Enhancing the Resistive Switching Behavior of WORM Memory Devices Using D-π-A Based Ester-Flanked Quinolines.

Donor-Acceptor systems are highly appreciated in the field of organic memory devices due to their efficient charge transport within the systems. In this work, we have designed and synthesized a D-π-A system constituting ester-flanked quinolines and functionalized triarylamines (TAA) through a single-step cross-coupling reaction to fabricate memory devices via Write-Once Read-Many times (WORM) non-volatile memory. Structure-property relationships are reconnoitered for these conjugated D-π-A systems through a series of UV, fluorescence, XRD, DFT, and memory characterizations. The UV and CV data show efficient charge transfer with intramolecular charge transfer occurring at 407-417 nm and a short band gap of 2.56-2.65 eV. An enhancement in the resistive switching behavior of the memory devices is observed for the compounds with simple TAA-quinoline and tert-butylphenyl substituted TAA and fluorophenyl substituted quinoline due to balanced charge distribution in the compounds. This enhanced switching induces an on/off ratio of 103 by generating a highly ordered arrangement in the thin films. The HOMO, LUMO levels, and the ESP images together estimate a charge transfer and charge trapping as the plausible mechanism for the solution-processable WORM memory devices. The longer retention time (103  s) and lower threshold voltages (-1.21--2.12 V) of the devices makes them intriguing compounds for memory applications.

Using fathers as a negative control exposure: Implications of measurement bias.

Negative control exposure analysis is a very effective tool in evaluating the effect of unmeasured confounding in observational epidemiological studies. Several biases, including recall bias, time-varying confounding factors, measurement bias and so on, can affect the credibility of negative control exposure analysis for causal interpretations. The article focuses on the implications of differential measurement error across exposed group and negative controls to causal interpretations on negative control exposure analysis.

A study of structural and functional connectivity in early Alzheimer's disease using rest fMRI and diffusion tensor imaging.

BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is a progressive neurodegenerative condition where in early diagnosis and interventions are key policy priorities in dementia services and research. We studied the functional and structural connectivity in mild AD to determine the nature of connectivity changes that coexist with neurocognitive deficits in the early stages of AD. METHODS: Fifteen mild AD subjects and 15 cognitively healthy controls (CHc) matched for age and gender, underwent detailed neurocognitive assessment and magnetic resonance imaging (MRI) of resting state functional MRI (rs-fMRI) and diffusion tensor imaging (DTI). Rest fMRI was analyzed using dual regression approach and DTI by voxel wise statistics. RESULTS: Patients with mild AD had significantly lower functional connectivity (FC) within the default mode network and increased FC within the executive network. The mild AD group scored significantly lower in all domains of cognition compared with CHc. But fractional anisotropy did not significantly (p < 0.05) differ between the groups. CONCLUSION: Resting state functional connectivity alterations are noted during initial stages of cognitive decline in AD, even when there are no significant white matter microstructural changes.

Characterization of m6A Modifiers and RNA Modifications in Uterine Fibroids.

Uterine leiomyoma or fibroids are prevalent noncancerous tumors of the uterine muscle layer, yet their origin and development remain poorly understood. We analyzed RNA expression profiles of 15 epigenetic mediators in uterine fibroids compared to myometrium using publicly available RNA sequencing (RNA-seq) data. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key N6-methyladenosine (m6A) modifiers in fibroids and their matched myometrium, showing no significant differences in concordance with our RNA expression profiles. To determine RNA modification abundance, mRNA and small RNA from fibroids and matched myometrium were analyzed by ultra-high performance liquid chromatography-mass spectrometry identifying prevalent m6A and 11 other known modifiers. However, no aberrant expression in fibroids was detected. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic subtype. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression, and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and diverse patient cohort.

Parkinson's disease cybrids, differentiated or undifferentiated, maintain morphological and biochemical phenotypes different from those of control cybrids.

