New Tools for Weight-Loss Therapy Enable a More Robust Medical Model for Obesity Treatment: Rationale for a Complications-Centric Approach

ObjectiveRecent advances in lifestyle intervention programs, pharmacotherapy, and bariatric surgery have enabled the development of medical models for the treatment of obesity. Regarding pharmacotherapy, in 2012 the U.S. Food and Drug Administration approved two new effective and safe weight-loss medications, phentermine/ topiramate extended release and lorcaserin, which has greatly augmented options for medically assisted weight loss.MethodsThe rationale for advantages of a complications-centric medical model over current body mass index (BMI)-centric indications for therapy is examined.ResultsCurrently, the baseline BMI level is the principle determinant of indications for obesity treatment using medication and surgery. However, the BMI-centric approach fails to target therapy to those obese patients who will benefit most from weight loss. In contrast, a complications-centric medical model is proposed that will earmark the modality and intensity of the therapeutic intervention based on the presence and severity of complications that can be ameliorated by weight loss.ConclusionThe complications-centric approach to “medicalizing” obesity care employs weight loss primarily as a tool to treat obesity-related complications and promotes the optimization of health outcomes, the benefit/risk ratio, and the cost-effectiveness of therapy. (Endocr Pract. 2013;19:864-874)     

Nest guarding in a damselfish: evidence of a role for parasites

A potential effect of parasitism on male egg loss while guarding was tested using damselfish Stegastes planifrons . Despite an apparent low energetic cost of the parasite on the male condition, there was a significant positive relationship between egg loss and parasite load. These data provide the first evidence that parasites could play a role in male guarding behaviour. The effect of the parasite could have resulted in low male condition compensated by an increase in filial cannibalism or in a lesser ability to protect the nest from predators.     

Weight loss maintenance following a primary care intervention for low-income minority women

Although the primary care setting offers an innovative option for weight loss interventions, there is minimal research examining this type of intervention with low-income minority women. Further, there is a lack of research on the long-term effects of these programs. The purpose of this investigation was to examine the weight loss maintenance of low-income African-American women participating in a primary care weight management intervention. A randomized controlled trial was conducted with overweight and obese women (N = 144) enrolled at two primary care clinics. Women received a 6-month tailored weight loss intervention delivered by their primary care physician and completed follow-up assessments 9, 12, and 18 months following randomization. The weight loss maintenance of the tailored intervention was compared to a standard care comparison group. The weight loss of intervention participants (-1.52 +/- 3.72 kg) was significantly greater than that of standard care participants (0.61 +/- 3.37 kg) at month 9 (P = 0.01). However, there was no difference between the groups at the 12-month or 18-month follow-ups. Participants receiving a tailored weight loss intervention from their physician were able to maintain their modest weight loss up to 3-6 months following treatment. Women demonstrated weight regain at the 18-month follow-up assessment, suggesting that more intensive follow-up in the primary care setting may be needed to obtain successful long-term weight loss maintenance.     

Formulating a Future for Diversity

SYNOPSIS. A significant reduction in the diversity of life onearth is already assured as a result of the loss and degradationof terrestrial and aquatic habitats over past centuries. Withcontinued human population growth, biodiversity will come undereven more pressure in coming decades. Yet significant opportunitiesdo exist to lessen the rate of extinction and thereby increasethe amount of biodiversity that is passed on to future generations.Strategies for biodiversity conservation must recognize ethical,ecological, and economic values of biodiversity if they areto have the greatest possible impact. All of these values areimportant in determining the costs of biodiversity loss andthe benefits of conservation. In recent years a coalescenceof scientific information, heightened economic value, and grassrootsactivism has stimulated an unparalleled global response to theloss of biodiversity. Linked efforts to save, study, and usethe earth's biodiversity sustainably and equitably stand thegreatest chance of substantially reducing the rate of diversity'sloss.     

