Biomedical subjects
Publications and source records attributed to M Barr.
Nursing home quality improvement has historically relied on annual surveys conducted by state agencies for its impetus. Such reviews play an important role for assuring that minimum standards are met. However, we need to search for incentives that will make it in the best interest of nursing homes to improve beyond the minimum. This article explores incentives that may play that role.
BACKGROUND: Triploid molar pregnancies are usually managed by evacuation of the uterine contents. CASE: A 25-year-old woman had a clomiphene citrate-induced twin pregnancy. Ultrasound scan at 13 weeks revealed one anomalous twin. Cytogenetic analysis revealed a karyotype of 69, XXY and a normal other twin. In an attempt to salvage the normal fetus, selective termination was successfully performed at 15 weeks by intracardiac potassium chloride injection. However, the placenta continued to grow and severe preeclampsia developed at 19 weeks, requiring pregnancy termination. CONCLUSION: Selective termination of a triploid twin does not guarantee resolution of molar growth and sequelae of the mole; severe preeclampsia can still develop.
We report on two sisters with an unusual form of craniosynostosis, protruding nasal spine, micrognathia, short limbs, lung hypoplasia, absent or hypoplastic gallbladder, short intestine with ileal distention, hypoplastic uterus, and intrauterine growth retardation. This combination of defects appears to be a newly recognized and probably autosomal recessive disorder.
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OBJECTIVE: Our purpose was to evaluate the value of the combination of femur and humerus length measurements in ultrasonographic screening for trisomy 21. STUDY DESIGN: Direct necropsy measurements were analyzed on 703 midgestational fetuses (641 normal, 62 with trisomy 21). The (leg+arm length)/foot length ratio was found to be significantly shortened for fetuses with trisomy 21. On the basis of necropsy data 576 midgestational pregnancies were evaluated ultrasonographically for (femur+humerus length)/foot length ratio to identify fetuses at increased risk for trisomy 21. RESULTS: An ultrasonographic (femur+humerus length)/foot length ratio < or = 1.75 gave a 15.3 odds ratio risk for trisomy 21 in our high-risk population and correctly identified 53% of fetuses with trisomy 21, with a false-positive rate of 7%. In addition, the use of this ratio eliminates the need for gestational age-corrected nomograms and complicated calculations in ultrasonographic screening. CONCLUSION: The (femur+humerus length)/foot length ratio may be an additional effective ultrasonographic marker for identification of fetuses at increased risk for trisomy 21.
Trisomy 21 develops as a result of nondisjunction of two homologous chromosomes during either the first or second meiotic division. One of the more important consequences of these genetic alterations is the predictable, although variable disturbance in the architecture of the craniofacial region [1]. Postnatal craniofacial morphology has been extensively studied in Down's syndrome (DS). However, little information is available on human prenatal development of the head and face in such patients. The time at which changes in craniofacial phenotype first emerge in Down's syndrome fetuses and at which physical growth begins to diverge from normal is unknown. To explore these questions, we compared prenatal craniofacial growth in 50 Down's syndrome fetuses with that of 555 fetuses judged to be "typical for body weight and age" using the method of log-linear allometry [2].
Normative data on human craniofacial growth during the fetal period and important to provide a broader perspective on normal morphogenesis as well as to serve as reference for analyzing craniofacial syndromes in which growth has gone awry. Over a 19-year period, the Teratology Unit at the University of Michigan Medical Center has collected data on 2,568 legally donated fetuses that have undergone necropsy examination at various gestational ages. From previous analyses, 609 of the total fetal population (25%) were designated as typical for age or body weight on the basis of normal morphology, absence of maceration, and general growth symmetry. Of the 609 fetuses reviewed, 54 were excluded secondary to incomplete data. The remaining 555 constitute the basis of this study. Seven craniofacial measurements were recorded, including head circumference (HC), brain weight, inner canthal and outer canthal distances, and distances from nasion to menton, outer canthus to tragus and auditory meatus to vertex. Statistical analysis was carried out using the single-factor allometric model of Sewall Wright. Size was estimated as the first unstandardized principal component of the logarithms of lengths and of cube roots of weights, and then allometry was expressed in the regressions of each log variable on size. Significant allometry was found as were significant differences in errors about the allometric relation, but no evidence for more than a single factor or of "nonlinearity" in the regression curves was noted. Although there were differences of specific allometric coefficients between the various measurements (i.e., the slope of the curve for IC was significantly smaller than the slope of the curve generated for HC), these specific growth rates remain in relatively strict proportion to one another from early in gestation (body weight, 54.2 gm) to later in gestation (body weight, 1,000 gm).
We isolated two S. pombe genes, scd1 and scd2, that are required for normal morphology and mating. scd1 and scd2 are homologous to CDC24 and BEM1, respectively, of S. cerevisiae. Epistasis analyses indicate that scd2 and ras1 converge upon scd1, which, in turn, interacts with cdc42sp, a RHO-like GTPase. Studies with the yeast two-hybrid system indicate that scd2 forms complexes with both scd1 and cdc42sp. Furthermore, biochemical studies indicate that the interaction between scd1 and scd2 is direct. The yeast two-hybrid data further suggest that scd1, scd2, cdc42sp, and ras1, in its GTP-bound state, act cooperatively to form a protein complex.