SH-SY5Y, control, and Parkinson's disease (PD) cybrids prepared from an Indian population were differentiated using retinoic acid (RA) for understanding their dopaminergic characteristics and neuritogenesis. Undifferentiated control and PD cybrids exhibited higher levels of TH mRNA, but lower c-RET expression, short neurites, low neuritic density, and low proportion of cells with neurites compared with the undifferentiated parent cell line, SH-SY5Y. The expression levels of DAT and Ptx3 were similar to SH-SY5Y. PD cybrids showed poor viability and lower differentiating potency than SH-SY5Y or control cybrids. RA treatment for 6 days elevated c-RET expression and corrected the neuritic morphology of the control, but not of PD cybrids. Cell viability was found to be reduced in differentiated control and PD cybrids. TH expression level was significantly elevated in SH-SY5Y following RA treatment, but not in both the cybrids. In differentiated control and PD cybrids, the TH immunofluorescence intensity was significantly lower compared with SH-SY5Y cells. MitoTracker Green fluorescence intensity of the mitochondria was higher in differentiated PD cybrids. Dopamine released into the medium was unaffected in the differentiated SH-SY5Y or in the control cybrids but was significantly elevated in PD cybrids. These results suggest that PD cybrids, differentiated or undifferentiated, maintained morphological and biochemical phenotypes significantly different from those of the control cybrids, or the differentiated SH-SY5Y cells, and therefore could be an ideal cellular model of the disease for pharmacological screening of drugs and for investigation of the pathophysiology of PD.

Prevalence of depression and anxiety in older people in low- and middle- income countries in Africa, Asia and South America: A systematic review and meta-analysis.

BACKGROUND: There is rapid growth of older people in Low- and Middle- Income Countries (LMICs). The aim of this review was to assess the literature on prevalence of anxiety and depression in this demographic, which to our knowledge, has not yet been conducted. METHODS: Databases including Medline, PsychInfo, Embase, Scielo and African Journals Online were searched for terms including "mental disorders", "neurotic disorders", "mood disorders" and "anxiety disorders". Studies published between 1990 and 2020 providing data on older people (≥50 years) in LMICs (defined by World Bank Criteria) were included and quality-assessed. Meta-analysis was conducted on a subset of higher-quality studies to derive pooled prevalence estimates of depression. RESULTS: One hundred and forty relevant studies were identified, of which thirty-two were included in meta-analysis. One hundred and fifteen studies reported depression prevalence only, 19 reported both depression and anxiety, and six reported anxiety only. In all studies identified, depression prevalence ranged from 0.5 % to 62.7 %, and Generalised Anxiety Disorder prevalence ranged from 0.2 % to 32.2 %. The pooled prevalence of depression on meta-analysis was 10.5 % (95 % CI, 8.9 % - 11.2 %). Reported prevalence rates of depression were significantly different in studies using ICD-10 compared with DSM criteria, and between community and clinical settings. LIMITATIONS: The search strategy contained bias towards English language papers and high income country (HIC) publications. There is significant heterogeneity within the meta-analysis. DISCUSSION: A wide range of methodologies and clinical criteria are used in prevalence studies of depression and anxiety in older people. Studies using screening tools found higher prevalence rates; clinicians and researchers should ensure diagnosis is made with gold-standard clinical criteria. Meta-analysis data suggest that rates of depression are similar in older people in LMICs compared to HICs but mental healthcare resources are limited, suggesting a large potential treatment gap.

Characterization of m6A modifiers and RNA modifications in uterine fibroids.

Uterine leiomyoma or fibroids are the most common prevalent noncancerous tumors of the uterine muscle layer. Common symptoms associated with fibroids include pelvic pain, heavy menstrual bleeding, anemia, and pelvic pressure. These tumors are a leading cause of gynecological care but lack long-term therapy as the origin and development of fibroids are not well understood. Several next-generation sequencing technologies have been performed to identify the underlying genetic and epigenetic basis of fibroids. However, there remains a systemic gap in our understanding of molecular and biological process that define uterine fibroids. Recent epitranscriptomics studies have unraveled RNA modifications that are associated with all forms of RNA and are thought to influence both normal physiological functions and the progression of diseases. We quantified RNA expression profiles by analyzing publicly available RNA-seq data for 15 known epigenetic mediators to identify their expression profile in uterine fibroids compared to myometrium. To validate our findings, we performed RT-qPCR on a separate cohort of uterine fibroids targeting these modifiers confirming our RNA-seq data. We then examined protein profiles of key m6A modifiers in fibroids and their matched myometrium. In concordance with our RNA expression profiles, no significant differences were observed in these proteins in uterine fibroids compared to myometrium. To determine abundance of RNA modifications, mRNA and small RNA from fibroids and matched myometrium were analyzed by UHPLC MS/MS. In addition to the prevalent N6-methyladenosine (m6A), we identified 11 other known modifiers but did not identify any aberrant expression in fibroids. We then mined a previously published dataset and identified differential expression of m6A modifiers that were specific to fibroid genetic sub-type. Our analysis also identified m6A consensus motifs on genes previously identified to be dysregulated in uterine fibroids. Overall, using state-of-the-art mass spectrometry, RNA expression and protein profiles, we characterized and identified differentially expressed m6A modifiers in relation to driver mutations. Despite the use of several different approaches, we identified limited differential expression of RNA modifiers and associated modifications in uterine fibroids. However, considering the highly heterogenous genomic and cellular nature of fibroids, and the possible contribution of single molecule m6A modifications to fibroid pathology, there is a need for greater in-depth characterization of m6A marks and modifiers in a larger and varied patient cohort.