Loss of blood at operation; a method for continuous measurement

A method for continuous measurement of surgical blood loss has been devised and has been used clinically in some 400 cases. The method combines volumetric measure of the suction loss and gravimetric measure of the sponge loss. The volumetric device automatically deducts the volume of rinse water used and thus measures the amount of blood collected in a metering cylinder. The suction loss scale shows continuously the amount of blood in the metering cylinder. The gravimetric device requires counting sponges into the weighing pan, and turning a dial scale to deduct the initial weight of the sponges. The volume of blood in the sponges is then read directly on the dial scale. Use of the instrument, which is under the supervision of the anesthesiologist, adds about two minutes per hour to the time normally required for counting the sponges; and about three minutes per hour is required for tending the volumetric instrument.In clinical use, knowing constantly the amount of blood loss permits the starting of transfusion before serious deficit develops, and then maintaining the patient's blood volume at a predetermined optimum level. In some 400 cases the continuous measurement of the blood loss served as a reliable guide for carrying out the loss-replacement plan within close limits of accuracy.     

Cardiomyocyte proliferation,a target for cardiac regeneration

Cardiac diseases, characterized by cardiomyocyte loss, lead to dramatic impairment of cardiac function and ultimately to congestive heart failure. Despite significant advances, conventional treatments do not correct the defects in cardiac muscle cell numbers and the prognosis of congestive heart failure remains poor. The existence, in adult mammalian heart, of low but detectable cardiomyocyte proliferative capacities has shifted the target of regenerative therapy toward new therapeutical strategy. Indeed, the stimulation of terminally differentiated cardiomyocyte proliferation represents the main therapeutic approach for heart regeneration. Increasing evidence demonstrating that the loss of mammalian cardiomyocyte renewal potential shortly after birth causes the loss of regenerative capacities, strongly support the hypothesis that a detailed understanding of the molecular mechanisms controlling fetal and postnatal cardiomyocyte proliferation is essential to identify targets for cardiac regeneration. Here, we will review major developmental mechanisms regulating fetal cardiomyocyte proliferation and will describe the impact of the developmental switch, operating at birth and driving postnatal heart maturation, on the regulation of adult cardiomyocyte proliferation, all these mechanisms representing potential targets for cardiac repair and regeneration.     

AQP9: a novel target for bone loss induced by microgravity

The aim of current study was to elucidate whether aquaporin-9 (AQP9) expression was involved in the progression of bone loss induced by microgravity. We used the hind-limb suspension (HLS) mice model to simulate microgravity and induce bone loss. It was found that HLS exposure decreased femur bone mineral density (BMD), and enhanced femur AQP9 mRNA and protein levels. Then, the relationship between AQP9 mRNA expression and BMD was studied and it was showed that femur AQP9 mRNA level was negatively related to femur BMD in mice exposed to HLS. We sought to exam the function of AQP9 in the femur using the AQP9-null mice. It was found that AQP9 knockout attenuated bone loss and inhibited osteoclastogenesis under the condition of HLS exposure, but had no similar effect on bone under normal physiological conditions. In addition, it was found that exposure to simulated hypergravity or exercise training, main countermeasures against microgravity, reduced AQP9 mRNA and protein levels in femur of mice. Moreover, it was found that both aging and estrogen deprivation, another two risk factors of bone loss, had no significant effect on femur AQP9 expression. In conclusion, AQP9 plays an important role in the development of microgravity-induced bone loss, and may be a potential target for the prevention or management of microgravity-induced bone loss.     

Formaldehyde as a pre-treatment for dermal collagen heterografts

The preparation, stability both in vitro and in vivo and resistance to bacterial collagenase of trypsin-purified pig dermal collagen cross-linked with a range of concentrations of formaldehyde in phosphate-buffered saline, was studied using ¹⁴C-labelled formaldehyde as a tracer. Washing in phosphate-buffered saline at 37°C produced rapid loss of formaldehyde over 6 weeks before stability was reached. After 19 weeks washing, 12–20% of the initial radioactivity remained, representing 6, 18 and 35 μmol formaldehyde/g of collagen after 21 days reaction with 0.1, 1 and 5% formaldehyde, respectively. Collagen, incorporating stable-bound formaldehyde arising from reaction with formaldehyde in concentrations of 0.5% or over, was totally resistant to bacterial collagenase.The stabilizing effect of formaldehyde cross-linking was also demonstrated by implants of fibrous pig dermal collagen in rats. After 8 weeks a significant constant amount of formaldehyde was retained in all implants. There was no net loss of mass over a 24 week period when pre-treated with 1% formaldehyde but some loss when pre-treated with 0.1% formaldehyde.     

