A widely distributed gene cluster compensates for uricase loss in hominids.

Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.

Fetal heart rate patterns and the incidence of adverse events after oral misoprostol administration for cervical ripening among low-risk pregnancies.

OBJECTIVE: Though misoprostol is commonly used for inpatient cervical ripening, its use in outpatient settings has been limited by safety concerns. This study was conducted to assess the association between early fetal heart tracing (FHT) and maternal tocodynamometry patterns and the incidence of adverse fetal and pregnancy outcomes after the administration of oral misoprostol for cervical ripening. METHODS: We conducted a retrospective cohort study of 9908 low-risk patients at ≥37 weeks gestation who received oral misoprostol for cervical ripening prior to rupture of membranes between 01/01/2012 and 12/31/2017 at Kaiser Permanente Northern California hospitals as inpatients. We excluded patients who received a different agent for cervical ripening or had any need for additional inpatient monitoring, including hypertensive disorders of pregnancy, diabetes, or intrauterine growth restriction. Abnormal FHT, abnormal uterine activity, and adverse pregnancy or fetal-related events documented in the electronic health record in the four hours after administration of the first and second doses of misoprostol were assessed using descriptive statistics. RESULTS: We found that 0.9% of patients experienced tachysystole after the first dose of misoprostol (0.6% without decelerations; 0.3% with decelerations). The incidence of variable decelerations only and other FHT abnormalities (i.e. bradycardia, late or prolonged decelerations, or absent or minimal variability) in the first hour after misoprostol administration were 7.1% and 6.7% respectively, and diminished over time. The need for tocolytic use was 0.2% in the first hour and declined over time to 0.03% in the fourth hour after the first dose. Urgent cesarean delivery occurred in 0.1% of patients after receiving the first dose of misoprostol. Patients who did not experience variable, prolonged, or late decelerations in the first hour after the initial misoprostol dose were less likely to have such FHT abnormalities in the subsequent three hours compared to patients who had other FHT abnormalities (11.8% among patients with no FHT abnormalities vs. 43.7% among patients with other FHT abnormalities; p <.001). The overall trends in outcomes over time were similar after the second dose of misoprostol. CONCLUSION: The risk of short-term adverse outcomes associated with misoprostol is low among relatively low-risk patients. FHT abnormalities occurred in up to 32% of patients in the first four hours of monitoring post-misoprostol. Patients with no FHT abnormalities in the first hour after receiving misoprostol had a low risk of developing adverse outcomes and FHT abnormalities on continued monitoring, while patients with any type of deceleration in the first hour were at higher risk of adverse outcomes and FHT abnormalities. Our data may inform the development of protocols for cervical ripening that allow reduced monitoring for a subset of low-risk patients, however, more research is needed to validate findings and develop clinical protocols.

Patient and Visit Characteristics Associated With Physical Restraint Use in the Emergency Department.

Objective Physical restraints are used in emergency departments (EDs) to address behavioral emergencies in situations in which less restrictive methods have failed. The objective of this study was to evaluate for associations between patient/visit characteristics and physical restraint use. Study Design This study was designed as a cross-sectional, retrospective study of all encounters at Kaiser Permanente Northern California EDs from January 1, 2016, to December 31, 2019, to evaluate differences in patient and visit characteristics between visits involving physical restraint use and those without. Methods Using electronic health record data, this study identified physical restraint use among ED encounters and extracted demographic, clinical, and facility characteristics. The authors calculated odds ratios for physical restraint placement, adjusting for patient and visit characteristics and accounting for within-patient clustering. Results Among 4,410,816 encounters (representing 1,791,673 patients), 6369 encounters (0.1%) involved physical restraint use among 5,554 patients (0.3%). Variables associated with the lowest odds of physical restraint included female sex, presentation to the ED in more recent years, and presence of intentional self-harm/suicidal ideation. Variables associated with the highest odds of physical restraint included higher visit acuity and weekend presentations to the ED. Discussion This study, which leveraged a large, diverse patient sample generalizable to the Northern California population, found several patient and visit characteristics associated with physical restraint use in the ED. Conclusion Results of this study may help identify patient groups and situational factors that are most likely to lead to physical restraint use and structural factors contributing to disparities in care, thereby informing interventions to reduce physical restraint use when possible.