Absent pulmonary valve syndrome: prenatal cardiac ultrasound diagnosis with autopsy correlation.

Absent pulmonary valve syndrome (APVS) is a rare conotruncal anomaly consisting of a severely hypoplastic pulmonary valve with annular stenosis, aneurysmal dilatation of main pulmonary artery with dilatation of one or both pulmonary artery branches, and a ventricular septal defect. Here, we report a prenatal echo diagnosis of APVS in a 27-year-old primi gravida at 20 weeks of gestation confirmed on fetal autopsy. A 'bow tie'-like hypoechoic shadow in fetal cardiac ultrasound observed by us in a modified four-chamber view was suggestive of aneurysmal dilatation of branch pulmonary arteries. The consequences of continuation of pregnancy including immediate neonatal complications and possible medical and multistaged surgical interventions were well explained. Parents opted for medical termination of pregnancy. Autopsy findings of the fetus were consistent with the prenatal echo diagnosis of APVS. The presence of patent ductus arteriosus seen in the autopsy may be the cause of severe heart failure evidenced by the abnormally large congested liver, dilated right heart chambers, and tricuspid valve annulus. We infer that the prenatal diagnosis of APVS may be possible with a high degree of accuracy with characteristic fetal echocradiographic findings such as 'bow tie'-like or 'ballooning'-like shadows observed in this case. The presence of ductus confirms definite fetal loss and the parents can be counselled accordingly. However, when the ductus is absent, decision-making is difficult as the fetus is going to survive.

Widespread intradermal accumulation of mononuclear leukocytes in lepromatous leprosy patients treated systemically with recombinant interferon gamma.

Intradermal administration of recombinant interferon gamma (rIFN-gamma) to lepromatous leprosy patients has converted the local histology toward a tuberculoid pattern. However, such changes have been confined to the site of injection. In contrast, in the present study, marked, intradermal accumulation of CD3+, CD4+, CD8+, and CD1a+ T cells and Leu-M5+ mononuclear phagocytes was induced at a distance from the sites of administration, in a dose-dependent manner, by 10 daily intramuscular injections of 10-30 micrograms rIFN-gamma/m2. Mononuclear cell infiltration began within 3 d of onset of rIFN-gamma therapy and persisted at least 8 wk. Intramuscular administration of rIFN-gamma to lepromatous patients receiving concurrent chemotherapy can safely induce widespread histologic features of an upgrading reaction.

Drug-induced rhinitis.

BACKGROUND: Rhinitis is characterized by inflammation of the mucous membranes lining the nose and can be divided into two categories, allergic and non-allergic. Drug-induced is a type of non-allergic rhinitis. OBJECTIVE: A review of the literature was conducted. Very little is known about this topic and there are no publications to date solely devoted to drug-induced rhinitis. METHODS: A PubMed and Medline search was conducted using a combination of the keywords; drug, medication, rhinitis, congestion, rhinorrhea, sneezing, pruritus, vasomotor, reflex, neurogenic, allergic and non-allergic. Medications that were found in the search were then cross-referenced with the physicians desk reference and Epocrates. The final literature search was conducted in August 2009. RESULTS: Three categories of drug-induced rhinitis exist based on the mechanism of action. These include local inflammatory, neurogenic and idiopathic types. Rhinitis medicamentosa, a form of drug-induced rhinitis, has unique characteristics. CONCLUSION: When possible, the offending medication should be discontinued or substituted. Although there are no established treatment recommendations for drug-induced rhinitis other than avoidance, clinical experience suggests that it would be reasonable to initiate use of an intranasal corticosteroid spray to treat symptomatically. The addition of an intranasal antihistamine in combination with use of an intranasal corticosteroid may be considered as step-up therapy if the intranasal corticosteroid alone is not effective.