Application of a weighing system for measuring total evaporative water loses in large ruminants

A weighing system originally designed for monitoring changes in the mass of humans due to fluid loss in hospital beds has been adapted to measure the total evaporative water loss of large domestic animals in studies of temperature regulation. Mass loss was monitored on a charge recording and regressed against time. The adaptation resulted in an overall reduction of 73% in the standard error of the regression coefficient of rate of total evaporative water loss. Accuracy was 48% better in the climate chamber than outdoors.     

A randomized pilot trial of a full subsidy vs. a partial subsidy for obesity treatment

Intensive obesity treatment is mandated by federal health care reform but is costly. A partial subsidy for obesity treatment could lower the cost of treatment, without reducing its efficacy. This study sought to test whether a partial subsidy for obesity treatment would be feasible, as compared to a fully subsidized intervention. The study was a pilot randomized trial. Participants (n = 50) were primary care patients with obesity and at least one comorbid condition (diabetes, hypertension, dyslipidemia, or obstructive sleep apnea). Each participant received eight weight loss counseling visits as well as portion-controlled foods for weight loss. Participants were randomized to full subsidy or partial subsidy (2 vs. 1 meal per day provided). The primary outcome was weight change after 4 months. Secondary outcomes included changes in blood pressure, waist circumference, and health-related quality of life. Participants in the full and partial subsidy groups lost 5.9 and 5.3 kg, equivalent to 5.3% and 5.1% of initial weight, respectively (P = 0.71). Changes in secondary outcomes were similar in the two groups. A partial subsidy was feasible and induced a clinically similar amount of weight loss, compared to a full subsidy. Large-scale testing of economic incentives for weight control is merited given the federal mandate to offer weight loss counseling to obese patients.     

DNA deletion as a mechanism for developmentally programmed centromere loss

A hallmark of active centromeres is the presence of the histone H3 variant CenH3 in the centromeric chromatin, which ensures faithful genome distribution at each cell division. A functional centromere can be inactivated, but the molecular mechanisms underlying the process of centromere inactivation remain largely unknown. Here, we describe the loss of CenH3 protein as part of a developmental program leading to the formation of the somatic nucleus in the eukaryote Paramecium. We identify two proteins whose depletion prevents developmental loss of CenH3: the domesticated transposase Pgm involved in the formation of DNA double strand cleavages and the Polycomb-like lysine methyltransferase Ezl1 necessary for trimethylation of histone H3 on lysine 9 and lysine 27. Taken together, our data support a model in which developmentally programmed centromere loss is caused by the elimination of DNA sequences associated with CenH3.     

The quest for a tumor suppressor gene phenotype

Our current definitions of the tumor suppressor gene (TSG) have been guided by the identification of the prototypical gene, RB1, a TSG that is implicated in the development of both the inherited and sporadic forms of retinoblastoma. The hallmark feature of this TSG is loss of function in tumoral cells, which can be restored by reintroduction of a normally functioning protein with concomitant reversion of tumorigenicity. Key to this discovery was that loss of function is often achieved by deletion of a normal copy of the TSG and retention of a mutated allele, which was either inherited or acquired. Suppression of tumorigenicity and the loss-of-function concept of TSGs was also demonstrated in early studies where normal cellular growth was achieved when tumorigenic cells were fused with normal cells. Thus loss of genetic content and restoration of gene function has guided studies aimed at the discovery of novel TSGs. Here we review the successes of TSG discovery using three approaches that are based on the genetic analysis of inherited predisposition to cancer, tumors that display chromosome loss, and tumorigenic cells that display a suppression of tumorigenicity as a result of transfer of normal chromosomes. Based on a review of the literature we conclude that the discovery of TSGs has been highly successful in the genetic analysis of inherited predisposition to cancer with a dominant mode of inheritance. In contrast, the latter two approaches have yielded a paucity of TSGs that exhibit features similar to the prototypical RB1 in that they are rarely inactivated by somatic mutations in tumors displaying LOH, although decreased gene expression is observed. Nevertheless, some of these genes have been shown to suppress tumorigenicity when normal function is restored in tumorigenic cells consistent with the loss-of-function concept. These observations continue to challenge our current definition of TSG.     

An approximation method for estimating cell loss from a growing tumor

A simple self-consistent calculational scheme is developed for estimating cell loss for a growing tumor (or other population) when the growth fraction can be estimated at regular intervals. This is applied to published data for a particular much-studied Ehrlich ascites tumor. The loss rate is found to be substantially higher than that estimated by previous, less precise means.     

