Estrogen-related receptor gamma regulates mitochondrial and synaptic genes and modulates vulnerability to synucleinopathy.

Many studies implicate mitochondrial dysfunction as a key contributor to cell loss in Parkinson disease (PD). Previous analyses of dopaminergic (DAergic) neurons from patients with Lewy-body pathology revealed a deficiency in nuclear-encoded genes for mitochondrial respiration, many of which are targets for the transcription factor estrogen-related receptor gamma (Esrrg/ERRγ). We demonstrate that deletion of ERRγ from DAergic neurons in adult mice was sufficient to cause a levodopa-responsive PD-like phenotype with reductions in mitochondrial gene expression and number, that partial deficiency of ERRγ hastens synuclein-mediated toxicity, and that ERRγ overexpression reduces inclusion load and delays synuclein-mediated cell loss. While ERRγ deletion did not fully recapitulate the transcriptional alterations observed in postmortem tissue, it caused reductions in genes involved in synaptic and mitochondrial function and autophagy. Altogether, these experiments suggest that ERRγ-deficient mice could provide a model for understanding the regulation of transcription in DAergic neurons and that amplifying ERRγ-mediated transcriptional programs should be considered as a strategy to promote DAergic maintenance in PD.

Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

Ectopic Cushing's Syndrome Secondary to Metastatic Paraganglioma.

Paraneoplastic or ectopic Cushing's syndrome (CS) is a rare cause of endogenous hypercortisolism. It is due to ectopic adrenocorticotropic hormone (ACTH) secretion and has been reported in association with a variety of neuroendocrine tumors such as small-cell lung carcinoma, carcinoid tumors, and medullary carcinoma of the thyroid. Paragangliomas (PGLs) are rare neuroendocrine tumors that can secrete catecholamines. Case reports and reports of ectopic ACTH secretion from metastatic PGLs causing CS are exceedingly rare. We present a case of a 38-year-old female, who presented with typical signs, symptoms, and complications of CS, secondary to a PGL with widespread metastases, which eventually led to her demise.

Tobacco smoking in young people seeking treatment for mental ill-health: what are their attitudes, knowledge and behaviours towards quitting?

INTRODUCTION: Tobacco smoking is a leading cause of preventable death and disease worldwide. Adults with mental ill-health smoke tobacco at substantially higher rates than other adults, with public health approaches effective in the population overall having less impact on those with mental ill-health. However, less is known about the tobacco smoking behaviours, attitudes and knowledge of young people with mental ill-health, despite this being the peak period of onset for both mental illness and cigarette smoking. METHODS: Young people attending a youth mental health centre (providing both primary and specialist care) in Melbourne, Australia were approached by youth peer researchers and asked to complete a survey about smoking behaviours, attitudes and knowledge. We examined smoking and associated attitudes in the sample overall, and as a function of the services accessed. RESULTS: In total, 114 young people completed the survey, with 56.3% reporting lifetime cigarette smoking, 42.0% smoking in the last 12 months and 28.6% in the past week. Of current regular smokers, 75.0% acknowledged they should quit in the future; however, only 23.5% planned to do so in the next month, with 44.4% confident that they could quit. Participants lacked knowledge about interactions between tobacco smoking, mental and physical health. CONCLUSIONS: Youth presenting for mental ill-health had high rates of cigarette smoking relative to population rates. Presentation at youth mental health services may represent a critical window for early intervention to reduce the lifetime impacts of cigarette smoking in mental ill-health. Interventions to support smoking cessation in this group are urgently needed.

Subjective morbidity following radial free flap reconstruction in head and neck tumour patients.

