Osteological evidence for smallpox: a possible case from seventeenth century Ontario

Identification of possible osteomyelitis variolosa in a Neutral Indian cemetery dated to just before A.D. 1650 provides the first recognition of smallpox in an archaeological context. The radiological literature is reviewed to support the identification. The ethnohistorical literature is at odds with the evidence presented and the historical background is briefly discussed, together with the ambiguities and contradictions in both primary and secondary sources.     

Changes in osteoarthritis associated with the development of a maritime economy among southern California Indians

The severity of osteoarthritis was studied in human skeletal remains from archaeological sites in the Santa Barbara Channel area of southern California. These remains were analyzed to better understand changes in activity patterns associated with the economic shift from hunting and gathering to intensive fishing and craft specialization that occurred in this area. The joints of 967 burials from seven archaeological sites occupied between 3500 B.C. and the time of European contact were scored for osteoarthritis. These data show that the rate at which people developed osteoarthritis increased through time. This suggests that the adaptive shift toward more intensive exploitation of the marine environment resulted in an increase in the time people spent in strenuous physical activity. The increase in osteoarthritis affected males to a greater extent than females. One interpretation of this is that the work load of men increased with the economic importance of fishing.     

Enterobacter cloacae SLD1a-1 gains a selective advantage from selenate reduction when growing in nitrate-depleted anaerobic environments

Enterobacter cloacae SLD1a-1 is capable of the complete reduction of selenate to selenium and the initial reaction is catalysed by a membrane-bound selenate reductase. In the present study, continuous culture experiments were employed to investigate the possibility that selenate reduction, via the selenate reductase, might provide sufficient energy to maintain cell viability when deprived of the preferred anaerobic terminal electron acceptor nitrate. The evidence presented indicates that the selenate reductase supports slow growth that retards the wash-out of the culture when switching to nitrate-depleted selenate-rich medium, and provides a proton motive force for sustained cell maintenance. In contrast, a strain of E. cloacae (sub sp. cloacae) that does not readily reduce selenate, cannot sustain cell maintenance when switching to a selenate-rich medium. This work demonstrates for the first time that respiratory linked selenate reduction gives E. cloacae SLD1a-1 a selective advantage when inhabiting selenate-contaminated environments and highlights the suitability of utilising E. cloacae SLD1a-1 when developing selenium remediation strategies.     

Bartter's syndrome associated with indirect hyperbilirubinemia: a possible clinical variety

This report deals with three cases of Bartter's syndrome whose symptomatology was associated with indirect hyperbilirubinemia. The bilirubin disorder was suggestive of Gilbert's syndrome, with no pathological findings being detected as far as the liver function was concerned. Furthermore, the unconjugated fraction of bilirubin increased after fasting. The therapy with indomethacin exerted beneficial effects on both electrolytes and bilirubin disorders, and the patients recovered a good healthy state. These findings suggest the possibility that Bartter's syndrome may coexist in a variety associated with indirect hyperbilirubinemia.     

Efficient class I major histocompatibility complex down-regulation by simian immunodeficiency virus Nef is associated with a strong selective advantage in infected rhesus macaques

Substitution of Y223F disrupts the ability of simian immunodeficiency virus (SIV) Nef to down-modulate major histocompatibility complex (MHC) class I from the cell surface but has no effect on other Nef functions, such as down-regulation of CD4, CD28, and CD3 cell surface expression or stimulation of viral replication and enhancement of virion infectivity. Inoculation of three rhesus macaques with the SIVmac239 Y223F-Nef variant revealed that this point mutation consistently reverts and that Nef activity in MHC class I down-modulation is fully restored within 4 weeks after infection. Our results demonstrate a strong selective pressure for a tyrosine at amino acid position 223 in SIV Nef, and they constitute evidence that Nef-mediated MHC class I down-regulation provides a selective advantage for viral replication in vivo.     

