of various mutations. Additional sequencing demonstrated the presence of three different single-base substitutions. Two of these mutations had already been described. A third one consisted of a C-to-T transition located at position 499 of the PBG deaminase mRNA and resulted in an Arg-to-Trp substitution. All three mutations were found in patients with cross-reacting immunological material (CRIM)-positive forms of AIP. The high frequency of these mutations make DGGE analysis of exon 10 a useful approach allowing the direct direction of the DNA abnormality in most of the families with the CRIM-positive subtype of AIP.


Genetic studies to characterize the origin of the mutation in placental aromatase deficiency. Placental aromatase deficiency has recently been shown to be due to expression of RNA transcripts encoding abnormal aromatase molecules with 29 extra amino acids. To establish whether this aromatase deficiency is a hereditary or sporadic disease, we examined the genetic defect of the aromatase gene in the family of a patient. Direct sequencing of fragments of the aromatase gene prepared by PCR revealed that the splicing donor sequence (GT) of intron 6 in controls was mutated to GC in the patient, whereas the parents showed signals of both GT and GC. Subcloning of PCR products of the parents gave two different types of clones with GT and GC sequences in this site. Furthermore, for diagnosis of this deficiency, competitive-oligo-nucleotide-priming PCR of genomic DNA was performed in the presence of both normal and mutational oligonucleotide primers labeled with two kinds of fluorescent dyes, and the products were separated by agarose gel electrophoresis and were detected fluorometrically in the gel. Genomic DNA of the patient gave a PCR product primed only by the mutational primer, whereas that of controls gave a product primed only by the normal primer. The PCR products of the parents were primed by both primers. The results obtained by this fluorometric method were also confirmed by differential hybridizations with specific oligonucleotide probes. Thus these findings indicate that this deficiency is an autosomal hereditary disease and that the patient is a homozygote, while the parents are heterozygotes, for this mutation.


Smoking and cancer.

Smoking and cancer. An extensive body of epidemiologic data has linked cigarette smoking to a wide variety of neoplastic diseases. Smokers have been found to incur an increased relative risk of mortality from cancer of the lung, head and neck, urinary tract, pancreas, and bladder. Recent work has also implicated smoking in the risk of leukemia and myeloma. The magnitude of these risks has prompted research aimed at identifying the carcinogens involved in specific smoking-related neoplasms, as well as potential genetic predispositions to the effects of these toxins. Mutations in tumor suppressor genes have been identified in both small-cell and non-small-cell lung cancer, and mutations in dominant oncogenes have been noted in the latter disease. A growing understanding of the molecular genetics of smoking-related cancers may translate into improved diagnosis and treatment. Detection of mutations in oncogenes or tumor suppressor genes in premalignant tissues might facilitate identification of individuals who have a hereditary predisposition to smoking-related carcinomas. In the future, tumor growth may be halted by replacement or substitution of mutated tumor suppressor gene functions or biochemical modulation of oncogene products. New forms of immunotherapy may also be targeted specifically toward mutant oncogenes in cancer cells.


Mechanisms of respiratory tissue injury from cigarette smoking. Cigarette smoking can be viewed as a chronic inflammatory disorder of the lower airways. Two of the major lung injuries that can result are chronic bronchitis and emphysema. Chronic bronchitis is characterized by chronic mucus hypersecretion and cough; emphysema is a destructive process of the alveolar spaces. Tissue injury may result from the actions of degradative enzymes derived from such inflammatory cells as neutrophils and monocytes. In addition, oxidative injury from inflammatory cells and from oxidants in smoke may participate in the pathogenesis of these smoking-related illnesses.


The impact of tobacco use and cessation on oral and dental diseases and conditions. Smoked and smokeless tobacco use produces profound effects on soft and hard tissues in and around the oral cavity. Because many of these changes are clinically observable, dentists, oral hygienists, and related health professionals are in ideal positions to give patients specific information concerning the oral ill effects of tobacco use. This article links tobacco use with a wide range of malignant, precancerous, and nonmalignant changes in the oral and perioral environment and addresses the documented benefits of quitting. Oral conditions less definitively linked to tobacco are also discussed.


The effects of smoking on postoperative recovery. Two recent studies have implicated smoking as a principal risk factor for increasing the time patients spend in the postanesthesia care unit (PACU) following a wide range of surgical procedures. Hospitals are performing an increasing number of surgical procedures, with growing pressure to do more on an outpatient basis. With more internal and external pressures to streamline the rising costs of medical care, increased focus is being placed on the length of stay in the PACU. More than 300 patients were examined in each study. PACU time varied from 15 minutes to 5 hours, with a median of 75 minutes. Anesthesia duration correlated most closely with the length of stay in the PACU. All other variables were found to be unrelated to the length of time in the PACU or secondary to anesthesia time. The only independent factor was a history of smoking. While there were comparable ratios of smokers in all tested groups, there was a marked difference between smokers and nonsmokers in length of PACU stay. Of the nonsmokers, 38% were found to have PACU stays of less than 1 hour, compared with 23% of the smokers. Only 7% of the nonsmokers required longer PACU stays, compared with 19% of the smokers. Among the various smoking groups, however, there were no significant differences. While previous studies have suggested that smokers may have higher rates of various perioperative complications, these two studies are significant in that they have identified a population previously overlooked. These people who stay longer in the PACU would not otherwise be identified as having complications, and their eventual outcome was good. But it suggests that even these patients, who may view themselves as "healthy smokers," are significantly different from their nonsmoking counterparts. Further, varying the degree of smoking from heavy to light does not negate the increased PACU time. Therefore, any degree of smoking must now be viewed as having serious consequences in the immediate postoperative period and must be discouraged.


Passive smoking: the medical and economic issues. Since the late 1970s, the dangers associated with passive (involuntary) smoking have been widely debated. While research throughout the world has produced findings showing sidestream smoke to be harmful and possibly deadly to nonsmokers, an equal number of studies have indicated that the harms have been overstated or misclassified or that they are nonexistent. Those debates have culminated in a report sponsored by the Environmental Protection Agency and other federal agencies. The report concludes that second-hand cigarette smoke kills 53,000 nonsmokers a year and is a major cause of indoor air pollution. This article identifies the major medical and economic issues in the debate on side-stream smoke. It affirms the federal government's position on the need to create more smoke-free environments and impose stronger smoking restrictions nationwide.


Impact and cost-effectiveness of smoking interventions. Cigarette smoking is the foremost preventable cause of death in the United States. Along with being a major contributor to lung cancer, chronic obstructive pulmonary disease, and cerebrovascular disease, smoking is one of several modifiable risk factors for coronary artery disease (CAD). The Coronary Heart Disease Policy Model is a computer simulation model of CAD in the United States. Using the model, one can project CAD incidence, prevalence, events, mortality, cost, cost-effectiveness, and gains in life expectancy from various risk factor modifications, including smoking interventions. The model projects that reducing the number of cigarettes smoked by 50% would increase the population-wide life expectancy of 35-year-old U.S. citizens by 0.4 year. Eliminating smoking would yield population-wide gains of 0.8 year for 35-year-old males and 0.7 year for 35-year-old females. These gains are comparable to those achieved with strict control of cholesterol levels, diastolic blood pressure, or weight. Gains for the smokers themselves would be much greater. On average, 35-year-old male smokers would live 1.2 years longer if they reduced the number of cigarettes smoked by 50%, and 2.3 years longer if they quit smoking. Females 35 years of age would live 1.5 years longer by cutting back by 50% and 2.8 years longer by quitting. These gains are equal to or greater than gains that individuals would realize by reducing serum cholesterol levels of 240-299 mg/dL to 200 mg/dL; controlling mild hypertension; or reducing weight from greater than or equal to 130% ideal body weight to ideal body weight. Gains projected by the Coronary Heart Disease Policy Model are comparable to those forecast by others, who have projected that young adults would gain approximately 0.2-8.7 years by quitting smoking, depending on their smoking history. Two studies have examined the cost-effectiveness of smoking interventions. One found that counseling smokers to quit would cost only $705-988 per year of life saved for males and $1,204-2,058 per year of life saved for females. The second study found that prescribing nicotine gum as an adjunct to counseling would cost only $4,113-6,465 per year of life saved for males and $6,880-9,473 per year of life saved for females. These cost-effectiveness ratios are more favorable than those of most other current healthcare interventions. Smoking cessation would increase population-wide life expectancy by about a year and the life expectancy of a smoker by several years.(ABSTRACT TRUNCATED AT 400 WORDS)


Corporate healthcare costs and smoke-free environments. Results from two studies were combined to assess potential market impact for programs to reduce health risks, as well as to define how small businesses can better control their healthcare operating expenses, widen their profit margins, and increase their productivity. The most effective solutions resulted from partnerships among the medical, business, and patient communities for the joint implementation of intensive smoking-cessation programs. In the first study, the chief executive officers of 1,100 small businesses in the Chicago area were polled regarding their opinions on healthcare costs. During the 4-year study period, 1986-1990, we observed a significant increase in their recognition of the impact of employee smoking on rising healthcare costs. From this study we identified three profile attributes of small-business leaders. First, these leaders possess a weak knowledge base regarding healthcare cost-containment methods; second, they understand the magnitude of the impact-rising healthcare costs have on corporate profitability; and third, they have a strong level of confidence (85%) that lifestyle modification programs for their employees, such as smoking cessation, can help control healthcare costs. In the second study we found that smoking-cessation programs with physician involvement, addiction assessment and treatment, and behavioral training and follow-up are preferred by those who want to stop smoking. Such programs have also enjoyed the highest level of sustained success.


