Prevention of diabetes complications in developing countries: time to intensify self-management education

The IDF report has indicated that about 80% of four million diabetes-related deaths that occur every year comes from the developing world. The IDF report suggests the need to focus more on preventing diabetes complications in poor countries. Thus, considering the economic constraints in combating the explosion of diabetes complications in the developing regions of the world, it appears that exploring culturally adaptable educational intervention programmes for specific regions would be the appropriate strategy. We believe that diabetes-related deaths could be reduced in developing countries through intensified diabetes self-management education.     

Risk-taking restraints in a bird with reduced egg-hatching success

Risk taking, as is any other phenotypic and/or behavioural trait, is determined by proximate constraints related to time or resource availability and by evolutionary adaptive restraints related to the differences in the costs of risk taking and its benefits in terms of fitness. Because risk taking is influenced by many confounding variables related to experimental design, environment, parents and offspring, few field studies have been reported which unambiguously separate the effects of restraints from those of constraints. We compared parental risk taking in blue tits (Parus caeruleus) during brood defence towards a nest predator in broods with experimentally reduced and natural egg-hatching success leaving the original number of eggs in the nest. The experimentally reduced broods had more time or resources available and lower risk-taking benefits compared to the control broods. 'Constraint' would predict more risk taking in broods having experimentally reduced egg-hatching success, whereas 'restraint' would predict the opposite effect with more risk taking in broods with natural egg-hatching success. We report, to our knowledge, the first field study experimentally demonstrating a brood defence restraint in response to reduced egg-hatching success. This demonstration was only possible after controlling for more than 20 potential confounding variables showing once more how complicated it is to separate proximate from evolutionary levels of analyses in natural populations.     

The position of lysosomes within the cell determines their luminal pH

We examined the luminal pH of individual lysosomes using quantitative ratiometric fluorescence microscopy and report an unappreciated heterogeneity: peripheral lysosomes are less acidic than juxtanuclear ones despite their comparable buffering capacity. An increased passive (leak) permeability to protons, together with reduced vacuolar H⁺–adenosine triphosphatase (V-ATPase) activity, accounts for the reduced acidifying ability of peripheral lysosomes. The altered composition of peripheral lysosomes is due, at least in part, to more limited access to material exported by the biosynthetic pathway. The balance between Rab7 and Arl8b determines the subcellular localization of lysosomes; more peripheral lysosomes have reduced Rab7 density. This in turn results in decreased recruitment of Rab-interacting lysosomal protein (RILP), an effector that regulates the recruitment and stability of the V1G1 component of the lysosomal V-ATPase. Deliberate margination of lysosomes is associated with reduced acidification and impaired proteolytic activity. The heterogeneity in lysosomal pH may be an indication of a broader functional versatility.     

Adeno-associated virus sensitizes HeLa cell tumors to gamma rays.

Infection with the helper virus-dependent human parvovirus adeno-associated virus (AAV) is known to interfere with cellular transformation in vitro and oncogenesis in vivo. Here we report on sensitization to gamma irradiation by AAV infection of cells in culture and of tumors established from HeLa cells grafted into immunodeficient (nude) mice: infection of HeLa cells with AAV type 2 enhanced cell killing and reduced plating efficiency after irradiation compared with uninfected cells. Similarly, HeLa cell tumors in nude mice displayed a reduced growth rate and were more sensitive to gamma irradiation when the animals were infected with AAV type 2 prior to or after tumor cell inoculation. Since no pathogenicity is known for AAV, the ability of this virus to render radiotherapy of human tumor cells more efficient may up open novel approaches in cancer treatment.     