Type 2 diabetes in non-obese Indian subjects is associated with reduced leptin levels: Study from Mumbai, Western India

Objective: Asian Indian subjects have a high tendency to develop Type 2 diabetes even though obesity is relatively uncommon. We evaluated the serum leptin levels in a group of non-obese Type 2 diabetic patients from Mumbai, Western India.Design: Cross sectional study.Methods: A total of 104 subjects consisting of 28 with Type 2 diabetes, 16 with impaired glucose tolerance and 60 age and sex-matched control subjects were given 75 g oral glucose tolerance test. Fasting serum leptin (IRMA), insulin and C-peptide were measured along with fasting and 2 h plasma glucose. The relation between these variables was studied by univariate and multiple regression analysis.Results: Type 2 diabetes was associated with marked (50–60%) reduction in serum leptin levels, in both men and women. Women, but not men, with impaired glucose tolerance exhibited 60% lower leptin. Serum leptin levels were positively correlated to body mass index (BMI; r = 0.501, p = 0.001) and calculated body fat percent (r = 0.525, p = 0.001) in all the study subjects with a better correlation in the normal subjects (r = 0.562 for BMI and 0.735 for body fat). On the other hand, serum leptin showed significant correlation to serum insulin (r = 0.362, p = 0.008) only in subjects with diabetes or IGT. In the multiple regression model, BMI was the only independent predictor of leptin, in all the subjects. However, in subjects with diabetes or impaired glucose tolerance, waist circumference (p = 0.003), gender (p = 0.007) and body fat (p = 0.009) were significant predictors of leptin, besides BMI. Gender-specific multiple regression revealed serum insulin as an independent predictor of leptin in men (p = 0.026). Therefore, lower serum leptin levels in diabetes is partly due to increased waist circumference, decreased BMI and male sex. These observations are consistent with the view that leptin levels in this cohort of non-obese Indians from Mumbai exhibit gender-specific relationship partly attributed to changes in serum insulin and waist circumference in men and to changes in BMI, in women.     

ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells

ICOS is expressed on activated T cells and particularly on CXCR5+ follicular Th cells in germinal centers (GC). Its deletion leads to a profound deficiency in memory B cell formation and switched Ab response in humans. Here, we show that in ICOS-deficient patients the generation of GCs is severely disturbed, and the numbers of circulating CXCR5+CD45RO+ memory CD4 T cells are significantly reduced, indicating an essential role of ICOS in the differentiation of CXCR5+CD4 T cells. The GC-specific CD57+CXCR5+ subpopulation is virtually absent. In ICOS-/- mice, the decrease of circulating CXCR5+CD4 T cells reflects the reduction of CXCR5+ follicular Th cells in lymph nodes and spleen. Therefore, in concurrence with the absence of CXCR5+ T cells in the blood of CD40L-deficient patients, these data support the hypothesis that circulating CD57+CXCR5+ T cells are GC derived and thus may serve as a surrogate marker for the presence of functional GCs in humans.     

Adverse effects associated with selective serotonin reuptake inhibitors and tricyclic antidepressants: a meta-analysis

BACKGROUND: The use of antidepressant medications and the resulting costs have increased dramatically in recent years, partly because of the introduction of selective serotonin reuptake inhibitors (SSRIs). An assessment of the clinical and economic aspects of SSRIs compared with the older tricyclic antidepressants (TCAs) was initiated to generate information for purchasers of these drugs as well as clinicians. One component of this study was an examination of the adverse effects associated with the use of these drugs. METHODS: Searches of bibliographic databases (for January 1980 through May 1996) and manual scanning of both peer-reviewed publications and other documents were used to identify double-blind, randomized controlled trials involving at least one SSRI and one TCA. For the study of adverse effects, only trials that had at least 20 patients in each trial arm and that reported rates of adverse effects in both arms were retained. In total 84 trials reporting on 18 adverse effects were available. Meta-analyses were undertaken to calculate pooled differences in rates of adverse effects. The question of whether the method of eliciting information from patients about adverse effects made a difference in the findings was also examined. Finally, differences in drop-out rates due to adverse effects were calculated. RESULTS: The crude rates of occurrence of adverse effects ranged from 4% (palpitations) to 26% (nausea) for SSRIs and from 4% (diarrhea) to 27% (dry mouth) for TCAs. The differences in the rates of adverse effects between the 2 types of drugs ranged from 14% more with SSRIs (for nausea) to 11% more with TCAs (for constipation). The results did not depend on the method of eliciting information from patients. There were no statistically significant differences between drug classes in terms of drop-outs due to adverse effects. INTERPRETATION: SSRIs and TCAs are both associated with adverse effects, although the key effects differ between the drug classes. Further explanation of the adverse effects and their relation to discontinuation of medication will require better studies involving prospective collection of quality-of-life data.     