Smoking and cardiovascular disease.

Smoking and cardiovascular disease. Cigarette smoking is the most preventable cause of cardiovascular morbidity and mortality. Smoking has been associated with a two-to fourfold increased risk of coronary heart disease, a greater than 70% excess rate of death from coronary heart disease, and an elevated risk of sudden death. These risks are compounded in the presence of hypertension, hypercholesterolemia, glucose intolerance, and diabetes, all of which exhibit a synergistic effect with smoking. The relationship between smoking and the risk of peripheral vascular disease has also been well documented. Smokers account for approximately 70% of patients with atherosclerosis obliterans and virtually all those with thromboangiitis obliterans. An association between smoking and cerebrovascular disease remains a matter of debate, although a higher risk of stoke and stroke-related mortality has been observed in smokers than in nonsmokers. Smoking has also been implicated in the development of cor pulmonale, but a direct association with congestive heart failure has not been established. Nicotine and carbon monoxide appear to play major roles in the cardiovascular effects of smoking. Both components adversely alter the myocardial oxygen supply/demand ratio and have been shown to produce endothelial injury, leading to the development of atherosclerotic plaque. Adverse effects on the lipid profile have been noted as well, but the relationship between these changes and the risk of cardiovascular disease remains to be confirmed. Notably, smoking cessation results in a dramatic reduction in the risk of mortality from both coronary heart disease and stroke. In light of the fact that the incidence of smoking has declined primarily among educated sectors of the U.S. population, future efforts must focus on providing effective education, including smoking cessation techniques, to the less-educated groups.


Rapid intravenous infusion of amphotericin B: a pilot study. The administration of amphotericin B in the conventional prolonged infusion over 4 to 6 hours is complicated by the acute toxicities of fevers and chills in 50% to 90% of patients and the chronic toxicities of increased creatinine levels and hypokalemia in 60% to 80% of patients. To determine the safety and toxicity of rapid infusions, we conducted a prospective, nonrandomized study in patients with clinical indications for antifungal therapy. Twenty-five granulocytopenic adults with acute leukemia and myelodysplastic syndromes were enrolled in a phase I trial using four sequentially shorter infusion durations: a standard infusion over 4 hours (n = 3) and shortened infusion durations at 3 hours (n = 3), 2 hours (n = 4), and 1 hour (n = 15). Toxicity was assessed by daily examinations of study subjects by one of the study investigators, by documentation of all infusion-related fevers and chills, and by daily monitoring of serum levels of creatinine, potassium, magnesium, and aspartate aminotransferase. Temperatures greater than 38 degrees C occurred in 16 of 25 (64%) patients, but only two had temperatures exceeding 40 degrees C. Chills were observed in 13 of 25 (56%) patients, but only one had severe symptoms. Serum creatinine increased more than 0.5 mg/dL (44.20 mumol/L) above the pretreatment baseline in 17 of 25 (68%) patients, and the absolute creatinine level was greater than or equal to 2.0 mg/dL (176.8 mumol/L) in 10 of 25 (40%) patients. Serum potassium levels dropped below the normal limit of 3.5 mEq/L (3.5 mmol/L) in all patients, but no patient had potassium levels below 2.5 mEq/L (2.5 mmol/L). Intravenous potassium supplementation was administered to all patients and exceeded 100 mEq/d in 12 of 25 (48%) patients. Rapid infusions of amphotericin B are safe, are associated with similar toxicity as prolonged infusions, and facilitate inpatient care by decreasing nursing time needed for administration and minimizing scheduling conflicts with other necessary intravenous medications. Shorter infusions also facilitate outpatient and home administration of amphotericin B.


A pilot study of oral corticosteroid therapy for idiopathic esophageal ulcerations associated with human immunodeficiency virus infection. To evaluate the efficacy and safety of oral prednisone therapy for idiopathic esophageal ulcerations (IEU) associated with human immunodeficiency virus (HIV) infection. Over a 14-month period, all HIV-infected patients with IEU as defined by clinical, endoscopic, and pathologic criteria were prospectively identified. Prednisone was initiated at a dose of 40 mg/d orally, tapering 10 mg/wk, for a total of 1 month of therapy. Patients were closely followed to determine the response to therapy as well as the occurrence of any side effects related to prednisone. All patients were requested to undergo endoscopy within 1 week of the completion of therapy. Of 14 patients identified with IEU, 12 consented to prednisone therapy. The mean duration of esophageal symptoms was 2.9 weeks, and odynophagia was the most common presenting symptom. Ten of 12 patients had the acquired immunodeficiency syndrome. Eleven of the 12 patients (92%) had a complete symptomatic response, usually within the first week of therapy. In some patients, the response was dramatic such that oral intake could be rapidly resumed and discharge from the hospital possible. Two patients completed 2 and 3 weeks of therapy, respectively, prior to death, both with a complete symptomatic response. Endoscopic re-examination in seven patients demonstrated complete ulcer healing in all six symptomatic responders, but a persistent ulceration in the one nonresponder. The oral corticosteroid regimen was well tolerated. Mild asymptomatic Candida esophagitis was identified in three of seven patients undergoing follow-up endoscopy. One patient developed self-limited herpes zoster during therapy. No systemic opportunistic infections were documented during or within 1 month of the completion of therapy. Oral corticosteroid therapy appears to be a highly efficacious and safe therapy for HIV-associated IEU. Further controlled studies will be necessary to conclusively establish efficacy, as well as determine the optimal dose and duration of therapy.


A predictive risk index for nosocomial pneumonia in the intensive care unit. To develop a scoring system for stratifying patients in intensive care units (ICUs) by risk of developing nosocomial pneumonia (NP) and to identify the time period associated with the highest risk. Two hundred and three patients 18 years of age or older and residing in the ICU for 72 hours or more were followed until development of NP or death or for 48 hours after discharge from the ICU. After the identification of independent risk factors for NP, a scoring system was developed to arrive at a predictive risk index for NP. Twenty-six (12.8%) patients developed NP. The presence of a nasogastric (NG) tube [odds ratio (OR) = 6.48, 95% confidence intervals (CI) = 2.11 to 19.82], upper abdominal/thoracic surgery (OR = 4.34, 95% CI = 1.43 to 13.14), and bronchoscopy (OR = 2.95, 95% CI = 1.02 to 8.52), most commonly performed for respiratory toilet, were identified as independent risk factors on multivariate analysis. The risks associated with endotracheal intubation and altered consciousness, although not independently significant, were highest when these factors were present for 1 to 4 days after the 72 hours required for study entry (endotracheal intubation, OR = 2.2 to 2.5; altered consciousness, OR = 1.4 to 2.0). The risk then declined; ORs of less than 1 were observed at 7 days. The risk associated with the NG tube was highest during the first 6 days (OR = 6.0 to 19.5). Although a subsequent decrease in risk was observed, the OR was still greater than 2 at 7 days. To obtain a predictive risk index for NP, a scoring system was developed using a multivariate model. This system has a sensitivity of 85% and a specificity of 66% in predicting NP in this ICU population. ICU patients can be stratified into high- and low-risk groups for NP using a bedside scoring system. Endotracheal intubation, altered mental status, and NG tube are associated with the highest risk of NP during the first 1 to 6 days of their presence after 72 hours of stay in the ICU. After this time period, the risk associated with these factors decreases. Bronchoscopy may be an independent risk factor for NP that has not been previously recognized. This procedure, often done in the ICU for respiratory toilet, may be an avoidable risk in this group of patients.


Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability. This study was designed to assess the prevalence and nature of autonomic dysfunction (AD) in 34 patients with systemic sclerosis (SSc). Patients were questioned for current symptoms possibly related to AD. Five noninvasive cardiovascular autonomic function tests and sequential plasma catecholamine estimations at rest, during standing, and during sustained handgrip were performed. Seven patients with manometrically documented esophageal involvement and high resting plasma adrenaline levels were treated with clonidine (75 to 375 micrograms/d). One month later, resting plasma catecholamine estimations and esophageal motility studies were repeated. Autonomic testing revealed AD in each patient, while symptoms were experienced by 33 of them. Findings on two of the three heart rate tests and both blood pressure tests were significantly impaired as compared with those in 25 matched control subjects. Mean resting plasma adrenaline levels were 18 times higher than in 10 matched controls (p less than 0.001). Plasma catecholamine (adrenaline, noradrenaline, and dopamine) concentrations and mean arterial blood pressures fluctuated inappropriately during standing and sustained handgrip in 28 (82%) of the patients. The presence of headaches correlated significantly with sympathetic overactivity and instability (p less than 0.05). Resting plasma adrenaline concentrations correlated inversely with disease duration (p less than 0.05). Significant suppression of sympathetic overactivity and increases in resting lower esophageal sphincter pressures were observed in the seven patients treated with clonidine. AD is extremely common in SSc. It is characterized by parasympathetic impairment and marked sympathetic overactivity, particularly in early disease. The potential role of AD in the pathogenesis of SSc deserves further study.


Effect of two French nurses' strikes on mortality in a geriatric hospital. To study the influence of the 1988 French nurses' strikes on mortality in a geriatric hospital. Two nurses' strikes affected the Charles Foix Hospital near Paris from June 29 to July 31 and from September 17 to October 22, 1988. Mortality was studied in nine geriatric wards of this hospital, including two rehabilitation units comprising 187 beds, and seven long-term care units comprising 1,132 beds. Monthly mortality rates were calculated from the hospital's administrative registers and expressed as deaths per 1,000 patient-days. These rates were calculated in each of the aforementioned nine units for the 36 months preceding the first strike (control period) and for the 12 months following it (study period). Over the control period, monthly mortality was significantly higher in rehabilitation units than in long-term care units (2.46 +/- 1.21 versus 0.83 +/- 0.47, p less than 0.001), but mortality rates among rehabilitation units, as well as among long-term care units, were comparable. Also, during the control period, large seasonal fluctuations in monthly mortality rates were observed in both rehabilitation units and long-term care units (peak in winter and nadir in summer). These rates tended to decrease from year to year in rehabilitation units but not in long-term care units. A statistical model based on time-series analysis of the control period data was used to calculate the expected monthly mortality rates for the study period in rehabilitation units and in long-term care units, respectively. Three of the 12 actual monthly mortality rates exceeded the upper limit of the 95% confidence interval of the 12 expected monthly mortality rates, in the units where the more severe care disruption occurred. A detailed analysis of discharge summaries of these units failed to identify a possible link between some of these deaths and a possible absence of care. The nurses' strikes did not induce a clear-cut increase in mortality in this population of elderly patients. However, we cannot exclude the possibility that these strikes had some negative effects on health. Our results fail to provide answers to the difficult ethical problems created by such stoppages.


Sinusitis in HIV-infected patients: a clinical and radiographic review. To describe the clinical, radiographic, and laboratory features of sinus disease in human immunodeficiency virus (HIV)-infected individuals. Seventy-two patients with a history of sinusitis identified from 1,461 consecutive admissions (667 patients) to the HIV ward at The Johns Hopkins Hospital. Retrospective chart review. The Johns Hopkins Hospital. Sinusitis was identified in 72 HIV-infected patients, predominantly individuals with a CD4 cell count of less than 200/mm3. A history of respiratory infections such as bacterial pneumonia, bronchitis, and otitis media was common. Although nasal congestion and postnasal drainage were found in the majority of patients, symptoms of sinusitis were often nonspecific and the diagnosis was incidental in 28 patients (33%). Magnetic resonance imaging or computed tomography was significantly more sensitive than plain radiography (p less than 0.001) in defining the extent of the disease, particularly with posterior sinus involvement, which occurred in the majority of the patients. The number of radiologically abnormal sinuses correlated inversely with the CD4 count. Although the majority of patients responded at least partially to antibiotic therapy, only 15% had complete resolution of clinical symptoms. Fifty-eight percent of patients had clinical and/or radiographic evidence of recurrent/persistent sinus infection, and chronicity correlated with a CD4 count less than 200/mm3 (p less than 0.001). Sinusitis in HIV-infected patients is common, severe, and difficult to treat. Patients with CD4 counts less than 200/mm3 are prone to disease involving multiple sinuses that responds incompletely to antibiotic therapy, often resulting in chronic sinusitis. Unlike the immunocompetent host, the majority of the HIV-infected patients with advanced immunodeficiency develop posterior sinus disease.


Long-term complications of arteriohepatic dysplasia. It has been stated that arteriohepatic dysplasia is a form of biliary paucity with a good prognosis. We wished to determine the long-term morbidity and mortality associated with arteriohepatic dysplasia. The charts of all patients with arteriohepatic dysplasia followed by the pediatric gastroenterologists of the University of Minnesota into adulthood were reviewed. Over the last 33 years, the pediatric gastroenterologists have followed 16 children with syndromic paucity, six of whom are now beyond age 18 years. Although five of six patients responded to medical therapy with improvement in their cholestasis and appeared stable clinically through childhood, five of six patients had complications of arteriohepatic dysplasia after age 16 years that resulted in severe morbidity (three) or death (two). These complications included hepatic failure (two), renal failure (one), cerebellar herniation (one), and hepatocellular carcinoma (one). In only one patient were symptoms of the complications present prior to the age of 18 years. As more patients with arteriohepatic dysplasia reach adulthood, it appears that this syndrome may be accompanied by long-term manifestations extending beyond childhood. It is important that physicians assuming management of these patients from pediatricians be aware that new abnormalities may appear without warning and that the hepatic disease may deteriorate despite apparent stability through childhood.


Reactive hemophagocytic syndrome--a clinicopathologic study of 40 patients in an Oriental population. The purpose of this investigation was to assess the clinical spectrum and outcome of reactive hemophagocytic syndrome (RHS) in an Oriental population. The investigation was a retrospective study of 40 consecutive patients with RHS diagnosed over a 4-year period in Queen Elizabeth Hospital, a community-based hospital in Hong Kong. The incidence of RHS in Hong Kong appeared to be comparable with that of Western countries. However, the spectrum of diseases associated with RHS was distinctly different. Forty percent of the cases were associated with malignant lymphoma. Another 40% of the cases were associated with infection, often due to bacteria, and infection due to the herpes group of viruses was uncommon, probably reflecting ethnic and geographic differences from the white population. Two patients had the acute lupus hemophagocytic syndrome, a distinctive form of RHS that occurs in patients with systemic lupus erythematosus. Treatment was basically supportive, with specific therapy also given for the underlying disease if present. Eighteen patients (45%) died of the acute disease, mostly as a result of complications of RHS or the underlying diseases. The development of disseminated intravascular coagulopathy was a poor prognostic factor. RHS is an uncommon disorder in Hong Kong and is often associated with malignant lymphoma or bacterial infection. A rigorous search for an underlying malignancy or infection is thus warranted once this diagnosis is made.


Association of anti-beta 2 glycoprotein I antibodies with lupus-type circulating anticoagulant and thrombosis in systemic lupus erythematosus. Antiphospholipid antibodies (including anticardiolipin antibodies and circulating anticoagulant) are associated with thrombosis in systemic lupus erythematosus. Since it has been shown that beta 2 glycoprotein I (beta 2 gp I) acts as a cofactor of anticardiolipin antibody binding to cardiolipin, the presence and clinical meaning of anti-beta 2gp I antibodies in sera from patients with lupus were examined. An enzyme-linked immunosorbent assay technique for the detection of anti-beta 2gp I antibodies was developed, and 47 lupus sera were studied retrospectively, as well as 88 healthy blood donors' sera. It was found that 17 of 47 patients with lupus (36%) had anti-beta 2gp I antibodies. Anti-beta 2gp I antibodies were statistically associated with anticardiolipin antibodies, thrombosis, and lupus anticoagulant. Eight of nine lupus patients with thrombosis had anti-beta 2gp I antibodies and lupus anticoagulant, and seven of them had anticardiolipin antibodies. Of 18 patients with anticardiolipin antibodies without anti-beta 2gp I antibodies or lupus anticoagulant, only one had thrombosis (due to nephrotic syndrome). Among anti-beta 2gp I-positive patients, 14 of 16 had lupus anticoagulant activity, whereas only three patients with lupus anticoagulant were anti-beta 2gp I-negative. The presence of anti-beta 2gp I antibodies is a new immunologic feature of lupus patients with thrombosis. In addition, since anti-beta 2gp I antibodies are closely associated with lupus anticoagulant activity, they may contribute to explain antiprothrombinase activity.