OBJECTIVE: Evaluation of post-operative donor site disability remains unaddressed in radial forearm free flap cases. This study aimed to assess donor site dysfunction following radial forearm free flap harvest using validated general, disease-specific and site-specific disability questionnaires. METHODS: In this retrospective case series of 24 patients at a tertiary academic medical centre, patients were assessed using the Short Form 36 Health Survey, Short Musculoskeletal Function Assessment questionnaire, and Disabilities of the Arm, Shoulder and Hand questionnaire. One-sample z-tests were performed, comparing means of the cohort to controls. RESULTS: Compared to population controls, the cohort had higher mean scores for the Disabilities of the Arm, Shoulder and Hand questionnaire (18.22 vs 10.1, p < 0.01), and Short Musculoskeletal Function Assessment questionnaire bothersome index (21.44 vs 13.77, p = 0.04), and a lower mean score for the Short Form 36 Health Survey physical component (38.88 vs 50, p < 0.01), indicating a greater disability for the cohort compared to controls. CONCLUSION: Radial forearm free flap harvest causes significant long-term donor site disability in head and neck tumour patients. The Disabilities of the Arm, Shoulder and Hand questionnaire is a concise tool for measuring this dysfunction.

The effectiveness of ultra-clean air operating theatres in the prevention of deep infection in joint arthroplasty surgery.

Deep infection was identified as a serious complication in the earliest days of total hip arthroplasty. It was identified that airborne contamination in conventional operating theatres was the major contributing factor. As progress was made in improving the engineering of operating theatres, airborne contamination was reduced. Detailed studies were carried out relating airborne contamination to deep infection rates. In a trial conducted by the United Kingdom Medical Research Council (MRC), it was found that the use of ultra-clean air (UCA) operating theatres was associated with a significant reduction in deep infection rates. Deep infection rates were further reduced by the use of a body exhaust system. The MRC trial also included a detailed microbiology study, which confirmed the relationship between airborne contamination and deep infection rates. Recent observational evidence from joint registries has shown that in contemporary practice, infection rates remain a problem, and may be getting worse. Registry observations have also called into question the value of "laminar flow" operating theatres. Observational evidence from joint registries provides very limited evidence on the efficacy of UCA operating theatres. Although there have been some changes in surgical practice in recent years, the conclusions of the MRC trial remain valid, and the use of UCA is essential in preventing deep infection. There is evidence that if UCA operating theatres are not used correctly, they may have poor microbiological performance. Current UCA operating theatres have limitations, and further research is required to update them and improve their microbiological performance in contemporary practice. Cite this article: Bone Joint J 2018;100-B:1264-9.

Subjective morbidity following fibular free flap reconstruction in head and neck cancer patients.

OBJECTIVE: This study aimed to evaluate the presence of subjective post-operative donor site morbidity after fibula free flap reconstruction in head and neck cancer patients, utilising three validated instruments: the 36-item Short Form Health Survey, the Short Musculoskeletal Function Assessment questionnaire and the Lower Limb Core Scale. METHODS: In this retrospective study, all head and neck cancer patients who underwent fibula free flap reconstruction between January 2009 and July 2014 were identified. All questionnaires and their respective subcomponents were scored. RESULTS: Twenty-one cases were included. Patients were found to have a higher Short Musculoskeletal Function Assessment bothersome index (22.42 vs 13.77, p = 0.03), a lower Short Form 36 Health Survey Physical Component Summary score (42.44 vs 50, p < 0.01) and a decreased Lower Limb Core Scale score (47.08 vs 90.52, p < 0.01), compared to US population norms. The Short Form 36 Health Survey Mental Component Summary scores and Short Musculoskeletal Function Assessment function index failed to demonstrate significant differences. Gender affected overall disability. CONCLUSION: In this study, significant long-term disability was demonstrated after fibular flap reconstruction, as measured by the Lower Limb Core Scale.

The genetics of congenital heart disease understanding and improving long-term outcomes in congenital heart disease: a review for the general cardiologist and primary care physician.

