Metamicrobiome diversity promotes the evolution of host-microbial mutualisms.

Ecological theory suggests that a host organism's internal spatial structure can promote the persistence of mutualistic microbes by allowing for the turnover of tissue occupied by non-beneficial or cheating microbes. This type of regulation, whereby a host preferentially rewards tissue occupied by beneficial members of its microbiome but sanctions tissue occupied by non-beneficial cheaters, is expected to generate a competition-extinction trade-off by allowing beneficial microbes to experience a lower extinction rate than competitively dominant cheaters. Using an adaptive dynamics approach, we demonstrate that although ecologically stable, microbial regulation via sanctioning is not stable in any evolutionary sense, as each individual host will be under pressure to reduce the costs incurred from cheater suppression in order to maximize its own fitness at the expense of the rest of the host population. However, increasing the diversity of non-beneficial cheaters in the host population metamicrobiome can lead to an increase in the relative fitness of hosts that actively sanction non-performing tissue, thus facilitating the evolutionary emergence and persistence of such strategies in host-microbial systems. These counter-intuitive results demonstrate how diversity at multiple levels of biological organization and spatiotemporal scales can interact to facilitate the establishment and maintenance of mutualistic relationships.

Not even wrong: the spurious measurement of biodiversity's effects on ecosystem functioning.

Understanding how biodiversity influences ecosystem functioning is one of the central goals of modern ecology. The early and often acrimonious debates about the relationship between biodiversity and ecosystem functioning were largely resolved following the advent of a statistical partitioning scheme that decomposed the net effect of biodiversity on ecosystem functioning into a "selection" effect and a "complementarity" effect. Here we show that both the biodiversity effect and its statistical decomposition into selection and complementarity are fundamentally flawed because these methods use a naïve null expectation based on neutrality, likely leading to an overestimate of the net biodiversity effect, and because they fail to account for the nonlinear abundance-ecosystem-functioning relationships widely observed in nature. Furthermore, under nonlinearity no such statistical scheme can be devised to partition the biodiversity effect. We also present an alternative approach that provides a more reasonable starting point for estimating biodiversity effects. Overall, our results suggest that all studies conducted since the early 1990s are likely to have overestimated the positive effects of biodiversity on ecosystem functioning.

Sitagliptin 100 mg vs glimepiride 1-3 mg as an add-on to insulin and metformin in type 2 diabetes (SWIM).

OBJECTIVE: To compare the effect of sitagliptin (100 mg) vs glimepiride (1-3 mg) as add-on therapy in Indian type 2 diabetes (T2DM) patients on treatment with insulin and metformin (SWIM study). RESEARCH DESIGN AND METHODS: This 24-week, controlled, open-label study randomized T2DM patients (n = 440) receiving a stable dose of metformin and insulin combination therapy to sitagliptin (100 mg) or glimepiride (1-3 mg) as add-on therapy. Baseline HbA1c was ≥7.3% and ≤8.5%. After a 6-week titration period for glimepiride (dose titrated every 2 weeks by 1 mg up to a maximum of 3 mg daily), patients were continued for 18 weeks on their respective tolerable doses of glimepiride (ranging from 1 mg to 3 mg) or sitagliptin (100 mg) along with metformin and insulin. RESULTS: Greater reductions in HbA1c and TDD of insulin were achieved with sitagliptin compared to glimepiride. HbA1c targets and reductions in TDD were achieved by more patients on sitagliptin than on glimepiride. Reductions in both body weight and BMI were also noted among patients on sitagliptin when compared to those on glimepiride, and more hypoglycemic events occurred with glimepiride treatment than with sitagliptin. CONCLUSIONS: Sitagliptin (100 mg), when compared to glimepiride (1-3 mg), bestowed beneficial effects to T2DM patients in terms of achieving greater glycemic control and also brought significant reductions in total daily dose of insulin required, bodyweight, BMI and hypoglycemic events. Overall, the results suggest that sitagliptin (100 mg) is a superior agent over glimepiride (1-3 mg) as an add-on to insulin-metformin therapy among Asian Indians with T2DM.

Assessing the Therapeutic Utility of Professional Continuous Glucose Monitoring in Type 2 Diabetes Across Various Therapies: A Retrospective Evaluation.

