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Although hundreds of knockout mice show infertility as a major phenotype, the causative genic mutations of male infertility in humans remain rather limited. Here, we report the identification of a missense mutation (D136G) in the X-linked TAF7L gene as a potential cause of oligozoospermia in men. The human aspartate (D136) is evolutionally conserved across species, and its change to glycine (G) is predicted to be detrimental. Genetic complementation experiments in budding yeast demonstrate that the conserved aspartate or its analogous asparagine (N) residue in yeast TAF7 is essential for cell viability and thus its mutation to G is lethal. Although the corresponding D144G substitution in the mouse Taf7l gene does not affect male fertility, RNA-seq analyses reveal alterations in transcriptomic profiles in the Taf7l (D144G) mutant testes. These results support TAF7L mutation as a risk factor for oligozoospermia in humans.

Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that binds with β-catenin and selectively disrupts the protein–protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development.

The rarity of mixed phenotype acute leukemia (MPAL) has precluded adequate data to incorporate minimal residual disease (MRD) monitoring into therapy. Fluidity in MPAL classification systems further complicates understanding its biology and outcomes; this includes uncertainty surrounding the impact of shifting diagnostic requirements even between iterations of the World Health Organization (WHO) classification. Our primary objective was to address these knowledge gaps. To do so, we analyzed clinicopathologic features, therapy, MRD, and survival in a centrally-reviewed, multicenter cohort of MPAL uniformly diagnosed by the WHO classification and treated with acute lymphoblastic leukemia (ALL) regimens. ALL induction therapy achieved an EOI MRD negative (

Background Deep brain stimulation (DBS) is considered standard of care for the treatment of medically refractory Parkinson disease (PD). The placement of brain electrodes is performed using contrast imaging to enhance blood vessel identification during stereotactic planning. We present our experience with a series of patients implanted using noncontrast imaging. Methods All cases of DBS surgery for PD performed between 2012 and 2018 with noncontrast imaging were retrospectively reviewed. Clinical features, postoperative imaging, and complications were analyzed. Results A total of 287 deep-seated electrodes were implanted in 152 patients. Leads were placed at the subthalamic nucleus and globus pallidus internus in 258 and 29 hemispheres, respectively. We identified 2 cases of intracranial hemorrhage (0.7%). Conclusions DBS lead placement can be performed without the use of intravenous contrast with a postoperative intracranial hemorrhage rate comparable with other reported series.

Introduction We report the prevalence of abnormal tandem gait (TG) in patients with idiopathic Parkinson disease (PD) and its association with symptoms of subjective unsteadiness, falls, freezing of gait, and cognitive impairment. Methods We assessed subjective balance impairment, fall history, antero-posterior postural instability, and TG in PD patients (Hoehn and Yahr (HY) stage 0–4). We recorded the age, sex, current medications, HY stage, Schwab and England (S&E) scale score, and MOCA score for each patient. Logistic regression was used to evaluate age-adjusted associations between TG and other demographic and clinical factors. Results A total of 102 patients with PD were assessed. Of those, 63.5% of HY 2 patients and 100% of HY 2.5 and 3 patients had a TG abnormality. The presence of TG abnormality was associated with subjective imbalance, falls, freezing of gait, S&E Conclusions TG abnormality is common in PD, precedes the development of antero-posterior postural instability, is associated with cognitive impairment, and may predict fall risk. A longitudinal study will help determine if TG is a predictor of impending progression from HY 2 to HY 3.

Introduction Anxiety and depression are common in PD, occurring in an estimated 30%–40% of PD patients. However, the extent to which these emotional symptoms interfere with Deep Brain Stimulation (DBS) outcomes is not well established. This study examined the association between pre-operative emotional well-being and postsurgical cognitive, emotional, and motor performance in PD. Methods Forty-nine PD patients underwent neurological, neuropsychological (global cognition, processing speed, language, visuospatial, memory), and emotional assessments pre- and post-DBS. Fifteen patients were administered the UPDRS. Patients were divided into Anxious (Anx; n = 21), Comorbid Anxious and Depressed (Anx + Dep; n = 15), and Emotionally Asymptomatic (EA; n = 13) based on BAI and BDI-II cutoffs, and compared on pre-post changes in neurocognitive, mood, and motor scores using analyses of covariance (ANCOVA), controlling for education, ethnicity, and disease duration. Results Pre-DBS, there were no significant differences between the three groups on any neuropsychological measure. Overall change from pre-to post-DBS revealed declines on multiple cognitive measures and lower symptom endorsement on the BAI among all participants. No group differences were observed on neurocognitive measures, mood, or UPDRS. Conclusions PD patients with mild-moderate anxiety or comorbid anxiety/depression pre-DBS do not show greater cognitive, emotional, and motor changes post-DBS compared to emotionally asymptomatic patients. These data emphasize the importance of discussing potential DBS outcomes, while keeping in mind that psychiatric comorbidity should not necessarily exclude patients from DBS. The notion that premorbid mood symptoms could disqualify a candidate for surgery would be a disservice, as this group performs comparably to asymptomatic peers.

