Trypsin inhibition by tapeworms: antienzyme secretion or pH adjustment?

The tapeworm Hymenolepis diminuta releases proteins that inhibit trypsin activity. These proteins may be either antienzymes or nonspecific macromolecules that interfere with trypsin. Saline solutions with initial pH values ranging from 5.5 to 10.0 were all acidified to pH 5.0 by tapeworms. If the initial pH was lower than 5.0, it was raised. Because trypsin activity is inhibited at pH 5.0, this intestinal parasite can protect itself from digestion by regulating its environmental pH or releasing trypsin inhibitors, or both.

Hatching of amphibian embryos: the physiological trigger.

Marbled salamander embryos hatch in water if the environmental oxygen pressure is 86 torr or less, but do not hatch if the environmental oxygen pressure is equivalent to that of air. Under hypoxic conditions, embryos hatch in aqueous and nonaqueous media with equal success. Increasing carbon dioxide pressure does not induce hatching, but does decrease the time to hatching by altering environmental pH.

Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk.

We analyzed the polymorphic (CAG)n and (GGN)n regions within the androgen receptor gene from participants in a population-based case-control study of prostate cancer in middle-aged (40-64 years) Caucasian men. The associations between repeat lengths and risk of prostate cancer and the effects of confounding and modifying factors, such as age, family history of prostate cancer, and body mass index, were evaluated. DNA was available for 301 cases and 277 controls. The overall age-adjusted relative odds of prostate cancer associated with the number of (CAG) repeats as a continuous variable was 0.97 [95% confidence interval (CI), 0.92-1.03], suggesting a 3% decrease in risk of prostate cancer for each additional (CAG) repeat. Further analyses identified several subgroups at increased risk. These were men with less than the median number of CAG repeats (< 22) that were younger [< 60 years; relative odds (RO), 1.47; 95% CI, 0.96-2.25], had an affected first-degree relative (RO, 1.59; 95% CI, 0.62-4.14), or were relatively thin (Quetelet index < 24.4; RO, 2.21; 95% CI, 1.07-4.69). Although only the latter result was statistically significant, these results are provocative and support the hypothesis that (CAG)n array length is a predictor of risk for prostate cancer. Similar analyses of (GGN)n showed that with the exception of men with a family history of prostate cancer and those in the highest quartile of body mass index, men with < or = 16 repeats had higher risk estimates than did men with > 16 repeats. Overall, those men who had < or = 16 repeats had a significant elevation in risk (RO, 1.60; 95% CI, 1.07-2.41). When both repeat lengths were considered jointly, the subgroup with two short repeats (CAG, < 22; GGN, < or = 16) had a 2-fold elevation in odds (RO, 2.05; 95% CI, 1.09-3.84) relative to those with two long repeats (CAG, > or = 22; GGN, > 16). These data suggest that determination of both androgen receptor repeats within germ-line DNA may be useful in assessing an individual's risk of developing prostate cancer.

Genetic predisposition to HIV-1 infection and acquired immune deficiency virus syndrome: a review of the literature examining associations with HLA [corrected].

Researchers have been studying the relationship between host HLA type and the immune response to HIV-1 since early in the AIDS epidemic. Although the literature is replete with suggestions of an association, the exact locus and nature is unclear. This article reviews the current HLA-HIV/AIDS literature, providing a complete summary of all significant associations reported in journal articles (N = 30) between 1982 and 1993. Consistent associations with alleles comprising the haplotype DQ2-DR3-B8-Cw7-A1 and AIDS progression support a genetic component in AIDS progression. DQ1-DR1-B35-Cw4-A11 and DR5 also show consistent associations with HIV/AIDS outcomes, although it is unclear whether they are measuring susceptibility to HIV-1 infection, AIDS progression, or both. The question of whether HLA influences susceptibility to HIV-1 infection remains unanswered, as well-designed studies addressing this topic are lacking. Similarly, further studies are needed to clarify if HLA type is associated with KS. Several issues that complicate across-study comparisons are discussed including heterogeneity of both HLA and AIDS, potential confounding by race or risk group, and other biases which may influence results. In addition, several proposed biologic mechanisms are explored.

A quantitative analysis of plasma osmotic pressure during metamorphosis of the bullfrog, Rana catesbeiana.

The plasma constituents contributing to osmotic pressure are, in decreasing order: Na+, Cl-, HCO3-, K+, glucose, amino acids, urea and protein. Plasma osmotic pressure increases from 180 mmoles/1 to 200 mmoles/1 throughout development.

African-American HLA class II allele and haplotype diversity.

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB1*1501) and some haplotypes of DRB1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.

African-American HLA class II allele and haplotype diversity.