Semen displacement as a sperm competition strategy

Using a sample of 652 college students, we examined several implications of the hypothesis that the shape of the human penis evolved to enable males to substitute their semen for those of their rivals. The incidence of double mating by females appears sufficient to make semen displacement adaptive (e.g., one in four females acknowledge infidelity, one in eight admit having sex with two or more males in a 24-hour period, and one in 12 report involvement in one or more sexual threesomes with two males). We also document several changes in post-ejaculatory behavior (e.g., reduced thrusting, penis withdrawal, loss of an erection) which may have evolved to minimize displacement of the male’s own semen. Consistent with predictions derived from a theoretical model (Gallup and Burch 2006), we discovered that most females report waiting at least 48 hours following an instance of infidelity before resuming sex with their in-pair partners.     

Effects of pH and fructose 2,6-bisphosphate on oxidized and reduced spinach chloroplastic fructose-1,6-bisphosphatase

This report describes the effects of pH and fructose 2,6-bisphosphate (an analog of fructose 1,6-bisphosphate) on the activity of oxidized and reduced fructose-1,6-bisphosphatase from spinach chloroplasts. Studies were carried out with either fructose 1,6-bisphosphate, the usual substrate, or sedoheptulose 1,7-bisphosphate, an alternative substrate. The reduction of the oxidized enzyme is achieved by a thiol/disulfide interchange. The pK values relative to each redox form for the same substrate (either fructose 1,6-bisphosphate or sedoheptulose 1,7-bisphosphate) are identical, suggesting the same site for both substrates on the active molecule. The finding that the analog (fructose 2,6-bisphosphate) behaves like a competitive inhibitor for both substrates also favours this hypothesis. The inhibitory effect of this sugar is more important when the enzyme is reduced than when it is oxidized. The shift in the optimum pH observed when [Mg2+] was raised is interpreted as a conformational change of oxidized enzyme demonstrated by a change in fluorescence. The reduced and oxidized forms have the same theoretical rates relative to both substrates, but the reduced form has an observed Vmax which is 60% of the theoretical Vmax while that of the oxidized form is only 37% of the theoretical Vmax. The reduced enzyme appears more efficient than the oxidized one in catalysis.     

Influence of dissolved oxygen concentration on intracellular pH for regulation of Aspergillus niger growth rate during citric acid fermentation in a stirred tank bioreactor

In this paper we report the regulation of Aspergillus niger growth rate during citric acid fermentation in a stirred tank bioreactor. For this, the influence of dissolved oxygen concentration in a medium on intracellular pH values and consequently on overall microbial metabolism was emphasized. Intracellular pH of mycelium grown under different concentrations of dissolved oxygen in the medium was determined. Sensitivity of proteins toward proton concentration is well recognized, therefore pH influences on the activities of key regulatory enzymes of Aspergillus niger were determined at pH values similar to those detected in the cells grown under lower dissolved oxygen concentrations. The results have shown significantly reduced specific activities of hexokinase, 6-phosphofructokinase and glucose-6-phosphate dehydrogenase in more acidic environment, while pyruvate kinase was found to be relatively insensitive towards higher proton concentration. As expected, due to the reduced specific activities of regulatory enzymes under more acidic conditions, overall metabolism should be hindered in the medium with lower dissolved oxygen concentration which was confirmed by detecting the reduced specific growth rates. From the studies, we conclude that dissolved oxygen concentration affects the intracellular pH and thus growth rate of Aspergillus niger during the fermentation process.     

