Pseudo-peptides derived from isomannide: inhibitors of serine proteases.

In this paper, we describe the synthesis of a novel class of pseudo-peptides derived from isomannide and several oxazolones as potential inhibitors of serine proteases as well as preliminary pharmacological assays for hepatitis C. Hepatitis C, dengue and West Nile fever are among the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes and are a primary target in the drug development field. Several pseudo-peptides were obtained in good yields from the reaction of isomannide and oxazolones, and their anti-HCV potential using the HCV replicon-based assay was shown.

Pseudo-peptides derived from isomannide as potential inhibitors of serine proteases.

Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.

N- t-Boc-amino acid esters of isomannide. Potential inhibitors of serine proteases.

Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N- t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.

Fine mapping of 10q and 18q for familial Alzheimer's disease in Caribbean Hispanics.

Familial Alzheimer's disease (AD [MIM 104300]) has been a focus of intense investigation, primarily in Caucasian families from Europe and North America families. Although the late-onset form of familial AD, beginning after age 65 years, has been linked to regions on chromosomes 10q and 12p, the specific genetic variants have not yet been consistently identified. Using a unique cohort of families of Caribbean Hispanics ancestry, we screened the genome using 340 markers on 490 family members from 96 families with predominantly late-onset AD. We observed the strongest support for linkage on 18q (LOD=3.14). However, 17 additional markers (chromosomes 1-6, 8, 10, 12, and 14) exceeded a two-point LOD score of 1.0 under the affecteds-only autosomal dominant model or affected sibpair model. As we previously reported the fine-mapping effort on 12p showing modest evidence of linkage, we focused our fine-mapping efforts on two other candidate regions in the current report, namely 10q and 18q. We added 31 family members and eight additional Caribbean Hispanic families to fine map 10q and 18q. With additional microsatellite markers, the evidence for linkage for 18q strengthened near 112 cM, where the two-point LOD score for D18S541 was 3.37 and the highest NPL score in that region was 3.65 (P=0.000177). This narrow region contains a small number of genes expressed in the brain. However, at 10q (134-138 cM), the NPL score decreased from 3.15 (P=0.000486) to 2.1 (P=0.0218), but two broad peaks remained overlapping with previously reported peaks. Our results provide modest support for linkage on 10q and 12p in this cohort of Caribbean Hispanic families with familial Alzheimer's disease, and strong evidence for a new locus on 18q.

A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families.

CONTEXT: Genetic determinants of Alzheimer disease (AD) have not been comprehensively examined in Caribbean Hispanics, a population in the United States in whom the frequency of AD is higher compared with non-Hispanic whites. OBJECTIVE: To identify variant alleles in genes related to familial early-onset AD among Caribbean Hispanics. DESIGN AND SETTING: Family-based case series conducted in 1998-2001 at an AD research center in New York, NY, and clinics in the Dominican Republic. PATIENTS: Among 206 Caribbean Hispanic families with 2 or more living members with AD who were identified, 19 (9.2%) had at least 1 individual with onset of AD before the age of 55 years. MAIN OUTCOME MEASURE: The entire coding region of the presenilin 1 gene and exons 16 and 17 of the amyloid precursor protein gene were sequenced in probands from the 19 families and their living relatives. RESULTS: A G-to-C nucleotide change resulting in a glycine-alanine amino acid substitution at codon 206 (Gly206Ala) in exon 7 of presenilin 1 was observed in 23 individuals from 8 (42%) of the 19 families. A Caribbean Hispanic individual with the Gly206Ala mutation and early-onset familial disease was also found by sequencing the corresponding genes of 319 unrelated individuals in New York City. The Gly206Ala mutation was not found in public genetic databases but was reported in 5 individuals from 4 Hispanic families with AD referred for genetic testing. None of the members of these families were related to one another, yet all carriers of the Gly206Ala mutation tested shared a variant allele at 2 nearby microsatellite polymorphisms, indicating a common ancestor. No mutations were found in the amyloid precursor protein gene. CONCLUSIONS: The Gly206Ala mutation was found in 8 of 19 unrelated Caribbean Hispanic families with early-onset familial AD. This genetic change may be a prevalent cause of early-onset familial AD in the Caribbean Hispanic population.

Survival in children with perinatal HIV infection and very low CD4 lymphocyte counts.