Labor Induction Outcomes with Outpatient Misoprostol for Cervical Ripening among Low-Risk Women.

OBJECTIVE: In 2012, two Kaiser Permanente Northern California (KPNC) hospitals began offering outpatient cervical ripening with oral misoprostol under a study protocol. We evaluated inpatient time from admission to delivery and adverse maternal and neonatal outcomes associated with outpatient use of misoprostol for cervical ripening among low-risk women with term pregnancies. STUDY DESIGN: We conducted a retrospective cohort study comparing three groups: women who received misoprostol (1) outpatient, under a study protocol; (2) inpatient, at the study sites; and (3) inpatient, at all KPNC hospitals. Data were obtained from between 2012 and 2017. The primary outcome was time from inpatient admission to delivery. Secondarily, we evaluated maternal and neonatal outcomes, including the duration and maximum rate of oxytocin administered, rate of cesarean delivery, incidence of chorioamnionitis and blood transfusion, Apgar scores, and neonatal intensive care unit admissions. Demographic and clinical characteristics and outcomes of the outpatient group were compared with both inpatient misoprostol groups using the appropriate statistical test. Variables included in the regression analysis were either statistically significant in the bivariate analyses or have been reported in the literature to be potential confounders: maternal age at admission, race/ethnicity, body mass index, cervical dilation at initial misoprostol, and parity. RESULTS: We analyzed data from 10,253 patients: (1) 345 outpatients, under a study protocol; (2) 1,374 inpatients, at the study sites; and (3) 9,908 inpatients, at all the Kaiser hospitals. Women in the outpatient group were more likely to be white than both inpatient groups (63.3 vs. 56.3% at study sites and 47.1% in all hospitals, p = 0.002 and <0.001, respectively); other demographics were clinically comparable. Most women undergoing labor induction were nulliparous; however, a greater proportion in the outpatient group were nulliparous compared with inpatient groups (70.8 vs. 61.8% and 64.3%, p = 0.002 and 0.01). On inpatient admission for delivery, women who received outpatient misoprostol were more likely to have a cervical dilation of ≥3 cm (39.8 vs. 12.5% at study sites and 9.7% at all KPNC hospitals, p < 0.001 for both). The outpatient group had a shorter mean time between admission and delivery (23.6 vs. 29.4 at study sites and 29.8 hours at all KPNC, p < 0.001 for both). The adjusted estimated mean difference between the outpatient and inpatient group at all the Kaiser hospitals in time from admission to delivery was -6.48 hours (p < 0.001), and the adjusted estimated mean difference in cervical dilation on admission was +1.02 cm (p < 0.001). There was no difference in cesarean delivery rates between groups. The rate of chorioamnionitis in the outpatient group was higher compared with inpatients at all hospitals (17.7 vs. 10.6%, p < 0.001), but similar when compared with the inpatients at the study sites (17.7 vs. 15.4%, p = 0.29). CONCLUSION: Outpatient use of misoprostol for cervical ripening under the study protocol was associated with reduced inpatient time from admission to delivery compared with inpatient misoprostol. Although there was a higher rate of chorioamnionitis among outpatients under the study protocol compared with inpatients at all hospitals, there was no difference when compared with inpatients at the study sites. There was no difference in rates of cesarean delivery or maternal or neonatal complications with outpatient misoprostol. KEY POINTS: · Outpatient misoprostol patients had 6.46 fewer hours from admission to delivery compared with inpatients at all hospitals.. · There was no difference in the rate of cesareans between the outpatient versus inpatient misoprostol groups.. · Other maternal and neonatal complications were low and comparable among outpatients and inpatients who received misoprostol; this study was not large enough to assess rare safety outcomes..

Variation in Vaginal Hysterectomy Rates in an Integrated Healthcare System.