We present genetic evidence for complex formation of STE5 and the STE11, STE7, and FUS3 protein kinases, the pheromone-responsive mitogen-activated protein kinase module of Saccharomyces cerevisiae. Interaction between STE5 and STE11 is not dependent on STE7, and interaction between STE5 and STE7 does not require STE11. The N-terminal regulatory domain of STE11 is both necessary and sufficient for interaction with STE5. Interaction between STE7 and STE11 is bridged by STE5, suggesting the formation of a multiprotein complex. We also demonstrate biochemical interaction between STE5 and STE11 by using a combination of bacterially expressed fusion proteins and extracts prepared from yeast. Our results suggest that STE5 is a scaffolding protein that facilitates interactions between components of the pheromone-responsive mitogen-activated protein kinase module. We further propose that such scaffolding proteins serve to inhibit cross-talk between functionally unrelated mitogen-activated protein kinase modules within the same cell.
Because of the increasing prenatal use of high-resolution ultrasonography to assess fetal growth and because growth aberration is one of the principal manifestations of abnormal intrauterine development, a more precise definition of normal growth is desirable. Our data set from autopsies of fetuses/neonates (50-4,000 g), collected with systematic attention to precision of measurement, is analyzed and presented. Previous computations of fetal growth curves appear to overstate the variation about the mean. Through the identification and exclusion of outliers and the use of appropriate curve fitting techniques, the problem of overestimation of variation about the mean has been largely eliminated. The new growth standards we present can be used to assess aberration from proportional growth and correlate it with gestational circumstances and particular morphological features of the fetus.
Somatic and visceral growth profiles of midgestation human fetuses with trisomy 21, 18, or 13 demonstrate that each disorder has a characteristic pattern of growth aberration. The most striking deviations are short limbs in trisomy 21, subnormal adrenal and lung weights in trisomy 18, and supranormal spleen and kidney weights in trisomy 13.
Occasionally there is a drug whose record in pregnancy is so frequently associated with adverse outcome of so specific a pattern that it becomes clear that its use must be restricted before scientific proof from epidemiological studies is obtained. I believe this to be the case with the drug class of ACEIs. There are mammalian models suggesting substantial fetotoxicity in a dose-related fashion. There is a strong and consistent pattern to the reported cases of ACEI-related adverse outcomes: the syndrome of oligohydramnios-anuria, neonatal hypotension, renal dysplasia, and hypocalvaria is too specific in association with the use of these drugs to be ignored. There is a very plausible biologic mechanism to explain the relationship. The features of ACEI fetopathy suggest that the underlying pathogenetic mechanism is fetal hypotension, which may also result from other exposures. Thus, while the fetopathy may not be truly specific to ACEIs, they are particularly liable to produce adverse fetal renal effects with their sequels (anuria-oligohydramnios, pulmonary hypoplasia, growth restriction) and hypocalvaria.
Canine distemper virus (CDV) infection occurred in captive leopards (Panthera pardus), tigers (Panthera tigris), lions (Panthera leo), and a jaguar (Panthera onca) in 1991 and 1992. An epizootic affected all 4 types of cats at the Wildlife Waystation, San Fernando, California, with 17 mortalities. CDV-infected raccoons were thought to be the source of infection in these cats. Two black leopards died at the Naibi Zoo, Coal Valley, Illinois, and 2 tigers died at the Shambala Preserve, Acton, California. Initial clinical signs were anorexia with gastrointestinal and/or respiratory disease followed by seizures. Canine distemper virus was isolated from 3 leopards, 3 tigers, and 3 lions that died or were euthanized when moribund. Monoclonal antibody testing identified the virus isolates as CDV. Gross and histopathologic findings were similar to those found in canids with distemper with a few exceptions. There were fewer lesions in the brain, and there was a pronounced type 2 cell proliferation in the lung, with inclusion bodies and CDV antigen demonstrated by immunohistology. Neutralizing antibody to CDV was found in high titers in serum from most animals but was absent or was found only in low titers in some cats that succumbed after CDV infection. There was a marked difference in neutralizing antibody titers when tests were done with different strains of CDV.
We have obtained serial measurements on 180 patients with clinically confirmed Brachmann-de Lange syndrome (BDLS) in order to derive standard growth curves. The patients were evaluated in our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation, a support group for families of affected individuals. The data were obtained from the records of pediatricians, other physicians, schools and parents, as well as from personal examination on each of these patients at least once, often periodically. The growth curves include height, weight and head circumference measurements from birth through adulthood. Prenatal growth and birth weights are below the 5th centile in most (68%) cases, with an average birth weight of 2,277 g. Growth persists below the normal curves in most of the patients throughout life. Height velocity is equal to the normal range but there is slower pubertal growth. Weight velocity is below the normal range throughout life until late adolescence. Average head circumference remains below the second centile. Thin body habitus coupled with slow growth and proportionate small stature is a manifestation of the syndrome, but is commonly mistaken for failure to thrive.