A clinical overview of dyslipidemias: treatment strategies. The strong epidemiologic relationship between specific lipoprotein levels (such as elevated low-density lipoprotein cholesterol or decreased high-density lipoprotein cholesterol) and the future development of coronary heart disease has been well documented. Within the past several years, landmark clinical trials have clearly demonstrated that the incidence of coronary heart disease events is reduced when lipoprotein abnormalities are corrected via pharmacologic therapy. These findings have prompted clinicians to become more vigilant with regard to recognition of dyslipidemias and institution of treatment. This review focuses on the more common primary and secondary dyslipidemias and the currently available lipid-lowering therapies for each disorder. Results of recent coronary angiographic trials are discussed, and implications for the medical management of established coronary heart disease are assessed.


New therapeutic agents in the treatment of inflammatory bowel disease. Despite intense investigation, the etiology of inflammatory bowel disease (IBD) remains unknown. Recent studies with new therapeutic agents provide insight into the pathogenesis of IBD through analysis of the clinical response to pharmacologic agents whose mechanism of action is understood. Until new agents are established, IBD will be treated with conventional drugs directed toward modifying the inflammatory responses responsible for gastrointestinal mucosal damage. Sulfasalazine, mesalamine (5-aminosalicylic acid), and corticosteroids will continue to be the mainstay of therapy for the foreseeable future. Antibiotics such as metronidazole and immunosuppressants such as 6-mercaptopurine and methotrexate are useful in Crohn's disease and ulcerative colitis in selected cases. Many new exciting agents are being investigated and show encouraging results in the treatment of IBD. This article reviews the agents used in IBD with an emphasis on new therapeutic agents.


The stigma of disease: implications of genetic screening. As the field of human genetics successfully continues to unravel the secrets of an individual's genetic makeup, the social processes of stigmatization and ostracism of those with "undesirable" traits have the potential to increase. An historical example that may shed light on the problems of applying genetic technology to disease prevention is the institution of quarantine. This essay discusses the concept of "quarantine mentality" and the desire for healthy society to separate itself from those labeled "ill" or abnormal, and addresses two episodes in American history when genetics was applied to the formulation of social policy toward the "diseased": the eugenics movement of the early 20th century and the early attempts of genetic screening programs for sickle cell anemia during the 1970s.


Expanding the boundaries of informed consent: disclosing alcoholism and HIV status to patients. Since informed consent became legally required in the therapeutic setting, the risks physicians were to disclose have been limited to the risks of particular procedures. Two recent court decisions in which disclosure of surgeons' alcoholism and positive human immunodeficiency virus status was required may begin to erode that limit. The grounds for this expansion of disclosure requirements were inherent in the 20-year-old "materiality" standard for disclosure; nevertheless, the change they signal is profound. These cases may signal a trend that, in the long term, could result in a shift in physician-patient communication and a significant loss of privacy for physicians.


Hepatic angiosarcoma.

Hepatic angiosarcoma. A patient with hepatic angiosarcoma is described. The significant aspects of this malignancy are delineated. This tumor constitutes only 2% of all primary tumors of the liver. The association with exposure to vinyl chloride and other carcinogens is reviewed. Diagnostic and therapeutic modalities are discussed.


Chronic hyponatremia due to resetting of the osmostat in a patient with gastric carcinoma. A 54-year-old schizophrenic patient who presented with hyponatremia and nephrotic-range proteinuria was subsequently discovered to have a gastric adenocarcinoma. Psychogenic water drinking, sodium depletion, and cardiac, adrenal, hepatic, and thyroid disease were excluded as causes of hyponatremia. The serum creatinine concentration was normal, and, although renal biopsy showed changes consistent with immune complex glomerulopathy, proteinuria remitted without treatment. Moderately severe hyponatremia persisted, and the diagnosis of gastric adenocarcinoma was made after the onset of early satiety 1 year later. Surgical exploration at the time of partial gastric resection revealed local metastatic lymph node involvement. Following the patient's uneventful recovery from surgery, studies of osmoregulation of vasopressin release and renal water handling were performed to determine the cause of chronic hyponatremia refractory to sodium chloride administration. Oral water loading studies revealed normal urinary diluting ability and appropriate suppression of plasma vasopressin concentrations. However, hypertonic sodium chloride infusion studies revealed a highly significant correlation between plasma osmolality and plasma vasopressin concentration, and a low osmotic threshold for vasopressin release based on linear regression analysis of the plasma vasopressin response to increasing plasma osmolality. Low osmotic threshold for vasopressin release was confirmed by exponential (log linear) and parabolic methods of data analysis. The findings in these studies are consistent with the typical features of the reset osmostat variant of the syndrome of inappropriate antidiuresis. To our knowledge, this is the first report of the occurrence of this syndrome in association with gastric adenocarcinoma.


Attenuated proestrous luteinizing hormone surges in middle-aged rats are associated with decreased pituitary luteinizing hormone-beta messenger ribonucleic acid expression. This study determined whether attenuated preovulatory luteinizing hormone surges in aging rats are associated with a decrease in pituitary luteinizing hormone content or luteinizing hormone beta-messenger ribonucleic acid expression on proestrus. Blood samples were taken every 90 minutes from 1:30 to 10:30 PM on proestrus in young (n = 8) and middle-aged (n = 12), regularly cyclic rats for plasma luteinizing hormone determination. On the next proestrus at 12 noon, rats were killed and the pituitaries were removed for luteinizing hormone content determination by radioimmunoassay and luteinizing hormone beta-messenger ribonucleic acid expression by dot blot analysis. Results were analyzed by one-way analysis of variance. Seven of the middle-aged rats had attenuated luteinizing hormone surges while the remaining five females had surges similar to those of young rats. On the next proestrus, all rats had similar quantities of pituitary luteinizing hormone. However, luteinizing hormone beta-messenger ribonucleic acid expression in middle-aged rats with attenuated luteinizing hormone surges was lower (p less than 0.05) than that of middle-aged and young rats with normal surges. Decreased luteinizing hormone beta-messenger ribonucleic acid expression, but not pituitary luteinizing hormone content at 12 noon on proestrus is correlated with attenuated luteinizing hormone surges in middle-aged rats.


Etiologic factors of recurrent abortion and subsequent reproductive performance of couples: have we made any progress in the past 10 years? We hypothesize that the diagnostic yield and pregnancy outcomes of patients with recurrent abortion have improved over the past 10 years. The study was performed in an academic medical center. Diagnoses and outcomes for group A, a published series of 100 patients investigated for recurrent abortion in the section between 1968 and 1977, was compared with those for group B, the 131 patients seen between 1987 and 1991. A standardized protocol was followed, enhanced by new techniques and autoimmune investigations in the latter group. Results were compiled retrospectively. Descriptive statistics and chi 2 analysis were used. No cause could be found in 37% of patients in group A compared with 24% of couples in group B (p less than 0.05). No clear difference could be shown in the subsequent outcomes of pregnancies. Our ability to establish a cause of recurrent abortion has improved slightly over the past 15 years. The gain is not yet reflected in successful pregnancy rates. Multicenter trials are indicated.


Electroejaculation in combination with in vitro fertilization and gamete micromanipulation for treatment of anejaculatory male infertility. Failure to ejaculate may be overcome by use of electroejaculation. However, such semen samples are often unsuitable for therapies like intrauterine insemination. The combination of electroejaculation with in vitro fertilization, including gamete micromanipulation, should improve chances of fertilization and pregnancy in such cases. Within a private infertility clinic electroejaculation in combination with intrauterine insemination was carried out in 18 cycles (10 couples). Four couples went on to receive therapy by electroejaculation plus in vitro fertilization, along with six other couples (15 cycles total) with semen too poor for intrauterine insemination. One term pregnancy arose in the electroejaculation-intrauterine insemination group, and one term pregnancy plus one continuing pregnancy arose from two couples (three cycles) who underwent in vitro fertilization with conventional insemination after electroejaculation. Six couples (nine cycles) had embryos arising only from gamete micromanipulation transferred, and this yielded two term pregnancies, one spontaneous abortion, and a biochemical pregnancy. Two couples (three cycles) failed to achieve fertilization even with micromanipulation; however, donor-inseminated eggs gave rise to two term pregnancies and one continuing pregnancy in these patients. This report confirms the feasibility of in vitro fertilization in conjunction with electroejaculation and extends the therapy to incorporate gamete micromanipulation.


