Repurposing of Anti-Diabetic Agents for the Treatment of Cognitive Impairment and Mood Disorders.

Impairments in cognitive function represent a consistent, non-specific, and clinically significant feature in metabolic, mood, and dementing disorders. The foregoing observation is instantiated by evidence demonstrating that these disorders share pathophysiological mechanisms including, but not limited to, aberrant insulin signaling, inflammation, and glucocorticoid activity. Moreover, these mechanisms have been consistently reported to increase vulnerability to and/or exacerbate impairments in cognitive function. Notwithstanding evidence suggesting a bidirectional relationship between disturbances in the metabolic milieu, mood, and increased risk for dementia, efficacious treatments that target cognitive impairments in these populations do not presently exist. Taken together, it is proposed that anti-diabetic agents may aid the management of mood disorders and future risk for dementia through disease modification by targeting underlying pathophysiological mechanisms (e.g., aberrant metabolic function) rather than focusing solely on symptom mitigation. The current aim is to provide a brief narrative review of extant studies that report on the potential neurotherapeutic effects of anti-diabetic agents on disturbances in mood and impairments in cognitive function.

Nitric Oxide and Major Depressive Disorder: Pathophysiology and Treatment Implications.

Major depressive disorder (MDD) is a multi-factorial and heterogeneous disease. Robust evidence suggests that inflammation is involved in the pathogenesis of MDD for a subpopulation of individuals. However, it remains unclear what traits and/or states precede the onset of inflammation in this subpopulation of individuals with MDD. Several recent studies have implicated nitric oxide (NO) as a critical regulator of neuroinflammation, thus suggesting a possible role in the pathophysiology of MDD. The aim of this review is to evaluate the evidentiary base supporting the hypothesis that the increased hazard for developing MDD in certain subpopulations may be mediated, in part, by inflammogenic trait and/or state variations in NO signaling pathways. We conducted a non-systematic literature search for English language studies via PubMed and Google Scholar, from 1985 to October 2014. Replicated evidence suggests that NO has contrasting effects in the central nervous system (CNS). Low concentrations of NO are neuroprotective and mediate physiological signaling whereas higher concentrations mediate neuroinflammatory actions and are neurotoxic. Certain polymorphisms in the neuronal nitric oxide synthase gene (NOS1) are associated MDD. Furthermore, state variations (e.g. decreased levels of essential co-factor, 5,6,7,8-tetrahydrobiopterin [BH4], enhanced microglial cell activity) in the NO signaling pathway are associated with an increased risk of developing MDD. Increased concentrations of NO enhance the production of reactive nitrogen species (RNS) and reactive oxygen species (ROS), which are associated with an increase in pro-inflammatory cytokines. Taken together, evidences suggest that abnormalities in NO signaling may constitute a trait-marker related to MDD pathophysiology, which could be explored for novel therapeutic targets.

Prevalence of fibromyalgia and co-morbid bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Fibromyalgia (FM) is a chronic disorder with high morbidity and significant health service utilization costs. Few studies have reported on the phenotypic overlap of FM and bipolar disorder (BD). The aim of this review is to qualitatively and quantitatively summarize the results and clinical implications of the extant literature on the co-occurrence of FM and BD. METHODS: A systematic search of PubMed/Medline, Cochrane, PsycINFO, CINAHL and Embase was conducted to search for relevant articles. Articles were included if incidence and/or prevalence of BD was determined in the FM sample. Results of prevalence were pooled from all studies. Pooled odds ratio (OR) was calculated based on case-control studies using standard meta-analytic methods. RESULTS: A total of nine studies were included. The pooled rate of BD comorbidity in samples of FM patients was 21% (n=678); however, results varied greatly as a function of study methodology. Case-controlled studies revealed a pooled OR of 7.55 of BD co-morbidity in samples of FM patients [95% Confidence Interval (CI)=3.9-14.62, FM n=268, controls n=413] with low heterogeneity (I(2)=0%). LIMITATIONS: The current study was limited by the low number of available studies and heterogeneity of study methods and results. CONCLUSIONS: These data strongly suggest an association between BD and FM. Future studies employing a validated diagnostic screen are needed in order to more accurately determine the prevalence of BD in FM. An adequate psychiatric assessment is recommended in FM patients with suspected symptoms consistent with BD prior to administration of antidepressants in the treatment of FM.

Sleep architecture variation: a mediator of metabolic disturbance in individuals with major depressive disorder.

Remarkable proportions of individuals diagnosed with major depressive disorder (MDD) have comorbid metabolic disturbances (i.e., obesity, type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia), and vice versa. Accumulating evidence suggests that common pathophysiologic pathways such as a chronic, low-grade, proinflammatory state mediate this frequent co-occurrence. However, it remains unclear what traits precede the onset and increase the risk for these pathologic states. The aim of our review was to evaluate the evidentiary base supporting the hypothesis that the increased hazard for metabolic disturbance in MDD subpopulations (and vice versa) is mediated in part by endophenotypic variations in sleep architecture. We conducted a PubMed search of all English-language literature with the following search terms: sleep disturbance, circadian rhythm, inflammation, metabolic syndrome, obesity, MDD, mood disorder, prodrome, T2DM, cytokine, interleukin, hypertension, dyslipidemia, and hypercholesterolemia. Longitudinal and meta-analysis data indicate that specific variations in sleep architecture (i.e., decreased slow-wave sleep [SWS], increased rapid eye movement [REM] density) precede the onset of depressive symptomatology for a subpopulation of individuals. The same sleep architecture variations also are associated with obesity, T2DM, and hypertension. Decreased SWS and increased REM density is correlated with an increase in proinflammatory cytokines (e.g., IL-6, tumor necrosis factor, etc.). This proinflammatory state has been independently shown to be associated with MDD and metabolic disturbances. Taken together, our review suggests that sleep architecture variation of increased REM density and decreased SWS may be an endophenotypic trait, which serves to identify a subpopulation at increased risk for depressive symptoms and metabolic disturbances. Future research is needed to discern the predictive value, sensitivity, and specificity of using sleep architecture variation as a biomarker for MDD and metabolic disturbances. Validation of this marker would have broad clinical implications, such as primary, secondary, and tertiary preventative health strategies.

