Clinical strategies for managing the overweight neurology patient.

Obesity and excess body fat contribute to both the risk for and progression of several prevalent neurologic conditions. While obesity treatment is not generally considered part of the job description of the neurologist, we summarize the evidence for this important relationship, and describe ways that being mindful of diet and lifestyle factors in the neurologic patient can yield dividends for patient outcomes.

Efficacy of a meal replacement diet plan compared to a food-based diet plan after a period of weight loss and weight maintenance: a randomized controlled trial.

BACKGROUND: Obesity has reached epidemic proportions in the United States. It is implicated in the development of a variety of chronic disease states and is associated with increased levels of inflammation and oxidative stress. The objective of this study is to examine the effect of Medifast's meal replacement program (MD) on body weight, body composition, and biomarkers of inflammation and oxidative stress among obese individuals following a period of weight loss and weight maintenance compared to a an isocaloric, food-based diet (FB). METHODS: This 40-week randomized, controlled clinical trial included 90 obese adults with a body mass index (BMI) between 30 and 50 kg/m2, randomly assigned to one of two weight loss programs for 16 weeks and then followed for a 24-week period of weight maintenance. The dietary interventions consisted of Medifast's meal replacement program for weight loss and weight maintenance, or a self-selected, isocaloric, food-based meal plan. RESULTS: Weight loss at 16 weeks was significantly better in the Medifast group (MD) versus the food-based group (FB) (12.3% vs. 6.9%), and while significantly more weight was regained during weight maintenance on MD versus FB, overall greater weight loss was achieved on MD versus FB. Significantly more of the MD participants lost >or= 5% of their initial weight at week 16 (93% vs. 55%) and week 40 (62% vs. 30%). There was no difference in satiety observed between the two groups during the weight loss phase. Significant improvements in body composition were also observed in MD participants compared to FB at week 16 and week 40. At week 40, both groups experienced improvements in biochemical outcomes and other clinical indicators. CONCLUSIONS: Our data suggest that the meal replacement diet plan evaluated was an effective strategy for producing robust initial weight loss and for achieving improvements in a number of health-related parameters during weight maintenance, including inflammation and oxidative stress, two key factors more recently shown to underlie our most common chronic diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT01011491.

Bromocriptine administration reduces hyperphagia and adiposity and differentially affects dopamine D2 receptor and transporter binding in leptin-receptor-deficient Zucker rats and rats with diet-induced obesity.

BACKGROUND: The dopamine (DA) D(2) receptor (D2R) agonist bromocriptine (BC) decreases body fat in animal and human models and increases lean muscle mass, improves glucose intolerance and insulin resistance, and reduces triglycerides and free fatty acids. We have previously shown a negative correlation between D2R and body weight in obese individuals and in rodents, and that chronic food restriction increases D2R binding in genetically obese rats. The purpose of this study was to assess whether the antiobesity and metabolic effects of BC are related to changes in midbrain DA and D2R activity by measuring D2R and DA transporter (DAT) binding in a genetic (leptin-receptor-deficient) and environmental (diet-induced) rodent obesity model. METHODS: Obese (fa/fa) (leptin-receptor-deficient), lean (FA/FA) Zucker rats and rats with diet-induced obesity (DIO) were treated with 10 mg/kg BC for 4 weeks. Body weight, food intake, locomotor activity and blood glucose levels were measured along with D2R- and DAT-binding levels using in vitro receptor autoradiography. RESULTS: BC decreased food intake and body fat and increased locomotor activity in both the (fa/fa) and DIO rats. Furthermore, BC increased D2R binding in (fa/fa) but not in DIO rats. Finally, BC increased DAT binding in DIO rats but not in the (fa/fa) rats. CONCLUSION: These observations are all consistent with the existence of unique leptin-DA interactions and the hypothesis that there is hyposensitivity of the DA system in obesity.

Efficacy of meal replacements versus a standard food-based diet for weight loss in type 2 diabetes: a controlled clinical trial.

PURPOSE: The purpose of this study is to compare the efficacy of a portion-controlled meal replacement diet (PCD) to a standard diet (SD) based on recommendations by the American Diabetes Association in achieving and maintaining weight loss among obese participants with type 2 diabetes. METHODS: This study is a university-based, controlled clinical trial. Participants were 119 men and women with diabetes with a body mass index between 25 and 40 kg/m(2), assigned randomly to one of two 34-week, 75% of predicted energy need diets (portion controlled or standard, self-selected, food based) and then followed by 1-year maintenance. RESULTS: Using intention-to-treat analyses, weight loss at 34 weeks and weight maintenance at 86 weeks was significantly better on PCD versus SD. Approximately 40% of the PCD participants lost > or =5% of their initial weight compared with 12% of those on the SD. Significant improvements in biochemical and metabolic measures were observed at 34 weeks in both groups. The retention rate and self-reported ease of adherence in the PCD group were significantly higher throughout the study. CONCLUSIONS: A diet using portion-controlled meal replacements yielded significantly greater initial weight loss and less regain after 1 year of maintenance than a standard, self-selected, food-based diet. As PCDs may help obese patients with type 2 diabetes adhere to a weight control program, diabetes educators may consider recommending them as part of a comprehensive approach to weight control.

