Effects of lorcaserin on fat and lean mass loss in obese and overweight patients without and with type 2 diabetes mellitus: the BLOSSOM and BLOOM-DM studies.

Body composition was determined using dual-energy X-ray absorptiometry (DXA) in a subset of patients without (BLOSSOM) and with (BLOOM-DM) type 2 diabetes who received diet and exercise counselling along with either lorcaserin 10 mg twice daily or placebo. DXA scans were performed on study day 1 (baseline), week 24 and week 52. Baseline demographics of the subpopulations (without diabetes, n = 189; with diabetes, n = 63) were similar between studies and representative of their study populations. At week 52, patients without diabetes on lorcaserin lost significantly more fat mass relative to those on placebo (-12.06% vs -5.93%; p = 0.008). In patients with diabetes, fat mass was also decreased with lorcaserin relative to placebo (-9.87% vs -1.65%; p < 0.05). More fat mass was lost in the trunk region with lorcaserin compared with placebo (without diabetes: -3.31% vs -2.05%; with diabetes: -3.65% vs -0.36%). Weight loss with lorcaserin was associated with a greater degree of fat mass loss than lean mass loss, and most of the fat mass lost for patients without and with diabetes was from the central region of the body.

Safety and tolerability review of lorcaserin in clinical trials.

Lorcaserin is a novel selective serotonin 2C receptor agonist indicated by the US Food and Drug Administration for chronic weight management in adults with obesity or overweight with ≥1 comorbidity. The safety and efficacy of lorcaserin were established during two Phase III clinical trials in patients without diabetes (BLOOM and BLOSSOM) and one Phase III clinical trial in patients with type 2 diabetes (BLOOM-DM). Headache was the most common adverse event experienced by patients during all Phase III trials. Additional adverse events occurring in >5% of patients receiving lorcaserin included dizziness, fatigue, nausea, dry mouth and constipation in patients without diabetes, and hypoglycaemia, back pain, cough and fatigue in patients with diabetes. In a pooled analysis of echocardiographic data collected during the three lorcaserin Phase III trials, the incidence of FDA-defined valvulopathy was similar in patients taking lorcaserin and the placebo. Here, the safety profile of lorcaserin at the FDA-approved dose of 10 mg twice daily is reviewed using data from the lorcaserin Phase III programme, with a focus on theoretical adverse events commonly associated with agonists of the serotonin receptor family. Based on the lorcaserin Phase III clinical trial data, lorcaserin is safe and well tolerated in the indicated patient populations.

Characterization of Brx, a novel Dbl family member that modulates estrogen receptor action.

Regulation of gene activation by the estrogen receptor (ER) is complex and involves co-regulatory proteins, oncoproteins (such as Fos and Jun), and phosphorylation signaling pathways. Here we report the cloning and initial characterization of a novel protein, Brx, that contains a region of identity to the oncogenic Rho-guanine nucleotide exchange (Rho-GEF) protein Lbc, and a unique region capable of binding to nuclear hormone receptors, including the ER. Western and immunohistochemistry studies showed Brx to be expressed in estrogen-responsive reproductive tissues, including breast ductal epithelium. Brx bound specifically to the ER via an interaction that required distinct regions of ER and Brx. Furthermore, overexpression of Brx in transfection experiments using an estrogen-responsive reporter revealed that Brx augmented gene activation by the ER in an element-specific and ligand-dependent manner. Moreover, activation of ER by Brx could be specifically inhibited by a dominant-negative mutant of Cdc42Hs, but not by dominant negative mutants of RhoA or Rac1. Taken together, these data suggest that Brx represents a novel modular protein that may integrate cytoplasmic signaling pathways involving Rho family GTPases and nuclear hormone receptors.

Isolated hyponatremia after transsphenoidal pituitary surgery.

A retrospective analysis was performed to study the fluid and sodium status of patients undergoing transsphenoidal surgery (TS) for Cushing's disease. We evaluated the time of onset, duration, and relative incidence of isolated hyponatremia and identified possible factors associated with it. Of 58 patients that underwent TS over 1 yr, 52 without postoperative diabetes insipidus or volume depletion were studied. Isolated hyponatremia after TS for Cushing's disease occurred in 21%, and symptomatic hyponatremia (plasma sodium, < or = 125 mmol/L) with new onset headache, nausea, and emesis occurred in 7.0% of all operated. These later patients escaped monitoring and intervention for 24 h. The development of hyponatremia began early in the postoperative period and progressed slowly over 7 days. Maximum antidiuresis occurred on postoperative day 7. Vasopressin levels measured in two patients while hypoosmolar suggested that unregulated vasopressin release contributed to the hyponatremia. Cortisol levels, glucocorticoid replacement, and pituitary adenoma size were similar in normonatremic and hyponatremic patients. Patients combining a history of an estrogenic milieu and documented posterior pituitary trauma at surgery experienced lower nadir plasma sodium. All hyponatremic patients were fluid restricted, and none developed progressive neurological symptoms, morbidity, or mortality. We speculate that the mild degree and slow rate of development of hyponatremia and/or active monitoring and intervention contributed to the good outcome.