Despite extensive efforts and a plethora of suggested targets and pathways, the mechanism via which metformin lowers blood glucose remains obscure. Obstacles that hamper progress in understanding metformin action include unexplained discrepancies between preclinical models and patients.We treated obese male C57BL/6J mice fed high fat diet with metformin provided in the form of a single dose, daily intraperitoneal injections, admixture to drinking water, or continuous infusion via intraperitoneal minipumps.The results suggest several superimposed components, via which metformin acts on blood glucose. These include (i) marked glucose lowering shortly after dosing, which fades rapidly with the decrease in metformin concentrations in plasma and liver, but could, at least to a major extent, rely on the mechanism also accounting for metformin's therapeutic action in humans; (ii) indirect action via reduced weight gain, which might be responsible for glucose lowering observed in many previous rodent studies; and (iii) deterioration of glucose homeostasis by prolonged treatment that can be unmasked by avoidance of dosing shortly before measuring blood glucose in combination with exclusion of weight-related actions via restricted feeding of the control mice.Our work raises the question whether elucidation of metformin's anti-diabetic mechanism(s) in rodent experiments may in the past have been hampered by failure to mimic clinical circumstances, as caused by insufficient consideration of pharmacokinetics and multiplicity of involved actions.

Palliative care in Parkinson's Disease (PD) is an effective intervention to improve quality of life, although historically, access and availability have been very restricted.We performed a retrospective cohort study using the National Inpatient Sample (NIS) data from 2007 to 2014. Diagnostic codes were used to identify patients with PD and palliative care referral. Trends were calculated and logistic analysis performed to identify predictors of palliative care use.We identified 397,963 hospitalizations from 2007 to 2014 for patients with PD. Of these, 10,639 (2.67%) were referred to palliative care. The rate of consultation increased from 0.85% in 2007 to 4.49% in 2014. For 1 unit in year increase, there was 1.23 time the odds of receiving palliative consultation (OR 1.23, CI 1.21-1.25, p 0.0001). Hispanics (OR 0.90, CI 0.81-1.01, p = 0.0550), Black (OR 0.90, CI 0.81-1.01, p = 0.0747) and White patients had similar rates of referral after adjustment. Women were less likely to be referred to palliative care (OR 0.90, CI 0.87-0.94, p 0.0001). Other factors strongly associated with a higher rate of referrals included private insurance when compared to Medicare (OR 2.14, CI 1.89-2.41, p 0.0001) and higher income (OR 1.41, CI 1.30-1.53, p 0.0001).There has been a significant increase in palliative care referrals among hospitalized patients with PD in the US, although the overall rate remains low. After controlling for confounders, racial and ethnic disparities were not found. Women, patients with Medicare/Medicaid, and those with lower income were less likely to be referred to palliative care.

Background Deep brain stimulation of the ventral intermediate nucleus (VIM) or caudal zona incerta (cZI) is effective for refractory essential tremor (ET). To refine stereotactic planning for lead placement, we developed a unique individualized anatomy-based planning protocol that targets both the VIM and the cZI in patients with ET. Methods 33 patients with ET underwent VIM-cZI lead implantation with targeting based on our protocol. Indirect targeting was adjusted based on anatomic landmarks as reference lines bisecting the red nuclei and ipsilateral subthalamus. Outcomes were evaluated through the follow-up of 31.1 ± 18.4 months. Active contact coordinates were obtained from reconstructed electrodes in the Montreal Neurological Institute space using the MATLAB Lead-DBS toolbox. Results Mean tremor improvement was 79.7% ± 22.4% and remained stable throughout the follow-up period. Active contacts at last postoperative visit had mean Montreal Neurological Institute coordinates of 15.5 ± 1.6 mm lateral to the intercommissural line, 15.3 ± 1.8 mm posterior to the anterior commissure, and 1.4 ± 2.9 mm below the intercommissural plane. No hemorrhagic complications were observed in the analyzed group. Conclusions Individualized anatomy-based VIM-cZI targeting is feasible and safe and is associated with favorable tremor outcomes.

The Notch signalling pathway mediates cell fate decisions and is tumour suppressive or oncogenic depending on the context. During lung development, Notch pathway activation inhibits the differentiation of precursor cells to a neuroendocrine fate. In small-cell lung cancer, an aggressive neuroendocrine lung cancer, loss-of-function mutations in NOTCH genes and the inhibitory effects of ectopic Notch activation indicate that Notch signalling is tumour suppressive. Here we show that Notch signalling can be both tumour suppressive and pro-tumorigenic in small-cell lung cancer. Endogenous activation of the Notch pathway results in a neuroendocrine to non-neuroendocrine fate switch in 10-50% of tumour cells in a mouse model of small-cell lung cancer and in human tumours. This switch is mediated in part by Rest (also known as Nrsf), a transcriptional repressor that inhibits neuroendocrine gene expression. Non-neuroendocrine Notch-active small-cell lung cancer cells are slow growing, consistent with a tumour-suppressive role for Notch, but these cells are also relatively chemoresistant and provide trophic support to neuroendocrine tumour cells, consistent with a pro-tumorigenic role. Importantly, Notch blockade in combination with chemotherapy suppresses tumour growth and delays relapse in pre-clinical models. Thus, small-cell lung cancer tumours generate their own microenvironment via activation of Notch signalling in a subset of tumour cells, and the presence of these cells may serve as a biomarker for the use of Notch pathway inhibitors in combination with chemotherapy in select patients with small-cell lung cancer.