One hundred twenty-two patients with clinically confirmed Brachmann-de Lange syndrome (BDLS) were evaluated developmentally. Recruitment was made from our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation parent support group. Developmental information was obtained from records of physicians, schools and developmental centers, or from parents on each of the 122 individuals, allowing division into four groups for study: group 1 (n = 48) underwent formal developmental assessments, which generated intelligence or developmental quotients, and had a completed parental questionnaire with specific developmental questions regarding ages of skills mastered; group II (n = 23) had additional developmental records available without formal testing, as well as the questionnaire; group III (n = 22) had only a completed questionnaire; and group IV (n = 29) had formal developmental testing or other developmental records but no available questionnaire. These data were analyzed in order to be able to predict attainable psychomotor development. Average scores on formal testing were found to be in the mild to moderate level of mental retardation, ranging from below 30 to 85, with an average intelligence quotient of 53, higher than previously reported. Visual-spatial memory and perceptual organization skills were found to be strengths. Younger individuals born before 1980 demonstrated higher scores on testing. Early intervention appears to play a major role in the level of developmental achievement.
We used a Saccharomyces cerevisiae genetic system to detect the physical interaction of RAS and RAF oncoproteins. We also observed interaction between RAS and byr2, a protein kinase implicated as a mediator of the Schizosaccharomyces pombe ras1 protein. Interaction with RAS required only the N-terminal domains of RAF or byr2 and was disrupted by mutations in either the guanine nucleotide-binding or effector-loop domains of RAS. We observed interaction between MEK (a kinase that phosphorylates mitogen-activated protein kinases) and the catalytic domain of RAF. RAS and MEK also interacted but only when RAF was overexpressed.
PURPOSE: Pneumocystis carinii pneumonia (PCP) and toxoplasmic encephalitis are the most frequent pulmonary and central nervous system opportunistic infections associated with human immunodeficiency virus (HIV) infection. We designed a prospective study to compare the effects of aerosolized pentamidine and dapsone in the prophylaxis of these infections in HIV-infected persons with CD4+ lymphocyte counts less than 250/mm3. PATIENTS AND METHODS: Two hundred seventy-eight patients seropositive for HIV who had acquired immunodeficiency syndrome (AIDS) or advanced AIDS-related complex were randomly assigned to receive intermittent dapsone (100 mg twice weekly) or aerosolized pentamidine (100 mg every 2 weeks). The proportion of patients remaining free of PCP or toxoplasmosis was analyzed with the log-rank test as a function of time, as were the effects of zidovudine or prophylaxis on survival. RESULTS: Dapsone and aerosolized pentamidine demonstrated similar efficacy in the primary and secondary prophylaxis of PCP, with 15 (18%) failures among patients receiving dapsone compared to 15 (14%) among those receiving aerosolized pentamidine (p = 0.4), after a mean length of follow-up of 42 and 44 weeks, respectively. Dapsone was more effective in the primary prophylaxis of toxoplasmic encephalitis, with six toxoplasmic encephalitis events occurring among those receiving aerosolized pentamidine, compared to none among those taking dapsone (p = 0.01). Primary prophylaxis for PCP was more effective than secondary prophylaxis with either therapy. Zidovudine therapy did not prevent PCP yet prolonged the PCP-free interval for those in whom either prophylactic therapy failed. Kaplan-Meier estimates did not show a difference in survival between the patients receiving either therapy, yet zidovudine use was associated with improved survival, independent of race and risk factor (Cox proportional hazards model, p = 0.001). The 1-month survival for patients developing PCP despite prophylaxis was better with those in whom dapsone failed than it was for those in whom aerosolized pentamidine failed (p = 0.08). CONCLUSION: Dapsone is as effective as aerosolized pentamidine in preventing PCP and has the advantage of a lower cost, easier administration, and possibly an additional preventive effect against toxoplasmosis. Zidovudine prolongs the PCP-free interval for patients receiving prophylaxis, regardless of which prophylactic agent is used.
OBJECTIVE: Our purpose was to determine whether the femur/foot length ratio is useful in the prenatal detection of trisomy 21. STUDY DESIGN: Direct necropsy measurements were analyzed on 436 midgestational fetuses (391 normal, 45 with trisomy 21). Necropsy leg/foot length ratio versus gestational age was found to be significantly different between normal fetuses and those with trisomy 21. On the basis of the necropsy data, 345 midgestational pregnancies were evaluated ultrasonographically for femur/foot length ratio versus gestation age to identify fetuses at risk for trisomy 21. RESULTS: A leg/foot length ratio versus gestation age < or = 2.3 correctly identified 84% of fetuses with trisomy 21 between 110 to 155 days gestation age at necropsy. An ultrasonographic femur/foot length ratio versus gestational age < or = 0.9 had an 18.3 odds ratio risk for trisomy 21 in our high-risk population and correctly identified 71% of fetuses with trisomy 21 (positive predictive value 0.24, negative predictive value 0.98). CONCLUSION: The femur/foot length ratio is an additional ultrasonographic marker for identification of fetuses at increased risk for trisomy 21.