Transient reduction of 5-methylcytosine and 5-hydroxymethylcytosine is associated with active DNA demethylation during regeneration of zebrafish fin

Although dedifferentiation, transformation of differentiated cells into progenitor cells, is a critical step in the regeneration of amphibians and fish, the molecular mechanisms underlying this process, including epigenetic changes, remain unclear. Dot blot assays and immunohistochemical analyses revealed that, during regeneration of zebrafish fin, the levels of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) are transiently reduced in blastema cells and cells adjacent to the amputation plane at 30 h post-amputation (hpa), and the level of 5mC, but not 5hmC, is almost restored by 72 hpa. We observed that the dedifferentiated cells showed reduced levels of 5mC and 5hmC independent of cell proliferation by 24 hpa. Furthermore, expressions of the proposed demethylation- and DNA repair-related genes were detected during fin regeneration. Taken together, our findings illustrate that the transient reduction of 5mC and 5hmC in dedifferentiated cells is associated with active demethylation during regeneration of zebrafish fin.     

Remarkably fast and selective aromatization of Hantzsch esters with MoOCl4 and MoCl5: a chemical model for possible biologically relevant properties of molybdenum-containing enzymes

Mo(VI) and Mo(V) salts both react selectively with Hantzsch esters to produce substitute pyridines in good-to-excellent yield (75-99%). The remarkable reactivity and selectivity of MoOCl(4) under reflux of acetonitrile and MoCl(5) in dichloromethane at room temperature encouraged us to propose that molybdenum-containing enzymes (such as xanthine or aldehyde oxidase) also participate to some degree in the metabolism of 1,4-dihydropyridine drugs in the liver analogous to NADH in the respiratory chain.     

Dopamine-dependent cytotoxicity of tetrahydrobiopterin: a possible mechanism for selective neurodegeneration in Parkinson's disease

Parkinson's disease is a neurodegenerative disorder associated with selective loss of dopaminergic neurons in the substantia nigra. While the underlying cause of this cell death is poorly understood, oxidative stress is thought to play a role. We have previously shown that tetrahydrobiopterin (BH4), an obligatory co-factor for tyrosine hydroxylase (TH), exerts selective toxicity on dopamine-producing cells and that this is prevented by antioxidants. This study shows that BH4-induced dopaminergic cell death is primarily mediated by dopamine, evidenced by findings that (i) BH4 toxicity is increased in proportion to cellular dopamine content; (ii) non-dopaminergic cells become susceptible to BH4 upon exposure to dopamine; and (iii) depletion of dopamine attenuates BH4 toxicity in dopamine-producing cells. BH4 causes lipid peroxidation, suggesting involvement of oxidative stress but the toxicity does not require enzymatic oxidation of dopamine. Instead, it seems to involve formation of quinone product(s) because (i) the cell death is attenuated by exposure to or induction of quinone reductase and (ii) BH4-treated cells show increased formation of protein-bound quinones, which is inhibited by thiol antioxidants. These data taken together suggest that the presence of both BH4 and dopamine is important in rendering dopaminergic cells vulnerable and that this involves formation of reactive dopamine quinone products.     

