A series of potent HIV-1 protease inhibitors containing a hydroxyethyl secondary amine transition state isostere: synthesis, enzyme inhibition, and antiviral activity.

A series of HIV-1 protease inhibitors containing a novel hydroxyethyl secondary amine transition state isostere has been synthesized. The compounds exhibit a strong preference for the (R) stereochemistry at the transition state hydroxyl group. Molecular modeling studies with the prototype compound 11 have provided important insights into the structural requirements for good inhibitor-active site binding interaction. N-Terminal extension of 11 into the P2-P3 region led to the discovery of 19, the most potent enzyme inhibitor in the series (IC50 = 5.4 nM). 19 was shown to have potent antiviral activity in cultured MT-4 human T-lymphoid cells. Comparison of analogs of 19 with analogs of 1 (Ro31-8959) demonstrates that considerably different structure-activity relationships exist between these two subclasses of hydroxyethylamine HIV-protease inhibitors.     

The Durability of Laparoscopic Nissen Fundoplication: 11-Year Outcomes

Laparoscopic Nissen fundoplication (LNF) has become the most commonly performed antireflux procedure since its introduction in 1991. There are few studies with greater than 5-year outcomes. Herein we report a series of 312 consecutive patients who underwent primary LNF before 1996. Follow-up of more than 6 years was available in 166 patients, and the mean follow-up was 11 years (median 11.1 years, range 6.1–13.3 years). Prospective data collection included preoperative and current symptom scores (scale 0 = none to 3 = severe), as well as the level of patient satisfaction and use of antireflux medications. Total symptom score for each patient was summed from seven symptoms for a maximum value of 21. Heartburn and regurgitation were the most improved symptoms; however, all symptoms were significantly improved (P < 0.01). The total symptom score at follow-up was 2.6 down from 7.5 at baseline, with a mean difference of −4.9 (range −12 to 3). The percentage of patients stating they would have the procedure again was 93.3%, and 70% were off daily antireflux medications. Outcomes at a mean of 11 years after LNF are excellent, and the majority of patients had their symptoms resolved or significantly improved and are satisfied with their results. Presented at the 47th Annual Meeting of the Society for Surgery of the Alimentary Tract, May 22, 2006, Los Angeles, CA     

Changing perspectives in children hospitalized with poststreptococcal acute glomerulonephritis

Changing perspectives in 95 children with poststreptococcal acute glomerulonephritis (PSAGN) in our hospital between 1979 and 1988 are reported. Between 1961 and 1970 an average of 31±6.3 patients/year with PSAGN were treated and 70% had antecedent pyoderma. In the present study antecedent pharyngitis was observed in 59 children und pyoderma in 36. In comparison to the decade ending in 1970 our data show: (1) a marked decline in the prevalence of PSAGN (P=<0.0005), (2) a predominance of antecedent pharyngeal infection (P=0.044), (3) a decline in urban and an increase in rural patients with PSAGN (P=0.0483); and in the last decade: (1) a predominance of antecedent pharyngeal infection in children over 6 years of age (P=0.0009) and (2) a predominance of antecedent pyoderma in black children (P=0.0004).     

HLA-A9 antibodies and epitopes

Fifty pregnancy alloantisera directed towards HLA-A23 and/or A24 antigens were investigated serologically in titration studies against the three sequenced HLA-A9 specificities, A23 (A*2301), A24 (A*2402) and A2403 (A*2403). The reaction patterns of the antisera fell into five categories which allowed the three HLA-A9 specificities to be easily differentiated. Based on the various titre cytotoxicity scores of the antisera five possible antibody specificities were defined: anti-A23; -A24; -A23/24; -A24/2403 and anti-A23/24/2403. One antiserum crossreacted with HLA-A1 and A24. Inspection of the amino acid sequences of 136 HLA-A, B and C molecules allowed the prediction of five unique epitopes corresponding to these antibody specificities, a possible epitope unique to A2403 and confirmation of a likely epitope shared by A1 and A24. These, together with the previously suggested epitopes HLA-A9/ A2/A28 and A1/A23/A24 together with the presence of Bw4 on the three HLA-A9 antigens suggests that the HLA-A9 family of antigens is characterized by a minimum of nine serologically definable epitopes.     

Systemic endotheliomatosis: a case report.

A 48-year-old Caucasian man was found to have a rare neoplastic process of vascular endothelial origin. The clinical presentation was that of plum-colored cutaneous plaques of the lower extremities. The histopathology, natural history, and treatment of this case are discussed and compared with previously reported cases. It is suggested that this disease entity represents a malignant state with systemic involvement and a poor prognosis.     

Prognostic Significance of p27, Ki-67, and Topoisomerase lla Expression in Clinically Nonfunctioning Pancreatic Endocrine Tumors

Nonfunctioning islet cell tumors or pancreatic endocrine tumors are the most common type of malignant islet cell tumor. Although previously detected usually at an advanced stage because of mass effect, the early detection rate of small localized disease has been increasing. To date it has been difficult to predict the clinical behavior in localized regional nonfunctioning tumors. To investigate potential markers predicting malignancy and poor prognosis in nonfunctioning pancreatic endocrine tumors, we analyzed the expression of Ki-67, topoisomerase IIα (Topollα), and p27, as well as a variety of clinicopathologic parameters in 76 cases of nonfunctioning islet cell tumors (23 benign cases and 53 malignant cases). Ki-67, Topollα, and p27 labeling indices were significantly different between benign and malignant tumors. Expression of Ki-67, Topollα, and p27 were associated with survival in patients with a malignant tumor in a univariate setting. However, only p27 and Topollα were jointly associated with survival in multivariate analysis. Immunohistochemical staining for p27, Topollα, and Ki-67 can be helpful in the diagnosis of nonfunctioning pancreatic endocrine tumor. Analysis of p27 and Topollα may also have potential utility as prognostic factors for malignant tumors.     

Extinction of the human leukocyte antigen homozygosity effect after two doses of the measles-mumps-rubella vaccine

We have reported associations between human leukocyte antigen (HLA) homozygosity and low measles antibody levels after one dose of the measles, mumps, and rubella (MMR) vaccine. Here, we examined associations between HLA homozygosity and immune responses to MMR after two doses of vaccine. We examined associations between HLA homozygosity and measles antibody levels in a group of 178 children (cohort 1) as well as associations between homozygosity and antibody levels and lymphoproliferative responses to MMR in 346 children (cohort 2). In cohort 1, HLA homozygotes and heterozygotes had similar increases in measles antibody levels after a second dose of measles vaccine. In cohort 2, HLA homozygosity was not associated with measles immune measures after two doses of vaccine. Homozygosity at the DPB locus was associated with increased rubella antibody levels, and homozygosity at the class IA alleles was associated with lower mumps lymphoproliferative response. Homozygosity at increasing numbers of loci was also associated with lower mumps antibody levels and lymphoproliferative response. Therefore, two doses of the MMR vaccine appear to induce sufficient antibody levels and lymphoproliferative responses against measles and rubella, regardless of HLA homozygosity status. However, children who are HLA homozygous may be less protected against mumps compared with children who are heterozygous.