Weight gain prevention among women

Objective: Women 25 to 45 years old are at risk for weight gain and future obesity. This trial was designed to evaluate the efficacy of two interventions relative to a control group in preventing weight gain among normal or overweight women and to identify demographic, behavioral, and psychosocial factors related to weight gain prevention. Research Methods and Procedures: Healthy women (N = 284), ages 25 to 44, with BMI < 30 were randomized to one of three intervention conditions: a clinic‐based group, a correspondence course, or an information‐only control. Intervention was provided over 2 years, with a follow‐up at Year 3. BMI and factors related to eating and weight were assessed yearly. Results: Over the 3‐year study period, 40% (n = 114) of the women remained at or below baseline body weight (±2 lbs), and 60% gained weight (>2 lbs). Intervention had no effect on weight over time. Independently of intervention, women who were older, not actively dieting to lose weight, and who reported less perceived hunger at baseline were more likely to be successful at weight maintenance. Weight maintenance also was associated with increasing dietary restraint (conscious thoughts and purposeful behaviors to control calorie intake) and decreasing dietary disinhibition (the tendency to lose control over eating) over time. Discussion: This study raises concern about the feasibility and efficacy of weight gain prevention interventions because most women were interested in weight loss, rather than weight gain prevention, and the interventions had no effect on weight stability. Novel approaches to the prevention of weight gain are needed.     

AL-12182, a novel 11-oxa prostaglandin analog with topical ocular hypotensive activity in the monkey

A series of 11-oxa prostaglandin analogs was evaluated for FP receptor binding and activation. Several compounds having aryloxy-terminated lower chains were found to be potent agonists. Topical ocular dosing of AL-12182, the isopropyl ester prodrug of the potent agonist 13, lowered intraocular pressure in the monkey by 40% accompanied by minimal conjunctival hyperemia in the rabbit. AL-12182 was synthesized on multigram scale starting with D-sorbitol.     

Structural and functional uncoupling of the enzymatic and angiogenic inhibitory activities of tissue inhibitor of metalloproteinase-2 (TIMP-2): loop 6 is a novel angiogenesis inhibitor

Tissue inhibitors of metalloproteinases (TIMPs) regulate tumor growth, progression, and angiogenesis in a variety of experimental cancer models and in human malignancies. Results from numerous studies have revealed important differences between TIMP family members in their ability to inhibit angiogenic processes in vitro and angiogenesis in vivo despite their universal ability to inhibit matrix metalloproteinase (MMP) activity. To address these differences, a series of structure-function studies were conducted to identify and to characterize the anti-angiogenic domains of TIMP-2, the endogenous MMP inhibitor that uniquely inhibits capillary endothelial cell (EC) proliferation as well as angiogenesis in vivo. We demonstrate that the COOH-terminal domain of TIMP-2 (T2C) inhibits the proliferation of capillary EC at molar concentrations comparable with those previously reported for intact TIMP-2, while the NH2-terminal domain (T2N), which inhibits MMP activity, has no significant anti-proliferative effect. Interestingly, although both T2N and T2C inhibited embryonic angiogenesis, only T2C resulted in the potent inhibition of angiogenesis driven by the exogenous addition of angiogenic mitogen, suggesting that MMP inhibition alone may not be sufficient to inhibit the aggressive neovascularization characteristic of aberrant angiogenesis. We further mapped the anti-proliferative activity of T2C to a 24-amino acid peptide corresponding to Loop 6 of TIMP-2 and show that Loop 6 is a potent inhibitor of both embryonic and mitogen-stimulated angiogenesis in vivo. These findings demonstrate that TIMP-2 possesses two distinct types of anti-angiogenic activities which can be uncoupled from each other, the first represented by its MMP-dependent inhibitory activity which can inhibit only embryonic neovascularization and the second represented by an MMP-independent activity which inhibits both normal angiogenesis and mitogen-driven angiogenesis in vivo. In addition, we report, for the first time, the discovery of Loop 6 as a novel and potent inhibitor of angiogenesis.     

