Automatic image-based tracking of gadolinium-filled balloon wedge catheters for MRI-guided cardiac catheterization using deep learning.
Magnetic Resonance Imaging (MRI) is a promising alternative to standard x-ray fluoroscopy for the guidance of cardiac catheterization procedures as it enables soft tissue visualization, avoids ionizing radiation and provides improved hemodynamic data. MRI-guided cardiac catheterization procedures currently require frequent manual tracking of the imaging plane during navigation to follow the tip of a gadolinium-filled balloon wedge catheter, which unnecessarily prolongs and complicates the procedures. Therefore, real-time automatic image-based detection of the catheter balloon has the potential to improve catheter visualization and navigation through automatic slice tracking. In this study, an automatic, parameter-free, deep-learning-based post-processing pipeline was developed for real-time detection of the catheter balloon. A U-Net architecture with a ResNet-34 encoder was trained on semi-artificial images for the segmentation of the catheter balloon. Post-processing steps were implemented to guarantee a unique estimate of the catheter tip coordinates. This approach was evaluated retrospectively in 7 patients (6M and 1F, age = 7 ± 5 year) who underwent an MRI-guided right heart catheterization procedure with all images acquired in an orientation unseen during training. The overall accuracy, specificity and sensitivity of the proposed catheter tracking strategy over all 7 patients were 98.4 ± 2.0%, 99.9 ± 0.2% and 95.4 ± 5.5%, respectively. The computation time of the deep-learning-based segmentation step was ∼10 ms/image, indicating its compatibility with real-time constraints. Deep-learning-based catheter balloon tracking is feasible, accurate, parameter-free, and compatible with real-time conditions. Online integration of the technique and its evaluation in a larger patient cohort are now warranted to determine its benefit during MRI-guided cardiac catheterization.


Financial viability of community health centers.
Local public officials have become greatly concerned about the impact of the continued demand for local subsidies for outpatient programs. This article examines two basic obstacles to the fiscal viability of inner city ambulatory programs, management practices and reimbursement policies. Findings are presented with respect to the relative importance of these obstacles and options are developed for the reform of existing subsidy programs.


The radiographic evaluation of keeled and pegged glenoid component insertion.
Radiolucent lines about the glenoid component of a total shoulder replacement are a common finding, even on initial postoperative radiographs. The achievement of complete osseous support of the component has been shown to decrease micromotion. We evaluated the ability of a group of experienced shoulder surgeons to achieve complete cementing and support in a series of patients managed with keeled and pegged glenoid components. We reviewed the initial postoperative radiographs of 493 patients with primary osteoarthritis who had been managed with total shoulder arthroplasty by seventeen different surgeons. One hundred and sixty-five patients were excluded because of inadequate radiographs, leaving 328 patients available for review. Of these, thirty-nine patients had a keeled component and 289 had a pegged component. The method of Franklin was used to grade the degree of radiolucency around the keeled components, and a modification of that method was used to grade the degree of radiolucency around the pegged components. The efficacy of component seating on host subchondral bone was evaluated with a newly constructed five-grade scale based on the percentage of the component that was supported by subchondral bone. Each radiograph was graded four times, by two separate reviewers on two separate occasions. Radiolucencies were extremely common, with only twenty of the 328 glenoids demonstrating no radiolucencies. On a numeric scale (with 0 indicating no radiolucency and 5 indicating gross loosening), the mean radiolucency score was 1.8 +/- 0.9 for keeled components and 1.3 +/- 0.9 for pegged components (p = 0.0004). After defining categories of "better" and "worse" cementing, we found that pegged components more commonly had "better cementing" than did keeled components (p = 0.0028). Incomplete seating was also common, particularly among patients with keeled components. Ninety-five of the 121 pegged components that had been inserted by the most experienced surgeon had "better cementing," compared with eighty-five of the 168 pegged components that had been inserted by the remaining surgeons (p < 0.00001). Perfectly cementing and seating a glenoid replacement is a difficult task. Radiolucencies and incomplete component seating occur more frequently in association with keeled components compared with pegged components. Surgeon experience may be an important variable in the achievement of a good technical outcome.


Patterns of opioid use in patients with trigeminal neuralgia undergoing neurosurgery.
First-line treatment for trigeminal neuralgia (TN) is pharmacological management using antiepileptic drugs (AEDs), e.g., carbamazepine (CBZ) and oxcarbazepine (OCBZ). Surgical intervention has been shown to be an effective and durable treatment for TN that is refractory to medical therapy. Despite the lack of evidence for efficacy in patients with TN, the authors hypothesized that patients with neuropathic facial pain are prescribed opioids at high rates, and that neurosurgical intervention may lead to a reduction in opioid use. This is a retrospective study of patients with facial pain seen by a single neurosurgeon. All patients completed a survey on pain medications, medical comorbidities, prior interventions for facial pain, and a validated pain outcome tool (the Penn Facial Pain Scale). Patients subsequently undergoing neurosurgical intervention completed a survey at the 1-month follow-up in the office, in addition to telephone interviews using a standardized script between 1 and 6 years after intervention. Univariate and multivariate logistic regression were used to predict opioid use. The study cohort consisted of 309 patients (70% Burchiel type 1 TN [TN1], 18% Burchiel type 2 [TN2], 6% atypical facial pain [AFP], and 6% TN secondary to multiple sclerosis [TN-MS]). At initial presentation, 20% of patients were taking opioids. Of these patients, 55% were receiving concurrent opioid therapy with CBZ/OCBZ, and 84% were receiving concurrent therapy with at least one type of AED. Facial pain diagnosis (for diagnoses other than TN1, odds ratio [OR] 2.5, p = 0.01) and facial pain intensity at its worst (for each unit increase, OR 1.4, p = 0.005) were predictors of opioid use at baseline. Neurosurgical intervention led to a reduction in opioid use to 8% at long-term follow-up (p < 0.01, Fisher's exact test; n = 154). Diagnosis (for diagnoses other than TN1, OR 4.7, p = 0.002) and postintervention reduction in pain at its worst (for each unit reduction, OR 0.8, p < 10-3) were predictors of opioid use at long-term follow-up. On subgroup analysis, patients with TN1 demonstrated a decrease in opioid use to 5% at long-term follow-up (p < 0.05, Fisher's exact test), whereas patients with non-TN1 facial pain did not. In the nonsurgical group, there was no statistically significant decrease in opioid use at long-term follow-up (n = 81). In spite of its high potential for abuse, opioid use, mostly as an adjunct to AEDs, is prevalent in patients with facial pain. Opportunities to curb opioid use in TN1 include earlier neurosurgical intervention.


[Changes in the ambulatory arterial pressure of normotensive obese children].
Obesity represents an important risk factor for cardiovascular disease and in children it is often associated to the future development of essential hypertension. To evaluate the early hemodynamic alterations in obese normotensive children, ambulatory monitoring was performed in 18 obese children aged 9.6 +/- 2.9 and in 33 controls of equivalent age by ICR 5200 (Spacelabs, USA). Blood pressure daily curves in the two groups were compared by MANOVA. Basal blood pressure did not differ in the two groups (115 +/- 17 mmHg and 79 +/- 7 mmHg respectively systolic and diastolic in controls and 115 +/- 12 mmHg and 79 +/- 6 mmHg in obese children). On the contrary ambulatory monitoring showed higher systolic values in obese children when compared to controls (112 +/- 7 versus 107 +/- 7, p less than 0.04) (MANOVA test, p less than 0.03). The difference was observed both during the day time (115 +/- 6 vs 111 +/- 7, p less than 0.03) and during the night (107 +/- 9 vs 102 +/- 8, p less than 0.5). No differences in diastolic pressure and in heart rate were observed. Those findings indicate that in obese children blood pressure alterations unrecognized at usual blood pressure checks are detectable by ambulatory 24 hour monitoring.


GRM7-related disorder: Five additional patients from three independent families and review of the literature.
Developmental and epileptic encephalopathies (DEEs) refer to a group of severe epileptic syndromes characterized by seizures as well as a developmental delay which can be a consequence of the underlying etiology and/or the epileptic encephalopathy. The genes responsible for DEEs are numerous and their number is increasing since the availability of Next-Generation Sequencing. Pathogenic variants in GRM7, encoding the metabotropic glutamate receptor 7, were recently shown as a cause of a severe DEE with autosomal recessive inheritance. To date, only ten patients have been reported in the literature, generally with severe phenotypes including early-onset epilepsy, microcephaly, brain anomalies, and spasticity. We report here 5 patients from 3 independent families with biallelic variants in the GRM7 gene. We review the literature and provide further elements for the understanding of the genotype-phenotype correlation of this rare syndrome.


Sensitive Troponin I and Stress Testing in the Emergency Department for the Early Management of Chest Pain Using 2-Hour Protocol.
Despite improvements in identifying high-risk patients with non-ST segment ACS (acute coronary syndrome), low risk patients presenting with atypical chest pain and non-diagnostic Electrocardiogram (ECG) continued to undergo unnecessary admissions and testing. Since 1992, our chest pain protocol included using 4-hour serial biomarkers from ED admission in combination with stress testing to evaluate these patients. Our study aimed at determining whether a new accelerated diagnostic protocol using sensitive cardiac troponin I (cTnI) 2 hours after admission to the ED followed by stress testing is safe and effective in emergency settings, allowing for appropriate triage, earlier discharge and reducing costs. We conducted a single center randomized trial at Presence St. Francis Hospital Chest pain center in Evanston, Illinois enrolling sixty-four consecutive patients with atypical chest pain and non-diagnostic ECG, participants were randomized to accelerated 2 hrs protocol or our pre-existing 4-hrs protocol. Sixty patients completed the protocol and were randomized to either a 2-hour (29 patients) or 4-hour protocol using both I-STAT and PATHFAST cTnI (31 Patients). Troponin I was evaluated at 0 and at 2 hours from ED presentation with and additional draw for patients in the 4-hour rule out-group. Patients with normal serial biomarkers were then evaluated with stress testing and qualified for earlier discharge if the stress test was negative, while those with a positive biomarker at any time were admitted. Thirty-six patients had exercise treadmill stress test and 24 patients had either nuclear or Echo stress test. Fifty-three patients had a normal stress test and were discharged home. One patient in the 4-hour group with normal serial troponins developed ventricular tachycardia/fibrillation during the recovery period of a regular stress test. Six patients had a positive PATHFAST cTnI and a normal I-STAT cTnI at 2-hours. Two out of these six patients evaluated by coronary angiography. One patient had severe tortuous coronaries but no significant obstructive lesion and one had a severe CAD who needed Coronary artery bypass grafting (CABG). Three of the six patients had a normal stress test and one patient decided to leave without further testing. None of the patients with a normal stress test had a major cardiac event or adverse cardiac outcome at six-month follow up. This study demonstrates that the 2 hours accelerated protocol using high sensitivity Troponin assay at 0 and 2 hours with comprehensive clinical evaluation and ECG followed by stress testing might be successful in identifying low-risk patient population who may benefit from early discharge from ED reducing associated costs and length of stay.