Survival of freeze-dried Lactobacillus bulgaricus KFRI 673 in chitosan-coated calcium alginate microparticles.

The aim of this study was to investigate the effect of alginate microparticles coated with three kinds of chitosans of different molecular weights on the survival of Lactobacillus bulgaricus KFRI 673 in simulated gastric (SGJ) and intestinal juices (SIJ) and on their stability during storage at 4 and 22 degrees C. L. bulgaricus KFRI 673 loaded in alginate microparticles was prepared by spraying the mixture of sodium alginate and cell culture into the calcium chloride solution using an air-atomizing device. When L. bulgaricus KFRI 673 was exposed to SGJ of pH 2.0 for 60 min, none of the microorganism survived. Contrary to this result, microbiological analysis indicated that microencapsulation in alginate microparticles improved the survival of acid-sensitive L. bulgaricus KFRI 673 in SGJ and that high molecular weight chitosan coating resulted in the highest survival in SGJ. To study storage stability of free and microencapsulated cells, in vitro studies were conducted at 4 and 22 degrees C during a 4 week period. Both free and microencapsulated cells showed similar stabilities during 4 weeks of storage at 4 degrees C. However, the stability of Lactobacillus at 22 degrees C was appreciably improved when loaded in high molecular weight chitosan-coated alginate microparticles. In conclusion, microencapsulation of lactic acid bacteria with alginate and chitosan coating offers an effective way of delivering viable bacterial cells to the colon and maintaining their survival during refrigerated storage.

Mucinous cystadenoma coexisting with stromal tumor with minor sex-cord elements of the ovary: a case report.

Mucinous neoplasms occur rarely in association with cystic teratoma, Sertoli-Leydig cell tumor, granulosa cell tumor or carcinoid tumor. Several cases of an ovarian stromal tumor with minor sex-cord elements have been reported in the literatures. However, there has been no report about an ovarian mucinous neoplasm coexisting with a stromal tumor with sex-cord elements yet. We report a case of an ovarian neoplasm composed of both mucinous cystadenoma and stromal tumor with minor sex-cord elements in a 58-yr-old female. The ovary including the mass measured 5 cm in size. On section, it revealed an unilocular cyst (4.5 cm in diameter) filled with mucinous fluid. There was a round, yellow, solid nodule, 1.5 cm in diameter within the wall. Microscopically, the cyst was lined by a single layer of endocervical mucinous epithelium and the nodule was composed of spindle cells showing an intersecting and whorled arrangement. There were cell nests showing polygonal shape with abundant cytoplasm among the spindle cells. They showed immunoreactivity for inhibin and did not have any connection with the adjacent mucinous epithelium. Therefore, we interpret the mucinous cystadenoma as having arisen de novo.

Extent of disease as an indication for pelvic radiation following radical hysterectomy and bilateral pelvic lymph node dissection in the treatment of stage IB and IIA cervical carcinoma.

The role of adjuvant pelvic radiation following radical hysterectomy and pelvic lymph node dissection in the treatment of stage IB and IIA cervical cancer is controversial. Patients most likely to benefit from postoperative radiation include those with lesions that invade deeply into the cervical stroma, extend into the parametria, or have metastasized to regional lymph nodes. Between 1977 and 1987, 95 patients were treated with this combined regimen at the University of California Irvine Medical Center and Long Beach Memorial Medical Center, including 30 patients with deep cervical stromal invasion alone, 9 patients with parametrial extension alone, 37 patients with lymph node metastasis alone, and 19 patients with both positive nodes and parametrial extension. The estimated 5-year survival for this high-risk population was 67%. Pelvic recurrences alone occurred in 12 (13%) patients, and 14 additional patients (15%) recurred outside of the radiation field. In the node-positive group, the 5-year survival was 78% when the parametrium was not involved but decreased to 39% when parametrial extension was documented (P < 0.05). Patients with grossly involved nodes or multiple nodal metastases were also more likely to recur. Finally, the estimated 5-year survival for patients with deep cervical stromal invasion as the sole indication for radiotherapy was 73%. A retrospective analysis identified tumor grade and cell type also to be of prognostic importance. Severe complications attributable to radiation combined with radical surgery included two small bowel obstructions and one urinary tract fistula. These data suggest that radical hysterectomy, pelvic lymphadenectomy, and adjuvant radiotherapy produce favorable survival results with limited morbidity in patients with high-risk cervical cancer independent of node status except in that subset of patients with both occult parametrial spread and nodal metastasis.