Red blood cell transfusion and cesarean section. Our objective was to determine the incidence of blood transfusion in patients delivered by cesarean section and to identify factors predictive of the need for transfusion. A chart review was performed on cesarean patients receiving blood transfusion over a year at the Medical College of Virginia Hospital and an equal number of randomly selected cesarean patients. Sixty-one (6.8%) patients received a packed red blood cell transfusion intraoperatively or postoperatively. Transfusion was associated with lower gestational ages, antepartum bleeding, arrest of descent, and longer postoperative stays. After stepwise logistic regression analysis, only antepartum bleeding and preoperative hemoglobin were significant independent predictors of the need for blood transfusion. Transfusion with cesarean section is common and is associated with antepartum bleeding and other primarily intrapartum and unpredictable factors.


Amnioinfusion: an aid in the ultrasonographic evaluation of severe oligohydramnios in pregnancy. Amnioinfusion was used in pregnancy complicated by severe oligohydramnios to enable a more comprehensive ultrasonographic evaluation of the pregnancy. Thirteen patients were referred to the Division of Obstetrical and Gynecological Ultrasound at the University of Miami because of severe oligohydramnios in which a definitive diagnosis could not be made. Nine patients were in the second trimester and four were in the early third trimester. All patients underwent amnioinfusion with warm physiologic saline solution and instillation of indigo carmine. Genetic amniocentesis was performed in 11 patients. After amnioinfusion a satisfactory comprehensive ultrasonographic examination could be performed on all patients. In most cases we were able to achieve a definitive diagnosis. Amnioinfusion with the addition of indigo carmine was a satisfactory technique to enable a more comprehensive ultrasonographic evaluation of pregnancy complicated by severe oligohydramnios.


Long-term outcome in fetal hydrops from parvovirus B19 infection. Parvovirus B19 infection in the fetus is associated with anemia and hydrops and can result in fetal death. Fetal transfusion has been used in an attempt to improve outcome; however, it is associated with its own perinatal morbidity. We report two cases of fetal parvovirus B19 infection that were confirmed by polymerase chain reaction for parvovirus B19 deoxyribonucleic acid in umbilical cord blood. Ultrasonographic signs of compromise were observed at 30 and 24 weeks of gestation. Both fetuses were hydropic and one fetus was also anemic. Serial sonograms demonstrated that the hydrops resolved spontaneously over 3 to 5 weeks after diagnosis. One infant was delivered at 32 weeks of gestation as a result of idiopathic preterm labor. The other infant was delivered at term. Both infants appeared relatively normal at birth and have developed normally in the first year of life. Thus fetal hydrops in association with parvovirus B19 infection does not always lead to poor long-term outcome. A conservative approach without in utero therapy may be appropriate for the management of some of these fetuses.


Experience with mepivacaine paracervical block in an obstetric private practice. The objective of this study was to determine the efficacy and safety of mepivacaine paracervical block in term, low-risk obstetric patients. Over a 3-year period all term, low-risk obstetric patients in the author's private practice were offered mepivacaine paracervical block anesthesia. One hundred eighty-two patients received 200 mg mepivacaine with each block. The patients who declined paracervical block were used as a control group to compare Apgar scores, subject to chi 2 analysis. Initial injections were 97.3% successful. Average duration of anesthesia was 59.7 minutes with the first injection. Fetal bradycardia occurred in 13.2% with an average duration of 4.5 minutes. The slightly higher incidence of low Apgar scores at 1 and 5 minutes in the study group was not statistically significant. One neonatal death occurred secondary to group B streptococcal sepsis in the study group. Mepivacaine paracervical block remains an anesthetic option in low-risk patients. The high success rate is limited by its short duration of action and the incidence of fetal bradycardia.


Refining the biophysical profile with a risk-related evaluation of test performance. Our objective was to determine the ability of biophysical profile variables to predict bad perinatal outcome in high-risk third-trimester pregnancy. The outcomes of 1146 fetuses were correlated with abnormal single or multiple variables occurring in biophysical profile done within 72 hours of delivery. Theoretic risks of poor outcomes for different combinations of abnormal variables, calculated with Shortlife's formula, were compared with the actual risks observed (chi 2 tests). Two hundred forty-six fetuses had at least one abnormal biophysical profile variable with the risk of bad outcome, for a single abnormal variable, ranging from 8% (body movements) to 100% (tone) and increasing from 14% (any variable abnormal) to 63% (all variables abnormal). In most (57%) observed combinations of biophysical profile variables, significant differences between theoretic and actual risks of bad outcomes were found. By stepwise logistic regression the best predictive model contained all variables except fetal movement. Dynamic biophysical profile variables appear to be interdependent. Not all combinations of abnormal variables occur and specific combinations improve prediction of poor outcome. Risk-related scales for biophysical profile outcomes might prove superior to more conventional scoring systems.


Excessive maternal weight and pregnancy outcome. This study was undertaken to determine the influences of increased maternal prepregnancy weight and increased gestational weight gain on pregnancy outcome. This was a longitudinal retrospective study of 7407 term pregnancies delivered from 1987 through 1989. After excluding cases with multiple fetuses, stillbirths, fetal anomalies, no prenatal care, selected medical and surgical complications, and those with incomplete medical records, 3191 cases remained for analyses by determination of odds ratios for obstetric outcomes, by chi 2 tests for significant differences and by adjustment for risk factors with stepwise logistic regression. Both increased maternal prepregnancy weight (body mass index) and increased maternal gestational weight gain were associated with increased risks of fetal macrosomia (p less than 0.0001), labor abnormalities (p less than 0.0001), postdatism (p = 0.002), meconium staining (p less than 0.001), and unscheduled cesarean sections (p less than 0.0001). They were also associated with decreased frequencies of low birth weight (p less than 0.001). The magnitude of the last was less than that of the other outcomes. Increased maternal weight gain in pregnancy results in higher frequencies of fetal macrosomia, which in turn lead to increased rates of cesarean section and other major maternal and fetal complications. Because these costs of increased maternal weight gain appear to outweigh benefits, weight gain recommendations for pregnancy warrant careful review.


A prospective randomized clinical trial comparing two oxytocin induction protocols. Our objective was to compare the safety and efficacy of two accepted oxytocin induction protocols that differ in oxytocin dose increments. At the Carolinas Medical Center in Charlotte, North Carolina, 151 women with indications for induction of labor were prospectively randomized into one of two oxytocin induction protocols. Safety and efficacy of the two protocols were analyzed with two-tailed t tests and chi 2. Time from induction to establishment of a regular labor pattern was significantly shorter in the experimental group compared with the traditional group (p = 0.03). However, no significant difference was seen from onset of induction to time of delivery. Incidences of hyperstimulation were not significantly different between the two protocols, but there was a trend toward a higher incidence of fetal heart rate changes in the experimental group (p = 0.08). These data suggest that induction with larger dose increments will shorten time to adequate labor without an associated increase in uterine hyperstimulation or poor neonatal outcome. The differences in heart rate changes are concerning and merit further investigation. If confirmed by further studies, an increased risk of cord compression could outweigh the benefit of a faster onset of contractions.


Intrauterine pressure and fluid absorption during continuous flow hysteroscopy. Our objectives were to document the causes of fluid absorption during continuous flow hysteroscopy and to determine under which operative conditions fluid overload may occur. Fifteen patients underwent operative hysteroscopy with 2% ethanol solution for uterine distention. Absorption of fluid was measured by blood alcohol, sodium, osmolarity, and hematocrit. Intrauterine pressures were measured with an obstetric pressure catheter. Alcohol absorption was noted in one patient during a myoma resection. Two additional patients, not in the study, had fluid absorption after partial perforations of the uterus. Under normal operative conditions there were no changes in sodium, osmolarity, or hematocrit. Intrauterine pressures ranged from 45 to 75 mm Hg. Experimental pressures of greater than 200 mm Hg were not associated with fluid absorption. Intravasation of fluid may occur through open uterine venous channels with extensive resections and under low pressures in the presence of unrecognized perforations.