Brain-stimulation induced blindsight: unconscious vision or response bias?
A dissociation between visual awareness and visual discrimination is referred to as "blindsight". Blindsight results from loss of function of the primary visual cortex (V1) which can occur due to cerebrovascular accidents (i.e. stroke-related lesions). There are also numerous reports of similar, though reversible, effects on vision induced by transcranial Magnetic Stimulation (TMS) to early visual cortex. These effects point to V1 as the "gate" of visual awareness and have strong implications for understanding the neurological underpinnings of consciousness. It has been argued that evidence for the dissociation between awareness of, and responses to, visual stimuli can be a measurement artifact of the use of a high response criterion under yes-no measures of visual awareness when compared with the criterion free forced-choice responses. This difference between yes-no and forced-choice measures suggests that evidence for a dissociation may actually be normal near-threshold conscious vision. Here we describe three experiments that tested visual performance in normal subjects when their visual awareness was suppressed by applying TMS to the occipital pole. The nature of subjects' performance whilst undergoing occipital TMS was then verified by use of a psychophysical measure (d') that is independent of response criteria. This showed that there was no genuine dissociation in visual sensitivity measured by yes-no and forced-choice responses. These results highlight that evidence for visual sensitivity in the absence of awareness must be analysed using a bias-free psychophysical measure, such as d', In order to confirm whether or not visual performance is truly unconscious.


miR-33-5p knockdown attenuates abdominal aortic aneurysm progression via promoting target adenosine triphosphate-binding cassette transporter A1 expression and activating the PI3K/Akt signaling pathway.
The aim of this study was to investigate the role of miR-33-5p in abdominal aortic aneurysm progression, which regulated adenosine triphosphate-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux and lipid accumulation in THP-1 macrophage-derived foam cells through the PI3K/Akt pathway. Quantitative reverse transcription polymerase chain reaction was used to evaluate the expression level of miR-33-5p and ABCA1 mRNA in abdominal aortic aneurysm patient and normal person tissues. The relationship between miR-33-5p and ABCA1 was examined by dual luciferase report assay. High-performance liquid chromatography was used to evaluate the levels of cholesterol contents. Cholesterol efflux detection was performed by liquid scintillator. The expression of inflammatory cytokines was detected by quantitative reverse transcription polymerase chain reaction. Western blot was applied to determine the expression levels of ABCA1, PI3K (p-PI3K), and Akt (p-Akt). The quantitative reverse transcription polymerase chain reaction analysis results revealed miR-33-5p overexpression in abdominal aortic aneurysm tissues, but the expression level of ABCA1 was lower in abdominal aortic aneurysm tissues than non-abdominal aortic aneurysm tissues. Subsequently, the dual luciferase report gene assay confirmed that ABCA1 was a target of miR-33-5p, and miR-33-5p-negative regulated ABCA1 expression. Moreover, the expression levels of p-PI3K, p-Akt, and ABCA1 were decreased in THP-1 cell transferred with ABCA1 siRNA, but knockdown of miR-33-5p had an opposite effect. Furthermore, knockdown of miR-33-5p decreased the expression of MMP-2, MMP-9, TNF-α, total cellular cholesterol, and promoted cholesterol efflux in THP-1-derived foam cells. Importantly, LY294002 (PI3K inhibitor) or si-ABCA1 completely inhibited the stimulatory effects of miR-33-5p inhibitor. This study has found that knockdown of miR-33-5p induced ABCA1 expression and promoted inflammatory cytokines and cholesterol efflux likely via activating the PI3K/Akt signaling pathway.


Dynamically Evolving Multifunctional Protective Layer for Highly Stable Potassium Metal Anodes.
The construction of an artificial protective layer is an effective method to solve the issues, such as uncontrolled dendrite growth and an unstable solid electrolyte interphase, at the K metal anode. This study proposes a new dynamic evolution strategy that integrates the advantages of previous in situ and ex situ fabrication processes. A multifunctional protective layer enriched with K-Ge alloy is prepared on the K metal electrode by simple surface modification and in situ reduction via an electrochemical process. The protective layer has good potassiophilicity, mechanical flexibility, and high ionic conductivity, which can inhibit dendrite growth and reduce side reactions. The protected K electrode with a protective layer exhibits dendrite-free K plating/striping behavior, and the symmetric cell can run stably for over 1000 h at 1 mA cm-2 and 1 mAh cm-2. Notably, full cells based on this electrode also present excellent rate and cycling performance compared to those of the bare K electrode. This peculiar strategy will open a new avenue for metal anode protection and can be extended to other high-energy battery systems.


A novel therapeutic approach for endometriosis using adipose-derived stem cell-derived conditioned medium- A new hope for endometriotic patients in improving fertility.
Endometriosis is defined as the growth of endometrial glands and stromal cells in a heterotopic location with immune dysregulation. It usually leads to chronic pelvic pain and subfertility. Although various treatments are available, the recurrence rate remains high. Adipose tissue is an abundant source of multipotent mesenchymal adipose-derived stem cells (ADSCs). ADSCs display effects on not only tissue regeneration, but also immune regulation. Thus, the current study aims to test the effects of ADSCs on the growth of endometriosis. ADSCs isolated from lipoaspiration-generated adipose tissue and their conditioned medium (ADSC-CM) were subjected to quality validation, including karyotyping as well as growth promotion and sterility tests for microbial contamination under Good Tissue Practice and Good Manufacturing Practice regulations. An autologous endometriosis mouse model was established by suturing endometrial tissue to peritoneal wall followed by treating with DMEM/F12 medium, ADSC-CM, ADSCs or ADSC-CM+ADSCs for 28 days. The area of endometriotic cysts and the degree of pelvic adhesion were measured. ICAM-1, VEGF and caspase 3 expression was assessed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. Moreover, the mice were allowed to mate and deliver. The pregnancy outcomes were recorded. The ADSC-CM was subjected to proteomics analysis with further data mining with Ingenuity Pathway Analysis (IPA). Both ADSC-CM and ADSCs passed quality validation. ADSC-CM reduced the area of endometriotic cysts. The inhibition by ADSC-CM was obliterated by adding ADSCs. The presence of ADSCs with or without ADSC-CM increased the peritoneal adhesion. ADSC-CM inhibited ICAM-1 and VEGF mRNA and protein expression, whereas the addition of ADSCs not only did not inhibit by itself, but also blocked the inhibition by ADSC-CM. The resorption rate was reduced by ADSC-CM. The number of live birth/dam and the survival rate of pup at 1 week-old were both increased by ADSC-CM in mice with endometriosis. IPA demonstrated that PTX3 was potentially critical for the inhibition of endometriosis by ADSC-CM due to its anti-inflammatory and antiangiogenic properties as well as its importance in implantation. ADSC-CM inhibited endometriosis development and improved pregnancy outcomes in mice. Potential translation to clinical treatment for human endometriosis is expected.


[The single missing tooth. Treatment possibilities from an orthodontic view point].
In patients with single missing teeth, a standard treatment plan does not exist. The treatment plan depends on the age and the facial profile, the malocclusion, the interdigitation, the available space, the amount of bone, the shape, color, and the level of the gingiva of the neighbouring teeth. Closing or opening the diastema should be considered. A diagnostic set-up of the final occlusion can provide more insight into the final result that can be expected from the treatment modalities. Orthodontic closure of the diastema is preferable, but not always feasible or desirable and compensatory extractions may be necessary. In children, auto-transplantation is an option. In adults with a sufficient amount of bone the placement of an implant may be the treatment of choice. Frequently, preimplantological bone augmentation is necessary because otherwise prosthodontic replacement is the only solution.


Management and supportive care measures for adverse events in patients with myelodysplastic syndromes treated with azacitidine*.
Myelodysplastic syndrome (MDS) treatment can initially worsen patients' clinical condition and they may discontinue therapy before achieving benefit. We present previously unpublished data from two large phase III trials describing common adverse events (AEs) associated with azacitidine and methods to manage them. In the Cancer and Leukemia Group B (CALGB) 9221 study, patients with any French-American-British (FAB) subtype of MDS were randomized to azacitidine or best supportive care (BSC). After 56 d, patients randomized to BSC with disease progression could cross over to receive azacitidine. In the AZA-001 study, patients with higher-risk MDS (FAB-defined refractory anemia with excess blasts (RAEB), RAEB in transformation, or chronic myelomonocitic leukaemia and IPSS int-2 or high) were randomized to azacitidine or to conventional care regimens (CCR), which included low-dose ara-C, BSC, or intensive chemotherapy. In both studies, azacitidine dose was 75 mg/m(2)/d SC for 7 d every 28 d. AEs were graded per National Cancer Institute's Common Toxicity Criteria version 2.0 (AZA-001) or CALGB Expanded CTC (CALGB 9221). In safety-evaluable patients in AZA-001 (N = 175) or CALGB 9221 (N = 150), the most common AEs with azacitidine included hematologic (eg, cytopenias) and non-hematologic administration-related events (eg, injection-site reactions and gastrointestinal disorders). Most AEs were transient and resolved during ongoing therapy (> 83%). Hematologic AEs, most frequently observed during early treatment cycles, decreased during subsequent cycles and were usually managed with dosing delays (23-29%). Gastrointestinal symptoms were primarily managed with anti-emetics and laxatives. Hematologic and non-hematologic AEs with azacitidine decreased in frequency as treatment continued. Awareness of the onset, duration and management of AEs can facilitate treatment, permitting patients to continue therapy for maximum benefit.