OBJECTIVES: To evaluate clinical conditions associated with mortality in HIV-infected children with CD4+ counts <100 cells/microl. METHODS: The Pediatric Spectrum of HIV Disease Project is a longitudinal medical record review study with eight study sites in the United States, which have been enrolling children since 1989. Survival time from baseline very low CD4 count (<100 cells/microl) to death was estimated using the Kaplan-Meier method. Cox proportional hazards models were used to evaluate the effect of clinical variables on mortality. RESULTS: Of 522 children (>/=1 year of age) with serial CD4+ T-lymphocyte measurements, the median age at the first very low CD4 count was 4.8 years. The estimated median survival following the first very low CD4 count was 36 months. The following factors present at the first very low CD4 count were independently associated with a higher risk of death: younger age, weight-for-age >2 standard deviations below the mean, and previously diagnosed AIDS. The subsequent development of cytomegalovirus (CMV)-associated disease, Mycobacterium avium intracellulare (MAI) infection, wasting syndrome, or esophageal candidiasis was also independently associated with a higher risk of death. CONCLUSION: Survival in HIV-infected children with very low CD4 counts before introduction of highly active antiretroviral therapy was highly variable. Poor nutritional status and the development of CMV disease or MAI infection were associated with the shortest survival times.

Left ventricular volumes and hemodynamic responses to postexercise ischemia in healthy humans.

PURPOSE: The purpose of this study was to determine the cardiac mechanisms involved in cardiovascular adjustments during postexercise circulatory occlusion (OCCL). METHOD: Heart rate (HR), mean arterial pressure (MAP), left ventricular end-diastolic (EDV) and end-systolic volumes (ESV), stroke volume (SV), cardiac output (CO), and total peripheral vascular resistance (total peripheral resistance (TPR)) were assessed in nine healthy volunteers during rest and static exercise at 30% of maximum voluntary contraction followed by either OCCL for 3 min or non-OCCL in a randomized crossover protocol. RESULTS: During handgrip, HR (+20%; P < 0.001), CO (+11%; P = 0.003), MAP (+18%; P = 0.001), and TPR (+6%; P = 0.004) increased, SV (-8%; P = 0.001) and EDV (-5%; P < 0.001) decreased, while ESV did not change (P > 0.05). These responses were similar between conditions (P > 0.05). During OCCL, HR, SV, and CO returned to baseline, whereas MAP (+19%; P < 0.001) and TPR (+9%; P = 0.004) remained elevated. EDV (+12%; P < 0.001) and ESV (+23%; P < 0.001) increased in parallel above resting values. CONCLUSION: Activation of muscle metaboreceptors during OCCL increased MAP by elevating TPR. Despite the higher afterload and increased ESV, CO and SV were kept similar to resting values because EDV also increased, implying the involvement of the Frank-Starling mechanism.

Serial thyroid function measurements in children with Hodgkin disease.

Thyroid function was measured serially in 28 children with Hodgkin disease diagnosed from 1971 to 1978. The patients' ages ranged from 4 to 16 years at diagnosis, and treatment consisted of chemotherapy only (four patients), radiation alone (15), or radiation plus chemotherapy (nine). None of the four children given chemotherapy only developed thyroid hypofunction, in contrast to 21 (88%) of the 24 children given high doses of radiation (P less than 0.001). Thyroid function in three patients with compensated hypothyroidism and in one child with primary hypothyroidism reverted to normal without thyroid replacement. One child given chemotherapy only and one child given radiation only became transiently hyperthyroid. These results indicate that patients given combined modality therapy for Hodgkin disease are at high risk for thyroid abnormalities. The results of long-term follow-up of thyroid function demonstrate, however, that all such thyroid abnormalities may not necessarily be permanent.

The development and standaridization of an ELISA method for the detection of Entamoeba histolytica antigens in fecal samples.

Recognizing the difficluties associated with the microscopic detection and identification of Entamoeba histolytica in fecal samples, an immunochemical method of detection of E. histolytica antigens in fe-es has been developed. For a number of reasons, e.g., the known fragility of E. histolytica trophozoites, it was felt that intestinal amebiasis would be associated with detectable levels of E. histolytica anti-ens in feces from infected patients. A technique for harvesting amebic antigens in fecal samples was developed. An enzyme labeled antibody technique was used to visualize the harvested antigens. The inherent problems of performing any immunochemical assay in fecal samples have been addressed. The enzyme labeled antibody method is simple and is designed to be more sensitive than microscopic stool examination methods. Preliminary results indicate that the method is specific and sensitive.