The goals of this retrospective clinical case series study were to describe the management of anesthesia, and to report perioperative complications in cats undergoing subcutaneous ureteral bypass (SUB) placement due to ureteral obstruction. Medical records of client-owned cats with ureteral obstruction and anesthetized for SUB placement between 2012 and 2015 in a veterinary teaching hospital were reviewed. Twenty-seven cases were identified. Duration of anesthesia and surgery (mean ± standard deviation) were 215 ± 42 min and 148 ± 36 min, respectively. Hypothermia was the most common intraoperative complication. Hypotension, hypocapnia, hypertension and bradycardia were also frequently observed. Out of 22 cats who experienced intraoperative hypotension, 17 received inotropes and vasopressors. There was a significant decrease in creatinine (P=0.008) and total solids (P=0.007) after SUB placement when compared with baseline values. Postoperative complications included pain, anorexia, nausea, hypertension, and urinary tract-related problems. No death occurred in the postoperative period. Successful management of anesthesia for SUB placement involves rigorous anesthetic monitoring and immediate treatment of complications. Perioperative complications appear to be common. This study could not identify risk factors associated with this procedure.

Sleep disorders are prevalent in Parkinson's disease but underreported in clinical settings. The contribution of sleep disorders to health-related quality of life (HRQOL) for patients with this degenerative neurological disease are not well known.To evaluate the impact of insomnia symptoms, obstructive sleep apnea (OSA), and poor sleep quality on HRQOL in a cohort of patients with idiopathic Parkinson's disease.We enrolled a convenience sample of 66 adults seen in the University of Miami Movement Disorders Clinic between July 2011 and June 2013. Participants completed validated questionnaires to determine insomnia symptoms, OSA risk, depression, anxiety, and HRQOL. All patients underwent unattended polysomnography to confirm OSA. Results were compared for those with and without insomnia symptoms. Principal component and regression analyses were performed to evaluate determinants of HRQOL.Participants were predominately Hispanic males with mild to moderate Parkinson's disease. Insomnia symptoms were reported for 46% of the study subjects. OSA (apnea-hypopnea index, ≥5) was noted in 47%, with a mean apnea-hypopnea index of 8.3 ± 11.0. Fairly bad to very bad sleep quality was reported by 21% of the participants. Insomnia (r = 0.71; P 0.001), daytime sleepiness (r = 0.36; P = 0.003), depression symptoms (r = 0.44; P 0.001), and anxiety symptoms (r = 0.33; P = 0.006) were significant correlates of poor sleep quality. OSA, severity of Parkinson's disease, and dopaminergic therapy were not. In the principal component analysis, sleep quality was a significant component of the "psychological factor" that in turn was a significant determinant of overall HRQOL.Insomnia symptoms, OSA, and subsequent poor sleep quality are prevalent in Parkinson's disease. In this single-center, exploratory study, we found that insomnia and poor sleep quality, but not OSA, play important roles in determining overall quality of life for patients with this disease. Clinical trial registered with www.clinicaltrials.gov (NCT02034357).

Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease.This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396.Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation.This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes.Boston Scientific.

Gait dysfunction in Parkinson's disease (PD) does not always respond to bilateral subthalamic nucleus deep brain stimulation (STN-DBS). Since right hemisphere motor networks may be dominant for gait control, identical stimulation of asymmetric circuits could account for gait dysfunction. We compared the effects of bilateral and unilateral STN-DBS on gait kinematics in PD patients who developed gait impairment after STN-DBS. Twenty-two PD patients with >50 % improvement in motor scores, but dopamine-resistant gait dysfunction 6-12 months after bilateral STN-DBS were blindly tested off dopaminergic effects in four randomly assigned DBS conditions: bilateral, right-sided, left-sided and off stimulation. Motor scores (MDS-UPDRS III), gait scores (MDS-UPRDS 2.11-2.13 + 3.9-3.13), turning time (seconds), stride length (meters) and velocity (meters/second) were measured 1 h after DBS changes. Motor and gait scores significantly improved with bilateral versus unilateral STN-DBS. Stride length and velocity (0.95 ± 0.06, 0.84 ± 0.07) significantly improved with bilateral (1.09 ± 0.04, 0.95 ± 0.05), right-sided (1.06 ± 0.04, 0.92 ± 0.05) and left-sided stimulation (1.01 ± 0.05, 0.90 ± 0.05) (p