Urorectal septal defects in a female and her offspring.
We report on a patient with an ectopic urethra opening into a septate vagina which was distended with urine. The anus and rectum were normal but separated from the urogenital sinus by a thin septum. After surgical repair the patient did well with the exception of recurrent urinary tract infections. At 16 years, she delivered a healthy boy by Cesarean section but miscarried a subsequent pregnancy 3 years later. The 12-13 week female fetus lacked a urethra and had an atretic vagina and cloacal anomalies consistent with a urorectal septum developmental defect. This report provides evidence that cloacal anomalies resulting from the improper development of the urorectal septum may have a genetic cause. Furthermore, we support the proposition previously set forth by Allen and Husmann [J Urol 145:1034-1039, 1991] that such anomalies be referred to as urorectal septal defects rather than cloacal anomaly variants. This terminology accurately represents the developmental defect and clearly distinguishes them from cloacal exstrophies, which are due to the abnormal development of the cloacal membrane and the subumbilical ventral abdominal wall.


Co-opted JNK/SAPK signaling in Wnt/beta-catenin-induced tumorigenesis.
Aberrant stimulation of the canonical Wnt pathway induces mammary tumorigenesis in mice. It has been well documented that two types of tumors, adenocarcinoma and adenocarcinoma with squamous metaplasia, develop in these mutants. However, the molecular mechanism underlying the induction of squamous transdifferentiation remains largely unknown. Here, we show that JNK/SAPK signaling plays an important role in Wnt-dependent mammary development and malignant transformation. The JNK/SAPK pathway is stimulated in pregnancy-mediated lobulo-alveolar morphogenesis, a process highly dependent on Wnt/beta-catenin signaling. Strong elevations of JNK/SAPK signaling are associated with squamous metaplasia of the Wnt-induced adenocarcinoma. Reconstitution of beta-catenin and JNK/SAPK signaling activities also promotes expression of the squamous cell marker in cultured epithelial cells. Furthermore, a synergistic activation of these two pathways can be identified in the malignant squamous cells of human endometrial and lung cancers. This is potentially a significant discovery in modern cancer therapy because of the effectiveness of an angiogenesis inhibitor, Avastin, for the treatment of adenocarcinoma, but not squamous cell carcinoma, in human lung cancers. Our finding may improve the usage of biomarkers to distinguish these two poorly differentiated tumor types, sharing similar histologic features.


Synchronizing terahertz wave generation with attosecond bursts.
We perform a joint measurement of terahertz waves and high-harmonics generated from argon atoms driven by a fundamental laser pulse and its second harmonic. By correlating their dependence on the phase delay between the two pulses, we determine the generation of THz waves in tens of attoseconds precision. Compared with simulations and models, we find that the laser-assisted soft collision of the electron wave packet with the atomic core plays a key role. It is demonstrated that the rescattering process, being indispensable in high-harmonic generation processes, dominates THz wave generation as well in a more elaborate way. The new finding might be helpful for the full characterization of the rescattering dynamics.


Spatiotemporal regulation of intracellular trafficking of Toll-like receptor 9 by an inhibitory receptor, Ly49Q.
Toll-like receptor (TLR) 9 recognizes unmethylated microorganismal cytosine guanine dinucleotide (CpG) DNA and elicits innate immune responses. However, the regulatory mechanisms of the TLR signaling remain elusive. We recently reported that Ly49Q, an immunoreceptor tyrosine-based inhibitory motif-bearing inhibitory receptor belonging to the natural killer receptor family, is crucial for TLR9-mediated type I interferon production by plasmacytoid dendritic cells. Ly49Q is expressed in plasmacytoid dendritic cells, macrophages, and neutrophils, but not natural killer cells. In this study, we showed that Ly49Q regulates TLR9 signaling by affecting endosome/lysosome behavior. Ly49Q colocalized with CpG in endosome/lysosome compartments. Cells lacking Ly49Q showed a disturbed redistribution of TLR9 and CpG. In particular, CpG-induced tubular endolysosomal extension was impaired in the absence of Ly49Q. Consistent with these findings, cells lacking Ly49Q showed impaired cytokine production in response to CpG-oligodeoxynucleotide. Our data highlight a novel mechanism by which TLR9 signaling is controlled through the spatiotemporal regulation of membrane trafficking by the immunoreceptor tyrosine-based inhibitory motif-bearing receptor Ly49Q.


Biology of the congenitally hypothyroid hyt/hyt mouse.
The hyt/hyt mouse has an autosomal recessive, fetal onset, characterized by severe hypothyroidism that persists throughout life and is a reliable model of human sporadic congenital hypothyroidism. The hypothyroidism in the hyt/hyt mouse reflects the hyporesponsiveness of the thyroid gland to thyrotropin (TSH). This is attributable to a point mutation of C to T at nucleotide position 1666, resulting in the replacement of a Pro with Leu at position 556 in transmembrane domain IV of the G protein-linked TSH receptor. This mutation leads to a reduction in all cAMP-regulated events, including thyroid hormone synthesis. The diminution in T3/T4 in serum and other organs, including the brain, also leads to alterations in the level and timing of expression of critical brain molecules, i.e. selected tubulin isoforms (M beta 5, M beta 2, and M alpha 1), microtubule associated proteins (MAPs), and myelin basic protein, as well as to changes in important neuronal cytoskeletal events, i.e. microtubule assembly and SCa and SCb axonal transport. In the hyt/hyt mouse, fetal hypothyroidism leads to reductions in M beta 5, M beta 2, and M alpha 1 mRNAs, important tubulin isoforms, and M beta 5 and M beta 2 proteins, which comprise the microtubules. These molecules are localized to layer V pyramidal neurons in the sensorimotor cortex, a site of differentiating neurons, as well as a site for localization of specific thyroid hormone receptors. These molecular abnormalities in specific cells and at specific times of development or maturation may contribute to the observed neuroanatomical abnormalities, i.e. altered neuronal process growth and maintenance, synaptogenesis, and myelination, in hypothyroid brain. Abnormal neuroanatomical development in selected brain regions may be the factor underlying the abnormalities in reflexive, locomotor, and adaptive behavior seen in the hyt/hyt mouse and other hypothyroid animals.


Inelastic rate coefficients based on an improved potential energy surface for N2 + N2 collisions in a wide temperature range.
A modification in the potential energy surface (PES) for N2-N2 interactions, reported in the literature [D. Cappelletti et al., Phys. Chem. Chem. Phys., 2008, 10, 4281], has been presented to improve its description of, particularly, the short range behavior for specific configurations, with the aim of producing a large database of vibration to vibration (V-V) and vibration to translation/rotation (V-T/R) energy transfer rate coefficients, with an increased accuracy extended to large temperature ranges relevant to the modeling of hypersonic gas flows. The modifications were introduced in a physically meaningful fashion and they are shown to improve the performance of the PES in a wide temperature range, not only for calculating rate coefficients, but also for determining a variety of physical properties. This new PES was then used to calculate V-V and V-T/R rate coefficients for inelastic N2-N2 collisions through a mixed quantum-classical method, based on the quantum treatment of molecular vibrations, for vibrationally excited states up to v = 40. Such a large V-T/R coefficient database is quite unprecedented, and the comparison of the efficiency of the related processes with the corresponding V-V coefficients shows that vibrational relaxation plays a very relevant role in high temperature regimes.


Miniature in vivo cameras for use in single-incision robotic surgery - biomed 2011.
Single-incision surgery provides numerous benefits over traditional open and laparoscopic surgery techniques including reduced pain, shortened recovery times, and minimal tissue scarring. The use of miniature in vivo robots inserted through a single incision offers additional advantages over conventional laparoscopy in improved maneuverability and dexterity. One consequence of performing surgical procedures through a small single incision is the loss of direct visualization through a large open incision or visualization via laparoscopic cameras inserted through additional ports. For this reason, a miniature in vivo actuated camera was designed to pass through a single incision and attach to a miniature in vivo robot, providing live video feedback at the control of the surgeon. The device was tested in a lab setting and porcine model surgery and demonstrated successful movement, control, and high-quality visualization, indicating the device's functionality and feasibility for use in single-incision robotic surgery.


Sweet Taste Perception and Dental Caries in 13- to 15-Year-Olds: A Multicenter Cross-Sectional Study.
Dietary habits and, in particular, the intake frequency of sucrose are of major importance for the development of dental caries. The perception of sweet taste is believed to have an influence on sucrose intake and therefore affects the predisposition to dental caries. The aim was to study the caries experience and sweet taste perception and to further analyze the possible relationship between the 2 tested variables in 13- to 15-year-old children from 3 different geographical areas. A cross-sectional survey comprising 669 children (220 Italian, 224 Mexican, and 225 Saudi Arabian) was conducted. The children were examined in their school setting. A sweet taste perception level was determined by the sweet taste threshold (TT) and sweet taste preference (TP). The sweet test was performed with sucrose solutions varying in concentration from 1.63 to 821.52 g/L. The International Caries Detection and Assessment System (ICDAS) and DMFS indices were used to diagnose caries. The highest mean value for TT was found for Italian children followed by Saudi and Mexican. Saudi schoolchildren showed the highest mean values for TP and DMFS, followed by Italian and Mexican. A statistically significant difference for TP, TT, DMFS, and initial caries was found between the 3 countries. A weak yet positive correlation was found between taste perception (TT and TP) versus DMFS and manifest caries in all 3 countries (r = 0.137-0.313). The findings of the present study showed a variation in sweet taste perception between the 3 countries, which may influence the caries outcome of the children in the individual countries.