Loss of degradation capacity of activated sludge for a xenobiotic after a period without its influent

Xenobiotic shock experiments were conducted on lab-scale continuous-flow activated sludge systems to examine activated sludge treatment performance and to determine the xenobiotic degrader loss after periods of xenobiotic absence. The systems were operated with normal influent of a xenobiotic and a biogenic substrate until steady state, and were then artificially disturbed by removing and re-adding the xenobiotic in the influent. Substantial xenobiotic leaks were found when xenobiotic absent time was approximately one mean cell residence time (theta(c)), and the system failed when xenobiotic absent time was longer than a theta(c). Amount of degrader at the time of dual substrate steady state was estimated to be approximately 6% of the total sludge. As the xenobiotic absence time was lengthened, degrader amount in the system was reduced exponentially at a half life of approximately three days. The loss rate could be attributed mainly to the rate of displacement by theta(c) operation, followed by endogenous decay and de-acclimation loss.     

Apoptosis: a process with a (beta)NAC for complexity

Most programmed cell deaths in the nematode C. elegans require ced-3 caspase activity. In a recent paper, reveal a new C. elegans death inhibitor, icd-1, whose loss can promote apoptosis independently of ced-3.     

Genome evolution: a double take for Paramecium

The surprising discovery of a whole-genome duplication in the otherwise compact genome of Paramecium tetraurelia displays the early forces driving gene retention and loss.     

Evidence for a halothane-dependent cyclic flux of calcium in rat-liver mitochondria.

The previously reported (Hall et al., Biochem. Soc. Trans. 1973) halothane-dependent, calcium-induced loss of respiratory control in rat liver mitochondria is relatively specific to calcium; the effect of strontium ions is much smaller, and comparable additions of potassium salts have no effect on mitochondrial respiration on succinate in the presence of halothane. The calcium-dependent loss of respiratory control can be prevented, or reversed, respectively, by the prior or subsequent addition of agents that either chelate extramitochondrial Ca2plus or inhibit calcium accumulation, or that inhibit the efflux of accumulatec calcium. These results suggest that the halothane-dependent, calcijm-induced loss of respiratory control is due to a cyclic flux of calcium uptake and release.     

TNF-alpha is a critical effector and a target for therapy in antiphospholipid antibody-induced pregnancy loss

The antiphospholipid syndrome (APS) is characterized by recurrent fetal loss, intrauterine growth restriction, and vascular thrombosis in the presence of antiphospholipid (aPL) Abs. Our studies in a murine model of APS induced by passive transfer of human aPL Abs have shown that activation of complement and recruitment of neutrophils into decidua are required for fetal loss, and emphasize the importance of inflammation in aPL Ab-induced pregnancy loss. In this study, we examine the role of TNF-alpha in pregnancy complications associated with aPL Abs in a murine model of APS. We show that aPL Abs are specifically targeted to decidual tissue and cause a rapid increase in decidual and systemic TNF-alpha levels. We identify the release of TNF-alpha as a critical intermediate that acts downstream of C5 activation, based on the fetal protective effects of TNF-alpha deficiency and TNF blockade and on the absence of increased TNF-alpha levels in C5-deficient mice treated with aPL Abs. Our results suggest that TNF-alpha links pathogenic aPL Abs to fetal damage and identify TNF blockade as a potential therapy for the pregnancy complications of APS.     

Evidence for a calmodulin-activated Ca2+ pump ATPase in dog erythrocytes

Previous work in several laboratories revealed little or no Ca2+ pump ATPase activity and little or no activation of the ATPase by calmodulin (CaM) in membranes isolated from dog red blood cells (RBCs). In the present work, intact RBCs from dogs were exposed to the ionophore, A23187, in the presence of Ca2+. A rapid, apparently first order, loss of ATP occurred under these conditions. The first order rate constant was 0.0944 min-1, or approximately 47% of that found in human RBCs under the same conditions. The anti-CaM drug, trifluoperazine, inhibited the loss of ATP and the Ca2+ activation curve of ATP loss in intact cells resembled that observed for CaM-activated Ca2+ pump ATPase in isolated human membranes. Taken together, these data are consistent with the interpretation that the dog RBC membrane contains a CaM-activated Ca2+ pump ATPase.