OBJECTIVES This study sought to determine whether there is a gender disparity in patients undergoing deep brain stimulation (DBS) surgery for Parkinson's disease (PD) at a single health system, and better understand the reasons for this discrepancy. MATERIALS AND METHODS We analyzed data from the University of Miami DBS Database, which included 3251 PD patients, using chi-square, repeated measures ANOVA, and t tests to examine gender differences in the number of patients referred for surgery, reasons for referral, number receiving/not receiving surgery, reasons for not receiving surgery, and postsurgical outcomes. RESULTS During the study period, 207 PD patients were referred for DBS (75.8% male), and 100 underwent surgery (77.0% male). Of those who did not receive surgery, the most common reasons were need for further medical optimization (26.2%), suboptimal performance on neuropsychological evaluation (22.4%), other reason (20.6%), lost to follow-up (18.7%), or patient preference (12.2%). However, in women one of the most common reasons was patient preference (28.0%), and this was significant compared to men (p

Myoid angioendothelioma are rare and benign vascular tumours of the spleen. Radiographic evaluation and diagnosis is often challenging and subjecting tissue samples to immuhistochemical analysis is often required to make a definitive diagnosis. Myoidangioendotheliomas can be managed with open or laparoscopic splenectomy with minimal risk of recurrent disease. Herein, we present a case of a myoid angioendothelioma in a patient with stage IV Wilms' tumour.

Background Symptomatic peri-lead edema is a rare complication of deep brain stimulation that has been reported to develop 4 to 120 days postoperatively. Case presentation Here we report the case of a 63-year-old Hispanic man with an 8-year history of Parkinson’s disease who underwent bilateral placement of subthalamic nucleus deep brain stimulation leads and presented with acute, symptomatic, unilateral, peri-lead edema just 33 hours after surgery. Conclusions We document a thorough radiographic time course showing the evolution of these peri-lead changes and their regression with steroid therapy, and discuss the therapeutic implications of these findings. We propose that the unilateral peri-lead edema after bilateral deep brain stimulation is the result of severe microtrauma with blood–brain barrier disruption. Knowledge of such early manifestation of peri-lead edema after deep brain stimulation is critical for ruling out stroke and infection and preventing unnecessary diagnostic testing or hardware removal in this rare patient population.

Background Disease-related gait dysfunction causes extensive disability for persons with Parkinson's disease (PD), with no effective therapies currently available. The potassium channel blocker dalfampridine has been used in multiple neurological conditions and improves walking in persons with multiple sclerosis. Objectives We aimed to evaluate the effect of dalfampridine extended release (D-ER) 10 mg tablets twice daily on different domains of walking in participants with PD. Methods Twenty-two participants with PD and gait dysfunction were randomized to receive D-ER 10 mg twice daily or placebo for 4 weeks in a crossover design with a 2-week washout period. The primary outcomes were change in the gait velocity and stride length. Results At 4 weeks, gait velocity was not significantly different between D-ER (0.89 m/s ± 0.33) and placebo (0.93 m/s ± 0.27) conditions. The stride length was also similar between conditions: 0.96 m ± 0.38 for D-ER versus 1.06 m ± 0.33 for placebo. D-ER was generally well tolerated with the most frequent side effects being dizziness, nausea and balance problems. Conclusions D-ER is well tolerated in PD patients, however it did not show significant benefit for gait impairment.

A 20-year-old man presented with frequent episodes of generalized rigidity. He had an 18-month history of painful muscle spasms, diaphoresis, and falls. These episodes were associated with anxiety related to pain and the bizarre, unpredictable nature of the symptoms. The patient was admitted with severe tonic spasm episodes lasting for up to 5 minutes, which were initially thought secondary to status dystonicus (video).

The canonical Wnt/β-catenin signalling pathway governs diverse developmental, homeostatic and pathological processes. Palmitoylated Wnt ligands engage cell-surface frizzled (FZD) receptors and LRP5 and LRP6 co-receptors, enabling β-catenin nuclear translocation and TCF/LEF-dependent gene transactivation. Mutations in Wnt downstream signalling components have revealed diverse functions thought to be carried out by Wnt ligands themselves. However, redundancy between the 19 mammalian Wnt proteins and 10 FZD receptors and Wnt hydrophobicity have made it difficult to attribute these functions directly to Wnt ligands. For example, individual mutations in Wnt ligands have not revealed homeostatic phenotypes in the intestinal epithelium-an archetypal canonical, Wnt pathway-dependent, rapidly self-renewing tissue, the regeneration of which is fueled by proliferative crypt Lgr5