Missense mutations in hMLH1 and hMSH2 are associated with exonic splicing enhancers

There is a critical need to understand why missense mutations are deleterious. The deleterious effects of missense mutations are commonly attributed to their impact on primary amino acid sequence and protein structure. However, several recent studies have shown that some missense mutations are deleterious because they disturb cis-acting splicing elements-so-called "exonic splicing enhancers" (ESEs). It is not clear whether the ESE-related deleterious effects of missense mutations are common. We have evaluated colocalization of pathogenic missense mutations (found in affected individuals) with high-score ESE motifs in the human mismatch-repair genes hMSH2 and hMLH1. We found that pathogenic missense mutations in the hMSH2 and hMLH1 genes are located in ESE sites significantly more frequently than expected. Pathogenic missense mutations also tended to decrease ESE scores, thus leading to a higher propensity for splicing defects. In contrast, nonpathogenic missense mutations (polymorphisms found in unaffected individuals) and nonsense mutations are distributed randomly in relation to ESE sites. Comparison of the observed and expected frequencies of missense mutations in ESE sites shows that pathogenic effects of >/=20% of mutations in hMSH2 result from disruption of ESE sites and disturbed splicing. Similarly, pathogenic effects of >/=16% of missense mutations in the hMLH1 gene are ESE related. The colocalization of pathogenic missense mutations with ESE sites strongly suggests that their pathogenic effects are splicing related.     

Bovine membrane-type 1 matrix metalloproteinase: molecular cloning and expression in the corpus luteum

Matrix metalloproteinase-2 (MMP-2) is produced as a zymogen, which is subsequently activated by membrane-type 1 metalloproteinase (MT1-MMP). The objectives of the present study were to clone bovine MT1-MMP and to investigate its expression in the corpus luteum. Corpora lutea were harvested from nonlactating dairy cows on Days 4, 10, and 16 of the estrous cycle (Day 0 = estrus; n = 3 for each age). The bovine MT1-MMP cDNA contained an open reading frame of 1749 base pairs, which encoded a predicted protein of 582 amino acids. Northern blotting revealed no differences (P > 0.05) in MT1-MMP mRNA levels between any ages of corpora lutea. Western blotting demonstrated that two species of MT1-MMP, the latent form ( approximately 63 kDa) and the active form ( approximately 60 kDa), were present in corpora lutea throughout the estrous cycle. Active MT1-MMP was lower (P < 0.05) in early stages of the corpus luteum than the mid and late stages, where MMP-2 activity, as revealed by gelatin zymography, was also elevated. Furthermore, immunohistochemistry revealed that MT1-MMP was localized in endothelial, large luteal, and fibroblast cells of the corpus luteum at different stages. Taken together, the differential expression and localization of MT1-MMP in the corpus luteum suggest that it may have multiple functions throughout the course of the estrous cycle, including activation of pro-MMP-2.     

Expression of the mRNA encoding truncated PPARα does not correlate with hepatic insensitivity to peroxisome proliferators

Two alternatively spliced forms of human PPAR mRNA, PPAR1 and PPAR2, have been identified. PPAR1 mRNA gives rise to an active PPAR protein while PPAR2 mRNA gives rise to a form of PPAR which lacks the ligand-binding domain. PPAR2 is unable to activate a peroxisome proliferator response element (PPRE) reporter gene construct in transient transfection assays. Both PPAR1 and PPAR2 mRNA are present in human liver, kidney, testes, heart, small intestine, and smooth muscle. In human liver, PPAR2 mRNA abundance is approximately half that of PPAR1 mRNA; a correlation analysis of PPAR1 and PPAR2 mRNA mass revealed an r-value of 0.75 (n = 18). Additional studies with intact liver from various species, showed that the PPAR2/PPAR1 mRNA ratios in rat, rabbit, and mouse liver were less than 0.10; significantly lower than the 0.3 and 0.5 ratios observed in monkey and human livers, respectively. To determine if a high PPAR2/PPAR1 mRNA ratio was associated with insensitivity to peroxisome proliferators, we treated human, rat, and rabbit hepatocytes with WY14643, a potent PPARa activator, and measured acyl CoA oxidase (ACO) mRNA levels. Rat ACO mRNA levels increased markedly in response to WY14643 while human and rabbit hepatocytes were unresponsive. Thus, although the PPAR2/PPAR1 mRNA ratio is low in rabbits, this species is not responsive to peroxisome proliferators. Further studies with male and female rats, which vary significantly in their response to peroxisome proliferators, showed little difference in the ratio of PPAR2/PPAR1 mRNA. These data suggest that selective PPAR2 mRNA expression is not the basis for differential species or gender responses to peroxisome proliferators.     