Lack of energy compensation over 4 days when white button mushrooms are substituted for beef.

Increasing intake of low energy density (ED) foods in place of high ED foods has been proposed as a strategy for preventing or treating obesity. This study investigated how substituting mushrooms for beef in a test lunch affected energy intake, fat intake, palatability, appetite, satiation and satiety in normal weight, overweight and obese adults. Each subject consumed a total of eight test lunches in our lab over two consecutive weeks. The order of presentation of four consecutive meat lunches and four consecutive mushroom lunches was randomized. Energy content of meat and mushroom lunches varied (783 kcal versus 339 kcal), while volume was held constant. Energy intakes were significantly higher during meat lunches than mushroom lunches (730+/-7.9 kcal versus 310+/-5.8 kcal). Subjects exhibited only partial compensation (11.4+/-12.0%) for this difference over 4 days. Total daily energy intake and fat intake were significantly greater in the meat condition than in the mushroom condition, while ratings of palatability, appetite, satiation and satiety did not differ significantly. These results suggest that substituting low ED foods for high ED foods in otherwise similar recipes can be an effective method for reducing daily energy and fat intake.

Amplification patterns of three genomic regions predict distant recurrence in breast carcinoma.

Currently used clinical and histopathological parameters imprecisely define the risk of distant recurrence in breast cancer, underscoring the need for more informative prognostic markers. In the present fluorescence in situ hybridization study of archived surgical specimens, we derived an algorithm for computing a prognostic index (PI) from DNA copy numbers of three genomic regions (CYP24, PDCD6IP, and BIRC5) for estrogen/progesterone receptor-positive (ER/PR+) cancers and a distinct PI (based on NR1D1, SMARCE1, and BIRC5) for estrogen/progesterone receptor-negative (ER/PR-) cancers. Among independent test cases stratified by PI, recurrence rates were significantly higher among high-risk patients than low-risk patients for both ER/PR+ (odds ratio = 9.52, 95% confidence interval >2.12, P = 0.0024) and ER/PR- (odds ratio = 12.3, 95% confidence interval >1.45, P = 0.0188) cancers. Among the entire population, recurrences were significantly more prevalent for cases with PI above the medians for both ER/PR+ (Fisher's exact, P = 1.19 x 10(-5)) and ER/PR- (P = 0.0025) patients and for the node-negative subsets (ER/PR+ node-negative, P = 0.042 and ER/PR- node-negative, P = 0.039). In conclusion, these markers perform well in comparison with other criteria for recurrence risk assessment and can be used with routinely formalin-fixed, paraffin-embedded surgical specimens.

Bromocriptine reduces steatosis in obese rodent models.

BACKGROUND/AIMS: Obesity is a risk factor for glucose intolerance, steatosis, and oxidative stress, characteristics of nonalcoholic fatty liver disease. Bromocriptine may have anti-obesity, insulin-sensitizing, lipolytic, and antioxidant properties. We, therefore, hypothesized that bromocriptine would improve markers of nonalcoholic fatty liver disease in obese rodent models. METHODS: We performed a randomized, controlled experiment in genetically obese fatty Zucker rats and diet-induced obese rats to assess for behavioral and peripheral anti-obesity actions of bromocriptine (10mg/kg) that would improve nonalcoholic fatty liver disease. RESULTS: Behaviorally, food intake decreased and locomotor activity increased in bromocriptine-treated fatty Zucker and dietary-induced obese rats. Peripherally, liver triglycerides were significantly reduced and hepatic manganese superoxide dismutase significantly increased in bromocriptine-treated fatty Zucker and diet-induced obese rats compared to controls. Blood glucose was significantly lower in bromocriptine-treated Zucker rats compared to fatty controls and was no different than that of lean controls. CONCLUSIONS: Improvements in obesigenic behaviors, glucose tolerance, hepatic lipid accumulation, and mitochondrial oxidative stress observed in genetically obese and diet-induced obese rodents indicate that bromocriptine may be promising as a broad-based therapy for nonalcoholic fatty liver disease.

Positive and negative determinants of target gene specificity in myb transcription factors.

The A-Myb and c-Myb transcription factors share a highly conserved DNA-binding domain and activate the same promoters in reporter gene assays. However, the two proteins have distinct biological activities, and expressing them individually in human cells leads to the activation of distinct sets of endogenous genes, suggesting that each protein has a unique transcriptional specificity. Here, the structural and functional features of the Myb proteins were compared, using assays of endogenous gene expression to measure changes in specificity. When the Myb proteins were tested in different cell types, they activated unique and nearly nonoverlapping sets of genes in each cellular context. Deletion and domain swap experiments identified small, discreet positive and negative elements in A-Myb and c-Myb that were required for the regulation of specific genes, such as DHRS2, DSIPI, and mim-1. The results suggest that individual functional elements in the transcriptional activation domains are responsible for activating specific cellular genes in a context-specific manner. The results also have important implications for interpreting results from reporter gene assays, which fail to detect the differences in activity identified through endogenous gene assays, and fusion protein constructs that alter the transcriptional activation domains and the activities of the Myb proteins.