Deep brain stimulation in the midbrain׳s central gray can relieve neuropathic pain in man, but for unclear reasons sometimes fails intraoperatively or in early weeks. Here we describe continuous bilateral stimulation in the central gray of two subjects with longstanding, severe neuropathic pain from spinal cord injury. Stimulation parameters were recursively adjusted over many weeks to optimize analgesia while minimizing adverse effects. In early weeks, adjustments were made in periodic office visits; subjects later selected ad libitum at home among several blinded choices while rating pain twice daily. Both subjects received significantly better pain relief when stimulus pulse rates were low. The best relief occurred with 2 Hz cycled on for 1s and off for 2s. After inferior parameters were set, pain typically climbed slowly over 1-2 days; superior parameters led to both slow and fast improvements. Over many weeks of stimulation at low pulse rates, both subjects experienced significantly less interference from pain with sleep. One subject, with major pain relief, also showed less interference with social/recreational ability and mood; the other subject, despite minor pain relief, experienced a significantly positive global impression of change. Oscillopsia, the only observed complication of stimulation, disappeared at low mean pulse rates (≤ 3/s). These subjects׳ responses are not likely to be unique even if they are uncommon. Thus daily or more frequent pain assessment, combined with slower periodic adjustment of stimulation parameters that incorporate mean pulse rates about one per second, will likely improve success with this treatment.

To compare the effects of power training (PWT) and a high-speed yoga program on physical performances in older patients with Parkinson disease (PD), and to test the hypothesis that both training interventions would attenuate PD symptoms and improve physical performance.Randomized controlled trial.A laboratory of neuromuscular research and active aging.Patients with PD (N=41; mean age ± SD, 72.2 ± 6.5y).Two high-speed exercise interventions (specifically designed yoga program and PWT) were given for 12 weeks (twice a week), and 1 nonexercise control group.Unified Parkinson Disease Rating Scale motor score (UPDRSMS), Berg Balance Scale (BBS), Mini-Balance Evaluation Systems Test (Mini-BESTest), Timed Up and Go, functional reach, single leg stance (SLS), postural sway test, 10-m usual and maximal walking speed tests, 1 repetition maximum (RM), and peak power (PPW) for leg press.For the posttests, both training groups showed significant improvements (P.05) in all physical measurements except functional reach on the more affected side, SLS, and postural sway compared with the pretests, and significantly better scores for UPDRSMS, BBS, Mini-BESTest, Timed Up and Go, functional reach on the less affected side, 10-m usual and maximal walking speed tests, 1RM, and PPW than controls, with no differences detected between the yoga program and PWT.Both the specially designed yoga program and PWT programs can significantly improve physical performance in older persons with PD.

To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder.The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria.172 cases were identified, of whom 143 (83%) were men. The mean±SD age of onset in years for the core features were as follows - RBD, 62±14 (range, 20-93), cognitive impairment (n=147); 69±10 (range, 22-90), parkinsonism (n=151); 68±9 (range, 20-92), and autonomic dysfunction (n=42); 62±12 (range, 23-81). Death age was 75±9 years (range, 24-96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10±12 (range, 1-61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n=97), Parkinson's disease with or without mild cognitive impairment or dementia (n=32), multiple system atrophy (MSA) (n=19), Alzheimer's disease (AD)(n=9) and other various disorders including secondary narcolepsy (n=2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n=1). The neuropathologic diagnoses were Lewy body disease (LBD)(n=77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n=59), MSA (n=19), AD (n=6), progressive supranulear palsy (PSP) (n=2), other mixed neurodegenerative pathologies (n=6), NBIA-1/LBD/tauopathy (n=1), and hypothalamic structural lesions (n=2). Among the neurodegenerative disorders associated with RBD (n=170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features.In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.

Used indirect immunofluorescence to put in evidence different types of auto-antibodies, involved in the etiopathogenesis of endocrine autoimmune diseases--thyroid auto-antibodies, anti-sperm antibodies, determined in the serum of both partners of the infertile couples, with infertility of unknown cause, ovary auto-antibodies, in early menopause cases. Besides the establish of a precise etiological diagnosis, this method offers the possibility to localize the auto-antibodies in the tissue and/or in the cells and also the chance to identify some types of auto-antibodies. In the case of thyroid auto-antibodies--antithyroglobulin and antimicrosomal antibodies, in the case of anti-sperm antibodies--anti-head, anti-intermediary piece, anti-acrosomal or anti-tail and anti-ovary antibodies--anti-oocyte, anti tecca granulosa or anti internal tecca.

The treatment of intractable heart failure (New York Heart Association--NYHA IV) with inotropic support is a well established adjunct in the control of clinical status of end-stage heart failure patients but usually needs many admissions and a long period of hospitalization. In this study we report on the follow-up findings of 64 patients for 18 months who were seen in an outpatients congestive heart failure program. All patients had their full standard oral drug treatment, received intensive patient teaching and weekly inotropic infusions. We assess the effects of this comprehensive therapeutic approach on: 1) the number of hospital admissions, 2) length of stay and 3) the number of emergency room visits during the ensuing year. These data were compared with similar data from the year before entry in the program for each patient. All our patients showed NYHA class IV heart failure and received dobutamine to manage their chronic heart failure in an outpatient setting. The cause of heart failure was ischaemic in 34 (53.12%), idiopathic in 14 (21.87%), hypertension in 10 (15.62%), pulmonary hypertension in 7 (10.93%) and valvular heart disease in 6 (9.37%) patients. The mean period of observation was 382 days. For the period before entry in the program patients had 67 emergency room visits, 184 admissions, and 832 days spent in the hospital. After enrollment all these figures significantly decreased (p0.001), patients heading 35 emergency room visits, 112 admissions and 518 days spent in the hospital. In conclusion, the intermittent inotropic therapy as an outpatient setting may be a valuable cost-effective therapeutic method, in patients with refractory heart failure and is associated with the reduction of emergency room visits, admissions and days spent in the hospital.

