Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Characteristics of ipsilateral, contralateral and bilateral masseter vestibular-evoked myogenic potential in healthy adults.

OBJECTIVE: This study aimed to characterise the ipsilateral, contralateral and bilateral masseter vestibular-evoked myogenic potential using clicks and 500 Hz tone burst stimuli in healthy adults. METHOD: Masseter vestibular-evoked myogenic potential was recorded from 20 healthy participants aged 19-28 years (11 males and 9 females). Masseter vestibular-evoked myogenic potential was recorded using 500 Hz tone burst and click stimuli in ipsilateral, contralateral and bilateral modes. RESULTS: A statistically significant difference was observed between ipsilateral and contralateral stimulation for p11 latency, n21 latency and p11-n21 amplitude for both click and 500 Hz tone burst stimuli. The amplitude of the p11-n21 complex was higher for ipsilateral, contralateral and bilateral stimulations for 500 Hz tone burst than for click stimulus. CONCLUSION: This study showed a significant difference for p11-n21 amplitude between click and 500 Hz tone burst evoked masseter vestibular-evoked myogenic potential. In addition, bilateral stimulation elicited a larger response than ipsilateral and contralateral stimulation.

Bioactive phytocompound mulberroside C and endophytes of Morus alba as potential inhibitors of HIV-1 replication: a mechanistic evaluation.

OBJECTIVES: Despite considerable advancement in antiretroviral therapy, development of safe, effective, and multi-targeted drugs for HIV still remains a big challenge. Endophytes are untouched and, hence, an important and novel sources in drug discovery endeavours. The present study was conducted to identify the anti-HIV compounds from Morus alba and endophytes isolated from it. METHODS: The extracts of isolated endophytes were screened using high-performance liquid chromatography (HPLC). Further, all samples were analysed for their cytotoxicity using a thiazolyl blue tetrazolium bromide assay. Subsequently, anti-HIV activity was performed using cell-based and cell-free assay. At the end, potential endophytes were identified using gene sequencing. RESULTS: A total of 27 endophytes were isolated from the eight stem bark samples of M. alba. Of the 27 endophytes, extracts of total of four endophytes showed a profile similar to the M. alba plant when analysed by HPLC. Further experimentation with extracts of these four endophytes, along with an extract of M. alba stem bark and its bioactive molecule, mulberroside C, revealed that all these six samples have good inhibitory potential for HIV. Among them, mulberroside C and two endophytic fungal extracts showed very potent anti-HIV activity. Subsequently, mechanistic studies at the molecular level showed that out of six test samples, three acted as protease inhibitors. Further, all four potential endophytes were identified using gene sequencing. CONCLUSIONS: The overall findings of these studies can help in the development of a novel anti-HIV candidate from mulberroside C, an extract of stem bark of M. alba and extracts of these endophytes. However, further validation and clinical studies are required to develop an anti-HIV drug.

Encoding of a binaural speech stimulus at the brainstem level in middle-aged adults.

OBJECTIVE: Binaural hearing is facilitated by neural interactions in the auditory pathway. Ageing results in impairment of localisation and listening in noisy situations without any significant hearing loss. The present study focused on comparing the binaural encoding of a speech stimulus at the subcortical level in middle-aged versus younger adults, based on speech-evoked auditory brainstem responses. METHODS: Thirty participants (15 young adults and 15 middle-aged adults) with normal hearing sensitivity (less than 15 dB HL) participated in the study. The speech-evoked auditory brainstem response was recorded monaurally and binaurally with a 40-ms /da/ stimulus. Fast Fourier transform analysis was utilised. RESULTS: An independent sample t-test revealed a significant difference between the two groups in fundamental frequency (F0) amplitude recorded with binaural stimulation. CONCLUSION: The present study suggested that ageing results in degradation of F0 encoding, which is essential for the perception of speech in noise.

Effect of Reduced Glutathione, Water Soluble Vitamin E Analogue and Butylated Hydroxytoluene on the Post Thaw Characteristics of Boar Spermatozoa.