STUDY OBJECTIVE: To describe trends in minimally invasive hysterectomy (MIH) and assess patient, surgical, and provider characteristics associated with differences in vaginal versus laparoscopic rates within an integrated healthcare system. DESIGN: A retrospective cohort study. SETTING: Kaiser Permanente Northern California from 2008 to 2018. PATIENTS: Patients who underwent MIH for benign conditions excluding uterine prolapse and incontinence surgeries. INTERVENTIONS: Hysterectomies. MEASUREMENTS AND MAIN RESULTS: A total of 27518 hysterectomies were performed for benign indications. Of these, the proportion of MIH increased from 29.1% (2008) to 96.7% (2018) (p <.001). The proportion of vaginal hysterectomies (VHs) of all hysterectomies did not change significantly over the study period (p = .07); however, the proportion of VH among MIH cases decreased from a high of 50.6% in 2008 to 13.2% in 2018 (p <.001). VH rates were lower in obese and morbidly obese patients (p <.001 and p = .02, respectively) and in women with uterine weights >250 g (p <.001). The differences persisted after controlling for patient demographic, clinical, and surgery characteristics. Low surgical volume was inversely associated with VH (adjusted relative risk, 7.19; 95% confidence interval, 6.62-7.81; p <.001). VH rates ranged from 11.5% to 27.8% across service areas (hospitals). Service area remained a significant predictor of VH after controlling for patient (including body mass index and uterine weight) and surgery-related characteristics. Postoperative hospital stay decreased from 33.8 ± 16.4 hours (2008) to 6.1 ± 12.2 (2018) for VH. Operative time was shorter for VH than laparoscopic hysterectomies (LHs) (1.7 vs 2.5 hours; p <.001). Overall operative/perioperative complications were low and not significantly different (VH vs LH). CONCLUSION: As the proportion of MIH increased, LH became the preferred route despite similar rates of postoperative stay and intraoperative complications and shorter operative time for VH compared with LH. Service area and provider volume were independent predictors of MIH route, suggesting that training and evidence-based guidelines for route selection may help preserve VH rates.

Teens' perspectives on yoga as a treatment for stress and depression.

OBJECTIVE: To understand adolescents' experiences and attitudes toward yoga, with a particular focus on acceptability and feasibility of a yoga intervention for depressed adolescents. DESIGN: Qualitative analysis of data from three focus groups and eight individual interviews, for a total of 22 teen participants. SETTING: Outpatient setting in a psychiatric hospital in the U.S. MAIN OUTCOME MEASURES: Teens were asked about their own and their peers' attitudes toward, and experiences with, hatha yoga; reactions to a study-created yoga video; and opinions on class logistics. RESULTS: Teens had both positive and negative attitudes toward, and experiences with, hatha yoga. They commented on "who does yoga;" many responses suggested a limited group (e.g., moms; people with money and time). Participants agreed that yoga could be potentially beneficial for depressed or stressed teens. Self-consciousness while being in a yoga class was a major concern. Overall, teens reacted favorably to the study-created yoga video. Teens had varied opinions about class logistics including class duration and size. Teens cited barriers to class, such as transportation, as well as barriers to home yoga practice. CONCLUSIONS: Key points for developing a yoga class that might be appealing to depressed or stressed teens include: creating a class with variety that teens will find interesting; taking concrete steps to decrease teen self-consciousness; incorporating messages relevant for teens and consistent with yoga philosophy; and actively countering stereotypes about who practices yoga. Limitations of this study include the lack of data from male teens.

Pioglitazone and statins lower incidence of Parkinson disease in patients with diabetes mellitus.