Obesity and lower urinary tract function in women: effect of surgically induced weight loss. The subjective and objective effects of massive weight loss on lower urinary tract function in morbidly obese women were examined. Thirteen subjects underwent a comprehensive evaluation of lower urinary tract function before and 1 year after surgically induced weight loss. We demonstrated significant improvements in lower urinary tract function after weight loss. Of 12 subjects who complained of incontinence before surgery only three complained of incontinence (p = 0.004) and only one requested treatment after weight loss. Objective and subjective resolution of both stress and urge incontinence was documented. Statistically significant changes were seen in measures of vesical pressure, the magnitude of bladder pressure increases with coughing, bladder-to-urethra pressure transmission with cough, urethral axial mobility, number of incontinence episodes, and the need to use absorptive pads. Weight reduction is desirable for obese women complaining of urinary incontinence and may obviate the need for further incontinence therapy.


The incidence of genital prolapse after the Burch colposuspension. Our objective was to determine the incidence of postoperative genital prolapse after the Burch colposuspension and to identify risk factors for the development of subsequent prolapse. The charts of 131 patients who had a Burch colposuspension performed by the senior author (S.L.S.) between 1977 and 1986 were reviewed at the Urodynamic Unit of St. George's Hospital, London. Emphasis was placed on the degree of genital prolapse on clinical examination and whether further surgery was required to correct the prolapse. Thirty-five patients (26.7%) required a total of 40 operations to correct genital prolapse after colposuspension. At 20 operations, more than one procedure was required to correct combined prolapse. The patient's age, weight, parity, menopausal status, and prior pelvic surgery did not affect the incidence of postoperative prolapse. The only preoperative risk factor identified was the presence of a large cystocele. Postoperative genital prolapse is a significant complication of the Burch colposuspension. It is unclear whether this is due to a disruption of the vaginal axis or to an intrinsic weakness of the pelvic floor in these women.


Evaluation of pretreatment transvaginal ultrasonography in the management of patients with endometrial carcinoma. The objective of this study was to evaluate the usefulness of pretreatment assessment with ultrasonography in patients with endometrial carcinoma. Fifty patients with endometrial carcinoma diagnosed by endometrial biopsy or curettage were studied before hysterectomy, bilateral salpingo-oophorectomy, and selected lymph node sampling. Ultrasonographic criteria for determination of tumor grade, depth of myometrial invasion, uterine volume, and tumor volume were established. Tumor grade was compared with preoperative and postoperative pathologic diagnoses, depth of invasion was compared with postoperative pathologic evaluation, and uterine volume and tumor volume were compared with postoperative evaluation of tumor grade and depth of invasion. Data were analyzed by chi 2 testing, and, where appropriate, sensitivity, specificity, and accuracy of the ultrasonographic measurements were determined. The following statistically significant correlations (p less than or equal to 0.05) were found. Ultrasonography predicted tumor grade as accurately as preoperative pathologic evaluation did. Depth of invasion less than or equal to 50% or greater than 50% significantly correlated. Uterine volume less than or equal to 200 ml predicted less than or equal to 50% depth of invasion 28 of 32 times. Uterine volume greater than 500 ml was noted in six cases; five of these had grade 2 or 3 tumor and four had depth of invasion greater than 50%. Tumor volume less than or equal to 20 ml predicted a grade 1 tumor in 25 of 39 cases and depth of invasion less than or equal to 50% in 34 of 39 cases. Tumor volume greater than 20 ml correlated with a grade 2 or 3 tumor in 11 of 11 cases and a depth of invasion greater than 50% in seven of 11 cases. In 25 grade 1 tumors diagnosed postoperatively by pathologic study, none was associated with a tumor volume greater than 20 ml. Pretreatment ultrasonographic measurements should be of value in the management of patients with endometrial carcinoma.


The treatment of pelvic soft tissue radiation necrosis with hyperbaric oxygen. The purpose of this study was to examine the therapeutic effects of hyperbaric oxygen on radiation-induced soft tissue necrosis in patients who previously received treatment for a gynecologic malignancy. Fourteen patients whose necrotic wounds failed to heal after 3 months of conservative therapy were enrolled in a prospective observational study. Outcome of hyperbaric oxygen treatment was measured by resolution of necrosis. Fourteen patients underwent 15 courses of hyperbaric oxygen treatments. All those with radiation necrosis of the vagina alone or in association with rectovaginal fistula had complete resolution of necrosis with hyperbaric oxygen. Only one treatment failure occurred. Hyperbaric oxygen is a safe, effective, and well-tolerated treatment for radiation-induced soft tissue necrosis.


The incidence of cerebral palsy.

The incidence of cerebral palsy. The clinician is often held responsible for obstetric events that are suspected of being related to cerebral palsy. To review the incidence of cerebral palsy and to aid the clinician in this situation, a search of published studies was conducted. Composite rates of cerebral palsy in different birth weight infants and cerebral palsy with and without serious mental retardation were calculated. The cumulative incidence rate at the age of 5 to 7 years was 2.7 cases of cerebral palsy for 1000 birth cohorts. Approximately 36% of all cerebral palsy occurred in the infant less than 2500 gm. Serious mental retardation (intelligence quotient less than 50) accompanied cerebral palsy approximately 30% of the time for the term infant and 18% of the time when the infant was less than 2500 gm. On the basis of a past estimation that 70% of cerebral palsy is of antepartum or unknown origin, the term infant at risk for intrapartum-attributed cerebral palsy may be about 1 in 2000 term births.


Home uterine activity monitoring in France: a randomized, controlled trial. We assessed the effectiveness of ambulatory tocodynamometry in reducing the preterm delivery rate in women at risk of preterm delivery such as women with risk factors and women previously hospitalized and discharged. In four public maternity units these women were randomly allocated to two groups: 84 had home uterine activity monitoring and daily midwife contact and 84 were given the standard care for high-risk women, which generally includes home visits by community midwives. The proportion of deliveries before 37 weeks' gestation was slightly higher in the monitored group than in the control group (32% vs 22%). The corresponding odds ratio was 1.7 (95% confidence interval: 0.9 to 3.5). Although the sample was small, these results suggest that home uterine activity monitoring was probably not beneficial to the population studied, or at least that any benefit would have been too small to justify extending this monitoring in this high-risk population.


Maternal hyperoxygenation in the treatment of intrauterine growth retardation. In the current study the efficacy of maternal hyperoxygenation on growth-retarded fetuses was evaluated. Thirty-six pregnant women with intrauterine growth retardation were studied. The patients were divided in oxygen-treated (n = 17) and untreated (n = 19) groups. Doppler analysis of the fetal circulation was performed on the arrival to the hospital, after 12 hours, and thereafter on alternate days until delivery. Fetal blood was sampled by cordocentesis for immediate blood gas analysis at entrance to the study and the day of delivery. Significant improvement in Doppler flow patterns in treated patients were found when compared with untreated women. The Doppler variations were associated with complementary modifications in fetal blood gas. These differences resulted in a significant modification in perinatal mortality with an incidence of 29% and 68% (p less than 0.01) in treated and untreated groups, respectively. Our data suggest a benefit of maternal hyperoxygenation in the treatment of fetal growth retardation.


Behavioral treatment of menopausal hot flushes: evaluation by ambulatory monitoring. We attempted to develop an effective behavioral treatment for menopausal hot flushes and to determine the active behavioral components of this procedure. Thirty-three women with frequent menopausal hot flushes were randomly assigned to receive eight sessions of training in paced respiration, muscle relaxation, or alpha-wave electroencephalographic biofeedback (placebo control). Hot flushes were objectively measured by means of 24-hour ambulatory monitoring of the sternal skin conductance level. Subjects undergoing paced respiration had significant reductions in hot flush frequency and respiration rate, as well as increases in tidal volume. Paced respiration training may be a useful treatment alternative for the reduction of hot flushes in women who cannot tolerate hormone replacement therapy.


Increased lipolytic activity and high ratio of free fatty acids to albumin in sera from women with preeclampsia leads to triglyceride accumulation in cultured endothelial cells. The null hypothesis of this study was that the triglyceride accumulation in endothelial cells exposed to sera from preeclamptic women was determined by the presence of triglyceride-rich lipoproteins in the sera. The accumulation of triglycerides in cultured endothelial cells was studied using incorporation of tritiated glycerol. Triglyceride-rich lipoproteins in the patient sera contributed little to the endothelial triglyceride accumulation. However, sera from preeclamptic women were found to have a higher molar ratio of free fatty acids to albumin compared with sera from women with normal pregnancies (1.6 +/- 0.5 vs 0.9 +/- 0.4, respectively, p less than 0.025). In addition, sera from preeclamptic women, compared with sera from normal pregnancies, showed enhanced lipolytic activity (release of free fatty acids 0.85 +/- 0.29 vs 0.17 +/- 0.16 mmol/ml per 24 hours, respectively; p less than 0.025) that further increased the free fatty acids/albumin ratio. Sera from preeclamptic women have both a higher ratio of free fatty acids to albumin and increased lipolytic activity, resulting in enhanced endothelial uptake of free fatty acids, which are further esterified into triglycerides.