BACKGROUND: There have been few large studies that have analyzed the effect of professional (masked) continuous glucose monitoring (P-CGM) on glycemic control in patients with type 2 diabetes (T2DM) who were on a broad spectrum of baseline therapies. METHODS: We performed a retrospective, blinded evaluation of glycemic control in 296 T2DM adults for 6 months following a 6- to 7-day study of their glycemic profile using masked P-CGM. At baseline, 91% of the patients were on some form of insulin treatment with oral hypoglycemic agents (OHA), while 7% were on one or more OHAs without insulin, and the remaining 2% were on GLP-1RAs. On the basis of the masked CGM profile, patients were counselled on diet and exercise change(s) in their baseline diabetes therapy by our professionally trained diabetes team. They also continued to receive regular treatment advice and dose titrations through our Diabetes Tele-Management System (DTMS®). The baseline changes in hemoglobin A1C (A1C) observed in these patients after 6 months of undergoing P-CGM was compared to a matched control group. RESULTS: P-CGM revealed that the predominant pattern of hyperglycemia was postprandial while previously unknown hypoglycemia was found in 38% of the patients; over half of the cases of hypoglycemia were nocturnal. The mean A1C of the P-CGM group dropped from 7.5 ± 1.4% at baseline vs. 7.0 ± 0.9% at 6 months (p < 0.0001). The frequency of performing self-monitoring of blood glucose (SMBG) was also found to be significantly increased in these patients from the baseline. Meanwhile, no significant improvement in A1C was noted in the control group during the same time frame (7.7 ± 1.1% at baseline vs. 7.4 ± 1.1% at 6 months; p = 0.0663) and frequency of SMBG remained almost unchanged. CONCLUSIONS: P-CGM can provide actionable data and motivate patients for diabetes self-care practices, resulting in an improvement in glycemic control over a wide range of baseline therapies.

Clinical Response of Levodopa Carbidopa Combination in Patients with Idiopathic Parkinsonism.

INTRODUCTION: Parkinson's disease is the most common form of a group of progressive neurodegenerative disorders. The use of levodopa as dopamine - replacement therapy is highly effective in ameliorating the symptoms of the disease and remains the standard drug with which other therapies are compared. AIM: To study the change in Unified Parkinson's Disease Rating scale (UPDRS) scores in patients receiving levodopa and carbidopa treatment (levodopa- carbidopa combination). MATERIALS AND METHODS: Study was conducted in Department of Neurology, Government Medical College, Trivandrum, India on 75 patients. All patients diagnosed with Idiopathic Parkinson's disease (PD) satisfying inclusion criteria were enrolled into the study. Informed written consent was taken from all patients. Baseline UPDRS scores were recorded followed by reassessment at the end of six month. Data was analysed using paired t-test with help of SPSS-16 statistical software. RESULTS: Baseline UPDRS was collected and after 6 months of treatment, it was reassessed. Baseline total score was 49.8; the follow-up score was 39.5. A decrease in score was seen in various components of UPDRS. CONCLUSION: Upon statistical analysis this difference was found to be significant, which implies that, there is improvement in patient's condition. Improvement was noted in Mentation, behaviour, mood, activities of daily living and motor functions. Hence there is positive treatment response for levodopa carbidopa therapy in patients with idiopathic PD.

CSII as an Alternative Therapeutic Strategy for Managing Type 2 Diabetes: Adding the Indian Experience to a Global Perspective.

BACKGROUND: Alternative insulin therapy with continuous subcutaneous insulin infusion (CSII) is offered with an objective of achieving better glycemic control, minimising glucose variability and thereby, preventing or reducing the risk of microvascular and macrovascular complications in people with type 1 or type 2 diabetes. Trials conducted across the world have demonstrated that CSII is more beneficial in terms of achieving better metabolic control in type 2 diabetes. Unawareness about the multiple benefits of CSII is a major hurdle to its widespread use. In India, insulin pumps are more popular in type 2 diabetes and we have been deploying pumps since 2004. Previously, we have reported reduction in HbA1c, body weight and total daily dose of insulin in patients on insulin pump therapy (IPT). OBJECTIVE: The objective of this study was to assess the attitude and behavior of type 2 diabetes patients on IPT. METHODS: A cross sectional survey was conducted among selected type 2 diabetes patients who have been on IPT for more than 3 years. We administered questionnaires to assess level of satisfaction with pump, improvement in quality of life (QoL), use of the advanced functions and average cost incurred by being on pump. Difference in scores between males and females were assessed using chiquare test for proportions and t-test for differences in means. RESULTS: Improvement in QoL after being on pump was appreciated by 92%. The level of satisfaction was rated as 'fully satisfied' by 52% of respondents while 26% found being on pump, 'satisfactory'. Ninety percent thought that the pump met their expectations. CONCLUSION: The attitude and behavior of type 2 diabetes patients on IPT is positive and promising.