To expand upon the limited comprehensive population-based data for childhood bacterial meningitis in Eastern Europe, the present study was conducted in the Iasi and Constanta districts of Romania. From March 2000 through March 2002, children

Acute leukemia frequently has been described as a late complication of chemotherapy with alkylating agents in patients treated for multiple myeloma. However, the simultaneous occurrence of multiple myeloma and acute leukemia in the same patient, without previous exposure to chemotherapy, is a rare association. We describe a case of concomitant involvement by multiple myeloma and acute monocytic leukemia. To our knowledge, only 9 such cases have been reported in the literature to date. We discuss the criteria used in diagnosing the 2 separate diseases and the possible mechanisms responsible for this occurrence.

The study of incidence, clinical manifestation and treatment of acute diarrhea with mixed etiology.Study of 48 patients with acute diarrhea with mixed etiology admitted in the Hospital of Infectious Diseases of Iaşi during 1995-1998.12 cases (24%) were mixed bacterial infections with the following microorganisms associations: Salmonella + Shigella (10 cazuri); Salmonella + Yersinia enterocolitica (1 case); Salmonella + Rotavirus (1 case). 16 cases (44%) had mixed digestive infections with parasites, in double or triple associations: Giardia intestinalis + Ascaris lumbricoides (10 cases); Giardia intestinalis + Ascaris lumbricoides + Entamoeba coli (1 case); Giardia intestinalis + Enterobius vermicularis (3 cases); Ascaris lumbricoides + Trichiuris trichiura (2 cases). The rest of 20 cases presented mixed infections with bacteria and parasites: Salmonella + Rotavirus + Giardia (2 cases), Salmonella + Shigella + Giardia intestinalis or Ascaris lumbricoides (6 cases), Salmonella + Giardia intestinalis (8 cases); Salmonella + Entamoeba coli (3 cases); Shigella + Trichiura trichiuris + Entamoeba coli (1 case). The majority was male patients from rural areas with age between 5 month and 56 years, the majority being children, 4 cases were found in immunosupressed patients. The clinical symptomatology was dominated by diarrheal syndrome (100%) and the diagnosis was established by clinical characters and confirmed by coproculture and parasitologic exam. The ethiological therapy was guided by antibiogram, in the majority of cases we used fluorochinolones (associated with ceftriaxone in severe cases), together with antiparasitic medications.In this study predominated the bacterial and parasitic infections, most frequently being isolated Salmonella, Shigella and Giardia intestinalis; the therapy associated fluorochinolones with antiparasitic medication.

To study the incidence, clinical manifestations and treatment of mumps virus meningitis.Study of 64 patients with mumps virus meningitis, admitted to the Clinic of Infectious Diseases of Iaşi during 1996-1999.The mumps virus meningitis had a high prevalence în 1998 (39%) most patients being males (62.5%) from the urban areas. 39.06% of cases were on the age group of 5-6 years old, 25% were in the age group 10-14 years old and 18.75% were adults patients. The clinical manifestation were dominated by headache (100%), fever (100%), vomiting (89%), photophobia (43.75%) and meningeal syndrome of contracture. The laboratory diagnosis was established by the cerebro-spinal fluid exam, together with the peripheric blood exam. The treatment was in all the cases with pathogenic (corticotherapy) and symptomatics with a very good evolution.All the cases with diagnosis mumps virus meningitis were well going, having good evolution and complete healing under symptomatic and pathogenic therapy.

It was first believed that all these endocrine cells are deriving from the neural crests; in time were discovered more than 40 different types of such cells with different origins and only 6 or 7 are deriving from the neural crests. Serotonin-secreting cells show yellow fluorescence, while those secreting cathecolamines show a green fluorescence, with formaldehyde. The most usual method for the stain of the cells of the endocrine diffuse system is the silver salts impregnation. In the electron microscopy the cells show dense granules, which are modified in appearance in the malignancies developed from such cells. Most of the hormones secreted in the intestine were found also to be hormones secreted in the central nervous system. The border between benign proliferation and malignant tumors arising from these endocrine cells is not well defined. DNES--diffuse neuroendocrine system.