Evidence of gene conversion associated with a selective sweep in Drosophila melanogaster

Since Drosophila melanogaster colonized Europe from tropical Africa 10 to 15 thousand years ago, it is expected that adaptation has played a major role in this species in recent times. A previously conducted multilocus scan of noncoding DNA sequences on the X chromosome in an ancestral and a derived population of D. melanogaster revealed that some loci have been affected by directional selection in the European population. We investigated if the pattern of DNA sequence polymorphism in a region surrounding one of these loci can be explained by a hitchhiking event. We found strong evidence that the studied region around the gene unc-119 was shaped by a recent selective sweep, including a valley of reduced heterozygosity of 83.4 kb, a skew in the frequency spectrum, and significant linkage disequilibrium on one side of the valley. This region, however, was interrupted by gene conversion events leading to a strong haplotype structure in the center of the valley of reduced variation.     

Functional polymorphisms of HSPA5: possible association with bipolar disorder

Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 (GRP78/BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar trio samples (NIMH trios), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH trios, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder.     

The use of nonmetric variation in estimating human population admixture: a test case with Brazilian blacks, whites, and mulattos

Measurements in populations which serve as valid indicators of biological relationship should be proportional to genetic distance. In order to test the utility of discrete cranial traits for estimating genetic distances among populations, estimates of admixture are obtained for gene frequency data and nonmetric cranial data in São Paulo mulattos (M). The gene frequency data serve as a control that the three populations are related as stated: estimates of admixture are obtained by using São Paulo whites (W) and blacks (B) as parental populations and by estimating the parameter of admixture, m, in the model p_M = (1 ? m) p_W + mp_B (Elston, 1971) where the p's are either gene frequencies or nonmetric trait frequencies. A test of goodness of fit of the model provides a means of ascertaining whether or not the data fit this linear model. While the gene frequency data indicate distances among the three populations which are highly compatible with the linear model of admixture, the nonmetric data show significant deviations from the model. This implies that the frequencies of the nonmetric traits in the populations used in this analysis are not a linear function of genetic distance. This discourages the use of nonmetric traits in making quantitative conclusions about genetic relationships. It also suggests the need for investigation of the use of other skeletal characters for estimating genetic distance, as well as approaches for such investigations through the study of hybrid individuals.     

Phosphotransferase activity associated with rat osseous plate alkaline phosphatase: a possible role in biomineralization.

1. Alkaline phosphatase from rat osseous plate catalyzed the transfer of phosphate from p-nitrophenylphosphate to glycerol, ethanolamines, Tris, glucose and 1-amino-1-methyl-2-propanol, in a wide range of pH. Serine did not stimulate phosphotransferase activity of the enzyme. 2. The best phosphotransferase acceptors were diethanolamine and glycerol while glucose was the poorest phosphotransferase acceptor used. 3. Diethanolamine and glycerol affected both VM and KM of p-nitrophenylphosphate hydrolysis with activation constants (KA) of 0.25 and 0.85 M, respectively. 4. A kinetic model was proposed for the phosphotransferase reaction observed with alkaline phosphatase from rat osseous plates.     

Reduced sexual dimorphism in upper arm muscle circumference associated with protein-deficient diet in a South American population

Animal experiments have demonstrated that individuals exhibit differing tendencies to arrest growth and resorb muscle tissue under nutritional stress. Since placental and adrenocortical hormones are active in promoting muscle tissue resorption, sex differences may exist. In order to identify such sex differences, the upper arm circumferences of 362 individuals, aged one to 60 years, living in an area of chronic protein-calorie malnutrition were compared by age and sex with published data collected from U.S. and highland Peruvian populations. Sexual dimorphism for arm muscle circumference in the malnourished population is less than in U.S. samples of comparable age-categories. The highland population is closer to U.S. samples in the degree of dimorphism. The reduction in muscle circumference of males in the malnourished population appears to be the cause of the comparatively greater similarity of the sexes where protein-calorie malnutrition is experienced from infancy through adolescence. High muscle relief and excellent tonus in these same males indicate that reduced muscle circumference is not the result of flaccidity or higher ratios of compressible fat to muscle tissue. Reduction of muscle tissue in undernourished males is a reduction in total metabolic demand. Such reductions are adaptive in areas of chronic nutritional stress.     