BACKGROUND: Antioxidant in freezing extender of boar semen improved post thaw sperm function. OBJECTIVE: The study compared the effects of reduced glutathione (GSH), water soluble vitamin E analogue Trolox and butylated hydroxytoluene (BHT) on quality of cryopreserved boar spermatozoa. MATERIALS AND METHODS: Using split sample technique three different antioxidants namely, GSH (1 mM), vitamin E (0.2 mM) and BHT (0.2 mM) were added to the freezing medium of lactose-egg yolk-glycerol extender, and samples were frozen using controlled freezing rate of 40°C/min from -6 to -140°C. Samples were evaluated for sperm motility, acrosomal status, plasma membrane integrity, mitochondrial membrane potential, lipid peroxidation and sperm DNA integrity after equilibration and after freezing. RESULTS: The supplementation of GSH, vitamin E and BHT resulted in significantly higher post thaw motility, live intact acrosome and plasma membrane intact sperm. The incidence of post thaw sperm lipid peroxidation was significantly reduced after addition of antioxidants. However, antioxidants treatment neither significantly improved mitochondrial membrane potential of live sperm sub-population nor sperm DNA integrity after freezing. There was no significant difference of the post thaw sperm characteristics among three antioxidants. Protective effect of GSH, vitamin E and BHT are comparable on cryopreserved boar spermatozoa.

Intermittent clobazam prophylaxis in hot water epilepsy is safe and effective: a prospective study.

PURPOSE: To evaluate the role of intermittent prophylaxis with clobazam in the management of HWE in a long-term prospective study. MATERIAL AND METHODS: Two hundred and sixty patients [M:F - 194:66] with HWE were recruited. Patients were divided into: (a) 'HWE alone' (n=198) - received intermittent clobazam prophylaxis, 1-1½h prior to hot water head bath (group A); (b) 62 patients (20.4%) with 'HWE with spontaneous seizures were treated with continuous AEDs along with intermittent clobazam therapy (group B). RESULTS: Patients (n=198) in group A was followed for mean of 17.6 ± 10.6 months (range: 3-57). One hundred and forty seven patients (74.2%) had excellent response with complete seizure freedom with clobazam therapy while 12 (6.1%) had >75% reduction in seizure frequency. Remaining 39 (19.7%) required additional standard AED along with clobazam and 18 patients among them developed spontaneous/unprovoked seizure at follow up of 6.7 ± 4.1 months. Forty five patients in group B were seizure free while on continuous AEDs. CONCLUSIONS: Intermittent clobazam prophylaxis prior to head water bath might be a preferred mode of treatment of pure HWE. Additional AEDs are required if they have associated non-reflex unprovoked seizure.

Yoga and epilepsy: What do patients perceive?

CONTEXT: Benefit of yoga therapy in the management of epilepsy is emerging. However, there is no data available about the knowledge, attitude and practice (KAP) of yoga amongst people living with epilepsy (PLWE). AIMS: This study was designed to explore the KAP about yoga among PLWE. SETTINGS AND DESIGN: The study was conducted on 300 PLWE attending the neurology out-patient services of a tertiary care hospital. METHODOLOGY: Three hundred PLWE (male:female=173:127; age: 31.6±12.4 years) attending the neurology out-patient services of a neuropsychiatry hospital were administered a pre-tested KAP questionnaire. RESULTS: About 87.4% were on regular anti-epileptic drugs and half (50.3%) on monotherapy. Use of complementary and alternative medicine by the respondents included: Ayurveda (26.7%), yoga (25.6%) and homeopathy (16.3%) or folk medicine (29.1%). Nearly 33.7% of the respondents reported that yoga is beneficial in managing epilepsy. More than half the respondents (54.8%) were willing to practice yoga. Those who practiced yoga opined that regular practice of yoga might reduce dosage of medication (62.8%), their side effects (51.3%) and frequency of seizures (54.5%). Majority of the patients were willing to practice yoga, if yoga services were offered. CONCLUSION: The gaps in KAP identified in this study point to the need for more systematic effort to bring about awareness of yoga in patients with epilepsy.

Effects of slow breathing exercise on cardiovascular functions, pulmonary functions & galvanic skin resistance in healthy human volunteers - a pilot study.

BACKGROUND & OBJECTIVES: Regular practice of slow breathing has been shown to improve cardiovascular and respiratory functions and to decrease the effects of stress. This pilot study was planned to evaluate the short term effects of pranayama on cardiovascular functions, pulmonary functions and galvanic skin resistance (GSR) which mirrors sympathetic tone, and to evaluate the changes that appear within a short span of one week following slow breathing techniques. METHODS: Eleven normal healthy volunteers were randomized into Pranayama group (n=6) and a non-Pranayama control group (n=5); the pranayama volunteers were trained in pranayama, the technique being Anuloma-Viloma pranayama with Kumbhak. All the 11 volunteers were made to sit in similar environment for two sessions of 20 min each for seven days, while the pranayama volunteers performed slow breathing under supervision, the control group relaxed without conscious control on breathing. Pulse, GSR, blood pressure (BP) and pulmonary function tests (PFT) were measured before and after the 7-day programme in all the volunteers. RESULTS: While no significant changes were observed in BP and PFT, an overall reduction in pulse rate was observed in all the eleven volunteers; this reduction might have resulted from the relaxation and the environment. Statistically significant changes were observed in the Pranayama group volunteers in the GSR values during standing phases indicating that regular practice of Pranayama causes a reduction in the sympathetic tone within a period as short as 7 days. INTERPRETATION & CONCLUSIONS: Beneficial effects of pranayama started appearing within a week of regular practice, and the first change appeared to be a reduction in sympathetic tone.

