No excess of DR*3/4 in Ashkenazi Jewish or Hispanic IDDM patients

The gene frequencies, haplotype relative risks, and zygotic assortments of HLA-DR in three ethnically defined samples of insulin-dependent diabetes mellitus (IDDM) patients were determined in a prospective family study. Although DR3 and DR4 were positively associated with IDDM in the probands of 123 northern European, 94 Ashkenazi Jewish, and 49 New York Hispanic families, significant excess of DR*3/4 heterozygotes was observed only among the probands from families of northern European ancestry. There was also a significant decrease in the frequency of Bw62,DR4 haplotypes derived by northern European patients from their mothers compared with their fathers. This difference, together with data reported in the literature, suggests that the expressivity of the susceptible genotype(s) in IDDM patients may be modified by protective maternal effects associated with Bw62,DR4 and probably other DR4 haplotypes. Samples of IDDM patients from populations with high frequencies of these modifiers should have different DR-gene frequencies contributed by fathers and mothers, capable of accounting for the observed Hardy-Weinberg disequilibrium. We postulate that, because the mechanism of action of these modifiers is distinct from that of the susceptibility gene, the difference must be considered in devising strategies for elucidation of the mode of inheritance of the disease and for understanding the molecular nature of the susceptibility.     

The intravitreal penetration of ceftriaxone in man following systemic administration

Seventeen patients who underwent vitreal surgery received ceftriaxone (Rocephin) 1-2 g intramuscularly at various time intervals before surgery. Specimens of serum and vitreous were assayed for ceftriaxone concentrations both by bioassay and high pressure liquid chromatography. All patients had detectable vitreous (and serum) ceftriaxone concentrations at all time periods. Vitreous ceftriaxone levels at the first 4.5 hr following the administration of the antibiotic ranged from 1.4-19.4 micrograms/ml and averaged 5.9 micrograms/ml. At 12-13 hr following ceftriaxone administration vitreous concentrations were 11.5 (+/- 9.0) micrograms/ml. Ceftriaxone in intramuscular administration could be used as prophylaxis against ceftriaxone-susceptible microorganisms in vitreal surgery. Ceftriaxone is the first antibiotic for which reliable penetration into the vitreous is demonstrable following intramuscular administration.     

A simple method for coating native polysaccharides onto nitrocellulose.

A method for coating native, non-derivatized, polysaccharide (PS) onto nitrocellulose (NC) for identifying PS-specific antibodies has been developed. The new feature of this method is that PS molecules are vacuum filtered onto NC in their native state by devices that can accommodate NC of different sizes and shapes. PS-coated NC disks were used to localize antibody secreting hybridoma cells cultured on filter paper disks. These were analyzed by blotting with size-matched PS-coated NC disks and specific antibodies secreted by individual colonies were detected by enzyme-linked immunoblot. In another application of this method, immune sera were separated by isoelectric focusing and the gels were blotted with PS-coated NC sheets. The spectrotype and isotype of antibodies that bound to the NC were examined using isotype specific enzyme-linked antibody. These immunoblots showed high resolution and specificity. The advantages of this method are that the PS used for coating does not need to be derivatized in order to bind the NC, and that smaller quantities of PS may be utilized by this coating method when compared to other techniques. This provides a useful tool to ask many questions regarding the immune response to PS.     

Characterization of cognitive functioning in a subgroup of children with congenital HIV infection.

The cognitive status of 12 clinically stable children with congenital HIV infection, nine of whom were neurologically impaired, age three to nine years, was assessed using the Kaufman ABC test. Seven of the children had ARC; five were diagnosed as having AIDS. The same children were evaluated by standard neurologic examinations with Characterization of tone and fine motor functioning. Two were diagnosed as being mildly retarded; six were borderline; and four tested as being of average intelligence. Visual-spatial perceptual based functioning was found to be more impaired than were abstract reasoning and verbally mediated skills in six (50%) of the patients. This pattern of impaired information processing was found irrespective of overall cognitive status. On neurological and physiatric examination abnormal developmental histories were obtained, or poor fine motor coordination, abnormal tone and gait, and impaired rapidly alternating movements were found in 9 of the 12 subjects. These findings suggest selective impairment in distinct areas of neurologic and neuropsychological functioning during stable phases of HIV infection in a select group of children. These patterns appear to persist over time. They differ from the clustering of impaired skills seen in children of comparable socio-cultural backgrounds without HIV infection. Similarities in functioning are noted between this subgroup of children with AIDS and ARC and comparable groups with cerebral palsy.     

Excess of DR3/4 in type I diabetes. What does it portend?

The HLA-DR genotypes of 158 new type I diabetic probands from simplex families are compared with those of 43 multiply affected sibships. There were no significant differences in the gene frequencies of the insulin-dependent diabetes mellitus (IDDM)-associated alleles, DR3 and DR4, and whereas the DR3/4 heterozygotes were as frequent among simplex probands as among the first affected of multiplex sibships, subsequently affected sibs displayed lower frequencies of this genotype in this as well as in previously reported samples, indicating that the excessive risk associated with DR3/4 heterozygosity depends on the order of affection and thus on environmental factors. It is proposed that the penetrance of the susceptibility gene is enhanced by epistatic effects of this genotype and that this enhancement is strongest under conditions of low environmental liability. Thus, the excessive risk for DR3/4 individuals appears to depend on secondary interactions between DR and the environmental factors that trigger the onset of this disease and does not in itself indicate the existence of distinct susceptibility alleles in coupling with these genes, i.e., of genetic heterogeneity or overdominance.     