Pregnancy wantedness: attitude stability over time

In this analysis we have compared two attitudinal reports, from interviews two years apart, of the same event for consistency over time. We have looked at women's self-reports, and at their proxy reports for partners' attitudes as well. The inconsistent reports of women's own views tended to shift slightly toward more favorable reports at the second interview (15 percent more positive versus 10 percent more negative). More specifically, 7.5 percent of women who reported at Time 1 that their most recent births had been unwanted switched to more favorable reports at Time 2, and about the same percentage of women who reported Table 4, the findings would suggest that some of the groups typically considered to be most "at risk" were those who were also most apt to report inconsistently. This findings should signal some concern in the policy community. Net of other factors, there is no effect of income, but a number of at-risk groups remained significantly more likely than others to change their reports over time. Of particular concern is the finding that women who reported their pregnancies as mistimed or unwanted were so much more likely to change their reports over time than were women who initially said that their pregnancies had been well timed. When we look at the direction of change, it is clear that, with some exceptions, the more "at risk" groups were more likely to shift in a more negative direction, while the less "at risk" groups were less likely to do so; and at times they were more likely to report more favorably at the second interview. Although somewhat hampered by small sample sizes in the analysis of Time 1 mistimed and unwanted reports, results confirmed that certain subgroups were not only more apt to report inconsistently, they were also more likely to do so in specific directions. To the extent that future survey questions can emphasize to respondents that they should focus on the time of conception, and not on current status, inconsistency across groups may be reduced.     

A naturally occurring variant of endothelial lipase associated with elevated HDL exhibits impaired synthesis

Human endothelial lipase (EL) is a member of a family of lipases and phospholipases that are involved in the metabolism of plasma lipoproteins. EL displays a preference to hydrolyze lipids in HDL. We report here that a naturally occurring low frequency coding variant in the EL gene (LIPG), glycine-26 to serine (G26S), is significantly more common in African-American individuals with elevated HDL cholesterol (HDL-C) levels. To test the hypothesis that this variant results in reduced EL function, we extensively characterized and compared the catalytic and noncatalytic functions of the G26S variant and wild-type (WT) EL. While the catalytic-specific activity of G26S EL is similar to WT EL, its secretion is markedly reduced. Consistent with this observation, we found that carriers of the G26S variant had significantly reduced plasma levels of EL protein. Thus, this N-terminal variant results in reduced secretion of EL protein, plausibly leading to increased HDL-C levels.     

Protein motions during catalysis by dihydrofolate reductases

Dihydrofolate reductase (DHFR) maintains the intracellular pool of tetrahydrofolate through catalysis of hydrogen transfer from reduced nicotinamide adenine dinucleotide to 7,8-dihydrofolate. We report results for pre-steady-state kinetic studies of the temperature dependence of the rates and the hydrogen/deuterium-kinetic isotope effects for the reactions catalysed by the enzymes from the mesophilic Escherichia coli and the hyperthermophilic Thermatoga maritima. We propose an evolutionary pattern in which catalysis progressed from a relatively rigid active site structure in the ancient thermophilic DHFR to a more flexible and kinetically more efficient structure in E. coli that actively promotes hydrogen transfer at physiological pH by modulating the tunnelling distance. The E. coli enzyme appeared relatively robust, in that kinetically severely compromised mutants still actively propagated the reaction. The reduced hydrogen transfer rates of the extensively studied Gly121Val mutant of DHFR from E. coli were most likely due to sterically unfavourable long-range effects from the introduction of the bulky isopropyl group.     

Repayment Flexibility Can Reduce Financial Stress: A Randomized Control Trial with Microfinance Clients in India

Financial stress is widely believed to cause health problems. However, policies seeking to relieve financial stress by limiting debt levels of poor households may directly worsen their economic well-being. We evaluate an alternative policy – increasing the repayment flexibility of debt contracts. A field experiment randomly assigned microfinance clients to a monthly or a traditional weekly installment schedule (N = 200). We used cell phones to gather survey data on income, expenditure, and financial stress every 48 hours over seven weeks. Clients repaying monthly were 51 percent less likely to report feeling “worried, tense, or anxious” about repaying, were 54 percent more likely to report feeling confident about repaying, and reported spending less time thinking about their loan compared to weekly clients. Monthly clients also reported higher business investment and income, suggesting that the flexibility encouraged them to invest their loans more profitably, which ultimately reduced financial stress.     

