Alloantibodies against low-frequency human platelet antigens do not account for a significant proportion of cases of fetomaternal alloimmune thrombocytopenia: evidence from 1054 cases

BACKGROUND: Maternal alloantibodies against the five common human platelet antigen (HPA) systems (HPA-1 to -3, -5, and -15) are found in only 20% of cases referred for fetal and neonatal thrombocytopenia (FMAIT) investigations. The question asked was whether mismatches for the remaining 11 low-frequency HPAs (HPA-4 and -6bw to -17bw) might in part explain the remaining 80% of cases.
STUDY DESIGN AND METHODS: A total of 1054 paternal DNA samples from referred FMAIT cases (among which 223 cases where antibodies against a common HPA were found) were genotyped for 11 low-frequency HPAs as well as a recently discovered polymorphism ( ITGA2B -C2320T). The initial genotyping was carried out by TaqMan and potential heterozygotes were confirmed by DNA sequencing. Clinical and serologic data were collected for each case with a heterozygote father.
RESULTS: In total, eight heterozygous fathers were identified: four for HPA-6w, one each for HPA-10w and -11w, and two for HPA-12w. Maternal antibodies against the corresponding antigen were identified in four of the eight cases. In two of these cases, antibodies against HPA-1a and HPA-1b were also found.
CONCLUSION: It was concluded that the minor alleles of HPA-4 and -6bw to -17bw are exceptionally rare in the Caucasian population and therefore do not explain the large number of FMAIT referrals which test negative for the common HPA antibodies.     

Development of innovative teaching materials: clinical pharmacology problem-solving (CPPS) units: comparison with patient-oriented problem-solving units and problem-based learning--a 10-year review

The First Teaching Clinic in Clinical Pharmacology, sponsored by the American College of Clinical Pharmacology in September 1992, was designed for the preparation and development of new clinical pharmacology problem-solving (CPPS) units. CPPS units are case histories that illustrate pertinent principles in clinical pharmacology. Each unit consists of the following sections: introduction, learning objectives, pretest, four clinical pharmacology scenarios, posttest, answers to pre- and posttest questions, and selected references. The clinical pharmacology content of the CPPS units place greater emphasis on clinical information, drug selection, and risk/benefit analyses, and thus they complement the basic pharmacology presented in the patient-oriented problem-solving (POPS) units. In general, the CPPS units are intended for use by students more advanced in clinical pharmacology than first- and second-year medical students. The CPPS unit "Clinical Pharmacology of Antiepileptic Drug Use: Clinical Pearls about the Perils of Patty" was developed for use by third- and fourth-year medical students doing rotations in neurology or clinical pharmacology; advanced pharmacy students; residents in neurology, pediatrics, internal medicine, and family practice; fellows in clinical pharmacology, and those taking the board examination in clinical pharmacology. The CPPS unit titled "Geriatric Clinical Psychopharmacology" was written for third- and fourth-year medical students; residents in psychiatry, family practice, and internal medicine;fellows in clinical pharmacology; and those studying for boards in clinical pharmacology. The CPPS unit "Anisocoria and Glaucoma" was written for more advanced students of clinical pharmacology. The CPPS unit titled "Antiepileptic Drugs" was intended for second-year medical students. The second teaching clinic was held in November 1993 and focused on the development and editing of the CPPS units and their evaluations by faculty and students from academic centers. Evaluations by faculty and students have been overwhelmingly positive. Requests to use the CPPS units in various clinical pharmacology teaching programs were received from numerous schools within the United States and from abroad. The third teaching clinic in September 1995 included a follow-up focused on the uses of drug information databases in case problem exercises. These examples are presented to demonstrate the variety of educational activities the American College of Clinical Pharmacology is sponsoring to fulfill its strategic initiative dedicated to offer innovative teaching programs and to develop new teaching materials in clinical pharmacology. Collectively, all of the teaching clinics, symposia, and workshop efforts, sponsored by the various academic professional societies alone or together over the past decade, are necessary if new and innovative teaching materials in the field of basic science and in the fields of pharmacology and clinical pharmacology are to be continuously developed to keep pace with the new, rapidly changing developments in medicine to provide the best treatment for patients in the 21st century.     

