Hypothalamic expression of GnRH-I and GnIH in the Eurasian tree sparrow over a single long day.

Seasonal reproductive cycles of most birds are regulated by photoperiod via neuroendocrine control. The present study aims to investigate the role of a single long day in triggering hypothalamic expressions of GnRH-I and GnIH in the Eurasian tree sparrow (Passer montanus). Sparrows were divided into two groups (n = 24 each) and pre-treated under short days (9L: 15D) for 4 days. On the fifth day, one group was exposed to long day (14L: 10D), while other was continued under short day for another 1 day. Birds of both the groups were sacrificed and perfused on fifth day at different time points, i.e., ZT 14, ZT 16 and ZT 18 and the expressions of GnRH-I and GnIH mRNAs and peptides were studied using real-time PCR and immunohistochemistry, respectively. In addition, testicular size was measured to know testicular development. Observations revealed that birds exposed to a single long day (14L: 10D) showed an increase in hypothalamic expressions of GnRH-I mRNA and peptide and decrease in levels of GnIH mRNA only at ZT 16 and ZT 18 with no significant change in GnIH peptide. However, no significant change in GnRH-I or GnIH expression was observed at any time point under short day and birds maintained high and low expression levels of GnIH and GnRH-I, respectively. Our results clearly indicate that the photoperiodic response system of sparrow is highly sensitive to light and responds even to single long day. Furthermore, they suggest that the GnRH-I and GnIH are expressed in the hypothalamus of tree sparrow in an anti-phasic manner and switching over of their expression occurs at late hours of exposure of birds to single long day.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Evaluation of stroke thrombectomy including patients where IV thrombolysis is contraindicated or has failed: a randomized trial of two novel thrombectomy devices.

BACKGROUND: Study was a PROBE design phase II randomized controlled trial (RCT). We assessed trial feasibility and technical efficacy and safety of two novel thrombectomy devices - ERIC (a retriever device) and SOFIA (a distal access catheter) - used alone or in combination depending on operator preference. METHODS: Four UK neuroscience centers enrolled adults with proximal large artery occlusion (LAO) stroke on imaging where arterial puncture was achievable within 5.5 hours (8.5 hours for posterior circulation) of symptom onset; National Institutes of Health Stroke Scale (NIHSS) ≥6 with limited ischemic change on CT imaging. Randomization was 2:1 into intervention arm (ERIC and/or SOFIA). Patients and core lab were blinded to allocation. Primary outcome was independent core lab adjudication of reperfusion (modified Thrombolysis in Cerebral Infarction (mTICI) scale). Secondary outcomes were modified Rankin score (mRS) at 90 and 365 days (independence and shift analysis), 30-day mortality, symptomatic intracranial hemorrhage (sICH), procedural complications and NIHSS change. RESULTS: Sixty-six patients were enrolled. TICI 2B/3 reperfusion was achieved in 72% in intervention compared with 90% in control arm on intention to treat (ITT) analysis (P=0.2) and 78% compared with 86% on per protocol analysis (P=0.7). Functional independence at 90 days was 40% (intervention) compared with 43% (control) on ITT analysis (P=1.0). sICH rates were low at 0% and 5%, respectively (P=0.3). The 30-day mortality was 9% intervention compared with 14% control (P=0.7). CONCLUSIONS: Study indicated feasibility of a phase II RCT trial approach for assessing new thrombectomy devices. In a broad LAO stroke population ERIC and SOFIA were not statistically different from control devices. Larger trials are needed.

Circadian rhythm in photoperiodic expressions of GnRH-I and GnIH regulating seasonal reproduction in the Eurasian tree sparrow, Passer montanus.