Pyoderma gangrenosum: guideline for wound practitioners.

Pyoderma gangrenosum (PG) is an atypical ulceration of the skin with unknown aetiology, usually associated with autoimmune systemic illnesses and haematological malignancies. Diagnosis is based on clinical suspicion and exclusion of other conditions. Treatment options vary greatly, ranging from conservative local and systemic immunosuppression to surgical measures, including amputation, but none is shown to be universally effective. Currently no guideline regarding escalation of treatment exists. Based on a review of the current literature and three illustrative cases of PG, a working treatment guideline is presented for wound practitioners.

Subcortical structural abnormalities in juvenile myoclonic epilepsy (JME): MR volumetry and vertex based analysis.

PURPOSE: Imaging studies in juvenile myoclonic epilepsy (JME) have shown abnormalities of the thalamus and frontal cortex. The purpose of this study was to systematically investigate the morphological changes in the deep gray matter (GM) structures using techniques of voxel based morphometry (VBM), MR volumetry and shape analysis. METHODOLOGY: The study included 40 patients with JME (M:F=21:19; age 22.8±5.3 years) and 19 matched controls (M:F=13:6; age 24.5±4.2 years). All subjects underwent MRI using standard protocol that included T1-3D TFE (Turbo Field Echo) images with 1mm thickness. VBM analysis and MR volumetry were performed. The volumes of deep subcortical GM structures were extracted and vertex-wise shape analysis was performed using FSL-FIRST (FSL-Integrated Registration and Segmentation Toolbox) software. RESULTS: VBM analysis with a thalamic mask revealed focal thalamic alterations in the anteromedial aspect of the thalamus (p<0.05, false discovery rate (FDR) corrected) which remained significant after adjusting for age, gender and intracranial volume (ICV). Significant volume loss was noted in both the thalami. Vertex-wise shape analysis showed significant focal surface reductions in the thalami bilaterally in patients that were predominantly seen in the medial as well as lateral aspects of the thalamus (p<0.05, FDR corrected). The disease duration correlated with left hippocampus volume while age of onset correlated with right hippocampus volume. CONCLUSIONS: This study confirms the presence of thalamic alterations in patients with JME. Shape analysis technique provided complementary information and disclosed the presence of focal atrophic changes in patients' thalami. The striatum and hippocampus did not show any significant alterations.

Hot water epilepsy clinical profile and treatment--a prospective study.

PURPOSE: This study characterized the demographic, clinical, EEG and imaging profile, and therapeutic outcome among patients with hot water epilepsy (HWE). METHODOLOGY: This prospective study included 70 patients with HWE (M:F=55:15; age: 25.3±8.4 years). Details of demography, seizure characteristics and outcome, and imaging/EEG observations were recorded. RESULT: There was male dominance. Majority of the patients belonged to Mandya: 30.5%, Ramanagara: 30.0% and Mysore: 15.2% districts of Karnataka, India. Forty-five patients (M:F=37:8; age: 24.6±10.1 years) had features of 'HWE alone'. Twenty-five (M:F=18:7; age: 26.7±7.9 years) had HWE with spontaneous seizures. The age at onset of seizures was comparable in both the groups - HWE: 18.7±10.2 years vs. HWE with spontaneous seizure: 16.8±10.3 years (p=0.34). The duration of seizures were more in HWE with spontaneous seizure group: 119.5±66.9 months compared to HWE alone: 69.9±13.8 months (p=0.028). Inter-ictal EEG (n=70) showed epileptiform activities in 15 patients (21.4%). The therapeutic outcome after 3-8 months of follow up were - (a) HWE group: 6 stopped hot water head bath; 39 were on intermittent clobazam therapy - seizure free: 33; and 6 received AEDs; (b) HWE with spontaneous seizure group: all were on AEDs and seizure free. CONCLUSIONS: Three-fourth of patients belonged to 'Mandya-Mysore belt of Karnataka'. There was increased duration of seizures among those with additional spontaneous seizure. About 3/4th subjects with HWE alone were seizure free with intermittent clobazam and remaining patients on AEDs were seizure free, confirming the earlier observations from this center.