Functional comparison of DCs generated in vivo with Flt3 ligand or in vitro from blood monocytes: differential regulation of function by specific classes of physiologic stimuli

Dendritic cells (DCs) are a family of leukocytes that initiate T- and B-cell immunity against pathogens. Migration of antigen-loaded DCs from sites of infection into draining lymphoid tissues is fundamental to the priming of T-cell immune responses. In humans, the major peripheral blood DC (PBDC) types, CD1c+ DCs and interleukin 3 receptor-positive (IL-3R+) plasmacytoid DCs, are significantly expanded in vivo with the use of Flt3 ligand (FL). DC-like cells can also be generated from monocyte precursors (MoDCs). A detailed comparison of the functional potential of these types of DCs (in an autologous setting) has yet to be reported. Here, we compared the functional capacity of FL-expanded CD1c+ PBDCs with autologous MoDCs in response to 3 different classes of stimuli: (1) proinflammatory mediators, (2) soluble CD40 ligand trimer (CD40L), and (3) intact bacteria (Escherichia coli). Significant differences in functional capacities were found with respect to changes in phenotype, migratory capacity, cytokine secretion, and T-cell stimulation. MoDCs required specific stimuli for the expression of functions. They responded vigorously to CD40L or E coli, expressing cytokines known to regulate interferon-gamma (IFN-gamma) in T cells (IL-12p70, IL-18, and IL-23), but required prostaglandin E2 (PGE2) during stimulation to migrate to chemokines. In contrast, PBDCs matured in response to minimal stimulation, rapidly acquired migratory function in the absence of PGE2-containing stimuli, and were low cytokine producers. Interestingly, both types of DCs were equivalent with respect to stimulation of allogeneic T-cell proliferation and presentation of peptides to cytotoxic T lymphocyte (CTL) lines. These distinct differences are of particular importance when considering the choice of DC types for clinical applications.     

Safety and efficacy of intravenous valproate in pediatric status epilepticus and acute repetitive seizures

Summary: Purpose: To evaluate the safety and efficacy of intravenous valproate (VPA) loading in children with status epilepticus (SE) or acute repetitive seizures. Methods: Retrospective review was performed on 40 pediatric patients with intravenous VPA loading. Patients were classified into two groups: SE (n = 18) and acute repetitive seizures (n = 22). Thirty‐one patients were VPA naïve and received a full loading dose of 25 mg/kg; nine had subtherapeutic plasma VPA levels and received a partial loading dose. Average infusion rate was 2.8 mg/kg/min. Heart rate and blood pressure were measured before, during, and after infusion. Results: Intravenous VPA loading stopped seizures in 18 patients with SE within 20 min. All 18 patients regained baseline mental status within 1 h of seizure cessation. Among 22 patients with acute repetitive seizures, only one had further seizures after VPA infusion. One patient in the SE group complained of transient tremors. No significant changes in blood pressure or heart rate were found in either group. Postinfusion plasma VPA levels ranged from 51 to 138 μg/ml (mean ± SD = 88 ± 21.5 μg/ml). Conclusions: Intravenous VPA loading is safe and effective for treating acute seizure emergencies in children.     

Sensitivity to Interaural Correlation of Single Neurons in the Inferior Colliculusof Guinea Pigs

Sensitivity to changes in the interaural correlation of 50-ms bursts of narrowband or broadband noise was measured in single neurons in the inferior colliculus of urethane-anaesthetized guinea pigs. Rate vs. interaural correlation functions (rICFs) were measured using two methods. These methods compensated in different ways for the inherent variance in interaural correlation between tokens with the same expected correlation. The shape of all rICFs could be best described by power functions allowing them to be summarized by two parameters. Most rICFs were best fit by a power below 2, indicating that they were only slightly nonlinear. However, there were a few fitted functions that had a power of 3–6, indicating marked curvature. Modeling results indicate that the nonlinearity of the majority of rICFs was explicable in terms of the monaural transduction stages; however, some of the rICFs with power greater than 2 require either multiple inputs to the coincidence detector or additional nonlinearities to be included in the model. Discrimination thresholds were estimated at reference correlations of −1, 0, and +1 using receiver operating characteristic (ROC) analysis of the spike-count distribution at each correlation. Thresholds spanned the full possible range, from a minimum of 0.1 to the maximum possible of 2. Thresholds were generally highest with a reference correlation of −1, intermediate with a reference of 0, and lowest with a reference correlation of +1. Thresholds were lowest for the most steeply sloped rICFs, but thresholds were not strongly correlated to the spike rate variance. The lowest thresholds occurred using narrowband noise that was compensated for internal delays, but they were still about three times larger than human psychophysical thresholds measured using similar stimuli. The data suggest that, unlike pure tone interaural time difference, discrimination of a population measure is required to account for behavioral interaural correlation discrimination performance.     