The present study investigates the involvement of circadian rhythm in photoperiodic expressions of GnRH-I and GnIH in the hypothalamus controlling seasonal reproduction in the Eurasian tree sparrow (Passer montanus). Groups of photosensitive birds were exposed for four weeks to resonance light dark cycles comprising of a light phase of 6 h (L) combined with dark phase of different durations (D) such that the period of LD cycles varied by 12 h increments viz. 12- (6 L/6D), 24- (6 L/18D), 36- (6 L/30D), 48- (6 L/42D), 60- (6 L/54D) and 72- (6 L/66D)h. In addition, a control group (C) was maintained under long day length (14 L/10D). Observations, recorded at the beginning and end of experiment, revealed significant testicular growth with corresponding increase in the hypothalamic expression of GnRH-I peptide but low levels of GnIH mRNA and peptide in the birds exposed to resonance cycles of 12, 36 and 60 h which were read as long days. On the other hand, birds experiencing resonance cycles of 24, 48 and 72 h read them as short days wherein they maintained their quiescent gonads and low levels of GnRH-I peptide but exhibited significant increase in GnIH mRNA and peptide expressions. Thus, sparrows responded to resonance light dark cycles differently despite the fact that each of them contained only 6 h of light. These findings suggest that an endogenous circadian rhythm is involved in photoperiodic expressions of above molecules and indicate a shift in their expressions depending upon whether the light falls in the photoinducible or non-photoinducible phase of an endogenous circadian rhythm.

Outcomes of preputioplasty in patients undergoing TIP urethroplasty (tubularization of incised urethral plate) for distal and mid penile hypospadias.

BACKGROUND: Preputioplasty as a part of hypospadias repair restores the normal appearance of phallus, which is especially important in distal and mid penile hypospadias. However possibility of its inherent complications such as iatrogenic phimosis or preputial breakdown are the cause of controversy and reluctance regarding this procedure.This study evaluates the results of preputial reconstruction with TIP urethroplasty in distal and mid penile hypospadias repair and analyses if preputioplasty may be offered to these patients. MATERIALS & METHODS: In this prospective observational study, 48 cases of distal and mid penile hypospadias underwent TIP urethroplasty and preputioplasty and results were assessed at 2 weeks, 3 months and 6 months. Major complications included preputial dehiscence, tight prepuce (iatrogenic phimosis) and minor complications included ventral tethering, persistent dorsal whorls and redundant prepuce. Data was analysed with Microsoft Excel spreadsheet where descriptive statistics were obtained. RESULTS: Preputioplasty was performed in 48 children with a mean age of 5.1 years. Preputioplasty dehiscence was seen in three (6%) patients, which gave an appearance of irregular prepuce on 6 m follow up. Two patients (4%) were confirmed to have preputial tightness at 3 months but this resolved conservatively in one patient and only one patient (2%) required circumcision for a tight prepuce. Minor complications included ventral tethering, persistence of dorsal whorls and redundant prepuce. Ventral tethering was present in 3 patients (6.25%). Redundant prepuce was observed in 2 patients (4.16%). Additionally, unsightly dorsal whorls were found to be persistent in 2 children (4.16%). None of these patients opted for circumcision. The rest of the children had a cosmetically and functionally normal prepuce. Two patients (4%) developed urethrocutaneous fistula at 3 months' follow-up. CONCLUSION: Preputial reconstruction is feasible with a good cosmetic outcome and minimal complications in patients of distal and mid penile hypospadias undergoing TIP urethroplasty. Mild preputial tightness evolves over time and resolves with conservative measures. In patients with very prominent dorsal whorls and underlying bulky tissues the preputioplasty does not appear to be of satisfactory cosmesis. To help the patient and parents take a well informed decision, it would be useful to explain all possible major and minor foreskin complications, and their rectification.

Intracerebral implantation of human neural stem cells and motor recovery after stroke: multicentre prospective single-arm study (PISCES-2).

BACKGROUND: Human neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute-chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study. METHODS: We undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2-13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation. FINDINGS: Twenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures. INTERPRETATION: Administration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials. FUNDING: ReNeuron, Innovate UK (application no 32074-222145). TRIAL REGISTRATION NUMBER: EudraCT Number: 2012-003482-18.