Prevention of Influenza Virus-Induced Immunopathology by TGF-β Produced during Allergic Asthma

Asthma is believed to be a risk factor for influenza infection, however little experimental evidence exists to directly demonstrate the impact of asthma on susceptibility to influenza infection. Using a mouse model, we now report that asthmatic mice are actually significantly more resistant to a lethal influenza virus challenge. Notably, the observed increased resistance was not attributable to enhanced viral clearance, but instead, was due to reduced lung inflammation. Asthmatic mice exhibited a significantly reduced cytokine storm, as well as reduced total protein levels and cytotoxicity in the airways, indicators of decreased tissue injury. Further, asthmatic mice had significantly increased levels of TGF-β1 and the heightened resistance of asthmatic mice was abrogated in the absence of TGF-β receptor II. We conclude that a transient increase in TGF-β expression following acute asthma can induce protection against influenza-induced immunopathology.     

A reassessment of demographic estimates for Pecos Pueblo

The original demographic estimates for Pecos Pueblo, New Mexico (Hooton, 1930) indicated a 60/40 male/female adult sex ratio and an average life expectancy at birth of 42.9 years. A reanalysis of sexes and ages for a subsample of the Pecos collection as well as a reevaluation of a more recent report suggests that the adult sex ratio for Pecos is probably closer to 50/50 and that the mean age at death should be greatly reduced, perhaps by as much as 15 to 20 years.     

Glutaredoxin serves as a reductant for methionine sulfoxide reductases with or without resolving cysteine

Methionine sulfoxide reductases A and B (MsrA and MsrB) have been known to be thioredoxin (Trx)-dependent enzymes that catalyze the reduction of methionine sulfoxide in a stereospecific manner. This work reports that glutaredoxin, another major thiol-disulfide oxidoreductase, can serve as a reductant for both MsrA and MsrB. Glutaredoxins efficiently reduced 1-Cys MsrA lacking a resolving Cys, which is not reducible by Trx. Glutaredoxins also reduced 3-Cys MsrA containing two resolving Cys. The glutaredoxin-dependent activity of the 3-Cys MsrA was comparable with the Trx-dependent activity. The kinetic data suggest that 1-Cys MsrA is more efficiently reduced by glutaredoxin than 3-Cys form. Also, glutaredoxins could function as a reductant for 1-Cys MsrB lacking a resolving Cys as previously reported. In contrast to the previous report, 2-Cys MsrB containing a resolving Cys was reducible by the glutaredoxins. Collectively, this study demonstrates that glutaredoxins reduce MsrAs and MsrBs with or without resolving Cys.     

Laboratory medicine needs higher profile with medical students,MDs, pathologists say.

Laboratory medicine is a troubled specialty these days, buffeted by the conflicting pressures of reduced funding for more work and a declining physician population. A consortium of laboratory physicians has produced a report on the future of pathology and laboratory medicine, which explores the problems facing the specialties and some potential solutions. Raising the profile of laboratory medicine among medical students and eventual unification of pathology and the various arms of laboratory medicine are among the suggested solutions.     

Indiscriminate degradation of RNAs in interferon-treated, vaccinia virus-infected mouse L cells.

In this report we used Northern blot hybridization analysis to characterize the fate of several species of viral RNA transcribed from internal and terminal regions of vaccinia DNA in interferon-treated, infected mouse L cells grown in suspension. All species of viral RNAs were expressed but were reduced in amount. Larger-sized RNAs were reduced more than smaller-sized RNAs. This reduction appears to be related to the activation of the interferon-mediated double-stranded RNA-dependent 2-5A synthetase-endoribonuclease system, as the rRNA cleavage pattern characteristic of this system was observed early in infection and in cell extracts in response to exogenous 2-5A. Thus, in interferon-treated, vaccinia-infected mouse L cells in suspension, there is indiscriminate degradation of viral and cellular RNAs, and this RNA breakdown might play a role in the interferon-mediated inhibition of protein synthesis.     