The excretional patterns of lactate, pyruvate and alpha-ketoglutarate in renal transplants.
The excretional patterns of lactate, pyruvate and alpha-ketoglutarate were investigated after renal transplantation in 36 patients. Fourteen patients had received a living-donor kidney with short ischemia time and good initial graft function, 22 had a cadaver transplant with an initial 125iothalamate clearance of more than 6 ml/min. The excretion of lactate and pyruvate did not vary significantly from that seen in normal controls or patients with uremia. In six patients with cadaver transplants, clearance values of alpha-ketoglutarate exceeded that of the glomerular filtration rate, indicating a net tubular secretion of this substance. During acute rejection episodes in 5 patients, no changes were seen in the excretional patterns of lactate, pyruvate and alpha-ketoglutarate.


Uncovering Sub-Structure and Genomic Profiles in Across-Countries Subpopulations of Angus Cattle.
Highlighting genomic profiles for geographically distinct subpopulations of the same breed may provide insights into adaptation mechanisms to different environments, reveal genomic regions divergently selected, and offer initial guidance to joint genomic analysis. Here, we characterized similarities and differences between the genomic patterns of Angus subpopulations, born and raised in Canada (N = 382) and Brazil (N = 566). Furthermore, we systematically scanned for selection signatures based on the detection of autozygosity islands common between the two subpopulations, and signals of divergent selection, via FST and varLD tests. The principal component analysis revealed a sub-structure with a close connection between the two subpopulations. The averages of genomic relationships, inbreeding coefficients, and linkage disequilibrium at varying genomic distances were rather similar across them, suggesting non-accentuated differences in overall genomic diversity. Autozygosity islands revealed selection signatures common to both subpopulations at chromosomes 13 (63.77-65.25 Mb) and 14 (22.81-23.57 Mb), which are notably known regions affecting growth traits. Nevertheless, further autozygosity islands along with FST and varLD tests unravel particular sites with accentuated population subdivision at BTAs 7 and 18 overlapping with known QTL and candidate genes of reproductive performance, thermoregulation, and resistance to infectious diseases. Our findings indicate overall genomic similarity between Angus subpopulations, with noticeable signals of divergent selection in genomic regions associated with the adaptation in different environments.


[The protective action of arbidol during a rise in respiratory diseases in 1990].
Prophylactic properties of a new chemical drug, arbidol, against acute respiratory diseases (ARD) were studied. Arbidol given daily in a dose of 0.2 g for 19 days reduced the morbidity rate 2.3-fold in adults during an outbreak of ARD. Geometric mean titres of antibodies to respiratory viruses among healthy persons did not change after treatment with arbidol indicating the lack of immunosuppressive properties in the drug. The prophylactic effect of arbidol may be due to both specific effect of the drug on influenza and parainfluenza viruses, and its interferon-inducing and immunity-stimulating properties.


Prostatic abscess: A systematic review of current diagnostic methods, treatment modalities and outcomes.
Prostatic abscesses (PAs) are an uncommon urologic presentation with widely varying approaches in their diagnoses and management. This study, therefore, aims to systematically review the literature of PAs to identify common clinical presentations, evaluate currently utilized diagnostic and treatment modalities, and assess their outcomes. A systematic review of the literature was performed using the MEDLINE and EMBASE databases, from January 1968 to June 2019. Outcome measures extracted from identified articles included age, the underlying disease, identified pathogens, diagnostic tool utilized, treatment used, and various subsequent clinical outcomes. The literature search yielded 683 articles, with a final twelve included in the review, representing a total of 210 patients. Transrectal ultrasonography (TRUS) was the most commonly used imaging tool used to identify PAs in all twelve studies. The PAs were treated with conservative antibiotic treatment in seven studies. Transurethral resection of the prostatic abscess (TURP) was utilized in eight studies with an average abscess size of 3.87 cm (3.0-4.0 cm) and with an average hospital stay of 10.22 days in those undergoing TURP. Transperineal aspiration was seen in five studies and offered a less invasive treatment modality. Finally, TRUS-guided needle aspiration was seen in seven studies with an average hospital stay of 23.25 days. This was the longest of any identified modalities with an additional high rate of abscess recurrence. Diagnosis and treatment practices of PAs remain widely varied in the literature due to a lack of clear guidelines. Based on the current evidence, we provide recommendations of treatment based on abscess size, patient age, and clinical condition. While smaller abscesses may be suited to antibiotic or TRUS-guided aspiration, transurethral approaches should be considered for larger and more complex abscesses. However, the current evidence remains poor with further research required to determine the optimum treatment modalities for patients.


One health security: an important component of the global health security agenda.
The objectives of the Global Health Security Agenda (GHSA) will require not only a "One Health" approach to counter natural disease threats against humans, animals, and the environment, but also a security focus to counter deliberate threats to human, animal, and agricultural health and to nations' economies. We have termed this merged approach "One Health Security." It will require the integration of professionals with expertise in security, law enforcement, and intelligence to join the veterinary, agricultural, environmental, and human health experts essential to One Health and the GHSA. Working across such different professions, which occasionally have conflicting aims and different professional cultures, poses multiple challenges, but a multidisciplinary and multisectoral approach is necessary to prevent disease threats; detect them as early as possible (when responses are likely to be most effective); and, in the case of deliberate threats, find who may be responsible. This article describes 2 project areas that exemplify One Health Security that were presented at a workshop in January 2014: the US government and private industry efforts to reduce vulnerabilities to foreign animal diseases, especially foot-and-mouth disease; and AniBioThreat, an EU project to counter deliberate threats to agriculture by raising awareness and implementing prevention and response policies and practices.


Combined Impact of Magnetic Force and Spaceflight Conditions on Escherichia coli Physiology.
Changes in bacterial physiology caused by the combined action of the magnetic force and microgravity were studied in Escherichia coli grown using a specially developed device aboard the International Space Station. The morphology and metabolism of E. coli grown under spaceflight (SF) or combined spaceflight and magnetic force (SF + MF) conditions were compared with ground cultivated bacteria grown under standard (control) or magnetic force (MF) conditions. SF, SF + MF, and MF conditions provided the up-regulation of Ag43 auto-transporter and cell auto-aggregation. The magnetic force caused visible clustering of non-sedimenting bacteria that formed matrix-containing aggregates under SF + MF and MF conditions. Cell auto-aggregation was accompanied by up-regulation of glyoxylate shunt enzymes and Vitamin B12 transporter BtuB. Under SF and SF + MF but not MF conditions nutrition and oxygen limitations were manifested by the down-regulation of glycolysis and TCA enzymes and the up-regulation of methylglyoxal bypass. Bacteria grown under combined SF + MF conditions demonstrated superior up-regulation of enzymes of the methylglyoxal bypass and down-regulation of glycolysis and TCA enzymes compared to SF conditions, suggesting that the magnetic force strengthened the effects of microgravity on the bacterial metabolism. This strengthening appeared to be due to magnetic force-dependent bacterial clustering within a small volume that reinforced the effects of the microgravity-driven absence of convectional flows.


Mistakes the newly promoted make.
Many newly promoted managers make identical mistakes, most of them preventable. Physician executives who are thinking of taking on a bigger job should consider the following eight mistakes: (1) misreading top management's agenda, (2) micromanaging your successor, (3) not updating technical skills, (4) assuming customs and taboos are negotiable, (5) not rewriting your job description to mirror your new role, (6) not mentally moving from management to leadership, (7) not adjusting to relationships, and (8) not identifying a likely successor.


Comparative effectiveness of standard endotracheal tubes vs. endotracheal tubes with continuous subglottic suctioning on ventilator-associated pneumonia rates.
Ventilator-associated pneumonia (VAP) accounts for the majority of nosocomial pneumonias, which may increase intensive care and prolonged hospital stays. Endotracheal tubes allowing continuous subglottic suctioning may reduce VAP; however, they are more expensive than standard endotracheal tubes not allowing continuous suctioning. he objective of this study was to measure the comparative costs associated with continuous subglottic suctioning endotracheal tubes (CSS-ETT) versus standard endotracheal tubes (S-ETT) among intubated patients and whether cost differential is offset by the occurrence of VAP in patients receiving either type of intubation. A retrospective chart review was conducted for 154 intubated adult patients (77 = S-ETT; 77 = CSS-ETT). The S-ETT group had one case of VAP; the CSS-ETT group had none. The mean total hospital charges were higher for the S-ETT group ($103,600; CSS-ETT= $88,500) (p = 0.3). Although the average number of intubation days and ICU days were greater for the CSS-ETT group, there were no cases of VAP compared to the S-ETT group. ased upon the one S-ETT VAP case and the VAP attributable costs, it is cost effective to use the CSS-ETT.


Multicentre, randomized comparison of two-stent and provisional stenting techniques in patients with complex coronary bifurcation lesions: the DEFINITION II trial.
The present study aimed to assess the benefits of two-stent techniques for patients with DEFINITION criteria-defined complex coronary bifurcation lesions. In total, 653 patients with complex bifurcation lesions at 49 international centres were randomly assigned to undergo the systematic two-stent technique (two-stent group) or provisional stenting (provisional group). The primary endpoint was the composite of target lesion failure (TLF) at the 1-year follow-up, including cardiac death, target vessel myocardial infarction (TVMI), and clinically driven target lesion revascularization (TLR). The safety endpoint was definite or probable stent thrombosis. At the 1-year follow-up, TLF occurred in 37 (11.4%) and 20 (6.1%) patients in the provisional and two-stent groups, respectively [77.8%: double-kissing crush; hazard ratio (HR) 0.52, 95% confidence interval (CI) 0.30-0.90; P = 0.019], largely driven by increased TVMI (7.1%, HR 0.43, 95% CI 0.20-0.90; P = 0.025) and clinically driven TLR (5.5%, HR 0.43, 95% CI 0.19-1.00; P = 0.049) in the provisional group. At the 1 year after indexed procedures, the incidence of cardiac death was 2.5% in the provisional group, non-significant to 2.1% in the two-stent group (HR 0.86, 95% CI 0.31-2.37; P = 0.772). For DEFINITION criteria-defined complex coronary bifurcation lesions, the systematic two-stent approach was associated with a significant improvement in clinical outcomes compared with the provisional stenting approach. Further study is urgently warranted to identify the mechanisms contributing to the increased rate of TVMI after provisional stenting. http://www.clinicaltrials.com; Identifier: NCT02284750.