Molecular genetic techniques were used to type nine loci in the HLA class II region in 241 unrelated African-Americans from New York City (NYC). Several effects attributable to recent genetic admixture were evident: the number of distinct class II alleles and haplotypes was larger in the African-Americans than in people of African or European origin, the allele frequencies were more consistently even, and linkage disequilibrium was present across the entire class II region. The African-American DRB1 allele frequencies almost always fell between frequencies among samples from northern Europe and the Gambia, two possible founding populations. The exceptions are attributed to the contribution of other genetically dissimilar African groups to the African-American gene pool. DRB1 allele frequencies (specifically DRB1*1501) and some haplotypes of DRB1-DPB1 were different in our NYC and the 11th International Histocompatibility Workshop (IHW) samples of African-Americans. The high level of allele and haplotype diversity found in African-Americans has important implications for the construction of pools of unrelated potential donors for tissue transplantation.

CCR5del32 in perinatal HIV-1 infection.

CCR5, a chemokine receptor, serves as a coreceptor for macrophage-tropic HIV-1 (1-3). A 32-bp deletion within the gene encoding CCR5, CCR5del32, has been shown to prevent HIV-1 infection of T cells in the absence of a wild-type allele. This alteration is present in low frequency in Caucasian populations (4-6). To investigate the effect of CCR5del32 in perinatal HIV-1 transmission and disease progression, two cohorts of perinatally exposed infected and uninfected children were analyzed for the presence of the allele. Polymerase chain reaction (PCR) was used to identify CCR5del32 in prevalent and prospective cases among 144 African American children from New York City and 73 Caucasian children from Barcelona, Spain. HIV-1 transmission; clinical manifestations of disease, including encephalopathy, opportunistic infections, and death before 2 years of age; survival; Centers for Disease Control and Prevention (CDC) classification; and degree of immunosuppression were compared in children with and without CCR5del32. The allele frequency in HIV-1-infected African Americans (0.016) was lower than in Catalan children (0.041). No evidence for a dominant protective effect of CCR5del32 for HIV-1 transmission or disease progression was found in these cohorts.

Influence of host genotype on progression to acquired immunodeficiency syndrome among children infected with human immunodeficiency virus type 1.

OBJECTIVE: To study the role of host genotype in pediatric infection with human immunodeficiency virus type 1 (HIV-1) and progression to acquired immunodeficiency syndrome (AIDS). METHODS: Human leukocyte antigen (HLA) class II and complement C4 genotypes were determined by means of molecular genetic techniques for 243 black children born to HIV-1-infected mothers in New York City and San Francisco. Survival, cumulative incidences of opportunistic infections and encephalopathy, and rates of CD4+ T cell decline were compared in children of different genotypes. RESULTS: Among HIV-1-infected children, the HLA-DR3 haplotype (DRB1*0301-DQA1*0501-DQB1*0201) was associated with increased incidence of encephalopathy, faster rate of CD4+ cell decline, and death before 2 years of age. Deletion of the C4A gene was independently associated with increased incidences of encephalopathy and early death. DPB1*0101 was associated with survival to at least 2 years of age. The presence of DQB1*0604 was associated with increased risk of HIV infection. CONCLUSIONS: These results are consistent with previously reported associations between HLA genotypes and faster progression to AIDS among HIV-infected adults. The DR3 haplotype and C4A deletion may reflect the same underlying mechanism of susceptibility in that the DR3 haplotype is in linkage disequilibrium with other C4A null alleles. In addition, the class II locus DPB1 may have an independent effect on survival.

MHC class II alleles associated with clinical and immunological manifestations of HIV-1 infection among children in Catalonia, Spain.

Children with perinatally-acquired HIV-1 infection were studied to determine if major histocompatibility complex (MHC) genes are involved in progression to pediatric AIDS. Molecular genetic techniques were used to genotype loci in the class II region (DRB1, DQA1, DQB1, DPA1, DPB1, LMP2 and LMP7). HIV-infected children were classified by clinical manifestations and degree of immunosuppression using age-specific CD4 T-lymphocyte counts at enrollment. Alleles at the DPB1 and DQB1 loci showed independent and opposite associations; DPB1*0301 showed a trend toward protection while DQB1*0201 appeared to be a risk factor for developing severe immunosuppression and severe clinical outcomes. Presence of DQB1*0201 conferred a greater than 10-fold increased odds of having severe clinical manifestations and a 2.8-fold increased odds of severe immunosuppression. Presence of DPB1*0301 was associated with a greater than 8-fold decreased odds of severe immunosuppression and severe clinical manifestations. These results support host genetic influences on HIV-1 outcomes in children.

Hardy-Weinberg testing for HLA class II (DRB1, DQA1, DQB1, and DPB1) loci in 26 human ethnic groups.

Testing the fit of population data to Hardy-Weinberg proportions is crucial in the validation of many current approaches in population genetic studies. In this paper, we tested fit to Hardy-Weinberg proportions using exact approaches for both the overall and individual heterozygote genotype data of four HLA Class II loci: DRB1, DQA1, DQB1, and DPB1, from 26 human populations. Eighty of 99 overall tests fit the Hardy-Weinberg expectation (73% for DRB1, 89% for DQA1, 81% for DQB1 and 81% for DPB1). Deviations from Hardy-Weinberg proportions were both locus and group specific. Although we could not rule out other mechanisms at work, the individual test results indicated that the departure was possibly partly due to recent admixture. Evidence for selection and other sources of deviation are also discussed.