PURPOSE OF REVIEW: This review has two purposes: to provide an updated review of the genetic causes of congenital heart disease (CHD) and the clinical implications of these genetic mutations, and to provide a clinical algorithm for clinicians considering a genetics evaluation of a CHD patient. RECENT FINDINGS: A large portion of congenital heart disease is thought to have a significant genetic contribution, and at this time a genetic cause can be identified in approximately 35% of patients. Through the advances made possible by next generation sequencing, many of the comorbidities that are frequently seen in patients with genetic congenital heart disease patients can be attributed to the genetic mutation that caused the congenital heart disease. These comorbidities are both cardiac and noncardiac and include: neurodevelopmental disability, pulmonary disease, heart failure, renal dysfunction, arrhythmia and an increased risk of malignancy. Identification of the genetic cause of congenital heart disease helps reduce patient morbidity and mortality by improving preventive and early intervention therapies to address these comorbidities. SUMMARY: Through an understanding of the clinical implications of the genetic underpinning of congenital heart disease, clinicians can provide care tailored to an individual patient and continue to improve the outcomes of congenital heart disease patients.

Radio frequency measurements of tunnel couplings and singlet-triplet spin states in Si:P quantum dots.

Spin states of the electrons and nuclei of phosphorus donors in silicon are strong candidates for quantum information processing applications given their excellent coherence times. Designing a scalable donor-based quantum computer will require both knowledge of the relationship between device geometry and electron tunnel couplings, and a spin readout strategy that uses minimal physical space in the device. Here we use radio frequency reflectometry to measure singlet-triplet states of a few-donor Si:P double quantum dot and demonstrate that the exchange energy can be tuned by at least two orders of magnitude, from 20 µeV to 8 meV. We measure dot-lead tunnel rates by analysis of the reflected signal and show that they change from 100 MHz to 22 GHz as the number of electrons on a quantum dot is increased from 1 to 4. These techniques present an approach for characterizing, operating and engineering scalable qubit devices based on donors in silicon.

Image guidance protocols: balancing imaging parameters against scan time.

OBJECTIVE: Optimisation of imaging protocols is essential to maximise the use of image-guided radiotherapy. This article evaluates the time for daily online imaging with TomoTherapy® (Accuray®, Sunnyvale, CA), separating mechanical scan acquisition from radiographer-led image matching, to estimate the time required for a clinical research study (VoxTox). METHODS: Over 5 years, 18 533 treatments were recorded for 3 tumour sites of interest (prostate, head and neck and central nervous system). Data were collected for scan length, number of CT slices, slice thickness, scan acquisition time and image matching time. RESULTS: The proportion of coarse thickness scans increased over time, with a move of making coarse scans as the default. There was a strong correlation between scan time and scan length. Scan acquisition requires 40 s of processing time. For coarse scans, each additional centimetre requires 8 s for acquisition. Image matching takes approximately 1.5 times as long, so each additional centimetre needs 20 s extra in total. Modest changes to the imaging protocol have minimal impact over the course of the day. CONCLUSION: This work quantified the effect of changes to clinical protocols required for research. The results have been found to be reassuring in the busy National Institutes of Health department. ADVANCES IN KNOWLEDGE: This novel method of data collection and analysis provides evidence of the minimal impact of research on clinical turnover. Whilst the data relate specifically to TomoTherapy, some aspects may apply to other platforms in the future.

Radio-frequency reflectometry on large gated two-dimensional systems.

We have embedded an AlGaAs/GaAs based, gated two-dimensional (2D) hole system (2DHS) into an impedance transformer LC circuit and show that by using radio-frequency reflectometry it is possible to perform sensitive, large bandwidth, electrical resistance measurements of 2D systems at millikelvin temperatures. We construct a simple lumped element model where the gated 2DHS is described as a resistive transmission line. The model gives a qualitative understanding of the experimental results. As an example, we use our method to map out the Landau level evolution in a 2DHS as a function of magnetic field and gate voltage.

Bfl-1/A1 functions, similar to Mcl-1, as a selective tBid and Bak antagonist.