Exploring atypical locations of mammalian neural stem cells: the human filum terminale.

Neurogenesis is a multifactorial event determined by local environmental cues, inherent cellular program as well as cellular milieu and may not necessarily be restricted to the SVZ and SGZ. NSCs have been isolated from or neurogenesis has been demonstrated in traditionally non neurogenic regions. This more permissive view of neurogenesis, however, is not widely accepted due to concerns regarding the methodologies used. Furthermore, it is compounded by the fact that the basal levels of increased neurogenesis in such regions has not been completely confirmed and thus precludes a paradigm shift. Were this non limited view of neurogenesis to be generally accepted after thorough investigation, it would open new avenues for regenerative medicine and stem cell therapy.

Role of TLR4 in the induction of inflammatory changes in adipocytes and macrophages.

In obesity, high levels of saturated fatty acids (SFAs) contribute to adipose tissue inflammation and dysfunction. Obesity-induced macrophage infiltration leads to insulin resistance, but the adipocyte itself may play a role in generating the inflammatory milieu. Given our recent findings of the role of TLR4 in myeloid biasing in obesity, we next investigated the role of TLR4 in adipocyte generated inflammatory responses to SFAs and lipopolysaccharides. We used WT and Tlr4-/- ear mesenchymal stem cell derived adipocytes (EMSC Ad) and bone marrow dendritic cells (BMDCs) to evaluate cell specific responses. Our work demonstrates a role for TLR4 in adipocyte- immune cell crosstalk and that SFA derived metabolites from adipocytes may induce proinflammatory stimulation of immune cells in a TLR4 independent manner.

Delaying clozapine: how long is too long?

BACKGROUND: Although clozapine is the most effective drug for treatment-resistant schizophrenia, its use remains restricted in clinical practice in India. The delay in initiating treatment with clozapine and its impact on disease outcome needs evaluation. AIM: To identify the implications of delaying clozapine initiation in clinical outcomes among people with treatment-resistant schizophrenia. METHODS: Subjects with treatment-resistant schizophrenia, stabilised on clozapine monotherapy, were recruited from the outpatient clinic of a general hospital psychiatry unit offering tertiary care services in Thrissur district, Kerala, India. A retrospective cohort design was employed, and information on duration of illness, total duration of treatment and duration of treatment with clozapine was collected. Present symptom status was measured using the Positive and Negative Syndrome Scale. Factors associated with higher symptom scores were analysed using an independent sample t test, Spearman correlation and multiple linear regression. RESULTS: Forty subjects stabilised on long-term clozapine therapy formed the study sample. The mean dose of clozapine used in the study population was 200 mg. The mean duration of antipsychotic treatment before starting clozapine was 89.3 months (7.4 years). The duration of treatment before starting clozapine was found to have a significant positive association with the total Positive and Negative Syndrome Scale score (correlation coefficient 0.40; p=0.01) and negative symptom score (correlation coefficient 0.33; p=0.04). The multiple regression analysis adjusting for covariates showed that the duration of treatment before starting clozapine was an independent factor associated with a higher negative symptom score in the Positive and Negative Syndrome Scale (slope ß=0.05; p=0.02; R2=0.27). CONCLUSION: Poor treatment outcomes in treatment-resistant schizophrenia could be secondary to a delay in initiating clozapine therapy.

The effect of poly-L-lysine/alginate bead membrane characteristics on the absorption of heparin.

During extracorporeal procedures like hemodialysis, heparin is administered to patients to prevent clotting. Unfractionated heparin has side effects such as excessive bleeding. It would be advantageous if the blood could be deheparinased before it returns to the patient. Previous work has indicated that poly-L-lysine/alginate beads can efficiently remove heparin from saline solutions 1. Heparin is irreversibly absorbed onto the beads. This article explores ways of optimizing the absorption process by performing in vitro rate experiments with varying physical parameters of the beads. Fetal calf serum and blood are also used in experiments to investigate the possibility of designing a safe and efficient reactor to absorb heparin. All the experiments were performed to obtain the required parameters for optimal reactor design. The results indicate that the absorption could be optimized by controlling the membrane thickness of the beads. The beads also showed efficient removal of heparin from whole blood.