BACKGROUND AND PURPOSE: The pharmacologic effects of pioglitazone on the incidence of Parkinson disease (PD) are not clear. No study has examined the interaction between pioglitazone and statin treatment on prevention of PD. This study analyzed the associations between pioglitazone, statins, and the incidence of PD in patients with diabetes mellitus (DM) in Taiwan. METHODS: We used the National Health Insurance database from 1996 to 2013. DM and PD were diagnosed according to the International Classification of Diseases, Ninth Revision, Clinical Modification codes. We used the propensity score-matching method to match the study groups. Cox regression analyses were employed to calculate the relative risk of the incidence of PD. RESULTS: There were 48 828 patients matched and categorized equally into the pioglitazone group and the non-pioglitazone group. The number of PD patients in the pioglitazone group and the non-pioglitazone group was 275 (1.1%) and 417 (1.7%), respectively. The pioglitazone group had a lower incidence of PD, with an adjusted hazard ratio (aHR) of 0.66 [95% confidence interval (CI): 0.57-0.78], and this benefit was dose-dependent. Of note, as compared with either pioglitazone or statin treatment, our results first showed that the combination of pioglitazone and statins further lowered the risk of PD, with an aHR of 0.78 (95% CI: 0.64-0.94; P = 0.010). CONCLUSIONS: Our study results suggested that pioglitazone could be a promising agent for reducing the incidence of PD in patients with DM, and works synergistically with statins.

Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure-Activity Relationships.

Quantitative structure-activity relationships (QSAR) models are often seen as a "black box" because they are considered difficult to interpret. Meanwhile, qualitative approaches, e.g., structural alerts (SA) or read-across, provide mechanistic insight, which is preferred for regulatory purposes, but predictive accuracy of such approaches is often low. Herein, we introduce the chemistry-wide association study (CWAS) approach, a novel framework that both addresses such deficiencies and combines advantages of statistical QSAR and alert-based approaches. The CWAS framework consists of the following steps: (i) QSAR model building for an end point of interest, (ii) identification of key chemical features, (iii) determination of communities of such features disproportionately co-occurring more frequently in the active than in the inactive class, and (iv) assembling these communities to form larger (and not necessarily chemically connected) novel structural alerts with high specificity. As a proof-of-concept, we have applied CWAS to model Ames mutagenicity and Stevens-Johnson Syndrome (SJS). For the well-studied Ames mutagenicity data set, we identified 76 important individual fragments and assembled co-occurring fragments into SA both replicative of known as well as representing novel mutagenicity alerts. For the SJS data set, we identified 29 important fragments and assembled co-occurring communities into SA including both known and novel alerts. In summary, we demonstrate that CWAS provides a new framework to interpret predictive QSAR models and derive refined structural alerts for more effective design and safety assessment of drugs and drug candidates.

Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations.

Nanomaterials (NMs) have gained prominence in technological advancements due to their tunable physical, chemical and biological properties with enhanced performance over their bulk counterparts. NMs are categorized depending on their size, composition, shape, and origin. The ability to predict the unique properties of NMs increases the value of each classification. Due to increased growth of production of NMs and their industrial applications, issues relating to toxicity are inevitable. The aim of this review is to compare synthetic (engineered) and naturally occurring nanoparticles (NPs) and nanostructured materials (NSMs) to identify their nanoscale properties and to define the specific knowledge gaps related to the risk assessment of NPs and NSMs in the environment. The review presents an overview of the history and classifications of NMs and gives an overview of the various sources of NPs and NSMs, from natural to synthetic, and their toxic effects towards mammalian cells and tissue. Additionally, the types of toxic reactions associated with NPs and NSMs and the regulations implemented by different countries to reduce the associated risks are also discussed.

Effects of therapeutic hypothermia on the gut microbiota and metabolome of infants suffering hypoxic-ischemic encephalopathy at birth.