The two levels of care for diabetes in a developing country: Mechanisms for improved intermediate health outcomes.

India has over 70 million citizens with diabetes, the second-most of any country worldwide. Disparities in learning skills, resources, education, and physician practices make it difficult to practically implement the diabetes management guidelines recommended by international scientific organizations. In its guidelines, the International Diabetes Federation advocates for three different levels of care based on availability of resources. This study investigates the differences in intermediate health outcomes between two diabetes care programs: one a comprehensive diabetes centre, the other a limited care setting. The comprehensive centre offers telemedicine and periodic diabetes education, empowering patients and providing 24-hour advice on lifestyle modifications, diet, and exercise. All patients of this centre practice self-monitoring of blood glucose. The subjects in the limited care setting receive minimal investigations and periodic physical follow-ups, and few patients have access to home glucose monitoring. The results showed that HbA1c (7.62 vs. 8.58, p=0.003), cholesterol (134.4 vs. 173.4, p<0.001), and diastolic blood pressure (72.9 vs. 77.0, p=0.016) were significantly lower in patients receiving comprehensive care, while the reductions in systolic blood pressure (134.6 vs. 138.7, p=0.202) did not achieve statistical significance. These reductions, which remained significant after correcting for confounding factors, could be attributed to more aggressive treatment regimens in the comprehensive care centre, as well as the real-time, frequent communication with medical professionals in the telemedicine program.

A Prospective Comparative Study of the Toxicity Profile of 5-Flurouracil, Adriamycin, Cyclophosphamide Regime VS Adriamycin, Paclitaxel Regime in Patients with Locally Advanced Breast Carcinoma.

INTRODUCTION: A 5-flurouracil, Adriamycin, Cyclophosphamide (FAC) and Adriamycin, Paclitaxel (AT) are two popular chemotherapeutic regimens for treatment of breast carcinoma. The most time tested and popular regimen is FAC. It is extensively studied for efficacy and toxicity. But data regarding toxicity profile and efficacy of AT regimen is sparse. AIM: To study the toxicity profile, severity of toxicities and clinical response rate of FAC and AT regimens in patients with locally advanced breast carcinoma. MATERIALS AND METHODS: A prospective observational study with 50 patients in each treatment arm. Study duration was 12 months from November 2012 to October 2013. Consecutive patients with locally advanced breast carcinoma receiving treatment with either FAC or AT regimen, satisfying inclusion criteria were enrolled into the study after getting informed written consent. Prior to initiation of treatment detailed medical history was taken from all patients. General clinical examination, examination of organ systems and local examination of breast lump were done. After each cycle of chemotherapy and after completion of treatment patients were interviewed and examined for clinical response and toxicities. Toxicities were graded with WHO toxicity grading criteria. All data were entered in a structured proforma. At least 50% reduction in tumour size was taken as adequate clinical response. STATISTICAL ANALYSIS: Data was analysed using Chi-square test with help of Excel 2007 and SPSS-16 statistical software. RESULTS: Different pattern of toxicities were seen with FAC and AT regimens. Anaemia, thrombocytopenia, stomatitis, hyperpigmentation, photosensitivity and diarrhoea were more common with patients receiving FAC regimen. Leucopenia, peripheral neuropathy, myalgia, arthralgia, vomiting and injection site reactions were more common in AT regimen. Both FAC and AT regimens gave 100% clinical response. CONCLUSION: FAC and AT regimens are equally efficacious but have different toxicity profiles. Patient's predisposition to toxicities may govern the selection of a particular regime.

The cryptic role of biodiversity in the emergence of host-microbial mutualisms.