Increased 5alpha-reductase and normal 11beta-hydroxysteroid dehydrogenase metabolism of C19 and C21 steroids in a young population with polycystic ovarian syndrome

OBJECTIVE: To test the hypothesis that 5alpha-reductase (5alphaR) and 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity are increased in adolescent and young-adult women with PCOS and that an altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis occurred in these subjects. DESIGN: Prospective non-randomized study in an academic research environment. PATIENTS: Eleven women, aged 14 to 25 years, were studied who were at least one year post-menarche and who had a diagnosis of PCOS based on a history of oligomenorrhea and elevated total and or free serum testosterone. INTERVENTION: 24-Hour urinary metabolites were assessed in nine subjects and five underwent stimulation with ovine corticotropin releasing factor (oCRF). OUTCOME MEASURES: C19 and C21 steroid urinary metabolite 5-alpha/5-beta pairs, 11-oxo/11-hydroxy products and the ratio of the total 5-alpha/5-beta reduced and 11-oxo/11-hydroxy products were compared to values in control women. Urinary cortisol (F) (sum of conjugated and free, and free F) and total F metabolites (the sum of THE, THF, 5alpha-THF, cortolones, and cortols) were determined. A 1 microg/kg oCRF stimulation test was performed with timed samples determined for plasma ACTH and serum F levels. RESULT: The 24-hour total and free urinary F were not different from control. However, the total F metabolites were markedly elevated (7922+/-2666 vs 5418+/-1549 microg/24 h, p<0.01). A marked increase in the total 5-alpha reduced C19 and C21 metabolites was observed in the PCOS population vs control (5084+/-1977 vs 2681+/-1188 microg/24 h, p<0.01). The total urinary 11-oxo/11-hydroxy metabolite ratio was not different, p=0.23. The basal values and response of both ACTH and F to oCRF stimulation were not different from those of controls. CONCLUSION: There is a marked increase in 5alphaR metabolism of both C19 and C21 steroids in younger women with PCOS.     

On the development of CNS lesions in natural canine distemper encephalomyelitis

Acute lesions within spinal cord white matter have been studied by light and electron microscopy in 3 dogs suffering from the acute form of canine distemper encephalomyelitis (CDE). Prominent features of these lesions were viral inclusions, giant cell formation, cellular degeneration, myelin breakdown and phagocytic activity by cells believed to be derived from local glia. The viral inclusions occurred in giant cells, many astrocytes, macrophages and occasional oligodendroglia. Only suggestions of active viral replication from cell membranes were present. On the basis of the above features, these CDE lesions were classed as being acute. Perivascular inflammation and parenchymal invasion by haematogenous cells were lacking. However, older, gliotic, demyelinated lesions were always associated with inflammation. The pattern of demyelination in acute CDE lesions differed from those seen in other conditions, in particular the autoimmune demyelinating diseases. In acute CDE lesions, individual fibres became separated from others by rings of cells, the processes of which systematically stripped the myelin from the outer layers of the sheath inwards until a naked segment of axon remained. Some of the macrophages were recognisable as astroglia. Elsewhere, unequivocal astrocytes containing myelin debris were common. The results suggest that inflammation in acute CDE lesions is not a primary event, and that viral invasion causes breakdown of tissue which is accompanied pari passu by myelin destruction. The latter might be related to the non-specific release of host factors (viz. hydrolytic enzymes) or humoral factors during the cellular degeneration. Local cells appeared to participate in the process of myelin phagocytosis. Overt inflammation and damage by haematogenous cells were features only of chronic lesions and have been described previously in studies on chronic CDE lesions. The results are interpreted in terms of their relevance to the study of human subacute sclerosing panencephalitis, of which CDE is considered the animal analogue, and multiple sclerosis, the paradigm of the human demyelinating diseases.