Prostate biopsy findings in Indian men: a hospital-based study.

AIMS: To review prostatic biopsy findings in Indian patients with elevated serum prostate-specific antigen (PSA) attending the Urology department at a tertiary care hospital. SETTINGS AND DESIGN: A retrospective study of 119 patients, who underwent TRUS-guided prostatic biopsy, was conducted. MATERIALS AND METHODS: A total of 119 patients undergoing TRUS-guided prostatic biopsy were evaluated. Age, presentation, PSA, digital rectal examination, number of cores, and final histology were analyzed. Minimum 10 cores biopsies were performed in 109/119 (92%) and 12 cores in 92/119 (77%). Patients were stratified into three groups based on their PSA: 4-10 ng/ml (group I), 10-20 ng/ml (group II), and >20 ng/ml (group III). STATISTICAL ANALYSIS: Unpaired t-test, Chi-square test, and logistic regression were calculated using an Excel (Ver 2007) and online calculators (P < 0.05 significant). RESULTS: Mean age was 67.6 years. Inflammatory pathology (30/119) was common at all PSA levels. In men with negative DRE and PSA > 10 ng/ml, inflammatory pathology was more likely (Chi 4.2798, P = 0.039). Cancer was found in 29/119 biopsies (group I 2/28, group II 3/45, and group III 24/46). Patients with PSA > 20 ng/ml were more likely to show cancer. Precursor lesions were noted in 10/119 (8.4%). On univariate analysis age, PSA, and DRE all showed significant association with histologic cancer but on multiple logistic regression analysis, only PSA (OR 1.03, P = 0.0021) and DRE (OR 8.07, P = 0.0007) were predictive of cancer. CONCLUSIONS: Cancer is less common and inflammatory lesions more common at all levels of PSA in our patients. The effect of antibiotics on PSA and biopsy in our patients needs to be explored.

Comparison of vestibular evoked myogenic potentials elicited by click and short duration tone burst stimuli.

INTRODUCTION: Vestibular evoked myogenic potentials are short latency electrical impulses that are produced in response to higher level acoustic stimuli. They are used clinically to diagnose sacculocollic pathway dysfunction. AIM: This study aimed to compare the vestibular evoked myogenic potential responses elicited by click stimuli and short duration tone burst stimuli, in normal hearing individuals. METHOD: Seventeen subjects participated. In all subjects, we assessed vestibular evoked myogenic potentials elicited by click and short duration tone burst stimuli. RESULTS AND CONCLUSION: The latency of the vestibular evoked myogenic potential responses (i.e. the p13 and n23 peaks) was longer for tone burst stimuli compared with click stimuli. The amplitude of the p13-n23 waveform was greater for tone burst stimuli than click stimuli. Thus, the click stimulus may be preferable for clinical assessment and identification of abnormalities as this stimulus has less variability, while a low frequency tone burst stimulus may be preferable when assessing the presence or absence of vestibular evoked myogenic potential responses.

Hyperemesis-gravidarum-induced Wernicke's encephalopathy: serial clinical, electrophysiological and MR imaging observations.

Wernicke's encephalopathy (W.E.), a potentially reversible condition caused by thiamine deficiency, is usually suspected in the setting of chronic alcoholism and might not be recognized when associated with other conditions. We describe a young pregnant woman who presented with rapidly evolving ataxia, diplopia and irrelevant speech following repeated vomiting. Characteristic brain MRI and rapid response to thiamine suggested that she had W.E. possibly due to hyperemesis gravidarum. A high index of suspicion is required, since delayed or lack of treatment may lead to high morbidity and mortality.

Synthesis and antitubercular screening of imidazole derivatives.

A series of imidazole based compounds were synthesized by reacting simple imidazoles with alkyl halides or alkyl halocarboxylate in presence of tetrabutylammonium bromide (TBAB). The compounds bearing carbethoxy group undergo amidation with different amines in the presence of DBU to give respective carboxamides. The synthesized compounds were screened against Mycobacterium tuberculosis where compound 17 exhibited very good in vitro antitubercular activity and may serve as a lead for further optimization.

Withdrawal of penicillamine from zinc sulphate-penicillamine maintenance therapy in Wilson's disease: promising, safe and cheap.