Akt, a Target of Phosphatidylinositol 3-Kinase, Inhibits Apoptosis in a Differentiating Neuronal Cell Line

Phosphatidylinositol (PI) 3-kinase has been suggested to mediate cell survival. Consistent with this possibility, apoptosis of conditionally (simian virus 40 T^ts) immortalized rat hippocampal H19-7 neuronal cells was increased in response to wortmannin, an inhibitor of PI 3-kinase. Downstream effectors of PI 3-kinase include Rac1, protein kinase C, and the serine-threonine kinase Akt (protein kinase B). Here, we show that activation of Akt is one mechanism by which PI 3-kinase can mediate survival of H19-7 cells during serum deprivation or differentiation. While ectopic expression of wild-type Akt (c-Akt) does not significantly enhance survival in H19-7 cells, expression of activated forms of Akt (v-Akt or myristoylated Akt) results in enhanced survival which can be comparable to that conferred by Bcl-2. Conversely, expression of a dominant-negative mutant of Akt accelerates cell death upon serum deprivation or differentiation. Finally, the results indicate that Akt can transduce a survival signal for differentiating neuronal cells through a mechanism that is independent of induction of Bcl-2 or Bcl-x_L or inhibition of Jun kinase activity.     

Ethnomedicine and ethnobotany of fright,a Caribbean culture-bound psychiatric syndrome

Background

Plant species have long been used as principal ingredients of traditional medicine in far-west Nepal. The medicinal plants with ethnomedicinal values are currently being screened for their therapeutic potential but their data and information are inadequately compared and analyzed with the Ayurveda and the phytochemical findings.

Methods

The present study evaluated ethnomedicinal plants and their uses following literature review, comparison, field observations, and analysis. Comparison was made against earlier standard literature of medicinal plants and ethnomedicine of the same area, the common uses of the Ayurveda and the latest common phytochemical findings. The field study for primary data collection was carried out from 2006-2008.

Results

The herbal medicine in far-west Nepal is the basis of treatment of most illness through traditional knowledge. The medicine is made available via ancient, natural health care practices such as tribal lore, home herbal remedy, and the Baidhya, Ayurveda and Amchi systems. The traditional herbal medicine has not only survived but also thrived in the trans-cultural environment with its intermixture of ethnic traditions and beliefs. The present assessment showed that traditional herbal medicine has flourished in rural areas where modern medicine is parsimoniously accessed because of the high cost and long travel time to health center. Of the 48 Nepalese medicinal plants assessed in the present communication, about half of the species showed affinity with the common uses of the Ayurveda, earlier studies and the latest phytochemical findings. The folk uses of Acacia catechu for cold and cough, Aconitum spicatum as an analgesic, Aesculus indica for joint pain, Andrographis paniculata for fever, Anisomeles indica for urinary affections, Azadirachta indica for fever, Euphorbia hirta for asthma, Taxus wallichiana for tumor control, and Tinospora sinensis for diabetes are consistent with the latest pharmacological findings, common Ayurvedic and earlier uses.

Conclusions

Although traditional herbal medicine is only a primary means of health care in far-west Nepal, the medicine has been pursued indigenously with complementing pharmacology and the Ayurveda. Therefore, further pharmacological evaluation of traditional herbal medicine deserves more attention.     

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site.