Neonatal hypoxic ischemic encephalopathy (HIE) in the perinatal period can lead to significant neurological deficits in later life. Total body cooling (TBC) is a neuroprotective strategy used in the treatment of HIE and has been shown to reduce seizures and improve neurodevelopmental outcomes in treated infants. Little is known, however, about the effects of HIE/TBC on the developing gut microbiota composition and subsequent metabolic profile. Ten term infants with HIE who received TBC at 33.5°C for 72h were recruited. A control group consisted of nine healthy full term infants. Faecal samples were collected from both groups at 2 years of age and stored at -20°C. 16S rRNA amplicon Illumina sequencing was carried out to determine gut microbiota composition and 1H NMR analysis was performed to determine the metabolic profile of faecal water. The gut microbiota composition of the HIE/TBC infants were found to have significantly lower proportions of Bacteroides compared to the non-cooled healthy control group. Alpha diversity measures detected significantly lower diversity in microbial richness in the HIE/TBC infant group compared to the control infants (Shannon index, <0.05). High inter-individual variation was found in gut microbiota composition and metabolic profile of both groups. Initial principal coordinate analysis and hierarchal clustering of compounds on MetaboAnalyst 3.0 indicated no clear separation in the metabolic profile of these two infant groups. These results suggest that there is no significant impact on the gut microbial development of HIE/TBC infants compared to healthy infants at 2years of life. To our knowledge this is the first study to report the gut microbiota composition and metabolic profile of infants who have experienced HIE/TBC at birth.

Clinical effectiveness of late maxillary protraction in cleft lip and palate: A methods paper.

OBJECTIVES: A prospective parallel cohort trial was conducted to compare outcomes of patients treated with maxillary protraction vs LeFort 1 maxillary advancement surgery. SETTING AND SAMPLE POPULATION: The primary site for the clinical trial is Children's Hospital Los Angeles; the satellite test site is Seattle Children's Hospital. All patients have isolated cleft lip and palate and a skeletal Class III malocclusion. MATERIAL AND METHODS: A total of 50 patients, ages 11-14, will be recruited for the maxillary protraction cohort. The maxillary surgery cohort consists of 50 patients, ages 16-21, who will undergo LeFort 1 maxillary advancement surgery. Patients with additional medical or cognitive handicaps were excluded from the study. RESULTS: Current recruitment of patients is on track to complete the study within the proposed recruitment period. CONCLUSION: This observational trial is collecting information that will examine dental, skeletal, financial and quality-of-life issues from both research cohorts.

Synergistic drug combinations from electronic health records and gene expression.

OBJECTIVE: Using electronic health records (EHRs) and biomolecular data, we sought to discover drug pairs with synergistic repurposing potential. EHRs provide real-world treatment and outcome patterns, while complementary biomolecular data, including disease-specific gene expression and drug-protein interactions, provide mechanistic understanding. METHOD: We applied Group Lasso INTERaction NETwork (glinternet), an overlap group lasso penalty on a logistic regression model, with pairwise interactions to identify variables and interacting drug pairs associated with reduced 5-year mortality using EHRs of 9945 breast cancer patients. We identified differentially expressed genes from 14 case-control human breast cancer gene expression datasets and integrated them with drug-protein networks. Drugs in the network were scored according to their association with breast cancer individually or in pairs. Lastly, we determined whether synergistic drug pairs found in the EHRs were enriched among synergistic drug pairs from gene-expression data using a method similar to gene set enrichment analysis. RESULTS: From EHRs, we discovered 3 drug-class pairs associated with lower mortality: anti-inflammatories and hormone antagonists, anti-inflammatories and lipid modifiers, and lipid modifiers and obstructive airway drugs. The first 2 pairs were also enriched among pairs discovered using gene expression data and are supported by molecular interactions in drug-protein networks and preclinical and epidemiologic evidence. CONCLUSIONS: This is a proof-of-concept study demonstrating that a combination of complementary data sources, such as EHRs and gene expression, can corroborate discoveries and provide mechanistic insight into drug synergism for repurposing.

Biodegradable interstitial release polymer loading a novel small molecule targeting Axl receptor tyrosine kinase and reducing brain tumour migration and invasion.

Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour. The neoplasms are difficult to resect entirely because of their highly infiltration property and leading to the tumour edge is unclear. Gliadel wafer has been used as an intracerebral drug delivery system to eliminate the residual tumour. However, because of its local low concentration and short diffusion distance, patient survival improves non-significantly. Axl is an essential regulator in cancer metastasis and patient survival. In this study, we developed a controlled-release polyanhydride polymer loading a novel small molecule, n-butylidenephthalide (BP), which is not only increasing local drug concentration and extending its diffusion distance but also reducing tumour invasion, mediated by reducing Axl expression. First, we determined that BP inhibited the expression of Axl in a dose- and time-dependent manner and reduced the migratory and invasive capabilities of GBM cells. In addition, BP downregulated matrix metalloproteinase activity, which is involved in cancer cell invasion. Furthermore, we demonstrated that BP regulated Axl via the extracellular signal-regulated kinases pathway. Epithelial-to-mesenchymal transition (EMT) is related to epithelial cells in the invasive migratory mesenchymal cells that underlie cancer progression; we demonstrated that BP reduced the expression of EMT-related genes. Furthermore, we used the overexpression of Axl in GBM cells to prove that Axl is a crucial target in the inhibition of GBM EMT, migration and invasion. In an in vivo study, we demonstrated that BP inhibited tumour growth and suppressed Axl expression in a dose-dependent manner according to a subcutaneous tumour model. Most importantly, in an intracranial tumour model with BP wafer in situ treatment, we demonstrated that the BP wafer not only significantly increased the survival rate but also decreased Axl expression, and inhibited tumour invasion. These results contribute to the development of a BP wafer for a novel therapeutic strategy for treating GBM invasion and increasing survival in clinical subjects.

The influence of comorbid disorders on the episodicity of bipolar disorder in youth.

OBJECTIVE: Bipolar disorder (BP) frequently co-occurs with other psychiatric disorders. We examine whether course of anxiety disorders (ANX), attention deficit hyperactivity disorder (ADHD), disruptive behavior disorders (DBD), and substance use disorders (SUD) influence likelihood of recovery and recurrence of depression and mania in BP youth. METHOD: Weekly ratings of psychiatric disorder intensity were obtained from 413 participants of the Course and Outcome of BP Youth project, followed for an average of 7.75 years. Multiple-event Cox proportional hazards regression analyses examined worsening of comorbid disorders as predictors of mood episode recovery and recurrence. RESULTS: Increased severity in ANX and SUD predicted longer time to recovery and less time to next depressive episode, and less time to next manic episode. Multivariate models with ANX and SUD found that significant effects of ANX remained, but SUD only predicted longer time to depression recovery. Increased severity of ADHD and DBD predicted shorter time to recurrence for depressive and manic episodes. CONCLUSION: There are significant time-varying relationships between the course of comorbid disorders and episodicity of depression and mania in BP youth. Worsening of comorbid conditions may present as a precursor to mood episode recurrence or warn of mood episode protraction.

Cheminformatics-aided pharmacovigilance: application to Stevens-Johnson Syndrome.

OBJECTIVE: Quantitative Structure-Activity Relationship (QSAR) models can predict adverse drug reactions (ADRs), and thus provide early warnings of potential hazards. Timely identification of potential safety concerns could protect patients and aid early diagnosis of ADRs among the exposed. Our objective was to determine whether global spontaneous reporting patterns might allow chemical substructures associated with Stevens-Johnson Syndrome (SJS) to be identified and utilized for ADR prediction by QSAR models. MATERIALS AND METHODS: Using a reference set of 364 drugs having positive or negative reporting correlations with SJS in the VigiBase global repository of individual case safety reports (Uppsala Monitoring Center, Uppsala, Sweden), chemical descriptors were computed from drug molecular structures. Random Forest and Support Vector Machines methods were used to develop QSAR models, which were validated by external 5-fold cross validation. Models were employed for virtual screening of DrugBank to predict SJS actives and inactives, which were corroborated using knowledge bases like VigiBase, ChemoText, and MicroMedex (Truven Health Analytics Inc, Ann Arbor, Michigan). RESULTS: We developed QSAR models that could accurately predict if drugs were associated with SJS (area under the curve of 75%-81%). Our 10 most active and inactive predictions were substantiated by SJS reports (or lack thereof) in the literature. DISCUSSION: Interpretation of QSAR models in terms of significant chemical descriptors suggested novel SJS structural alerts. CONCLUSIONS: We have demonstrated that QSAR models can accurately identify SJS active and inactive drugs. Requiring chemical structures only, QSAR models provide effective computational means to flag potentially harmful drugs for subsequent targeted surveillance and pharmacoepidemiologic investigations.