Use of the fetal chest in estimating fetal weight. This study was designed to develop formulas using the chest circumference instead of the abdominal circumference for estimating fetal weight. Ultrasonographic measurements of the chest circumference, biparietal diameter, abdominal circumference, humeral length, and femoral length were obtained in 75 term fetuses of uncomplicated pregnancies within 24 hours of delivery. Three equations for fetal weight estimation that used the chest circumference, instead of the abdominal circumference, in combination with the biparietal diameter or the humeral length were developed by regression analysis. The average mean errors of fetal weight estimation for these equations vary from 7.1% to 7.6%. These equations may be used in predicting the birth weight when the fetal abdomen is altered by certain fetal abnormalities.


A comparison of circulating hormone levels in postmenopausal women receiving hormone replacement therapy. Seventeen postmenopausal subjects were randomized into this comparative study of esterified estrogen 0.625 mg (Estratab), esterified estrogen 0.625 mg plus 1.25 mg methyltestosterone (Estratest H.S.), or conjugated estrogen 0.625 mg (Premarin). Sixteen subjects completed the study in which plasma hormone concentrations of estrone and estradiol were assessed at various time points. There were no significant differences among the treatment groups.


Prenatal diagnosis of human parvovirus B19 in nonimmune hydrops fetalis by polymerase chain reaction. Nonimmune hydrops fetalis is a potentially lethal condition reflecting the clinical manifestation of several pathologic processes. Recently maternal infection by human parvovirus B19 has been reported to result in nonimmune fetal hydrops. We sought to develop a rapid and sensitive test to detect the presence of this agent in utero. Using a cloned isolate of the virus, we developed an assay based on enzymatic amplification of a segment of the human parvovirus B19 genome that allows direct detection of this agent in samples of fetal blood and amniotic fluid. The method detected as few as 100,000 genome equivalences and was specific for the viral genome alone. We used this assay to evaluate nine fetuses initially seen with nonimmune hydrops. Three cases were found to be positive for the human parvovirus B19 genome. The method is powerful in that it is rapid, sensitive, and simple. This assay may have general applicability in evaluation of nonimmune hydrops and in documentation of the natural history of fetal human parvovirus infections.


Angina and normal coronary arteries in women: gynecologic findings. Our aim was to evaluate the hypotheses that women with severe angina and normal coronary arteries (syndrome X) have an increased incidence of hysterectomy and show a positive cardiac response to 17 beta-estradiol replacement therapy. The gynecologic histories of 30 women with syndrome X were determined. Anginal and 17 beta-estradiol insufficiency symptoms were recorded daily for 1 month. Subsequently, 20 of the women underwent hyperemic response testing before and after 2 months of estrogen replacement therapy. Hyperemic response results were compared with those of 12 asymptomatic post-menopausal women not receiving estrogen replacement therapy. Symptoms were recorded daily during estrogen replacement therapy. A total of 18 women (60%) underwent hysterectomy. All were experiencing hot flushes. Hyperemic response was diminished in women with syndrome X compared with controls. Hyperemic response increased and anginal symptoms decreased during estrogen replacement therapy. The incidence of hysterectomy was increased and estrogen replacement therapy alleviated cardiac symptoms and enhanced hyperemic response in a group of women with syndrome X.


Effects of danazol at the immunologic level in patients with adenomyosis, with special reference to autoantibodies: a multi-center cooperative study. We attempted to evaluate the effects of danazol on autoantibodies, in particular, to phospholipids, and on the immune system in patients with adenomyosis. Forty-two patients with adenomyosis who had high titers of autoantibodies were randomly chosen, and they received 400 mg/day of danazol for 4 months (n = 22) or underwent hysterectomy (n = 20). Among the six autoantibodies we investigated, the incidence of antiphosphatidylinositol immunoglobulin G was the highest (42.9%), followed by antiphosphatidylglycerol immunoglobulin G (38.1%). The autoantibody titers decreased with time and were comparable to the control values 16 weeks after treatment in both groups. Total serum levels of immunoglobulin G and M were high before treatment, but immunoglobulin M levels decreased significantly in week 8 during treatment with danazol, whereas C4 levels increased and C3 levels decreased with danazol. Danazol has an inhibitory effect on the autoimmunologic response associated with adenomyosis.


Serial measurements of platelet angiotensin II binding in two patients with hypertension in pregnancy: case reports. Serial estimations of platelet angiotensin II binding were made in two patients with hypertension developing in the third trimester of pregnancy. The fall in platelet angiotensin II binding that is seen in normotensive pregnancy did not occur in these two patients.


Resident research in obstetrics and gynecology: development of a program with comparison to a national survey of residency programs. The objective of this report is to describe our recently established resident research program and to compare this program with those of other obstetrics and gynecology residency training programs in the United States. The components of our program are described. Data for comparison from other programs were obtained from questionnaires, phone follow-up and the Directory of Obstetrics and Gynecology Residency Programs of the Council on Resident Education in Obstetrics and Gynecology. We initiated a residency research program in 1987 with acceptable projects defined, a time for completion of manuscripts established, and a Resident Research Day organized with presentation of articles, critique by a guest speaker, and an awards banquet. Nationally, less than 60% of residency programs have research requirements. Of the 208 programs responding to the written questionnaire 86% of programs associated with a university required research compared with 10% of community-based residency programs. While more than a third of residency programs in obstetrics and gynecology do not have resident research programs, the trend is for programs to establish research as a required portion of training. An outline of a recently established program is provided.


Nonimmune fetal hydrops caused by bilateral type III congenital cystic adenomatoid malformation of the lung at 17 weeks' gestation. Type III congenital cystic malformation of the lung with nonimmune hydrops and oligohydramnios was diagnosed at 17 weeks by ultrasonography. Massive fetal cardiac compression with probable associated left- and right-sided failure causing both the oligohydramnios and the ascites, respectively, was thought to be the underlying pathophysiologic mechanism of this unusual clinical presentation. Pathologic examination after termination of the pregnancy confirmed the prenatal diagnosis.


Pregnancy complicated by chronic cardiomyopathy and an automatic implantable cardioverter defibrillator. The dismal prognosis of dilated cardiomyopathy and its resulting tachyarrhythmias has recently been improved by technical advances such as the automatic implantable cardioverter defibrillator. We report a successful pregnancy in a patient with chronic cardiomyopathy and malignant tachyarrhythmias necessitating use of this device, with a documented defibrillator discharge and monitored fetal response.


Repeated external cephalic version at term. External version was performed three times in a patient at term because of spontaneous reversion to breech presentation. She was then delivered vaginally. Spontaneous reversion to breech presentation can be managed with additional external cephalic version procedures.


Successful pregnancy outcomes after amniotic fluid embolism. Two patients who survived cardiorespiratory arrest occurring in association with amniotic fluid embolism syndrome were seen during the subsequent pregnancy. Both had uneventful pregnancies and delivered at term without complications. These are the only case reports of pregnancy after amniotic fluid embolism, and they support a model of amniotic fluid embolism involving chemically abnormal amniotic fluid rather than an unusual sensitivity to normal amniotic fluid.


Hepatotoxicity with the administration of nifedipine for treatment of preterm labor. Nifedipine, a calcium channel blocker, is becoming increasingly popular as a tocolytic medication. Previous reports of hepatitis associated with nifedipine in the medical literature have been published. We present the first case reported of a patient with preterm labor treated with nifedipine who had development of a concurrent elevation in serum liver enzyme levels.


Vaginal foreign body extraction by forceps: a case report. Cases in which foreign bodies have been inserted into the vagina are uncommon but do occur. The technique and use of obstetric forceps for the extraction of an orange as a vaginal foreign body is described in this case report. Tucker-McLane forceps are the forceps of choice for this technique in this case.


Leiomyomatosis peritonealis disseminata treated with a gonadotropin-releasing hormone agonist. A case report. To our knowledge, this is the first report of documented growth regression of leiomyomatosis peritonei while the patient was receiving a gonadotropin-releasing hormone agonist. This further documents the role of gonadal steroids in the growth of this tumor.