The study of incidence, clinical manifestations and prognosis of meningitis with anaerobic and non-fermentative bacteria.Retrospective study of 10 patients with severe forms of purulent meningitis admitted in the Hospital of Infectious Diseases of Iaşi, during 1.01.1990-31.12.1998.3 of them were diagnosed with etiology with polymicrobial flora and the rest had etiology with: Peptostreptococcus (2 cases), Acinetobacter calcoaceticus (4 cases), Eikenella corrodens (1 case). The majority were male sex (8 cases), and from rural area (9 cases). The age of patients ranged from 2.5 to 59 years (the majority being adults of group of age 50-60 years). The gate of entrance was: iatrogenic in the majority of cases (6 cases), posttraumatic (2 cases) and othogen (2 cases); 3 cases being with cerebrospinal fluid fistula and 8 patients being in coma. The factors associated with poor prognosis were: the immunosuppression (chronic etilism--4 cases; bronchopneumonia--2 cases, pulmonary cancer--1 case) and the presence of the focal neurological findings on the noser of illness. The diagnosis was established by clinical characters and confirmed by isolating germs from cerebrospinal fluid. The treatment was done at the beginning with first intervention antibiotic association with a high spectrum and then according to the antibiogramme. The evolution was severe even under treatment with 3 deaths, the mortality being of 30.0%.We wished to present these cases as a general remark on the severity of illness, generally appeared on a suppressed ground, together with the rarity of those germs implicated in the etiology of purulent meningitis.

The clinical success was analysed several times, based upon the good results obtained and unfortunately not on a basis of correct scientific researches, as the cellular and ultrastructural investigations. In the randomized study a more numerous failures are seen in the first, respectively second year, after the application of the implant. The failures were predominantly observed in case of mandible implants. The quality of the bone is an essential factor for the success of the implant without correlation with the age of the patient. The most objective choice of the patients as well as a correct conceived and executed therapeutical plan, the follow-up cooperation with the patient, in what concerns the strict oral hygiene, would had to an increasing number of successfully solved cases. The success of the implant may be ensured when besides the content of the patient, the long-term stability of the soft and bone peri-implant tissues is achieved. By this is also obtained by morphological stability, which may be evaluated following clinical X-ray parameters. This stability is under dependence of the biological status. Conclusively this means an established biomechanical balance and stable relationships between the immune defense system of the least and the pathogenic potential of the microorganisms.

Clinical, bacteriological and therapeutically study on iatrogenic staphylococcal meningitis.Retrospective analysis of 33 cases of iatrogenic staphylococcal meningitis admitted to the Hospital of Infectious Diseases of Iaşi in the interval 1988-1997.In the interval under study the recorded incidence was 1-5 cases per year. The predisposing factors were neurosurgical procedures for endocranial processes (12 cases), operated chronic otomastoiditis (11 cases), ventriculoatrial or peritoneal shunt (5 cases) and neurosurgical assessment (5 cases). The onset was slow, with persisting and mild headache persistence recurrence of fever, vomiting and convulsions followed by meningeal contracture and encephalitic phenomena. In 24 patients cerebrospinal fluid was typical for purulent meningitis. The causal agents were isolated in 25 cases being Staphylococcus aureus (20 cases) and Staphylococcus epidermidis sensitive to usual antistaphylococcal agents. Three therapeutically schemes were used the association cefotaxim î gentamycin proving to be the most effective vancomycin was required in but 2 cases. Three deaths were recorded.The symptoms of iatrogenic staphylococcal meningitis are mild marked by the underlying disease the most effective treatment being the association of cefotaxim with an aminoglycoside.

A transdermal nitroglycerin (TNG) patch (10 mg.24 h-1), using a daily overnight 8-h free interval, was assessed by means of a multicentre trial in 96 elderly patients with stable angina (age greater than or equal to 65 years). The main entry requirement was a reproducible exercise-induced ST depression (greater than or equal to 1 mm) appearing at a load of 60 to 90 W, during an incremental bicycle ergometer test (10 W.min-1). During the study only one other antianginal drug and sublingual TNG tablets were allowed. The protocol consisted of a run-in period (mean 10 days), followed by a double-blind, randomized, parallel, placebo-controlled 28-day phase and a single-blind active treatment phase of the same duration. The exercise test parameters, the number of spontaneous anginal attacks and any unwanted effects were evaluated at the end of every study phase. In the double-blind phase, no ergometric values changed with placebo while transdermal TNG significantly improved total workload and double product by 36.4% and 7.7% at the maximal workload respectively and by 49.8% and 13.5% at the time to onset of 1 mm ST depression respectively and reduced ST depression (-58.8%) at the equivalent baseline workload. Anginal attacks decreased by 61.5% and 30.8% with TNG patch and placebo respectively. A similar trend was seen at the end of the single-blind active treatment period in patients who had received placebo in the double-blind phase. Nine patients failed to complete the study; six for unwanted effects (four in the active group and two in the placebo group) and three for other reasons.(ABSTRACT TRUNCATED AT 250 WORDS)