The importance of sulfate reduction associated with Ulva lactuca thalli during decomposition: a mesocosm experiment

The decay of the macroalga Ulva lactuca was followed for 54 days in a controlled laboratory experiment. The experiment focused on the activity of sulfate reducers in different compartments (water, thalli and sediment) of the experimental system. In addition to sulfate reduction, the concentrations of sulfide, carbon dioxide, sulfate, carboxylic acids and pH were determined at regular intervals. Interestingly, 90% of the system-integrated sulfate reduction was carried out in the water column by thallus-associated sulfate reducers. The sediment accounted for about 10% of the integrated sulfate reduction activity, while sulfate reduction carried out by free-living sulfate reducers was insignificant and represented less than 1% of total sulfate reduction. Sulfate reduction rates in the water column were below the detection limit at the beginning of the experiment and were detected after 1 week of incubation. Sulfate reduction rates associated with thalli were measurable immediately after the experiment was started and increased very rapidly, reaching extremely high rates after 1 week of incubation. Sediment sulfate reduction rates had increased to twice the initial value by day 30 after which they remained constant. Thallus-associated sulfate reduction rates (SRR) were of the same level in all layers of the algal mat throughout the experiment. Our results indicate that sulfate-reducing bacteria were present on the thalli when the experiment was initiated and that the water column colonization by sulfate-reducing bacteria from the sediment was less important. This would explain the rapid accumulation of hydrogen sulfide in the water column during macroalgal decay events in coastal marine environments.     

The ankyrin repeat containing SOCS box protein 5: a novel protein associated with arteriogenesis

Arteriogenesis, the growth of pre-existing collateral arteries, can be induced in rabbit by occlusion of the femoral artery. In order to identify and characterize genes differentially expressed during the early phase of arteriogenesis, cDNA of collateral arteries 24h after femoral ligation or sham operation was subjected to suppression subtractive hybridization. We identified the ankyrin repeat containing SOCS box protein 5 (asb5) and cloned the rabbit full-length cDNA. Asb5 was demonstrated to be a single-copy gene. We localized the asb5 protein in vivo in endothelial and smooth muscle cells of collateral arteries as well as in satellite cells. Asb5 was significantly upregulated in growing collateral arteries on mRNA and protein level. The infusion of doxorubicin in rabbit led to a significant decrease of the asb5 mRNA. In summary, our data show that asb5 is a novel protein implicated in the initiation of arteriogenesis.     

Inhibition of human colon carcinoma cell growth by ammonia: a non-cytotoxic process associated with polyamine synthesis reduction

Ammonia, produced by bacterial degradation of unabsorbed and endogenous nitrogenous compounds, is found to be present at millimolar concentrations in the colon lumen. From in vivo animal experiments, this metabolite has been shown to alter colonic epithelial cell morphology and to increase compensatory cell proliferation when present in excess. In this in vitro study, using the human colon adenocarcinoma HT-29 Glc(-/+) cell line treated with increasing doses of NH(4)Cl, we found that 20 mM NH(4)Cl, a concentration close to that found in the large intestine lumen, was able to increase the volume of vacuolar lysosomes and to repress HT-29 Glc(-/+) cell proliferation. This growth-inhibitory effect was not correlated with decrease of cell viability, with modification of cell differentiation and change of the cell distribution in the different cell cycle phases, thus indicating a proportional slowdown in all cell cycle phases. In contrast to what is found in healthy colonocytes, ammonia was not metabolized by HT-29 cells into carbamoyl-phosphate (carbamoyl-P) and citrulline, indicating that ammonia was likely acting on cells by itself. This agent was shown to markedly reduce cellular ornithine decarboxylase (ODC) activity resulting in a threefold decrease in the capacity of HT-29 cells to synthetize polyamines, these latter metabolites being strictly necessary for cell growth. The unexpected finding that ammonia is acting as an antimitotic agent against tumoral HT-29 colonic cells may be related to the inability of these cells to metabolize this compound.