Distinct changes in gene expression induced by A-Myb, B-Myb and c-Myb proteins.

The c-Myb, A-Myb and B-Myb transcription factors have nearly identical DNA-binding domains, activate the same reporter gene constructs in animal cells, but have different biological roles. The Myb proteins are often coexpressed in the same cells, raising questions about whether they activate similar or distinct gene expression profiles, and whether they cooperate or compete in regulating the same promoters. Here, recombinant adenoviruses were used to express each protein in human mammary cells, and then microarray assays were used to assess global changes in gene expression. Each Myb protein induced a unique and specific set of changes, displaying activities far more complex than revealed by standard reporter gene assays. These results have important implications for the roles of various Myb proteins in normal and transformed human cells, for regulatory pathways that might modify their activities and for the importance of acquired mutations that may qualitatively alter their functions in tumors.

Low mitochondrial DNA variation among American alligators and a novel non-coding region in crocodilians.

We analyzed 1317-1823 base pairs (bp) of mitochondrial DNA sequence beginning in the 5' end of cytochrome b (cyt b) and ending in the central domain of the control region for 25 American alligators (Alligator mississippiensis) and compared these to a homologous sequence from a Chinese alligator (A. sinensis). Both species share a non-coding spacer between cyt b and tRNA(Thr). Chinese alligator cyt b differs from that of the American alligator by 17.5% at the nucleotide level and 13.8% for inferred amino acids, which is consistent with their presumed ancient divergence. Only two cyt b haplotypes were detected among the 25 American alligators (693-1199 bp surveyed), with one haplotype shared among 24 individuals. One alligator from Mississippi differed from all other alligators by a single silent substitution. The control region contained only slightly more variation among the 25 American alligators, with two variable positions (624 bp surveyed), yielding three haplotypes with 22, two, and one individuals in each of these groups. Previous genetic studies examining allozymes and the proportion of variable microsatellite DNA loci also found low levels of genetic diversity in American alligators. However, in contrast with allozymes, microsatellites, and morphology, the mtDNA data shows no evidence of differentiation among populations from the extremes of the species range. These results suggest that American alligators underwent a severe population bottleneck in the late Pleistocene, resulting in nearly homogenous mtDNA among all American alligators today.

Microsatellite DNA analyses support an east-west phylogeographic split of American alligator populations.

We examined the population genetic structure of American alligators (Alligator mississippiensis) sampled from 12 localities across the southeastern United States. The primary goal of this study was to determine the extent of population differentiation among alligators from four Florida lakes using eight microsatellite loci and compare the results to additional sites located at varying distances from them. Analyses of population structure revealed little differentiation (F(ST)=0.039; Rho=0.012) among the four Florida lakes, Apopka, Griffin, Orange and Woodruff, which are all located in the St. John&'s River watershed in north-central Florida. Further, there was little differentiation among these samples and samples collected from the Everglades National Park (F(ST)=0.044; Rho=0.009) and south Georgia (F(ST)=0.045; Rho=0.032). Therefore, these six samples were pooled together as a "FL/sGA group." Similarly, samples collected in the western extent of the range, Anahuac National Wildlife Refuge in Texas and Salvador Wildlife Management Area, Marsh Island Wildlife Refuge and Rockefeller Wildlife Refuge in Louisiana, also lacked population structure (F(ST)=0.024; R(ST)=0.040). These four populations were pooled into the "TX/LA group." Comparisons of these two groups with samples taken from the Santee Coastal Reserve in South Carolina and Mobile, Alabama yielded three to four times more differentiation among groups (F(ST)=0.131; Rho=0.187). These and other analyses support the hypothesis of an east-west phylogeographic split in American alligator populations and are consistent with studies of many freshwater fish and aquatic and terrestrial turtles distributed throughout this same geographic region.

Detection by microsatellite analysis of early embryonic mortality in an alligator population in Florida.

In the 1980s, alligators (Alligator mississippiensis) of Lake Apopka (Florida, USA) underwent a population decline associated with decreased egg viability, effects that have been associated with endocrine-disrupting, persistent organochlorine pesticides. It is currently unknown whether the decreased egg viability is due to fertilization failure or early embryonic death. Therefore, we conducted a preliminary study to evaluate the use of microsatellite DNA loci to determine the fertilization status of nonviable eggs. Using microsatellite analysis, we compared genotypes from blasto-disks and embryos with the genotypes from females trapped at the nest. Four of five nonviable egg samples tested yielded evidence of fertilization. No evidence of unfertilized eggs was obtained, but amplifiable DNA could not be obtained from one entirely nonviable clutch. Thus, we demonstrate that early embryonic mortality in alligators can be detected by microsatellite analysis, but also suggest substantial effort is needed to improve the recovery of DNA and amplification of alligator microsatellite loci.