A Randomized Controlled Trial of Device Guided, Slow-Paced Respiration in Women with Overactive Bladder Syndrome.

PurposeWe evaluated the effects of device guided, slow-paced respiration on urgency associated urinary symptoms, perceived stress and anxiety, and autonomic function in women with overactive bladder syndrome.Materials and methodsWe performed a randomized, parallel group trial of slow-paced respiration to improve perceived stress and autonomic dysfunction as potential contributors to overactive bladder. Ambulatory women who reported at least 3 voiding or incontinence episodes per day associated with moderate to severe urgency were randomized to use a portable biofeedback device to practice daily, slow, guided breathing exercises or a control device which appeared identical and was reprogrammed to play music without guiding breathing. During 12 weeks we evaluated changes in urinary symptoms by voiding diaries, perceived stress and anxiety by validated questionnaires, and autonomic function by heart rate variability and impedance cardiography.ResultsIn the 161 randomized participants, including 79 randomized to paced respiration and 82 randomized to the control group, the average ± SD baseline frequency of voiding or incontinence associated with moderate to severe urgency was 6.9 ± 3.4 episodes per day. Compared to controls the participants randomized to paced respiration demonstrated greater improvement in perceived stress (average Perceived Stress Scale score decrease 2.8 vs 1.1, p=0.03) but not in autonomic function markers. During 12 weeks the average frequency of voiding or incontinence associated with moderate to severe urgency, which was the study primary outcome, decreased by a mean of 0.9 ± 3.2 episodes per day but no significant between group difference was detected.ConclusionsAmong women with overactive bladder slow-paced respiration was associated with a modest improvement in perceived stress during 12 weeks. However, it was not superior to a music listening control for reducing urinary symptoms or changing autonomic function

The Drosophila caspase Ice is important for many apoptotic cell deaths and for spermatid individualization, a nonapoptotic process

Caspase family proteases play important roles in the regulation of apoptotic cell death. Initiator caspases are activated in response to death stimuli, and they transduce and amplify these signals by cleaving and thereby activating effector caspases. In Drosophila, the initiator caspase Nc (previously Dronc) cleaves and activates two short-prodomain caspases, Dcp-1 and Ice (previously Drice), suggesting these as candidate effectors of Nc killing activity. dcp-1-null mutants are healthy and possess few defects in normally occurring cell death. To explore roles for Ice in cell death, we generated and characterized an Ice null mutant. Animals lacking Ice show a number of defects in cell death, including those that occur during embryonic development, as well as during formation of adult eyes, arista and wings. Ice mutants exhibit subtle defects in the destruction of larval tissues, and do not prevent destruction of salivary glands during metamorphosis. Cells from Ice animals are also markedly resistant to several stresses, including X-irradiation and inhibition of protein synthesis. Mutations in Ice also suppress cell death that is induced by expression of Rpr, Wrinkled (previously Hid) and Grim. These observations demonstrate that Ice plays an important non-redundant role as a cell death effector. Finally, we demonstrate that Ice participates in, but is not absolutely required for, the non-apoptotic process of spermatid differentiation

The alpha-synuclein 5'untranslated region targeted translation blockers: anti-alpha synuclein efficacy of cardiac glycosides and Posiphen

Increased brain α-synuclein (SNCA) protein expression resulting from gene duplication and triplication can cause a familial form of Parkinson's disease (PD). Dopaminergic neurons exhibit elevated iron levels that can accelerate toxic SNCA fibril formation. Examinations of human post mortem brain have shown that while mRNA levels for SNCA in PD have been shown to be either unchanged or decreased with respect to healthy controls, higher levels of insoluble protein occurs during PD progression. We show evidence that SNCA can be regulated via the 5'untranslated region (5'UTR) of its transcript, which we modeled to fold into a unique RNA stem loop with a CAGUGN apical loop similar to that encoded in the canonical iron-responsive element (IRE) of L- and H-ferritin mRNAs. The SNCA IRE-like stem loop spans the two exons that encode its 5'UTR, whereas, by contrast, the H-ferritin 5'UTR is encoded by a single first exon. We screened a library of 720 natural products (NPs) for their capacity to inhibit SNCA 5'UTR driven luciferase expression. This screen identified several classes of NPs, including the plant cardiac glycosides, mycophenolic acid (an immunosuppressant and Fe chelator), and, additionally, posiphen was identified to repress SNCA 5'UTR conferred translation. Western blotting confirmed that Posiphen and the cardiac glycoside, strophanthidine, selectively blocked SNCA expression (~1 μM IC(50)) in neural cells. For Posiphen this inhibition was accelerated in the presence of iron, thus providing a known APP-directed lead with potential for use as a SNCA blocker for PD therapy. These are candidate drugs with the potential to limit toxic SNCA expression in the brains of PD patients and animal models in vivo

Assessing the utilization of high-resolution 2-field HLA typing in solid organ transplantation.