Phosphorylation states of the (Na+ + K+)-transporting ATPase in preparations from lamb kidney and electric-eel (Electophorus electricus) electric organ.
Phosphorylation states of the (Na+ + K+)-transporting ATPase were studied in highly purified preparations isolated from electric-eel electric organ and from lamb kidney. The steady-state level of phosphorylated lamb kidney enzyme, obtained by reaction with [gamma-32P]ATP, was not appreciably reduced in the presence of ADP unless oligomycin was present. The phosphorylated form of the electric-eel electric-organ enzyme was reduced by at least 95% under the same conditions, suggesting that the E1P state in the kidney enzyme is more transitory than that in electric organ. The level of phosphorylation from [32P]Pi was higher in the lamb kidney preparation than in the electric-organ preparation, and the difference in stimulation of phosphorylation by ouabain in the two preparations was striking. Ouabain increased the level of phosphorylation by 35% in the kidney preparation and 734% in the electric-organ preparation. The E2P state seems to be stabilized by ouabain in the latter preparation. These findings, as well as the different reactivities of the thiol groups to blocking reagents in these preparations, suggest that the tertiary structure in the enzyme isolated from these two sources is different.


Microbial community and metabolic function analysis of cigar tobacco leaves during fermentation.
Cigar tobacco leaves (CTLs) contain abundant bacteria and fungi that are vital to leaf quality during fermentation. In this study, artificial fermentation was used for the fermentation of CTLs since it was more controllable and efficient than natural aging. The bacterial and fungal community structure and composition in unfermented and fermented CTLs were determined to understand the effects of microbes on the characteristics of CTLs during artificial fermentation. The relationship between the chemical contents and alterations in the microbial composition was evaluated, and the functions of bacteria and fungi in fermented CTLs were predicted to determine the possible metabolic pathways. After artificial fermentation, the bacterial and fungal community structure significantly changed in CTLs. The total nitrate and nicotine contents were most readily affected by the bacterial and fungal communities, respectively. FAPROTAX software predictions of the bacterial community revealed increases in functions related to compound transformation after fermentation. FUNGuild predictions of the fungal community revealed an increase in the content of saprotrophic fungi after fermentation. These data provide information regarding the artificial fermentation mechanism of CTLs and will inform safety and quality improvements.


Development of stiff shoulder in asymptomatic volunteers during ten-year follow-up in Japan.
The purpose of this study was to longitudinally evaluate relationships between the incidence of stiff shoulder and sagittal alignments of the cervical spine, age-related changes on magnetic resonance imaging (MRI) and life styles of the subjects. The subjects were 69 men and 93 women. The mean follow-up period was 11.3 +/- 0.7 years. Sagittal alignments of the cervical spine were classified into the following 4 types: lordosis, straight, kyphosis and sigmoid. MRI findings were evaluated for the progression of 1) decrease in signal intensity of disc, 2) posterior disc protrusion, and 3) disc space narrowing. Stiff shoulder was found in 29.6% of the subjects over the 10 years. In the group of subjects 30-49 years old, the incidence of stiff shoulder was 40.4%, and it was higher than those in other age groups. Stiff shoulder was significantly more frequent in women (45.2%) than in men. Its incidence was significantly lower in those who regularly participated in sports or exercise. There were no significant relationship between the incidence of stiff shoulder and the progressions in any of MRI findings during the follow-up period. Stiff shoulder was more frequent in middle-aged, female and non-exercising subjects. There was no correlation between the incidence of stiff shoulder and sagittal alignments of the cervical spine, or progression of age-related changes of the cervical disc on MRI.


Anti-adipogenic and anti-oxidant effects of a standardised extract of Moro blood oranges (Citrus sinensis (L.) Osbeck) during adipocyte differentiation of 3T3-L1 preadipocytes.
Particular features in the pulp of blood oranges are marked levels of anthocyanin, a class of polyphenolic compounds well known to exert numerous health-promoting actions on human wellbeing including anti-obesity effects. In this study, we investigated in vitro, the antioxidant and anti-adipogenic activities of Morosil®, a standardised extract of Moro blood oranges. During adipocyte differentiation, 3T3-L1 cells were treated with concentrations of extract containing 2.5, 5, 10, 25 μM of anthocyanins. After seven days of treatment and differentiation, we measured reactive oxygen species production, non-proteic thiol groups content, adipokine secretion and triglyceride accumulation together with mRNA expression of adipogenic transcription factors such as PPARγ, C/EBPα, SREBP-1c. Furthermore, both ACCα, FAS protein expression and citrate synthase activity were measured. Results show that Morosil® exerts antioxidant and anti-adipogenic activities during adipocyte differentiation of 3T3-L1 pre-adipocytes.


Global Survey of Clinical Oncology Workforce.
A lack of well-trained clinical oncologists can result in significant cancer health disparities. The magnitude of this problem around the world is poorly described in the literature. A comprehensive global survey of the clinical oncology workforce was conducted. Data on the number of clinical oncologists in 93 countries were obtained from 30 references. The mortality-to-incidence ratio was estimated by using data on incidence and mortality rates from the GLOBOCAN 2012 database; the ratio was > 70% in 26 countries (28%), which included 21 countries in Africa (66%) and five countries in Asia (26%). Eight countries had no clinical oncologist available to provide care for patients with cancer. In 22 countries (24%), a clinical oncologist would provide care for < 150 patients with a new diagnosis of cancer. In 39 countries (42%), a clinical oncologist would provide care for > 500 patients with cancer. In 27 countries (29%), a clinical oncologist would provide care for > 1,000 incident cancers, of which 25 were in Africa, two were in Asia, and none were in Europe or the Americas. The economic and social development status of a country correlates closely with the burden of cancer and the shortage of human resources. Addressing the shortage of clinical oncologists in regions with a critical need will help these countries meet the sustainable development goals for noncommunicable diseases by 2030.


The causality of borrowing: Lexical loans in Eurasian languages.
All languages borrow words from other languages. Some languages are more prone to borrowing, while others borrow less, and different domains of the vocabulary are unequally susceptible to borrowing. Languages typically borrow words when a new concept is introduced, but languages may also borrow a new word for an already existing concept. Linguists describe two causalities for borrowing: need, i.e., the internal pressure of borrowing a new term for a concept in the language, and prestige, i.e., the external pressure of borrowing a term from a more prestigious language. We investigate lexical loans in a dataset of 104 concepts in 115 Eurasian languages from 7 families occupying a coherent contact area of the Eurasian landmass, of which Indo-European languages from various periods constitute a majority. We use a cognacy-coded dataset, which identifies loan events including a source and a target language. To avoid loans for newly introduced concepts in languages, we use a list of lexical concepts that have been in use at least since the Chalcolithic (4000-3000 BCE). We observe that the rates of borrowing are highly variable among concepts, lexical domains, languages, language families, and time periods. We compare our results to those of a global sample and observe that our rates are generally lower, but that the rates between the samples are significantly correlated. To test the causality of borrowing, we use two different ranks. Firstly, to test need, we use a cultural ranking of concepts by their mobility (of nature items) or their labour intensity and "distance-from-hearth" (of culture items). Secondly, to test prestige, we use a power ranking of languages by their socio-cultural status. We conclude that the borrowability of concepts increases with increasing mobility (nature), and with increased labour intensity and "distance-from-hearth" (culture). We also conclude that language prestige is not correlated with borrowability in general (all languages borrow, independently of prestige), but prestige predicts the directionality of borrowing, from a more prestigious language to a less prestigious one. The process is not constant over time, with a larger inequality during the ancient and modern periods, but this result may depend on the status of the data (non-prestigious languages often remain unattested). In conclusion, we observe that need and prestige compete as causes of lexical borrowing.


Effect of the Biopolymer Carrier on Staphylococcus aureus Bacteriophage Lytic Activity.
The use of implant materials is always associated with the risk of infection. Moreover, the effectiveness of antibiotics is reduced due to antibiotic-resistant pathogens. Thus, selecting the appropriate alternative antimicrobials for local delivery systems is correlated with successful infection management. We evaluated immobilization of the S. aureus specific bacteriophages in clinically recognized biopolymers, i.e., chitosan and alginate, to control the release profile of the antimicrobials. The high-titre S. aureus specific bacteriophages were prepared from commercial bacteriophage cocktails. The polymer mixtures with the propagated bacteriophages were then prepared. The stability of the S. aureus bacteriophages in the biopolymer solutions was assessed. In the case of chitosan, no plaques indicating the presence of the lytic bacteriophages were observed. The titre reduction of the S. aureus bacteriophages in the Na-alginate was below 1 log unit. Furthermore, the bacteriophages retained their lytic activity in the alginate after crosslinking with Ca2+ ions. The release of the lytic S. aureus bacteriophages from the Ca-alginate matrices in the TRIS-HCl buffer solution (pH 7.4 ± 0.2) was determined. After 72 h-0.292 ± 0.021% of bacteriophages from the Ca-alginate matrices were released. Thus, sustained release of the lytic S. aureus bacteriophages can be ensured.


[Churg-Strauss syndrome in a 15-year old boy].
A 15 year-old boy was admitted in our hospital with the clinical signs of cardiopulmonary deterioration. His history showed bronchial asthma since 3 years. Furthermore he revealed signs of polyneuropathy, exanthema and a transitory pulmonary infiltration. Elevation of eosinophilic granulocytes and IgE confirmed the diagnosis of a Churg-Strauss syndrome. A rapid improvement of the symptoms was achieved by high-dose steroids and symptomatic therapy. The impaired systolic and diastolic myocardial function improved, but a cardiomyopathy with a shortening fraction below 25% persisted. The Churg-Strauss syndrome is a rare disease in childhood and is classified as a systemic granulomatosis of the vessels. The marked perimyocarditis with consecutive restrictive cardiomyopathy is a rare manifestation in childhood and adolescence. The prognosis of this disease is mainly influenced by the cardiac involvement.