A multicenter open study was carried out in order to evaluate the tolerability and antianginal efficacy of the nitroglycerin "multilayer transdermal system". Forty eight cardiologic centers enrolled 506 outpatients (123 females and 383 males), mean age: 61 +/- 8 (SD) years, with effort angina (43%), angina at rest (17%) and mixed angina (40%), not well controlled by their previous antianginal therapy (greater than or equal to 2 anginal attacks a weeks). The duration of the treatment with 5 or 10 mg/die was 10 weeks with a control every 2 weeks. At the end of the study, the weekly frequency of anginal attacks was reduced by 88%, and 60% of the patients were free from anginal attacks. In 117 patients, studied by ergometer test, the exercise time increased by 31% (p less than 0.001) and the ST depression decreased by 63% (p less than 0.001). The treatment was interrupted in 9.1% of the patients: in 4.55% for unwanted effects (headache and/or local intolerance) and in 4.55% for other reasons. The same unwanted effects, but of mild or moderate severity, were observed in 18.4% of the patients, most of them during the first 2 weeks of the treatment. In conclusion, the "multilayer system" for delivering transdermal nitroglycerin showed a good clinical and ergometer efficacy and was well tolerated and accepted by the anginal patients in study.

To ask what controls the periodic accumulation and destruction of the mitotic across the cell cycle, we have developed a cell-free system from clam embryos that reproduces several aspects of cyclin behavior. One or more rounds of cyclin proteolysis and resynthesis occur in vitro, and the destruction of the cyclins is highly specific. The onset, duration, and extent of cyclin destruction and the appropriately stagered disappearance of cyclin A and cyclin B are correctly regulated during the first cycle in the cell-free system. Just as in intact cells, lysates made from early interphase cells require further protein synthesis to reach the cyclin destruction point, and lysates made from later stages do not. Using the cell-free system we show that cyclin disappearance requires ATP and Mg2+. By combining lysates from different cell cycle stages, we show that (a) interphase lysates do not contain a dominant inhibitor of cyclin destruction and (b) the timing of cyclin destruction is determined by the cell cycle stage of the cytoplasm rather than the cell cycle stage of the substrate cyclins themselves. Among a large variety of agents tested, only a few affect cyclin destruction. Tosyl-lysine chlormethyl ketone (TLCK, a protease inhibitor), 6-dimethylaminopurine (6-DMAP, a kinase inhibitor), certain sulfhydryl-blocking agents, ZnCl2 and EDTA (but not EGTA) completely block cyclin destruction in vitro. Addition of 1 mM Ca2+ to the cell-free system has no effect on cyclin stability, but 5 mM Ca2+ leads to the rapid destruction of cyclins and a small number of other proteins.

The resting and exertional haemodynamic effects of acute and chronic discontinuous (one tablet every 6 h) treatment with 5 mg of buccal nitroglycerin (BN) have been assessed in nine postinfarction heart failure patients. At rest, pulmonary artery (PAP), pulmonary wedge (PWP), and right atrial pressures (RAP) were reduced by 42%, 55% and 77%, respectively, after the first dose and by 26%, 32% and 45%, respectively, after the chronic (three weeks) treatment with BN. During exercise, at the same workload, PAP, PWP and RAP were significantly reduced by 44%, 54% and 62%, respectively, after acute treatment and by 28%, 34% and 44%, respectively, after chronic treatment. The maximal workload (Kgm) increased by 179% and 166% and the exercise time increased by 78% and 71% after acute and chronic therapy, respectively. At the maximal workload, after acute BN, overall haemodynamics were better than in the basal state. PAP, PWP and RAP were still reduced by 19%, 31% and 31%, respectively, after acute treatment, while after chronic phase the results did not differ from control. The severity of cardiac failure, according to the Weber classification, was reduced by acute and chronic therapy. We can conclude that the buccal nitroglycerin showed clear efficacy in improving overall haemodynamic parameters both at rest and during exercise in post-myocardial infarction patients with heart failure. The discontinuous treatment maintained the effect of nitroglycerin without clear evidence of tolerance during chronic therapy.

A 33-year-old man presented a complete antrio-ventricular block due to two hydatid cysts localized in the interventricular septum and interrupting both bundle branches. Intracardiac rupture within the right ventricle led to extensive pulmonary hydatidosis and death.

A case with sudden disappearance of the pathologic Q waves of an old posterior myocardial infarction after a superimposed acute anterior infarction is reported. This phenomena probably is due to the loss of the opposing electromotive forces in the anterior myocardial wall after acute anterior myocardial necrosis. When a third acute lateral myocardial infarction occurred, new Q waves in the corresponding leads could be observed. Pathologic examinations documented three temporally and spaciously separate infarctions. Such correlations allow a better understanding of the electrocardiographic changes in patients with successive myocardial infarctions.

The case of a 75-year-old man with acute myocardial infarction is presented. Two ventricular parasystolic foci, one in the right bundle branch, the other in the left bundle branch system were demonstrated with the aid of a His bundle recording, in the presence of atrial fibrillation.