The persistence of mutualisms in host-microbial - or holobiont - systems is difficult to explain because microbial mutualists, who bear the costs of providing benefits to their host, are always prone to being competitively displaced by non-mutualist 'cheater' species. This disruptive effect of competition is expected to be particularly strong when the benefits provided by the mutualists entail costs such as reduced competitive ability. Using a metacommunity model, we show that competition between multiple cheaters within the host's microbiome, when combined with the spatial structure of host-microbial interactions, can have a constructive rather than a disruptive effect by allowing the emergence and maintenance of mutualistic microorganisms within the host. These results indicate that many of the microorganisms inhabiting a host's microbiome, including those that would otherwise be considered opportunistic or even potential pathogens, play a cryptic yet critical role in promoting the health and persistence of the holobiont across spatial scales.

Genetic polymorphisms of catechol-O-methyltransferase modify the neurobehavioral effects of mercury in children.

Mercury (Hg) is neurotoxic and children may be particularly susceptible to this effect. A current major challenge is identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. This study examined the hypothesis that genetic variants of catechol-O-methyltransferase (COMT) that are reported to alter neurobehavioral functions that are also affected by Hg in adults might modify the adverse neurobehavioral effects of Hg exposure in children. Five hundred and seven children, 8-12 yr of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at seven subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the clinical trial, genotyping assays were performed for single-nucleotide polymorphisms (SNPs) of COMT rs4680, rs4633, rs4818, and rs6269 on biological samples provided by 330 of the trial participants. Regression-modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Similar analysis was performed using haplotypes of COMT SNPs. Among girls, few interactions for Hg exposure and COMT variants were found. In contrast, among boys, numerous gene-Hg interactions were observed between individual COMT SNPs, as well as with a common COMT haplotype affecting multiple domains of neurobehavioral function. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with common genetic variants of COMT, and may have important implications for strategies aimed at protecting children from the potential health risks associated with Hg exposure.

Modification of neurobehavioral effects of mercury by genetic polymorphisms of metallothionein in children.

Mercury (Hg) is neurotoxic, and children may be particularly susceptible to this effect. A current major challenge is the identification of children who may be uniquely susceptible to Hg toxicity because of genetic disposition. We examined the hypothesis that genetic variants of metallothionein (MT) that are reported to affect Hg toxicokinetics in adults would modify the neurotoxic effects of Hg in children. Five hundred seven children, 8-12 years of age at baseline, participated in a clinical trial to evaluate the neurobehavioral effects of Hg from dental amalgam tooth fillings. Subjects were evaluated at baseline and at 7 subsequent annual intervals for neurobehavioral performance and urinary Hg levels. Following the completion of the clinical trial, we performed genotyping assays for variants of MT isoforms MT1M (rs2270837) and MT2A (rs10636) on biological samples provided by 330 of the trial participants. Regression modeling strategies were employed to evaluate associations between allelic status, Hg exposure, and neurobehavioral test outcomes. Among girls, few significant interactions or independent main effects for Hg exposure and either of the MT gene variants were observed. In contrast, among boys, numerous significant interaction effects between variants of MT1M and MT2A, alone and combined, with Hg exposure were observed spanning multiple domains of neurobehavioral function. All dose-response associations between Hg exposure and test performance were restricted to boys and were in the direction of impaired performance. These findings suggest increased susceptibility to the adverse neurobehavioral effects of Hg among children with relatively common genetic variants of MT, and may have important public health implications for future strategies aimed at protecting children and adolescents from the potential health risks associated with Hg exposure. We note that because urinary Hg reflects a composite exposure index that cannot be attributed to a specific source, these findings do not support an association between Hg in dental amalgams specifically and the adverse neurobehavioral outcomes observed.

Cost-effective use of telemedicine and self-monitoring of blood glucose via Diabetes Tele Management System (DTMS) to achieve target glycosylated hemoglobin values without serious symptomatic hypoglycemia in 1,000 subjects with type 2 diabetes mellitus--a retrospective study.