BACKGROUND: Penicillamine, once considered the cornerstone of treatment for Wilson disease (WD), is rather expensive and toxic, and often causes neurological worsening. Zinc sulphate, aiming at the treatment of free-copper toxicosis, has emerged as effective, safe and cheap alternative. AIM: To assess the effect of withdrawal of penicillamine from maintenance treatment with penicillamine and zinc sulphate. PATIENTS AND METHODS: 45 patients of WD (M:F: 28:17; age at diagnosis: 13.5+/-63 years), on both penicillamine (P) and zinc sulphate (Zn), couldn't continue penicillamine due to financial constraints. Their clinical data, disability and impairment scores (Schwab and England (S&E) score, Neurological Symptom Score (NSS), and Chu staging) and follow-up data of patients maintained only on zinc sulphate were recorded. RESULTS: Majority of patients (84.4%) had neuropsychiatric manifestations. The mean duration of treatment with penicillamine (P) and zinc sulphate (P+Zn), before stopping penicillamine, was 107.4+/-67.3 months. 40 patients improved variably, while the rest didn't. They received only zinc sulphate for 27.2+/-8.5 months (range: 12 to 34) and 44 patients (97.7%) remained status quo or improved marginally. Only one patient reported worsening in dysarthria. Their disability and impairment scores during combination (penicillamine and zinc sulphate) and Zn alone were: Chu (1.3+/-0.5 vs. 1.5+/-1.9; p=0.4), NSS (1.8+/-3.1 vs. 1.5+/-2.3; p=0.03) and S&E (96.4+/-5.6 vs. 98.6+/-3.5; p=0.03). There were no adverse effects. CONCLUSIONS: Withdrawal of penicillamine from zinc sulphate/penicillamine maintenance therapy for patients with Wilson's disease was effective, safe and economic, for almost all patients. This retrospective study reiterates that zinc sulphate may be used as a preferred mode of treatment for patients with Wilson's disease.

Modulation of cardiac autonomic balance with adjuvant yoga therapy in patients with refractory epilepsy.

The practice of yoga regulates body physiology through control of posture, breathing, and meditation. Effects of yoga on autonomic functions of patients with refractory epilepsy, as quantified by standardized autonomic function tests (AFTs), were determined. The yoga group (n=18) received supervised training in yoga, and the exercise group (n=16) practiced simple routine exercises. AFTs were repeated after 10 weeks of daily sessions. Data were compared with those of healthy volunteers (n=142). The yoga group showed significant improvement in parasympathetic parameters and a decrease in seizure frequency scores. There was no improvement in blood pressure parameters in either group. Two patients in the yoga group achieved normal autonomic functions at the end of 10 weeks of therapy, whereas there were no changes in the exercise group. The data suggest that yoga may have a role as an adjuvant therapy in the management of autonomic dysfunction in patients with refractory epilepsy.

Effects of dexamethasone on cerebral perfusion and water diffusion in patients with high-grade glioma.

BACKGROUND AND PURPOSE: The mechanisms by which the glucocorticoid dexamethasone produces its therapeutic action in patients with intracranial tumors still remain unclear. The purpose of this study was to investigate whether dexamethasone affects cerebral perfusion and water molecule diffusion by using quantitative dynamic susceptibility contrast perfusion MR imaging (DSC-MR imaging) and diffusion tensor MR imaging (DT-MR imaging). METHODS: Ten consecutive patients with glioblastoma multiforme underwent DSC-MR imaging and DT-MR imaging before and 48-72 hours after dexamethasone treatment (16 mg/day). Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and water mean diffusivity () were measured for enhancing tumor, nonenhancing peritumoral edematous brain, and normal-appearing contralateral white matter before and after steroid therapy. The percentage change in CBF, CBV, MTT, and for the 3 tissue types was calculated for each patient, a mean value obtained for the population, and the statistical significance determined by using a paired-samples Student t test. RESULTS: After dexamethasone treatment, there was no significant change in tumor CBF, CBV, or MTT. Edematous brain CBV and MTT were also unchanged. There was, however, an increase in edematous brain CBF (11.6%; P = .05). was reduced in both enhancing tumor (-5.8%; P = .001) and edematous brain (-6.0%; P < .001). There was no significant change in CBF, CBV, MTT, or for normal-appearing contralateral white matter after treatment. CONCLUSION: These data suggest that dexamethasone does not significantly affect tumor blood flow but may, by reducing peritumoral water content and local tissue pressure, subtly increase perfusion in the edematous brain.

A small library of trisubstituted pyrimidines as antimalarial and antitubercular agents.

A small library of 20 trisubstituted pyrimidines were synthesized and evaluated for their in vitro antimalarial and antitubercular activities. Out of the total screened compounds, 16 compounds have shown in vitro antimalarial activity against Plasmodium falciparum in the range of 0.25-2microg/mL and 8 compounds have shown antitubercular activity against Mycobacterium tuberculosis H(37)Ra, at a concentration of 12.5microg/mL.