The vulvodynia guideline.
To provide a review of the literature and make known expert opinion regarding the treatment of vulvodynia. Experts reviewed the existing literature to provide new definitions for vulvar pain and to describe treatments for this condition. Vulvodynia has been redefined by the International Society for the Study of Vulvovaginal Disease as vulvar discomfort in the absence of gross anatomic or neurologic findings. Classification is based further on whether the pain is generalized or localized and whether it is provoked, unprovoked, or both. Treatments described include general vulvar care, topical medications, oral medications, injectables, biofeedback and physical therapy, dietary changes with supplementations, acupuncture, hypnotherapy, and surgery. No one treatment is clearly the best for an individual patient. Vulvodynia has many possible treatments, but very few controlled trials have been performed to verify efficacy of these treatments. Provided are guidelines based largely on expert opinion to assist the patient and practitioner in dealing with this condition.


Proteomic analysis of cancer-cell mitochondria.
Mitochondrial dysfunction and mutations in mitochondrial DNA have been frequently reported in cancer cells. Mitochondrial gene-expression signatures of transformed cells have been identified; however, the phenotypic effects of these genetic alterations remain to be established. Identification of mitochondrial proteins that are aberrantly expressed in cancer cells has been made possible by the recent development of mitochondrial functional proteomics and could identify new markers for early detection and risk assessment, as well as targets for therapeutic intervention.


Changing trends in the use of cartilage restoration techniques for the patellofemoral joint: a systematic review.
The patellofemoral (PF) joint contains the thickest articular cartilage in the human body. Chondral lesions to this area are often misdiagnosed and can predispose to secondary osteoarthritis if left untreated. Treatment options range from arthroscopic debridement to cartilage restoration techniques such as microfracture (MFx), autologous chondrocyte implantation (ACI), and osteochondral autograft transplantation. The purpose of this study was to systematically assess the trends in surgical techniques, outcomes, and complications of cartilage restoration of the PF joint. This review has been conducted according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The electronic databases PubMed, MEDLINE, and EMBASE were searched from January 1, 2007 to April 30, 2018. The Methodological Index for Non-randomized Studies (MINORS) was used to assess study quality. A two-proportion z test was used to determine whether the differences between the proportions of cartilage restoration techniques used from 2007 to 2012 and 2013-2018 were statistically significant. Overall, 28 studies were identified, including 708 patients (824 knees) with a mean age of 39.5 ± 10.5 years and a mean follow-up of 39.1 ± 16.0 months. Majority of patients were treated with ACI (45.5%) and MFx (29.6%). A significant increase in the use of the third generation ACI occurred with a simultaneous decreased usage of the conventional MFx over the last 5 years (p < 0.001). All techniques had significant (p < 0.05) improvements in clinical outcomes. The overall complication rate was 9.2%, of which graft hypertrophy (2.7%) was the most prevalent. ACI was the most common restoration technique. The use of third generation ACI has increased with a concurrent decline in the use of conventional MFx over the latter half of the past decade (p < 0.001). Overall, the various cartilage restoration techniques reported improvements in patient reported outcomes with low complication rates. Definitive conclusions on the optimal treatment remain elusive due to a lack of high-quality comparative studies. Level IV, Systematic Review of Level-II-IV studies.


Ion chromatographic analysis of selected free amino acids and cations to investigate the change of nitrogen metabolism by herbicide stress in soybean (glycine max).
A simple and reliable method for the determination of NH4+, K+, Na+, aspartic acid, asparagine, glutamine, and alanine by ion chromatography has been developed. It is suitable for monitoring changes of nitrogen metabolism in soybean because it can accurately measure concentrations o asparagine and NH4+, two key substances for nitrogen storage and transport in this plant species Analysis of asparagine distribution in soybean indicated that higher levels (up to 18.4 micromol g(-1) of fresh mass) occur in stems and lower levels in roots (2.0 micromol g(-1) of fresh mass) and leaves (1.6 micromol g(-1) of fresh mass). When the herbicide metsulfuron-methyl (0.5, 5, and 50 ppb) was applied via the nutrient solution to the root system, asparagine concentrations increased 3-6 times in stems roots, and leaves. Metsulfuron-methyl is known to impair the synthesis of branched amino acids and, in consequence, protein synthesis. Thus, nitrogen consumption was limited, leading to ar accumulation of asparagine. The possible use of this physiological response in agricultural practice to identify herbicide stress in soybean and to detect low-level residues of sulfonylurea herbicides ir the soil is discussed.


A species-specific periplasmic flagellar protein of Serpulina (Treponema) hyodysenteriae.
We have previously reported that a 46-kDa protein present in an outer membrane protein preparation seemed to be a species-specific antigen of Serpulina hyodysenteriae (Z. S. Li, N. S. Jensen, M. Bélanger, M.-C. L'Espérance, and M. Jacques, J. Clin. Microbiol. 30:2941-2947, 1992). The objective of this study was to further characterize this antigen. A Western blot (immunoblot) analysis and immunogold labeling with a monospecific antiserum against this protein confirmed that the protein was present in all S. hyodysenteriae reference strains but not in the nonpathogenic organism Serpulina innocens. The immunogold labeling results also indicated that the protein was associated with the periplasmic flagella of S. hyodysenteriae. N-terminal amino acid sequencing confirmed that the protein was in fact a periplasmic flagellar sheath protein. The molecular mass of this protein, first estimated to be 46 kDa by Western blotting, was determined to be 44 kDa when the protein was evaluated more precisely by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the protein was glycosylated, as determined by glycoprotein staining and also by N-glycosidase F treatment. Five other periplasmic flagellar proteins of S. hyodysenteriae, which may have been the core proteins and had molecular masses of 39, 35, 32, 30, and 29 kDa, were antigenically related and cross-reacted with the periplasmic flagellar proteins of S. innocens. Finally, serum from a pig experimentally infected with S. hyodysenteriae recognized the 44-kDa periplasmic flagellar sheath protein. Our results suggest that the 44-kDa periplasmic flagellar sheath protein of S. hyodysenteriae is a species-specific glycoprotein antigen.


Target-Driven Annular DNA Walker Coupled with Electrochemiluminescent Silicon Quantum Dots for APE1 Bioanalysis.
Functional DNA walkers with substantial nanostructures have been extensively investigated; however, their stability still faces challenges when exposed to diverse nuclease in clinical biological samples, resulting in the unreliability of actual assessment. This work proposed a target-driven annular DNA walker with enhanced stability enabling the sensitive and reliable response to different concentrations of apurinic/apyrimidinic endonuclease 1 (APE1), by preparing silicon quantum dots (SiQDs) as electrochemiluminescence (ECL) emitters. Specifically, the SiQDs showed significant strong and stable ECL signals by purifying the microenvironment of SiQDs through the dialysis removal of the gel-like layers surrounding the SiQDs. The relative standard deviation (RSD) of their ECL signal had been improved 16.59 times under consecutive scanning compared to that of SiQDs without dialysis, demonstrating a significant improvement in ECL stability. Subsequently, in the presence of APE1, the designed annular DNA walker was activated to move along the numerous quenching probes within the continuous cross-based DNA orbits, which were immobilized to the SiQD-modified electrode, providing ECL readout signals. The linear range of this ECL biosensor was 1.0 × 10-13 U·μL-1 to 1.0 × 10-7 U·μL-1, and the limit of detection (LOD) was as low as 1.766 × 10-14 U·μL-1. This work provides a novel structure of a DNA walker with nuclease resistance for clinical sample detection and designs a new strategy for synthesizing SiQDs with favorable ECL performance, tremendously expanding the ECL application of SiQDs.


Bicaudal D2, dynein, and kinesin-1 associate with nuclear pore complexes and regulate centrosome and nuclear positioning during mitotic entry.
BICD2 is one of the two mammalian homologues of the Drosophila Bicaudal D, an evolutionarily conserved adaptor between microtubule motors and their cargo that was previously shown to link vesicles and mRNP complexes to the dynein motor. Here, we identified a G2-specific role for BICD2 in the relative positioning of the nucleus and centrosomes in dividing cells. By combining mass spectrometry, biochemical and cell biological approaches, we show that the nuclear pore complex (NPC) component RanBP2 directly binds to BICD2 and recruits it to NPCs specifically in G2 phase of the cell cycle. BICD2, in turn, recruits dynein-dynactin to NPCs and as such is needed to keep centrosomes closely tethered to the nucleus prior to mitotic entry. When dynein function is suppressed by RNA interference-mediated depletion or antibody microinjection, centrosomes and nuclei are actively pushed apart in late G2 and we show that this is due to the action of kinesin-1. Surprisingly, depletion of BICD2 inhibits both dynein and kinesin-1-dependent movements of the nucleus and cytoplasmic NPCs, demonstrating that BICD2 is needed not only for the dynein function at the nuclear pores but also for the antagonistic activity of kinesin-1. Our study demonstrates that the nucleus is subject to opposing activities of dynein and kinesin-1 motors and that BICD2 contributes to nuclear and centrosomal positioning prior to mitotic entry through regulation of both dynein and kinesin-1.


Effects of Neuronic Shutter Observed in the EEG Alpha Rhythm.
The posterior alpha (α) rhythm, seen in human electroencephalogram (EEG), is posited to originate from cycling inhibitory/excitatory states of visual relay cells in the thalamus. These cycling states are thought to lead to oscillating visual sensitivity levels termed the "neuronic shutter effect." If true, perceptual performance should be predictable by observed α phase (of cycling inhibitory/excitatory states) relative to the timeline of afferentiation onto the visual cortex. Here, we tested this hypothesis by presenting contrast changes at near perceptual threshold intensity through closed eyelids to 20 participants (balanced for gender) during times of spontaneous α oscillations. To more accurately and rigorously test the shutter hypothesis than ever before, α rhythm phase and amplitude were calculated relative to each individual's retina-to-primary visual cortex (V1) conduction delay, estimated from the individual's C1 visual-evoked potential (VEP) latency. Our results show that stimulus observation rates (ORs) are greater at a trough than a peak of the posterior α rhythm when phase is measured at the individual's conduction delay relative to stimulus onset. Specifically, the optimal phase for stimulus observation was found to be 272.41°, where ORs are 20.96% greater than the opposing phase of 92.41°. The perception-phase relationship is modulated by α rhythm amplitude and is not observed at lower amplitude oscillations. Collectively, these results provide support to the "neuronic shutter" hypothesis and demonstrate a phase and timing relationship consistent with the theory that cycling excitability in the thalamic relay cells underly posterior α oscillations.