Opportunities for Nano-Formulations in Type 2 Diabetes Mellitus Treatments.

Diabetes mellitus has been a threat to humans for many years. Amongst the different diabetes types, type 2 diabetes mellitus is the most common, and this is due to drastic changes in human lifestyle such as lack of exercise, stressful life and so on. There are a large number of conventional treatment methods available for type 2 diabetes mellitus. However, most of these methods are curative and are only applicable when the patient is highly symptomatic. Effective treatment strategies should be geared towards interfering with cellular and bio molecular mechanisms associated with the development and sustenance of the disease. In recent years, research into the medical potential of nanoparticles has been a major endeavor within the pharmaceutical industries. Nanoparticles display unique and tuneable biophysical characteristics which are determined by their shape and size. Nanoparticles have been used to manifest the properties of drugs, and as carriers for drug and vaccine delivery. Notwithstanding, there are further opportunities for nanoparticles to augment the treatment of a wide range of life threatening diseases that are yet to be explored. This review article seeks to highlight the application of potential nano-formulations in the treatment of type 2 diabetes mellitus. In addition, the activity of nanomedicine supplements in reversing insulin resistance is also discussed.

Borderline personality disorder in transition age youth with bipolar disorder.

OBJECTIVE: To determine the longitudinal impact of borderline personality disorder (BPD) on the course and outcome of bipolar disorder (BP) in a pediatric BP sample. METHOD: Participants (N = 271) and parents from the Course and Outcome of Bipolar Youth (COBY) study were administered structured clinical interviews and self-reports on average every 8.7 months over a mean of 93 months starting at age 13.0 ± 3.1 years. The structured interview for DSM-IV personality disorders (SIDP-IV) was administered at the first follow-up after age 18 to assess for symptoms of BPD. BPD operationalized at the disorder, factor, and symptom level, was examined as a predictor of poor clinical course of BP using all years of follow-up data. RESULTS: The number of BPD symptoms was significantly associated with poor clinical course of BP, above and beyond BP characteristics. Affective dysregulation was most strongly associated with poor course at the factor level; the individual symptoms most strongly associated with poor course were dissociation/stress-related paranoid ideation, impulsivity, and affective instability. CONCLUSION: BPD severity adds significantly to the burden of BP illness and is significantly associated with a more chronic and severe course and outcome beyond what can be attributable to BP characteristics.

Visible red and infrared light alters gene expression in human marrow stromal fibroblast cells.

OBJECTIVES: This study tested whether or not gene expression in human marrow stromal fibroblast (MSF) cells depends on light wavelength and energy density. MATERIALS AND METHODS: Primary cultures of isolated human bone marrow stem cells (hBMSC) were exposed to visible red (VR, 633 nm) and infrared (IR, 830 nm) radiation wavelengths from a light emitting diode (LED) over a range of energy densities (0.5, 1.0, 1.5, and 2.0 Joules/cm2) Cultured cells were assayed for cell proliferation, osteogenic potential, adipogenesis, mRNA and protein content. mRNA was analyzed by microarray and compared among different wavelengths and energy densities. Mesenchymal and epithelial cell responses were compared to determine whether responses were cell type specific. Protein array analysis was used to further analyze key pathways identified by microarrays. RESULT: Different wavelengths and energy densities produced unique sets of genes identified by microarray analysis. Pathway analysis pointed to TGF-beta 1 in the visible red and Akt 1 in the infrared wavelengths as key pathways to study. TGF-beta protein arrays suggested switching from canonical to non-canonical TGF-beta pathways with increases to longer IR wavelengths. Microarrays suggest RANKL and MMP 10 followed IR energy density dose-response curves. Epithelial and mesenchymal cells respond differently to stimulation by light suggesting cell type-specific response is possible. CONCLUSIONS: These studies demonstrate differential gene expression with different wavelengths, energy densities and cell types. These differences in gene expression have the potential to be exploited for therapeutic purposes and can help explain contradictory results in the literature when wavelengths, energy densities and cell types differ.