The G glycoprotein of human respiratory syncytial viruses of subgroups A and B: extensive sequence divergence between antigenically related proteins.

Two major antigenic subgroups (designated A and B) have been described for human respiratory syncytial virus (RSV). Previously, on the basis of reactivity patterns with monoclonal antibodies, the greatest intersubgroup variation was shown to occur in the G protein, the putative attachment glycoprotein. To delineate the molecular basis for this variation, we have determined the nucleotide and deduced amino acid sequences of the G mRNAs and proteins representing a subgroup A (Long strain) and a subgroup B (18537 strain) virus. These sequences were compared to the available G mRNA sequence for another subgroup A (A2 strain) virus. The Long G protein shared 94% amino acid identity with the A2 G protein. In contrast, the 18537 G protein shared only 53% amino acid identity with the A2 sequence; interestingly, most of the sequence divergence occurred in the proposed extracellular domain of the G protein. This extensive divergence for the G protein was significantly greater than that observed for other RSV proteins. Despite this considerable divarication, the proposed extracellular domains of the G proteins contained a single region of highly conserved sequence and secondary structure that may represent a conserved structural or function domain, perhaps involved in attachment to cellular receptors. Furthermore, this conserved region may comprise part of an epitope that is shared between the two subgroup G proteins and may significantly contribute to the fact that, despite extensive overall amino acid sequence divergence, the RSV G proteins maintain significant antigenic relatedness.     

HLA class II alleles in Chinese patients with hepatocellular carcinoma

BACKGROUND/AIMS: Recent reports of an association between human leucocyte antigens (HLA) and persistence of hepatitis B virus infection, and the familial clustering of hepatocellular carcinoma raise the question of genetic susceptibility. Previous studies have been limited to serological phenotyping of HLA B and DR antigens. The aim of this study was to use molecular genotyping to investigate HLA class II as a risk factor for the development of hepatocellular carcinoma in Hong Kong Chinese. METHODS: We determined HLA DRB1, DQA1, DQB1 and DPB1 alleles in 123 hepatitis B surface antigen positive patients (84 with hepatocellular carcinoma and 39 without) and 124 matched controls. RESULTS: The alleles DRB1*1501 (36% of HCC patients versus 19% of controls, odds ratio=2.44), DQA1*0102 (42% versus 26%, odds ratio=2.07), and DPB1*0501 (80% versus 63%, odds ratio=2.35) were significantly more common in patients with hepatocellular carcinoma, and DQA1*03 (36% versus 56%, odds ratio=0.53), DQB1*0302 (4.% versus 13%, odds ratio=0.25) and DPB1*0201 (14% versus 29%, odds ratio=0.4) were found at significantly lower frequencies. CONCLUSIONS: Although none of these associations was significant after correction for multiple testing, this report suggests that further investigations are warranted.     

Genotype,serum level of hepatitis C virus RNA and liver histology as predictors of response to interferon-α 2α therapy in Japanese patients with chronic hepatitis C

Abstract: To determine whether pretreatment HCV-RNA level, hepatitis C virus genotypes, alanine aminotransferase and histology correlate with subsequent response to interferon-α therapy or not, serum HCV-RNA levels and genotype were determined by branched DNA signal amplification assay and genotype-specific polymerase chain reaction in 43 patients with chronic active hepatitis C. Response to recombinant interferon-α 2α (504 million units in total) was defined as complete and sustained CR→SR, n=12), complete response followed by relapse (CR→Rel, n=17), and no response (NR, n=10), excluding dropouts (n=4). Patients who showed CR→SR had a lower HCV-RNA level (0.438 × 10⁶ eq/ml) compared to CR→Rel (2.452 × 10⁶ eq/ml, p=0.008) and NR (4.882 × 10⁶ eq/ml, p=0.009). A higher proportion of patients with CR→SR had type 2a HCV (67%) compared to the CR→Rel (28%) and the NR (0%). There was a trend for type 1b hepatitis C virus infection to have higher serum HCV-RNA levels. There was no correlation between pretreatment HCV-RNA level and alanine aminotransferase. However, no relation between pretreatment HCV-RNA level and liver histology was observed; a high proportion of patients with CAH2a showed CR→SR, compared to those with CAH2b (p=0.001). Moreover, the patients with CAH2b who had low level hepatitis C virus viremia did not show CR→SR. These data indicate that pre-treatment serum HCV-RNA levels, genotype and liver histology are good predictors of subsequent response to interferon-α therapy in Japanese patients with chronic hepatitis C virus infection.     

Isolation of an additional member of the fibroblast growth factor receptor family, FGFR-3.