Integrated Long-Term Care 'Neighbourhoods' to Support Older Populations: Evolving Strategies in Japan and England.
Western countries are currently facing the public health challenge of a rapidly aging population and the associated challenge of providing long-term care services to meet its needs with a reduced working age population. As people age, they will increasingly require both health and social care services to maintain their quality of life and these will need to be integrated to provide cost-effective long-term care. The World Health Organization recommended in 2020 that all countries should have integrated long-term care strategies to better support their older populations. Japan, with the most rapidly ageing society in the world, started to address this challenge in the 1990s. In 2017, it introduced a national policy for integrated long-term health and social care services at a local geographical level for older people. England has recently embarked on its first plan aiming for the integration of services for older people. In this article, we compare these approaches to the integration of long-term care systems, including the strengths of each. The paper also considers the effects of historical, cultural and organizational factors and the emerging role of technology. Finally, we identify critical lessons that can inform strategy development in other countries, and highlight the need to provide more international comparisons.


Using value of information to prioritize research needs for migratory bird management under climate change: a case study using federal land acquisition in the United States.
In response to global habitat loss, many governmental and non-governmental organizations have implemented land acquisition programs to protect critical habitats permanently for priority species. The ability of these protected areas to meet future management objectives may be compromised if the effects of climate change are not considered in acquisition decisions. Unfortunately, the effects of climate change on ecological systems are complex and plagued by uncertainty, making it difficult for organizations to prioritize research needs to improve decision-making. Herein, we demonstrate the use of qualitative value of information analysis to identify and prioritize which sources of uncertainty should be reduced to improve land acquisition decisions to protect migratory birds in the face of climate change. The qualitative value of information analysis process involves four steps: (i) articulating alternative hypotheses; (ii) determining the magnitude of uncertainty regarding each hypothesis; (iii) evaluating the relevance of each hypothesis to acquisition decision-making; and (iv) assessing the feasibility of reducing the uncertainty surrounding each hypothesis through research and monitoring. We demonstrate this approach using the objectives of 3 U.S. federal land acquisition programs that focus on migratory bird management. We used a comprehensive literature review, expert elicitation, and professional judgement to evaluate 11 hypotheses about the effect of climate change on migratory birds. Based on our results, we provide a list of priorities for future research and monitoring to reduce uncertainty and improve land acquisition decisions for the programs considered in our case study. Reducing uncertainty about how climate change will influence the spatial distribution of priority species and biotic homogenization were identified as the highest priorities for future research due to both the value of this information for improving land acquisition decisions and the feasibility of reducing uncertainty through research and monitoring. Research on how changes in precipitation patterns and winter severity will influence migratory bird abundance is also expected to benefit land acquisition decisions. By contrast, hypotheses about phenology and migration distance were identified as low priorities for research. By providing a rigorous and transparent approach to prioritizing research, we demonstrate that qualitative value of information is a valuable tool for prioritizing research and improving management decisions in other complex, high-uncertainty cases where traditional quantitative value of information analysis is not possible. Given the inherent complexity of ecological systems under climate change, and the difficulty of identifying management-relevant research priorities, we expect this approach to have wide applications within the field of natural resource management.


Systematic review with meta-analysis of studies comparing intraoperative neuromonitoring of recurrent laryngeal nerves versus visualization alone during thyroidectomy.
The role of intraoperative neuromonitoring (IONM) of the recurrent laryngeal nerve (RLN) during thyroid surgery is still debatable. The aim of this meta-analysis was to evaluate the potential improvement of IONM versus RLN visualization alone (VA) in reducing the incidence of vocal cord palsy. A literature search for studies comparing IONM versus VA during thyroidectomy was performed. Studies were reviewed for primary outcome measures: overall, transient, and permanent RLN palsy per nerve and per patients at risk; and for secondary outcome measures: operative time; overall, transient and permanent RLN palsy per nerve at low and high risk; and the results regarding assistance in RLN identification before visualization. Twenty studies comparing thyroidectomy with and without IONM were reviewed: three prospective, randomized trials, seven prospective trials, and ten retrospective, observational studies. Overall, 23,512 patients were included, with thyroidectomy performed using IONM compared with thyroidectomy by VA. The total number of nerves at risk was 35,513, with 24,038 nerves (67.7%) in the IONM group, compared with 11,475 nerves (32.3%) in the VA group. The rates of overall RLN palsy per nerve at risk were 3.47% in the IONM group and 3.67% in the VA group. The rates of transient RLN palsy per nerve at risk were 2.62% in the IONM group and 2.72% in the VA group. The rates of permanent RLN palsy per nerve at risk were 0.79% in the IONM group and 0.92% and in the VA group. None of these differences were statistically significant, and no other differences were found. The current review with meta-analysis showed no statistically significant difference in the incidence of RLN palsy when using IONM versus VA during thyroidectomy. However, these results must be approached with caution, as they were mainly based on data coming from non-randomized observational studies. Further studies including high-quality multicenter, prospective, randomized trials based on strict criteria of standardization and subsequent clustered meta-analysis are required to verify the outcomes of interest.


GDNF is required for neural colonization of the pancreas.
The mammalian pancreas is densely innervated by both the sympathetic and parasympathetic nervous systems, which control exocrine and endocrine secretion. During embryonic development, neural crest cells migrating in a rostrocaudal direction populate the gut, giving rise to neural progenitor cells. Recent studies in mice have shown that neural crest cells enter the pancreatic epithelium at E11.5. However, the cues that guide the migration of neural progenitors into the pancreas are poorly defined. In this study we identify glial cell line-derived neurotrophic factor (GDNF) as a key player in this process. GDNF displays a dynamic expression pattern during embryonic development that parallels the chronology of migration and differentiation of neural crest derivatives in the pancreas. Conditional inactivation of Gdnf in the pancreatic epithelium results in a dramatic loss of neuronal and glial cells and in reduced parasympathetic innervation in the pancreas. Importantly, the innervation of other regions of the gut remains unaffected. Analysis of Gdnf mutant mouse embryos and ex vivo experiments indicate that GDNF produced in the pancreas acts as a neurotrophic factor for gut-resident neural progenitor cells. Our data further show that exogenous GDNF promotes the proliferation of pancreatic progenitor cells in organ culture. In summary, our results point to GDNF as crucial for the development of the intrinsic innervation of the pancreas.


Strong association of a renin intronic dimorphism with essential hypertension.
The objectives of this project were two-fold: to identify the genetic mutation that has been detected as an MboI dimorphism in intron 9 of the human renin (REN) gene and to confirm a previously reported, putative association between the REN MboI dimorphism and clinical diagnosis of essential hypertension (EHT) in a population of Gulf Arabs from the United Arab Emirates. Sequencing of the MboI dimorphic site was carried out on DNA of randomly chosen cases and controls. A retrospective case-control study was carried out in 689 unrelated subjects (326 first-time, clinically diagnosed hypertensives and 363 age- and gender-matched normotensive subjects), selected from the resident population of the Abu Dhabi Emirate. A polymerase chain reaction/MboI-RFLP based method was employed to compare genotype and allele distributions. Nucleotide sequences at the MboI site of the cut and uncut alleles were determined to be GATC and GGTC, respectively. This A>G mutation is located 10,631 base pairs (bp) 3' to the start of the REN gene, and 79 bp 3' to the end of exon 9. The genotype distributions of the REN 10631A>G dimorphism were found to be significantly different between hypertensive and normotensive subjects (x2= 42.29, df=2, p<0.001). Frequencies of A alleles were 0.54 in EHT vs. 0.37 in normotensive subjects, which is even more demarcated than what was found previously. The frequency of AA genotypes was higher in the hypertensive group than in the normotensive group (34.7% vs. 14.0%). The quantification of the association of A alleles with increased risk of EHT was assessed with corresponding odds ratios (OR), which gave the following values: OR of GG vs. AG genotypes, 1.3 (95% confidence interval [CI]: 0.90-1.88); OR of GG vs. AA, 3.75 (95% CI: 2.41-5.86). In conclusion, REN 10631A alleles are significantly associated with EHT in the Emirati population. This has now been found in two different and therefore independent sample populations from the Abu Dhabi Emirate. Moreover, this genetic effect seems to be acting in a recessive fashion. Hence, either the REN gene itself, or another gene that is in linkage disequilibrium with REN 10631A>G, is implicated in the pathogenesis of EHT in Emirati.


Sequential computation of elementary modes and minimal cut sets in genome-scale metabolic networks using alternate integer linear programming.
Elementary (flux) modes (EMs) have served as a valuable tool for investigating structural and functional properties of metabolic networks. Identification of the full set of EMs in genome-scale networks remains challenging due to combinatorial explosion of EMs in complex networks. It is often, however, that only a small subset of relevant EMs needs to be known, for which optimization-based sequential computation is a useful alternative. Most of the currently available methods along this line are based on the iterative use of mixed integer linear programming (MILP), the effectiveness of which significantly deteriorates as the number of iterations builds up. To alleviate the computational burden associated with the MILP implementation, we here present a novel optimization algorithm termed alternate integer linear programming (AILP). Our algorithm was designed to iteratively solve a pair of integer programming (IP) and linear programming (LP) to compute EMs in a sequential manner. In each step, the IP identifies a minimal subset of reactions, the deletion of which disables all previously identified EMs. Thus, a subsequent LP solution subject to this reaction deletion constraint becomes a distinct EM. In cases where no feasible LP solution is available, IP-derived reaction deletion sets represent minimal cut sets (MCSs). Despite the additional computation of MCSs, AILP achieved significant time reduction in computing EMs by orders of magnitude. The proposed AILP algorithm not only offers a computational advantage in the EM analysis of genome-scale networks, but also improves the understanding of the linkage between EMs and MCSs. The software is implemented in Matlab, and is provided as supplementary information . email@example.com. Supplementary data are available at Bioinformatics online.