The prosurvival Bcl-2-family member Bfl-1/A1 is a transcriptional target of nuclear factor-kappaB (NF-kappaB) that is overexpressed in many human tumors and is a means by which NF-kappaB inhibits apoptosis, but its mode of action is controversial. To better understand how Bfl-1 functions, we investigated its interaction with proapoptotic multidomain proteins Bax and Bak, and the BH3-only proteins Bid and tBid. We demonstrate that in living cells Bfl-1 selectively interacts with Bak and tBid, but not with Bax or Bid. Bfl-1/Bak interaction is functional as Bfl-1 suppressed staurosporine (STS)-induced apoptosis in wild-type and Bax-deficient cells, but not in Bak-/- cells. We also show that Bfl-1 blocks tumor necrosis factor-alpha (TNFalpha)-induced activation of Bax indirectly, via association with tBid. C-terminal deletion decreased Bfl-1's interaction with Bak and tBid and reduced its ability to suppress Bak- and tBid-mediated cell death. These data indicate that Bfl-1 utilizes different mechanisms to suppress apoptosis depending on the stimulus. Bfl-1 associates with tBid to prevent activation of proapoptotic Bax and Bak, and it also interacts directly with Bak to antagonize Bak-mediated cell death, similar to Mcl-1. Thus, part of the protective function of NF-kappaB is to induce Mcl-1-like activity by upregulating Bfl-1.

Constitutive proteasome-mediated turnover of Bfl-1/A1 and its processing in response to TNF receptor activation in FL5.12 pro-B cells convert it into a prodeath factor.

Bfl-1/A1 is generally recognized as a Bcl-2-related inhibitor of apoptosis. We show that Bfl-1 undergoes constitutive ubiquitin/proteasome-mediated turnover. Moreover, while Bfl-1 suppresses apoptosis induced by staurosporine or cytokine withdrawal, it is proapoptotic in response to tumor necrosis factor (TNF) receptor activation in FL5.12 pro-B cells. Its anti- versus proapoptotic effect is regulated by two proteolytic events: (1) its constitutive proteasome-mediated turnover and (2) its TNF/cycloheximide (CHX)-induced cleavage by mu-calpain, or a calpain-like activity, coincident with acquisition of a proapoptotic phenotype. In vitro studies suggest that calpain-mediated cleavage of Bfl-1 occurs between its Bcl-2 homology (BH)4 and BH3 domains. This would be consistent with the generation of a proapoptotic Bax-like BH1-3 molecule. Overall, our studies uncovered two new regulatory mechanisms that play a decisive role in determining Bfl-1's prosurvival versus prodeath activities. These findings might provide important clues to counteract chemoresistance in tumor cells that highly express Bfl-1.

Smoking reduction and the rate of decline in FEV(1): results from the Lung Health Study.

Previous findings from the Lung Health Study have shown that smoking cessation and sustained abstinence substantially reduce the rate of decline in forced expiratory volume (FEV(1)) among smokers with early chronic obstructive pulmonary disease (COPD) when compared with continuing smoking. Intermittent quitters demonstrated rates of FEV(1) decline intermediate between those of sustained quitters and continuing smokers. In this study, data from 1,980 participants were analysed from 10 centres of the Lung Health Study in the USA and Canada. All participants were smokers with mild-to-moderate COPD who were unable to quit smoking at any time during the 1st yr of the study. No linear relationship was found between reduction in cigarettes per day and changes in FEV(1) during the 1st yr of the study. However, examination of the data revealed that this relationship was nonlinear. Further analysis found that smokers who reduced their cigarettes per day to very low amounts had smaller declines in FEV(1) than those who did not. Reduction in cigarettes per day was associated with only minimal changes in the presence of chronic respiratory symptoms. In conclusion, compensatory changes in smoking behaviour may account for the limited and unpredictable impact of smoking reduction on lung function decline and symptom prevalence when compared with smoking cessation.

Otorhinolaryngological manifestations of the mucopolysaccharidoses.