Stage II carcinoma of the ovary: an analysis of survival after comprehensive surgical staging and adjuvant therapy.

Ninety-three women with FIGO stage II epithelial ovarian carcinoma underwent comprehensive surgical staging and were randomized prospectively to therapy consisting of either intraperitoneal radioactive phosphorus or oral melphalan. No patient had gross residual disease at the time of randomization. Ten of the forty-five women treated with melphalan experienced severe bone marrow depression at some time during therapy and two women expired from leukemia. Four of the forty-eight women treated with intraperitoneal phosphorus required surgical reexploration for intestinal obstruction or bowel injury. Twenty-one women died of their disease. Survival was not statistically different between the two treatment arms. The 5-year actuarial survival was 78%.     

Colonic Drug Delivery: Enhanced Release of Indomethacin from Cross-Linked Chondroitin Matrix in Rat Cecal Content

Pharmaceutical Research -     

Tinnitus: evaluation of biofeedback and stomatognathic treatment

Thirty-two patients with disabling tinnitus received stomatognathic treatment and biofeedback therapy according to a cross-over design. The evaluation of treatment outcomes showed some improvements at the group level: decrease of tinnitus intensity, mood improvement and reduction of clinical signs of dysfunction in the masticatory system. Qualitative observations indicated numerous positive changes in patients' emotional and cognitive orientation vis à vis tinnitus. Some possible predictors of positive treatment outcome were observed: comparatively low severity of tinnitus, normal hearing or compensated hearing loss, occlusal interferences, jaw fatigue, diurnal bruxism and fluctuations in tinnitus intensity. Left-sided tinnitus seemed to be a negative predictor of stomatognathic and biofeedback treatment outcome. Consequently, stomatognathic and biofeedback treatment seem to have some positive effects on subgroups of tinnitus patients.     

Intracellular survival of persistent group A streptococci in cultured epithelial cells

Group A streptococcus (GAS) is the principle etiologic agent of bacterial pharyngotonsillitis and a wide range of other diseases. Failure to eradicate GAS from patients has been documented in 5-30% of patients with pharyngotonsillitis, in spite of the continued sensitivity of GAS to penicillin and other beta-lactams. It was recently proposed that eradication failure might be attributed to the ability of GAS to maintain an intracellular reservoir during antibiotic treatment. We have previously shown that strains derived from patients with bacterial eradication failure, despite antibiotic treatment (persistent strains), adhered to and were internalized by cultured epithelial cells more efficiently than strains that were successfully eradicated. Since, penicillin and other beta-lactams do not penetrate well into mammalian cells, intracellular survival of GAS is crucial in order to persist during prolonged antibiotic treatment. In this study, we compared the survival of GAS strains from cases of eradication failure and eradication success, using an epithelial cell culture model. We found that persistent strains show significantly increased intracellular survival, compared to the 'eradication success' strains. This finding supports the idea that an intracellular reservoir of GAS plays a role in the etiology of antibiotic eradication failure.     

Treatment of septic thrombocytopenia with immune globulin

Thrombocytopenia frequently complicates systemic infection and results from multiple possible mechanisms. We and others have demonstrated that platelet-associated IgG (PAIgG) levels are elevated in the majority of patients with septic thrombocytopenia. Corticosteroids may be undesirable as a treatment for thrombocytopenia for patients with severe infection because of their potential for suppressing the immune response. We hypothesized that septic thrombocytopenia is, in most cases, an immune disorder analogous to idiopathic thrombocytopenic purpura (ITP) which might respond to intravenous gamma-globulin as a treatment for increasing the platelet count in this disorder. Intravenous immune globulin (IVIG), 400 mg/kg daily for 3 days, was administered in a randomized double-blind placebo-controlled trial. Twenty-nine patients who developed thrombocytopenia during a documented, septic episode were studied. Patients with disseminated intravascular coagulation (DIC), hypersplenism, or drugs known to cause thrombocytopenia were excluded. Elevated PAIgG levels were documented in 52% of evaluable patients. Mean platelet counts in the IVIG group rose from 43K at study entry to 178K (411% rise) by Day 9. In the placebo group platelets rose from 51K to 125K (261% rise;P = 0.02). Seventy-seven percent of the IVIG group had a minimum peak rise of 35K, vs 56% of the placebo group. Three patients in the placebo group had a serious bleeding episode, vs one in the IVIG group. The use of IVIG to treat septic thrombocytopenia not associated with DIC leads to a more rapid, more sustained, and greater increase in platelet count than placebo. Its use is recommended in the septic patient who is bleeding or is likely to need invasive or surgical procedures.