Abundance of macrofauna in dense seagrass is due to habitat preference,not predation

Summary Two main hypotheses compete to explain why prey abundance decreases when seagrass density is reduced. One proposes that predators are more successful amongst seagrass of lower density; the other invokes habitat choice by prey. We reduced the density of seagrass in the presence, and in the absence, of predators in a field experiment to discriminate between these hypotheses. When seagrass was manipulated abundances of all six prey species decreased simultaneously both in the presence and in the absence of predators. We conclude that correlations of prey abundance and shoot density within a seagrass bed are proximately due to habitat preference of dense seagrass by prey. We report another experiment which supports this conclusion and shows that habitat preference is exercised at the earliest opportunity. However, the habitat preferences may have been selected by predation pressure.     

Acarbose improves health and lifespan in aging HET3 mice

To follow‐up on our previous report that acarbose (ACA), a drug that blocks postprandial glucose spikes, increases mouse lifespan, we studied ACA at three doses: 400, 1,000 (the original dose), and 2,500 ppm, using genetically heterogeneous mice at three sites. Each dose led to a significant change (by log‐rank test) in both sexes, with larger effects in males, consistent with the original report. There were no significant differences among the three doses. The two higher doses produced 16% or 17% increases in median longevity of males, but only 4% or 5% increases in females. Age at the 90th percentile was increased significantly (8%–11%) in males at each dose, but was significantly increased (3%) in females only at 1,000 ppm. The sex effect on longevity is not explained simply by weight or fat mass, which were reduced by ACA more in females than in males. ACA at 1,000 ppm reduced lung tumors in males, diminished liver degeneration in both sexes and glomerulosclerosis in females, reduced blood glucose responses to refeeding in males, and improved rotarod performance in aging females, but not males. Three other interventions were also tested: ursolic acid, 2‐(2‐hydroxyphenyl) benzothiazole (HBX), and INT‐767; none of these affected lifespan at the doses tested. The acarbose results confirm and extend our original report, prompt further attention to the effects of transient periods of high blood glucose on aging and the diseases of aging, including cancer, and should motivate studies of acarbose and other glucose‐control drugs in humans.     

Reduced oxygen tension results in reduced human T cell proliferation and increased intracellular oxidative damage and susceptibility to apoptosis upon activation

Cell culture and in vitro models are the basis for much biological research, especially in human immunology. Ex vivo studies of T cell physiology employ conditions attempting to mimic the in vivo situation as closely as possible. Despite improvements in controlling the cellular milieu in vitro, most of what is known about T cell behavior in vitro is derived from experiments on T cells exposed to much higher oxygen levels than are normal in vivo. In this study, we report a reduced proliferative response and increased apoptosis susceptibility after T cell activation at 2% oxygen compared to in air. To explain this observation, we tested the hypothesis of an impaired efficacy of intracellular protective mechanisms including antioxidant levels, oxidized protein repair (methionine sulfoxide reductases), and degradation (proteasome) activities. Indeed, after activation, there was a significant accumulation of intracellular oxidized proteins at more physiological oxygen levels concomitant with a reduced GSH:GSSG ratio. Proteasome and methionine sulfoxide reductase activities were also reduced. These data may explain the increased apoptotic rate observed at more physiological oxygen levels. Altogether, this study highlights the importance of controlling oxygen levels in culture when investigating oxygen-dependent phenomena such as oxidative stress.     

Simultaneous mating with multiple males reduces fertilization success in the myobatrachid frog Crinia georgiana

Approximately 50% of matings in the frog Crinia georgiana involve two or more males. We report reduced fertilization success as a major cost of mating with multiple males. For single-male matings, fertilization success was consistently high averaging 96%. Only 68% of eggs were fertilized when females were amplexed by two males and this dropped to 64% when females were amplexed by three to five males. Multiple regression analysis revealed the reduction in fertilization success was significantly related to the number of amplectant males but not to clutch size or three measures of water quality (depth, temperature and oxygen concentration) at the site of oviposition. The most likely cause of reduced fertilization success is struggles amongst males which interfere with effective sperm transfer.