The fibroblast growth factors are a family of polypeptide growth factors involved in a variety of activities including mitogenesis, angiogenesis, and wound healing. Fibroblast growth factor receptors (FGFRs) have previously been identified in chicken, mouse, and human and have been shown to contain an extracellular domain with either two or three immunoglobulin-like domains, a transmembrane domain, and a cytoplasmic tyrosine kinase domain. We have isolated a human cDNA for another tyrosine kinase receptor that is highly homologous to the previously described FGFR. Expression of this receptor cDNA in COS cells directs the expression of a 125-kDa glycoprotein. We demonstrate that this cDNA encodes a biologically active receptor by showing that human acidic and basic fibroblast growth factors activate this receptor as measured by 45Ca2+ efflux assays. These data establish the existence of an additional member of the FGFR family that we have named FGFR-3.     

Release of prolactin in response to microinjection of morphine into mesencephalic dorsal raphe nucleus

Blood samples were collected via jugular catheters from ovariectomized rats at 10-min intervals for 1 h before and 2 h after microinjection of 0.5 microliter of either saline vehicle or morphine sulfate (10 micrograms) into the dorsal raphe nucleus (DRN) or adjacent periaqueductal gray by means of chronically-implanted guide cannulae. Prolactin was measured by radioimmunoassay, and mean preinjection and mean postinjection values were compared for each rat (t test) as well as for each treatment group (paired t test). Neither saline in DRN nor morphine in the surrounding periaqueductal gray significantly altered circulating prolactin. A significant rise in prolactin was observed following injection of morphine into DRN. This effect of morphine was prevented by pretreatment of the animals with the narcotic antagonist naltrexone (10 mg/kg i.v.), indicating the involvement of opiate receptors. These results indicate that DRN is one site at which systemically-administered morphine might act, and suggest the possibility of participation of this mechanism in modulation of prolactin release by endogenous opioids.     

Small-intestinal mucosa in pseudoobstruction syndromes

The purpose of this investigation was to determine the frequency and severity of small intestinal mucosal damage in pseudoobstruction syndromes. One hundred eighty-nine interpretable biopsies from 12 patients were blindly reviewed by two investigatiors. The underlying disorders were scleroderma in 7 and idiopathic intestinal pseudoobstruction in 5. All 12 had small-intestinal dilatation on small-bowel series. Eight of the 12 patients had biopsies characterized by moderate, to severe mucosal damage; 3 of these had some biopsies which were flat. The damage did not correlate with: (1) types and numbers of organisms recovered from small intestinal aspirates; (2) duration of illness; (3) degree of dilatation of the proximal small bowel; (4) concentrations of deconjugated bile salts in small intestinal fluid; or (5) amount of fat absorbed in fat-balance studies. We conclude that mucosal damage is common in pseudoobstruction syndromes. The pathogenesis of the damage and its relationship to intraluminal bacteria remain undefined.     

The natural history of Kaposi's sarcoma in the acquired immunodeficiency syndrome

Kaposi's sarcoma is a multifocal systemic neoplasm histologically characterized by proliferating fibroblastic and microvascular elements. Initial signs include macules, papules, or nodules on the skin or mucosal surface. Lesions are frequently found on the trunk, arms, and head and neck. In general, sites of involvement and tumor load do not correlate with prognosis. A general decrease in the functional capacities of T and B cells is found in most patients. Kaposi's sarcoma is reported as the initial manifestation of the acquired immunodeficiency syndrome (AIDS) in approximately 30% of cases. Most cases are in men, although it has been reported in all risk groups. Kaposi's sarcoma in AIDS is more frequent among whites and homosexuals than blacks and intravenous drug abusers. Overall mortality is approximately 41%, with over 60% of patients alive at 1 year and 50% at 22 months. Overall survival is 18 months; however, some patients who have had the disease for 3 to 4 years are still doing well.     

Analysis of CD34+ cell subsets in stem cell harvests can more reliably predict rapidity and durability of engraftment than total CD34+ cell dose, but steady state levels do not correlate with bone marrow reserve

In peripheral blood stem cell transplantation (PBSCT), the number of CD34+ cells transplanted has been shown to correlate well with both rapidity and durability of engraftment. However, it is clear that engraftment does not necessarily correlate with total CD34+ cell numbers in some patients. Consequently, there is increasing interest in evaluating the role of CD34+ subsets in haemopoietic recovery as a more accurate marker of harvest quality. We analysed the numbers of CD34+ cell subsets, namely Thy-1+, L-Selectin+ and CD38-, and correlated this with engraftment in 86 patients undergoing PBSCT. Adequate engraftment was defined as being a platelet count greater than 50 x 10(9)/l and a neutrophil count greater than 1.0 x 10(9)/l. CD34+L-Selectin+ provided the best prediction of engraftment rapidity, although the improvement over total CD34+ cell dose was minor. Only the dose of CD34+Thy-1+ cells transplanted correlated with durable engraftment. The probability of adequate 3-month engraftment increased with the dose of CD34+ cells transplanted, but 10% of patients receiving > 5 x 10(6)/kg still showed poor engraftment at 3 months. However, all patients receiving > 2.5 x 10(5)/kg CD34+Thy-1+ showed adequate engraftment at this time point. We also demonstrated that CD34+Thy-1+ progenitors were restricted to the bone marrow under normal conditions and, during stem cell mobilization, their kinetics generally paralleled total CD34+ numbers.