Pathophysiology of hyponatremia after transsphenoidal pituitary surgery.

Hyponatremia after pituitary surgery is presumed to be due to antidiuresis; however, detailed prospective investigations of water balance that would define its pathophysiology and true incidence have not been established. In this prospective study, the authors documented water balance in patients for 10 days after surgery, monitored any sodium dysregulation, further characterized the pathophysiology of hyponatremia, and correlated the degree of intraoperative stalk and posterior pituitary damage with water balance dysfunction. Ninety-two patients who underwent transsphenoidal pituitary surgery were studied. To evaluate posterior pituitary damage, a questionnaire was completed immediately after surgery in 61 patients. To examine the osmotic regulation of vasopressin secretion in normonatremic patients, water loads were administered 7 days after surgery. Patients were categorized on the basis of postoperative plasma sodium patterns. After pituitary surgery, 25% of the patients developed spontaneous isolated hyponatremia (Day 7 +/- 0.4). Twenty percent of the patients developed diabetes insipidus and 46% remained normonatremic. Plasma arginine vasopressin (AVP) was not suppressed in hyponatremic patients during hypoosmolality or in two-thirds of the normonatremic patients after water-load testing. Only one-third of the normonatremic patients excreted the water load and suppressed AVP normally. Hyponatremic patients were more natriuretic, had lower dietary sodium intake, and had similar fluid intake and cortisol and atrial natriuretic peptide (ANP) levels compared with normonatremic patients. Normnonatremia, hyponatremia, and diabetes insipidus were associated with increasing degrees of surgical manipulation of the posterior lobe and pituitary stalk during surgery. The pathophysiology of hyponatremia after transsphenoidal surgery is complex. It is initiated by pituitary damage that produces AVP secretion and dysfunctional osmoregulation in most surgically treated patients. Additional events that act together to promote the clinical expression of hyponatremia include nonatrial natriuretic peptide-related excess natriuresis, inappropriately normal fluid intake and thirst, as well as low dietary sodium intake. Patients should be monitored closely for plasma sodium, plentiful dietary sodium replacement, mild fluid restriction, and attention to symptoms of hyponatremia during the first 2 weeks after transsphenoidal surgery.

Use of herbal therapies by adults seen in an ambulatory care research setting: an exploratory survey.

OBJECTIVE: To identify and characterize patterns of use of herbal products among patients participating in selected research clinics. DESIGN: Survey of three National Institutes of Health (NIH) ambulatory care research clinics. SUBJECTS: Convenience sample of 490 adult patients (168 male, 322 female) attending rheumatology, liver, and endocrinology/metabolic research clinics. RESULTS: Of the patients surveyed, 16.7%: (n = 82) reported using herbs. There were no significant sociodemographic differences between herb and nonherb users. Indications for herb use differed among the disease groups; patients in the endocrine and rheumatology clinics were taking herbs predominantly for "energy" or "wellness"; those attending the liver clinic tended to use herbal therapies as treatment for their disease. Mean and median monthly expenditure for herbal products was $30 and $10, respectively. There was a significant positive correlation between number of herbs used and use of other dietary supplements (p < 0.0001). CONCLUSIONS: One in six patients in ambulatory clinical research settings may be taking herbal products in addition to prescribed treatment. This figure is lower than in the general population, possibly because the patients may stop using herbs when participating in a research project. Although empirical evidence on the beneficial or adverse effects of herb therapy alone or in combination with drug therapies is limited, clinical researchers should be aware of the potential for confounding clinical trial results.

Cortisol, obesity, and the metabolic syndrome: a cross-sectional study of obese subjects and review of the literature.