A case of hidradenitis suppurativa treated with gonadotropin-releasing hormone agonist and by total abdominal hysterectomy with bilateral salpingo-oophorectomy. We report on a patient with hidradenitis suppurativa with premenstrual exacerbations, who was treated successfully with total abdominal hysterectomy and bilateral salpingo-oophorectomy combined with estrogen substitution. As a trial, she was initially treated successfully with a gonadotropin-releasing hormone agonist and subsequently a gonadotropin-releasing hormone agonist in combination with estrogen substitution.


Autonomic nervous system regulation of baseline heart rate in the fetal lamb. We examined 29 chronically instrumented fetal lambs from 125 to 143 days' gestation to investigate the effects of fetal behavioral states and autonomic nervous system maturation on baseline fetal heart rate. Behavioral states were defined from electrocorticographic analysis as low-voltage fast activity or high-voltage slow activity. Decrease and increase in baseline fetal heart rate subsequent to administration of propranolol and methylatropine represented beta-sympathetic and parasympathetic activity. Baseline fetal heart rate decreased with gestation in both states, with steeper regression in low-voltage fast activity (p less than 0.001). Positive correlation was noted between gestational age and percent decrease baseline fetal heart rate in both states with steeper regression in high-voltage slow activity (p less than 0.001), and between gestational age and percent increase baseline fetal heart rate with steeper regression in low-voltage fast activity (p less than 0.001). Fetal heart rate beta-sympathetic and parasympathetic tones increased with age in both states, with elevation of beta-sympathetic tone in high-voltage slow activity and parasympathetic tone in low-voltage fast activity. Sympathetic and parasympathetic systems influence baseline fetal heart rate in these behavioral states and with age.


Effects of sustained hypoxemia on the sheep fetus at midgestation: endocrine, cardiovascular, and biophysical responses. The purpose of our study was to examine the effects of induced hypoxia on endocrine, cardiovascular, and biophysical measurements of the ovine fetus at 0.6 (83 to 93 days) of gestation and to compare the fetal responses at this earlier gestation with those reported near term. Fourteen fetal sheep were studied (9 in the hypoxia group and 5 in the control group) at 0.6 of gestation during a 24-hour control period, 8 hours of either sustained hypoxemia or room air, and a 40-hour recovery period. Induced fetal hypoxemia resulted in a progressive lactic metabolic acidosis; however, all fetuses had recovered within 24 hours. The fetal endocrine response was variable with norepinephrine, the only measured hormone showing a significant hypoxia-related increase (p less than 0.05). Fetal heart rate and mean arterial blood pressure showed little hypoxia-induced change, although fetal heart rate was significantly increased over the first 2 hours (p less than 0.05). The percent time fetal breathing movements, electroocular activity, and nuchal muscle activity likewise showed little hypoxia-induced change. The cardiovascular and biophysical response of the preterm fetus to induced hypoxemia is thus much less pronounced than that of the older gestational-aged fetus; this difference may impact on survival and the success of antenatal assessment protocols.


Intracellular calcium and the signaling mechanism of luteinizing hormone-releasing hormone in rat granulosa cells. The purpose of these studies was to determine the source(s) of the increase in intracellular free calcium in response to luteinizing hormone-releasing hormone in ovarian granulosa cells. Rat granulosa cells were cultured and loaded with fura-2-acetoxy-methyl ester, a fluorescent calcium indicator dye, and intracellular free calcium measured by microspectrofluorometry. The source of the luteinizing hormone-releasing hormone induced increase in intracellular Ca++ was investigated with various calcium channel blockers (verapamil, diltiazem, and nifedipine), high K+ buffer, and perifusion with media lacking Ca++. All three voltage-sensitive calcium channel blockers (10(-5) mol/L) tested were ineffective in blocking the luteinizing hormone-releasing hormone induced intracellular Ca++ increase. Treatment with high K+ buffer also had no effect. Perifusion with media lacking calcium resulted in a gradual loss of the luteinizing hormone-releasing hormone response, an effect that was accelerated by repeated stimulation with hormone. Transient replacement of extracellular Ca++ failed to restore the response but continued perifusion with Ca(++)-replete media allowed a luteinizing hormone-releasing hormone response 10 minutes later. The luteinizing hormone-releasing hormone induced intracellular Ca++ increase does not appear to result from the opening of voltage-sensitive or K(+)-dependent Ca++ channels. To the contrary, this response likely results from the release of Ca++, primarily from intracellular stores.


Comparative analysis of normal and growth-retarded placentas with phosphorus nuclear magnetic resonance spectroscopy. Phosphorus 31 magnetic resonance spectroscopy studies were carried out on placentas from normal vaginal and elective cesarean deliveries without antenatal complications and from pregnancies complicated by intrauterine growth retardation of unknown cause to determine differences. Perchloric acid extraction was performed on frozen tissue, and quantitative analysis was carried out for well-resolved resonances representing adenosine triphosphate, sugar phosphate, inorganic phosphorus, diphosphoglycerate, glycerophosphorylethanolamine, and glycerophosphorylcholine. Adenosine triphosphate levels were highest in the growth-retarded group. There were significantly higher levels of sugar phosphate, diphosphoglycerate, and glycerophosphorylcholine in the placentas of the growth-retarded pregnancies compared with those from normal placentas. These differences may represent a response to hypoxia and an increase in the amount of blood in the placenta. The results demonstrate the utility of nuclear magnetic resonance spectroscopy for studying the pathology of abnormal placentas to gain a better understanding of the pathology and represent early steps toward in vivo spectroscopic studies of the placenta.


Electrocortical activity, electroocular activity, and breathing movements in fetal sheep with prolonged and graded hypoxemia. Our objective was to determine the effect of a prolonged and graded reduction in fetal arterial oxygen saturation on electrocortical activity and associated biophysical variables. Fourteen unanesthetized fetal sheep were studied between 126 and 135 days' gestation with continuous monitoring of electrocortical and electroocular activity and breathing movements, during a 24-hour control period, and subsequently during 4 days of prolonged and graded hypoxemia induced by progressively lowering the maternal inspired oxygen concentration. Graded reduction in fetal arterial oxygen saturation resulted in little change in arterial pH until close to 30% when metabolic acidemia was apparent. The incidence of low-voltage electrocortical activity, electroocular activity, and breathing movements were marginally decreased with hypoxemia alone; however, a significant decrease was not apparent until associated with the onset of fetal acidemia. Hypoxemia of a chronic nature must approach the level at which acidemia becomes apparent before a marked change in fetal behavioral activity is noted.


What occupational therapists can do to eliminate racial barriers to health care access. Now is the time for the American Occupational Therapy Foundation and individual institutions of higher education that house occupational therapy programs to step into the leadership vacuum created by this issue. We must not only design new minority scholarships programs, but also be prepared to defend existing ones. Given the current confusion and fluctuations of opinion on this issue, what is policy now may not be policy after the next presidential election. The Council on Ethical and Judicial Affairs of the AMA has recommended recruiting minority students, procuring greater scholarship assistance, and pursuing affirmative action in school admission and faculty hiring as strategies for eradicating racial barriers to equal access to health care. As an allied medical profession, we must follow the Council's lead.


A cross-cultural test of the validity of occupational therapy assessments with patients with schizophrenia. The validity and use of psychosocial assessments in occupational therapy are ongoing concerns (Moyer, 1984) and were the focus of this study. Fifty African patients with schizophrenia and 10 nondysfunctional African volunteers took an an assessment battery that included the Schroeder, Block, Campbell Adult Psychiatric Sensory Integration Evaluation (SBC) (Schroeder, Block, Trottier, & Stowell, 1978), a daily activity, work, and leisure activity interview based on the Model of Human Occupation (Kielhofner, 1985), and a culture-specific test of functional performance. Data on subjects' psychiatric histories and demographics were collected. Rationale for the assessments used, methods for devising the functional assessment, methods and procedures for data collection, and analysis are presented. A stronger relationship was found to exist between subjects' performances on the SBC and the functional activity test than between interviews based on the Model of Human Occupation and the functional activity test, both for patients and for the whole sample. All assessments were found to differentiate between patients and nonpatients, although the SBC was the best discriminator. Among psychiatric history variables, the strongest relationships were between measures of seriousness of illness and both the SBC and functional activity assessment. The most effective way to measure performance dysfunction and seriousness of illness in persons with schizophrenia was to measure the underlying sensorimotor impairment or to use a culture-specific test of functional performance.