Smoking cessation and outcome after ischemic stroke or TIA.

OBJECTIVE: To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. METHODS: We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. RESULTS: At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48-0.90). CONCLUSION: Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

Participation of endogenous circadian rhythm in photoperiodic time measurement during ovarian responses of the subtropical tree sparrow, Passer montanus.

Resonance experiment was employed to investigate the mechanism of photoperiodic time measurement during initiation of ovarian growth and functions in the subtropical population of female tree sparrow (Passer montanus) at Shillong (Latitude 25 degrees 34 'N, Longitude 91 degrees 53 'E). Photosensitive birds were subjected to various resonance light dark cycles of different durations such as: 12-(6L:6D), 24-(6L:18D), 36-(6L:30D), 48-(6L:42D), 60-(6L:54D) and 72-(6L:66D) h along with a control group under long days (14L:10D) for 35 days. Birds, exposed to long days, exhibited ovarian growth confirming their photosensitivity at the beginning of the experiment. The birds experiencing resonance light/dark cycles of 12, 36 and 60 h responded well while those exposed to 24, 48 and 72 h cycles did not. Serum levels of estradiol-17beta ran almost parallel to changes in the follicular size. Further, histomorphometric analyses of ovaries of the birds subjected to various resonance light dark cycles revealed distinct correlation with the ovarian growth and the serum levels of estradiol-17beta. No significant change in body weight was observed in the birds under any of the light regimes. The results are in agreement with the avian external coincidence model of photoperiodic time measurement and indicate that an endogenous circadian rhythm is involved during the initiation of the gonadal growth and functions in the female tree sparrow.

Methysergide-induced valvular heart disease: a report of 2 cases.

Methysergide is a serotonin antagonist and is used as a long-term prophylactic treatment for migraine. Although many patients experience adequate control of migraine episodes, methysergide has been reported to cause retroperitoneal and pleuropulmonary fibrosis. Cardiovascular side effects mainly in the form of valvular fibrosis have been less recognized. We report 2 cases of methysergide-related mitral valve fibrosis.

Failure modes of left ventricular reconstruction or the Dor procedure: a multi-institutional perspective.

BACKGROUND: Complex ventricular reconstruction (CVR) is now being employed increasingly thanks to the pioneering work of Dor. However, little is known about the failure mode of CVR. We present experience from three centres with CVR and an analysis of the failure modes. METHODS: Between January 1997 and February 2005, 284 patients underwent CVR in three centres in Australia and USA. All of the procedures were performed as adjuncts to coronary artery surgery and/or valvular surgery. Patients were followed-up clinically and/or echocardiographically. Failure modes were classified as fatal or non-fatal. Non-fatal failure mode (NFM) was defined as either persistent heart failure, recurrence of LV scar, need for ventricular assistance, persistent ventricular arrhythmia, or a combination. RESULTS: Operative mortality rate (OMR) was 8% (23 deaths). This fatal failure mode was most related to urgency of surgery and cardiogenic shock in 15 patients (5.3% of OMR), stroke in 5 patients (1.8%) or postoperative bi-ventricular failure (1%). Non-fatal failure modes accounted for morbidity in 26 patients (9%). This was predominantly due to persistent septal dyskinesis in 7 patients (2.46%), persistent mitral regurgitation in 5 (1.8%), postoperative ventricular tachycardia in 4 (1.4%), sub-optimal myocardial protection in 4 (1.4%) use of a large, stiff patch in 4 (1.4%). One hundred and ninety-nine of the surviving 261 patients (76%) were in NYHA Class I. CONCLUSIONS: Complex ventricular reconstruction is a robust technique that has lasting benefit. Failure modes have been identified and could be minimized by appropriate patient and procedure selection.

Infective aortitis associated with the nonpatent remnant of a ductus arteriosus.

Infective aortitis is a rare condition, which occurs most commonly in association with some form of structural abnormality of the heart or vessel wall. We describe the successful excision of an infected, nonpatent remnant of the ductus arteriosus.