Congenital patellar syndrome.

Congenital patellar syndrome is bilateral isolated absence of patella. Congenital patellar aplasia or hypoplasia associated with genetic disorders belongs to a clinically diverse and genetically heterogeneous group of lower limb malformations. Absence of patella as an isolated anomaly is extremely rare and we discuss such a case in a 9-year-old boy.

Programming effects of maternal and gestational obesity on offspring metabolism and metabolic inflammation.

With the increasing prevalence of obesity in women of reproductive age there is a need to understand the ramifications of this on offspring. The purpose of this study is to investigate the programming effects of maternal obesity during preconception and the preconception/gestational period on adiposity and adipose tissue inflammation in offspring using an animal model. Adult female C57Bl/6J mice were assigned either normal diet, high fat diet (HFD) prior to pregnancy, or HFD prior to and through pregnancy. Some offspring were maintained on normal diet while others started HFD later in life. Offspring were assessed for body composition and metabolic responses. Lipid storing tissues were evaluated for expansion and inflammation. Male offspring from the preconception group had the greatest weight gain, most subcutaneous adipose tissue, and largest liver mass when introduced to postnatal HFD. Male offspring of the preconception/gestation group had worsened glucose tolerance and an increase in resident (CD11c-) adipose tissue macrophages (ATMs) when exposed to postnatal HFD. Female offspring had no significant difference in any parameter between the diet treatment groups. In conclusion, this study demonstrates that prenatal and pregnancy windows have independent programming effects on offspring. Preconception exposure affects body composition and adiposity while gestation exposure affects metabolism and tissue immune cell phenotypes.

Reverse total shoulder arthroplasty using a trabecular metal glenoid base plate: functional and radiological outcomes at two to five years.

AIM: We present the medium-term clinical results of a reverse total shoulder arthroplasty with a trabecular metal glenoid base plate. PATIENTS AND METHODS: We reviewed 125 consecutive primary reverse total shoulder arthroplasties (RTSA) implanted in 124 patients for rotator cuff arthropathy. There were 100 women and 24 men in the study group with a mean age of 76 years (58 to 89). The mean follow-up was 32 months (24 to 60). No patient was lost to follow-up. RESULTS: There were statistically significant improvements in the mean range of movement and Oxford Shoulder Score (p < 0.001). Kaplan-Meier survivorship at five years was 96.7% (95% confidence interval 91.5 to 98.7) with aseptic glenoid failure as the end point. Radiologically, 63 shoulders (50.4%) showed no evidence of notching, 51 (40.8%) had grade 1 notching, ten (8.0%) had grade 2 notching and one (0.8%) had grade 4 notching. Radiolucency around the glenoid base plate was found in one patient (0.8%) and around the humeral stem in five (4.0%). In all, three RTSA (2.4%) underwent revision surgery for aseptic mechanical failure of the glenoid within 11 months of surgery due to malseating of the glenosphere. CONCLUSION: The clinical results of this large independent single unit series are comparable to those from previous series of RTSA reported in the literature. A trabecular metal base plate is safe and effective in the medium-term. Cite this article: Bone Joint J 2016;98-B:969-75.

Determination of inter- and intra-species genetic relationships among six Eucalyptus species based on inter-simple sequence repeats (ISSR).

Eucalyptus is the most economically important hardwood plantation tree cultivated in tropical and subtropical countries. Inter-simple sequence repeat (ISSR) markers were used to evaluate genetic relationships within and between individuals of six Eucalyptus species. A total of 583 loci (265 to 1535 bp) were amplified from 149 individuals belonging to the six Eucalyptus species using seven ISSR primers (two to three nucleotide repeats anchored with one or two nucleotides at the 3' or 5' region). The ISSR fragments indicated significant polymorphism and genetic diversity among the individuals. Cluster analysis and principal component analysis revealed the occurrence of wide genetic diversity among populations of E. tereticornis Sm., E. camaldulensis Dehnh. and E. urophylla S.T. Blake and narrow genetic diversity among populations of E. citriodora Hook. and E. grandis W. Hill ex Maiden. Genetic diversity was high in E. tereticornis Sm. (47.27%) and low in E. citriodora (18.64%). Maximum Nei's genetic identity (0.897) was observed between E. camaldulensis and E. tereticornis species, whereas maximum genetic diversity (0.286) was found between individuals of E. citriodora and E. grandis.