The mucopolysaccharidoses (MPS) are a family of related inherited metabolic disorders where, due to specific lysosomal enzyme deficiencies, partially degraded glycosaminoglycans (GAGs) accumulate in the body's cells. Due to the ubiquitous nature of GAGs in the body this deposition can occur in many tissue types and may interfere with cellular function. Although these conditions are rare, there is a propensity for the disease process to cause problems with the function of the ears, noses and throats of affected patients. In this review, we present an overview of the clinical manifestations of MPS in general and highlight the problems specifically presenting in the field of otorhinolaryngology.

Neurokinin-1 receptor resensitization precedes receptor recycling.

Following agonist binding, neurokinin-1 receptors undergo rapid desensitization followed by internalization and recycling. Desensitization requires receptor phosphorylation but does not require internalization, whereas resensitization is thought to require internalization and recycling. Our previous data, however, have suggested that, following activation and desensitization, the return of responsiveness to the neurokinin-1 agonist substance P (termed "resensitization") occurs hours before internalized receptors are recycled back to the plasma membrane. To further investigate this novel mechanism of neurokinin-1 receptor resensitization, we have studied the time courses of neurokinin-1 receptor responsiveness, recycling, and dephosphorylation by measuring cellular Ca(2+) responses, ligand-receptor binding, and receptor phosphorylation, respectively. Concentration-response curves and competition binding curves were obtained at various times following desensitization. The effects of the nonhydrolyzable GTP analog Gpp(NH)p on substance P binding were also studied to assess receptor-G protein coupling. After receptor activation and desensitization, Ca(2+) signaling in response to substance P occurred within 90 min, whereas the return of receptor binding required 240 min. Receptor dephosphorylation was greater than 90% complete 20 min after agonist washout. In addition, the return of substance P responsiveness coincided with a return in sensitivity of substance P binding to Gpp(NH)p, indicating a return in receptor-G protein coupling. These data show that the resensitization of responsiveness to substance P precedes receptor recycling. This may result from a conversion of nonfunctional neurokinin-1 receptors to functional receptors at the plasma membrane.

Distribution of vascular amyloid in scrapie-affected sheep with different genotypes.

Vascular amyloidosis in the brain is a pathological feature of ovine scrapie. Its occurrence varies between sheep, but whether this variation reflects differences in the host or the infecting scrapie strain (or both) is not clear. To investigate whether amyloidosis, like vacuolation and PrPsc distribution, is associated with genotype, the brains from 131 sheep representing a range of genotypes commonly associated with scrapie were examined histologically and immunohistochemically. Vascular amyloidosis was absent in 66 sheep, 59 of which were of the ARQ/ARQ genotype and seven the ARQ/AHQ genotype. In contrast, it was found in four of 39 ARQ/VRQ sheep (10.2%) and in 10 of 26 VRQ/VRQ sheep (38.4%). The distribution of amyloid was highly variable, but the most severely affected areas were the lateral geniculate nuclei (five cases) and the ventral thalamic nuclei (four cases). No amyloidosis was found in the medulla or in the basal nuclei. From this preliminary study it was concluded that amyloidosis is relatively rare in sheep with scrapie. Moreover, its occurrence appeared to depend on the presence of at least one valine at codon 136.

Extramedullary hematopoiesis presenting as a focal splenic mass: a case report.

We report the ultrasound, computed tomographic, and magnetic resonance imaging findings in a case of extramedullary hematopoiesis presenting as a focal splenic mass in a patient with myelodysplastic syndrome. Ultrasound demonstrated a well-circumscribed hyperechoic mass, whereas computed tomography showed a heterogeneous mass better visualized after administration of intravenous contrast. On magnetic resonance imaging, the lesion was hypointense to the spleen on T1-weighted images, with increased signal on T2-weighted images, and demonstrated enhancement after intravenous contrast administration. Extramedullary hematopoiesis should be considered in the differential diagnosis for a splenic mass in any patient with a hematologic disorder.