OBJECTIVE: Circulating cortisol and psychosocial stress may contribute to the pathogenesis of obesity and metabolic syndrome (MS). To evaluate these relationships, a cross-sectional study of 369 overweight and obese subjects and 60 healthy volunteers was performed and reviewed the previous literature. DESIGN AND METHODS: Overweight and obese subjects had at least two other features of Cushing's syndrome. They underwent measurements representing cortisol dynamics (24 h urine cortisol excretion (UFC), bedtime salivary cortisol, 1 mg dexamethasone suppression test) and metabolic parameters (BMI, blood pressure (BP); fasting serum triglycerides, HDL, insulin, and glucose). Subjects also completed the Perceived Stress Scale (PSS). UFC, salivary cortisol, and weight from 60 healthy volunteers were analyzed. RESULTS: No subject had Cushing's syndrome. UFC and dexamethasone responses were not associated with BMI or weight. However, salivary cortisol showed a trend to increase as BMI increased (P < 0.0001), and correlated with waist circumference (WC) in men (rs = 0.28, P = 0.02) and systolic BP in women (rs = 0.24, P = 0.0008). Post-dexamethasone cortisol levels were weak to moderately correlated with fasting insulin (rs = -0.31, P = 0.01) and HOMA-IR (rs = -0.31, P = 0.01) in men and systolic (rs = 0.18, P = 0.02) and diastolic BP (rs = 0.20, P = 0.009) in women. PSS results were higher in obese subjects than controls, but were not associated with cortisol or metabolic parameters. As expected, WC correlated with fasting insulin, HOMA-IR, and systolic BP (adjusted for BMI and gender; P < 0.01). Literature showed inconsistent relationships between cortisol and metabolic parameters. CONCLUSION: Taken together, these data do not support a strong relationship between systemic cortisol or stress and obesity or MS.

The proto-oncoprotein Brx activates estrogen receptor beta by a p38 mitogen-activated protein kinase pathway.

The estrogen receptors (ERs) are ligand-inducible transcription factors that play key roles in the control of growth and differentiation in reproductive tissues. We showed that the novel Dbl family proto-oncoprotein Brx enhances ligand-dependent activity of ERalpha via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ERbeta. This enhancement is not affected by inhibition of p44/42 mitogen-activated protein kinase (MAPK) activation by PD98059. However, addition of the p38 MAPK inhibitor SB202190 abrogates the enhancement of ERbeta activity by Brx, showing that p38 MAPK activity is required for the enhancement of ERbeta function by Brx. In COS-7 cells, transfection of Brx leads to activation of endogenous p38 MAPK activity. Co-expression of the beta2 isoform of human p38 MAPK and a constitutively active form of the p38 MAPK kinase MKK6 (MKK6-EE) synergistically augments ligand-dependent activity of ERbeta. Our findings suggest that p38 MAPKs may be important regulators of ERbeta activity.

Streptococcal toxic shock-like syndrome presenting with hypoglycemia and reversible paralysis.

A patient with pharyngitis progressive to Toxic Shock-Like Syndrome presented to the emergency department with a chief complaint of lower extremity paralysis. This paraplegia was completely reversed with the administration of intravenous glucose. Hypoglycemia-induced paraplegia has not previously been reported in the medical literature, and this report emphasizes the importance of considering low-blood glucose as a potential etiology for patients who present with these neurological symptoms.

Expression of brx proto-oncogene in normal ovary and in epithelial ovarian neoplasms.

OBJECTIVE: We previously identified a protein, Brx, that interacted with estrogen receptor alpha. Sequence analysis determined that Brx is a novel member of the Dbl family of oncoproteins involved in signaling pathways that regulate cell growth. Because the Brx protein was found to be highly expressed in hormoneresponsive breast epithelium, the objective of this study was to determine whether Brx was expressed in both normal and neoplastic ovarian tissues. STUDY DESIGN: A polyclonal antiserum directed against the Brx protein was used to perform immunolocalization on sections from 5 normal ovaries and 20 ovarian neoplasms. Chromosomal localization of the brx gene was accomplished by means of fluorescence in situ hybridization. Northern and Western blot analyses were performed on extracts prepared from human ovaries. RESULTS: Brx protein was localized to the cytoplasm of granulosa cells from mature graafian follicles, the corpus luteum, and islands of hilar cells in normal ovaries. In tumors with low malignant potential and ovarian carcinomas the neoplastic epithelium stained strongly for Brx protein. Northern and Western blot analyses, respectively, confirmed expression of Brx messenger ribonucleic acid and protein in normal ovary. Finally, the brx gene was localized to 15q25. CONCLUSION: The proto-oncogene brx is expressed in specific normal human ovarian tissues and is also present in ovarian epithelial neoplasms.