HLA typing in solid organ transplantation (SOT) is necessary for determining HLA-matching status between donor-recipient pairs and assessing patients\u27 anti-HLA antibody profiles. Histocompatibility has traditionally been evaluated based on serologically defined HLA antigens. The evolution of HLA typing and antibody identification technologies, however, has revealed many limitations with using serologic equivalents for assessing compatibility in SOT. The significant improvements to HLA typing introduced by next-generation sequencing (NGS) require an assessment of the impact of this technology on SOT. We have assessed the role of high-resolution 2-field HLA typing (HR-2F) in SOT by retrospectively evaluating NGS-typed pre- and post-SOT cases. HR-2F typing was highly instructive or necessary in 41% (156/385) of the cases. Several pre- and posttransplant scenarios were identified as being better served by HR-2F typing. Five different categories are presented with specific case examples. The experience of another center (Temple University Hospital) is also included, whereby 21% of the cases required HR-2F typing by Sanger sequencing, as supported by other legacy methods, to properly address posttransplant anti-HLA antibody issues

A pilot treatment study for mild traumatic brain injury: Neuroimaging changes detected by MEG after low-intensity pulse-based transcranial electrical stimulation

BackgroundMild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members, Veterans, and civilians. However, few treatments are available for mTBI, partially because the mechanism of persistent mTBI deficits is not fully understood.MethodsWe used magnetoencephalography (MEG) to investigate neuronal changes in individuals with mTBI following a passive neurofeedback-based treatment programme called IASIS. This programme involved applying low-intensity pulses using transcranial electrical stimulation (LIP-tES) with electroencephalography monitoring. Study participants included six individuals with mTBI and persistent post-concussive symptoms (PCS). MEG exams were performed at baseline and follow-up to evaluate the effect of IASIS on brain functioning.ResultsAt the baseline MEG exam, all participants had abnormal slow-waves. In the follow-up MEG exam, the participants showed significantly reduced abnormal slow-waves with an average reduction of 53.6 ± 24.6% in slow-wave total score. The participants also showed significant reduction of PCS scores after IASIS treatment, with an average reduction of 52.76 ± 26.4% in PCS total score.ConclusionsThe present study demonstrates, for the first time, the neuroimaging-based documentation of the effect of LIP-tES treatment on brain functioning in mTBI. The mechanisms of LIP-tES treatment are discussed, with an emphasis on LIP-tES's potentiation of the mTBI healing process

Abnormal white matter blood-oxygen-level-dependent signals in chronic mild traumatic brain injury

Concussion, or mild traumatic brain injury (mTBI), can cause persistent behavioral symptoms and cognitive impairment, but it is unclear if this condition is associated with detectable structural or functional brain changes. At two sites, chronic mTBI human subjects with persistent post-concussive symptoms (three months to five years after injury) and age- and education-matched healthy human control subjects underwent extensive neuropsychological and visual tracking eye movement tests. At one site, patients and controls also performed the visual tracking tasks while blood-oxygen-level-dependent (BOLD) signals were measured with functional magnetic resonance imaging. Although neither neuropsychological nor visual tracking measures distinguished patients from controls at the level of individual subjects, abnormal BOLD signals were reliably detected in patients. The most consistent changes were localized in white matter regions: anterior internal capsule and superior longitudinal fasciculus. In contrast, BOLD signals were normal in cortical regions, such as the frontal eye field and intraparietal sulcus, that mediate oculomotor and attention functions necessary for visual tracking. The abnormal BOLD signals accurately differentiated chronic mTBI patients from healthy controls at the single-subject level, although they did not correlate with symptoms or neuropsychological performance. We conclude that subjects with persistent post-concussive symptoms can be identified years after their TBI using fMRI and an eye movement task despite showing normal structural MRI and DTI

Hospital resource utilization in a national cohort of functionally single ventricle patients undergoing surgical treatment

Objective: To provide a detailed overview of health resource utilization from birth to 18 years old for functionally single ventricle (f-SV) patients and identify associated risk factors./ Methods: All f-SV patients treated between 2000-2017 in England and Wales were linked to hospital and outpatient records using data from the Linking AUdit and National datasets in Congenital HEart Services (LAUNCHES) project. Hospital stay was described in yearly age intervals and associated risk factors were explored using quantile regression./ Results: A total of 3,037 f-SV patients were included, 1409 (46.3%) undergoing a Fontan procedure. During the first year of life the median days spent in-hospital was 60 (IQR 37-102), mostly inpatient days, mirroring a mortality of 22.8%. This decreases to between 2-9 in-hospital days/year afterwards. Between 2-18 years most hospital days were outpatient, with a median of 1-5 days/year./ Lower age at the first procedure, hypoplastic left heart syndrome/mitral atresia, unbalanced atrioventricular septal defect, preterm birth, congenital/acquired comorbidities, additional cardiac risk factors and severity of illness markers were associated with fewer days-at-home and more ICU days in the first year of life. Only markers of early severe illness were associated with fewer days-at-home in the first 6 months post Fontan procedure./ Conclusions: Hospital resource utilization in f-SV is not uniform, decreasing tenfold during adolescence compared to the first year of life. There are subsets of patients with worse outcomes during their first year of life, or with persistently high hospital usage throughout their childhood, which could be the target of future research

Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice.

OBJECTIVES: Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants. METHODS: Lupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function. RESULTS: MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody . CONCLUSIONS: These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus

Sulfa or Sulfone Prophylaxis and Geographic Region Predict Mutations in the Pneumocystis carinii Dihydropteroate Synthase Gene

To determine factors associated with mutations in the Pneumocystis carinii dihydropteroate synthase (DHPS) gene, a prospective study of human immunodeficiency virus (HIV)-infected patients with confirmed P. carinii pneumonia was conducted in Atlanta, Seattle, and San Francisco. Clinical information was obtained from patient interview and chart abstraction. DHPS genotype was determined from DNA sequencing. Overall, 76 (68.5%) of 111 patients had a mutant DHPS genotype, including 22 (81.5%) of 27 patients from San Francisco. In multivariate analysis, sulfa or sulfone prophylaxis and study site were independent predictors of a mutant genotype. Fourteen (53.8%) of 26 patients who were newly diagnosed with HIV infection and had never taken prophylaxis had a mutant genotype. The significance of geographic location as a risk factor for mutant genotype and the high proportion of mutant genotypes among persons never prescribed prophylaxis, including those newly diagnosed with HIV infection, provide indirect evidence that these mutations are transmitted from person to person either directly or through a common environmental source