OBJECTIVE: This study assessed the effectiveness, safety, and costs of the Diabetes Tele Management System (DTMS(®); Dr. Jothydev Kesavadev, Jothydev's Diabetes and Research Center, Kerala, India)-based health care in type 2 diabetes (T2D) patients in South India. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study using electronic health records in our Center. The study sample comprised T2D patients enrolled in DTMS-based management, 30-75 years old, eligible for a glycosylated hemoglobin (HbA1c) target <6.5% and actively participating in various components of DTMS such as regular reporting of self-monitoring of blood glucose (SMBG) values and dose adjustments via telemedicine. We analyzed HbA1c, lipid profile, and other parameters measured at the first visit and on subsequent physical visits at months 3 and 6 and estimated the incidence of hypoglycemia. RESULTS: We analyzed records of 1,000 subjects with 6-month follow-up data (mean age, 53.2 ± 9.8 years; 64% male). Patients had an average of 17 ± 2 telemedicine follow-ups and reported 66,745 SMBG values over 6 months. The mean ± SD HbA1c value was 8.5 ± 1.4% at the initial visit and was reduced to 6.3 ± 0.6% at 6 months (P<0.0001). The rate of SMBG values <70 mg/dL was approximately 0.04/patient/month, with 84% patients reporting no hypoglycemia. The recurring extra cost to patient for DTMS, not considering cost of oral drugs and insulin, was equivalent to 9.66 U.S. dollars/month. CONCLUSIONS: DTMS, based on telemedicine follow-up and multidisciplinary care with SMBG-based monitoring, appears to be safe and cost-effective in the intensive treatment of T2D without serious co-morbidities. This system also avoids limitations of a traditional health care such as the need for very frequent physical visits for each and every drug dose adjustment, diet, and exercise advice.

Competition-colonization trade-offs, competitive uncertainty, and the evolutionary assembly of species.

We utilize a standard competition-colonization metapopulation model in order to study the evolutionary assembly of species. Based on earlier work showing how models assuming strict competitive hierarchies will likely lead to runaway evolution and self-extinction for all species, we adopt a continuous competition function that allows for levels of uncertainty in the outcome of competition. We then, by extending the standard patch-dynamic metapopulation model in order to include evolutionary dynamics, allow for the coevolution of species into stable communities composed of species with distinct limiting similarities. Runaway evolution towards stochastic extinction then becomes a limiting case controlled by the level of competitive uncertainty. We demonstrate how intermediate competitive uncertainty maximizes the equilibrium species richness as well as maximizes the adaptive radiation and self-assembly of species under adaptive dynamics with mutations of non-negligible size. By reconciling competition-colonization tradeoff theory with co-evolutionary dynamics, our results reveal the importance of intermediate levels of competitive uncertainty for the evolutionary assembly of species.

Evolution of dispersal in a predator-prey metacommunity.

Dispersal is crucial to allowing species inhabiting patchy or spatially subdivided habitats to persist globally despite the possibility of frequent local extinctions. Theoretical studies have repeatedly demonstrated that species that exhibit a regional metapopulation structure and are subject to increasing rates of local patch extinctions should experience strong selective pressures to disperse more rapidly despite the costs such increased dispersal would entail in terms of decreased local fitness. We extend these studies to consider how extinctions arising from predator-prey interactions affect the evolution of dispersal for species inhabiting a metacommunity. Specifically, we investigate how increasing a strong extinction-prone interaction between a predator and prey within local patches affects the evolution of each species' dispersal. We found that for the predator, as expected, evolutionarily stable strategy (ESS) dispersal rates increased monotonically in response to increasing local extinctions induced by strong predator top-down effects. Unexpectedly for the prey, however, ESS dispersal rates displayed a nonmonotonic response to increasing predator-induced extinction rates-actually decreasing for a significant range of values. These counterintuitive results arise from how extinctions resulting from trophic interactions play out at different spatial scales: interactions that increase extinction rates of both species locally can, at the same time, decrease the frequency of interaction between the prey and predator at the metacommunity scale.

Metacommunity theory explains the emergence of food web complexity.

Food webs are highly complex ecological networks, dynamic in both space and time. Metacommunity models are now at the core of unified theories of biodiversity, but to date they have not addressed food web complexity. Here we show that metacommunity theory can explain the emergence of species-rich food webs with complex network topologies. Our analysis shows that network branching in the food web is maximized at intermediate colonization rates and limited dispersal scales, which also leads to concomitant peaks in species diversity. Increased food web complexity and species diversity are made possible by the structural role played by network branches that are supported by omnivore and generalist feeding links. Thus, in contrast to traditional food web theory, which emphasizes the destabilizing effect of omnivory feeding in closed systems, metacommunity theory predicts that these feeding links, which are commonly observed in empirical food webs, play a critical structural role as food webs assemble in space. As this mechanism functions at the metacommunity level, evidence for its operation in nature will be obtained through multiscale surveys of food web structure. Finally, we apply our theory to reveal the effects of habitat destruction on network complexity and metacommunity diversity.