Insights into the mechanism of the reaction between tetrachloro-p-benzoquinone and hydrogen peroxide and their implications in the catalytic role of water molecules in producing the hydroxyl radial.
Detailed mechanisms for the formation of hydroxyl or alkoxyl radicals in the reactions between tetrachloro-p-benzoquinone (TCBQ) and organic hydroperoxides are crucial for better understanding the potential carcinogenicity of polyhalogenated quinones. Herein, the mechanism of the reaction between TCBQ and H2O2 has been systematically investigated at the B3LYP/6-311++G** level of theory in the presence of different numbers of water molecules. We report that the whole reaction can easily take place with the assistance of explicit water molecules. Namely, an initial intermediate is formed first. After that, a nucleophilic attack of H2O2 onto TCBQ occurs, which results in the formation of a second intermediate that contains an OOH group. Subsequently, this second intermediate decomposes homolytically through cleavage of the O-O bond to produce a hydroxyl radical. Energy analyses suggest that the nucleophilic attack is the rate-determining step in the whole reaction. The participation of explicit water molecules promotes the reaction significantly, which can be used to explain the experimental phenomena. In addition, the effects of F, Br, and CH3 substituents on this reaction have also been studied.


A Comprehensive Investigation into the Association Between Mthfr C677t, A1298c, and Ace I/D Variants and Risk of Migraine: an Updated Meta-Analysis of Genetic Association Studies with Trial Sequential Analysis and Meta-Regression.
Many homeostatic genes are thought to play a role in the susceptibility to migraine, making it a highly complex neurovascular disease. In this meta-analysis, our primary objective was to evaluate whether or not MTHFR variants (such as C677T and A1289C) and ACE I/D were associated with an increased risk of migraine. Using a PRISMA-based systematic literature-review guideline, internet sources such as PubMed and Google Scholar were searched to identify the genes of interest and migraine risk. To pool the data, odds ratios with 95% confidence intervals were calculated utilizing different genetic models. Cochran's Q Test and I2 statistics were used to access heterogeneity, while Begg's and Egger's tests were used to identify publication bias. All tests were two-sided, and a p-value of < 0.05 was regarded as statistically significant. The present meta-analysis observed that the C677T variant is significantly associated with the increased risk of migraine (allele model: OR:1.19, CI [1.07-1.33], I2 = 78%) and its clinical subtype i.e., MA (allele model: OR: 1.26, CI [1.09-1.45], I2 = 80%) in the overall population. Concerning the ACE- I/D, it significantly increased the risk of overall migraine and both clinical subtypes after utilizing the dominant genetic models (OR: 1.14, CI [1.01-1.29], I2% = 32). Concerning the MTHFR A1289C, only the codominant model (HR vs HT) and recessive model significantly increased the risk of overall migraine. Therefore, the findings of the present meta-analysis showed that MTHFR-C677T is an important risk factor for migraine and its clinical subtype.


[Prevention of postoperative eventration].
Since 1952 the authors have been using silk N8 and N6 for suturing the laparotomy wounds. The suture involves the peritoneum with the aponeurosis and muscle 2,5--3 cm off from both sides of the incision. In some cases they place intermediate stitches (silk) on the aponeurosis. Such suturing of the laparotomy wound is thought to be the most reliable and physiological one. The authors have made 1910 operations on the gastrointestinal tract (both planned and urgent) not followed by eventrations.


Usability of the inductive tongue computer interface: Internet use, speaking, and drinking - evaluated by two users with disabilities.
Tongue computer interfaces have shown promising for both computer control and for control of assistive technologies and robotics. Still, evidence is lacking in relation to their usability resulting in speculations on their effectiveness for general computer use and their impact on other activities such as speaking, drinking, and eating. This paper presents the results of such a usability study performed with two individuals with tetraplegia. The results show a high acceptance of the Inductive Tongue Computer Interface with an average rating of 2.6 on a scale from 1 (normal) to 10 (unacceptable) and a low impact on speech after only 3 days of use.Clinical Relevance- This study emphasizes the applicability and adoptability of the Inductive Tongue Interface as a useful assistive technology for individuals with severe disabilities.


Treatment of anorexia nervosa with behavior modification. Effectiveness of formula feeding and isolation.
Anorexia nervosa has been treated with a variety of therapies. One seemingly successful modality, behavioral modification, has in most cases been used concurrently with various drugs, making the contributions of each impossible to separate. Eight patients meeting rigorous criteria for anorexia nervosa were treated in this study exclusively with behavioral therapy (reward contingent on weight gain). All had a substantial weight gain while hospitalized, and on short-term follow-up are maintaining or continuing to gain toward their normal weight range on individualized positive-reinforcement programs.


Operant down-conditioning of the soleus H-reflex in people after stroke.
Through operant conditioning, spinal reflex behaviors can be changed. Previous studies in rats indicate that the sensorimotor cortex and corticospinal tract are essential in inducing and maintaining reflex changes induced through conditioning. In people with incomplete spinal cord injury (SCI), an operant down-conditioning protocol decreased the soleus H-reflex size and improved walking speed and symmetry, suggesting that a partially preserved spinal cord can support conditioning-induced plasticity and benefit from it. This study examined whether down-conditioning can decrease the soleus H-reflex in people with supraspinal injury (i.e., cortical or subcortical stroke). Operant down-conditioning was applied to the soleus H-reflex in a cohort of 12 stroke people with chronic spastic hemiparesis (>12 months from stroke onset of symptoms). Each participant completed 6 baseline and 30 conditioning sessions over 12 weeks. In each baseline session, 225 control H-reflexes were elicited without any feedback on H-reflex size. In each conditioning session, 225 conditioned H-reflexes were elicited while the participant was asked to decrease H-reflex size and was given visual feedback as to whether the resulting H-reflex was smaller than a criterion value. In six of 12 participants, the conditioned H-reflex became significantly smaller by 30% on average, whereas in other 6 participants, it did not. The difference between the subgroups was largely attributable to the difference in across-session control reflex change. Ten-meter walking speed was increased by various extent (+0.04 to +0.35, +0.14 m/s on average) among the six participants whose H-reflex decreased, whereas the change was 0.00 m/s on average for the rest of participants. Although less than what was seen in participants with SCI, the fact that conditioning succeeded in 50% of stroke participants supports the feasibility of reflex down-conditioning in people after stroke. At the same time, the difference in across-session control reflex change and conditioning success rate may reflect a critical role of supraspinal activity in producing long-term plasticity in the spinal cord, as previous animal studies suggested.


to luteinizing.
The effect of luteinizing hormone-releasing hormone (LHRH) on plasma prolactin (PRL) was studied in eight acromegalic patients. After LHRH injection a significant increase in plasma prolactin levels was obtained in three of them. This non specific prolactin response to LHRH represents an additional proof of the well known abnormalities of pituitary hormone response to various stimuli in acromegaly.


Left Atrial Function and Arrhythmias in Relation to Small Vessel Disease on Brain MRI: The Multi-Ethnic Study of Atherosclerosis.
Background Atrial fibrillation (AF) is associated with increased stroke risk and accelerated cognitive decline, but the association of early manifestations of left atrial (LA) impairment with subclinical changes in brain structure is unclear. We investigated whether abnormal LA structure and function, greater supraventricular ectopy, and intermittent AF are associated with small vessel disease on magnetic resonance imaging of the brain. Methods and Results In the Multi-Ethnic Study of Atherosclerosis, 967 participants completed 14-day ambulatory electrocardiographic monitoring, speckle tracking echocardiography and, a median 17 months later, magnetic resonance imaging of the brain. We assessed associations of LA volume index and reservoir strain, supraventricular ectopy, and prevalent AF with brain magnetic resonance imaging measures of small vessel disease and atrophy. The mean age of participants was 72 years; 53% were women. In multivariable models, LA enlargement was associated with lower white matter fractional anisotropy and greater prevalence of microbleeds; reduced LA strain, indicating worse LA function, was associated with more microbleeds. More premature atrial contractions were associated with lower total gray matter volume. Compared with no AF, intermittent AF (prevalent AF with <100% AF during electrocardiographic monitoring) was associated with lower white matter fractional anisotropy (-0.25 SDs [95% CI, -0.44 to -0.07]) and greater prevalence of microbleeds (prevalence ratio: 1.42 [95% CI, 1.12-1.79]). Conclusions In individuals without a history of stroke or transient ischemic attack, alterations of LA structure and function, including enlargement, reduced strain, frequent premature atrial contractions, and intermittent AF, were associated with increased markers of small vessel disease. Detailed assessment of LA structure and function and extended ECG monitoring may enable early identification of individuals at greater risk of small vessel disease.


Development and Validation of a Simultaneous RP-HPLCUV/DAD Method for Determination of Polyphenols in Gels Containing S. terebinthifolius Raddi (Anacardiaceae).
Topical gels containing extracts of Schinus terebinthifolius have been used to treat bacterial vaginosis. It has been reported that this species has antimicrobial, anti-inflammatory and anti-ulcerogenic properties, which can be attributed to the presence of phenolic compounds. In this work, a sensitive and selective reversed-phase HPLC-UV/DAD method for the simultaneous assay of six polyphenols that could be present in S. terebinthifolius was developed. The method was shown to be accurate and precise. Peak purity and similarity index both exceeded 0.99. Calibration curves were linear over the concentration range studied, with correlation coefficients between 0.9931 and 0.9974. This method was used to determine the polyphenol content of a hydroalcoholic extract and pharmacy-compounded vaginal gel. Although the method is useful to assess the 6 phenolic compounds, some compounds could not be detected in the products. A sensitive, selective, accurate and precise reversed-phase HPLC-UV/DAD method for the simultaneous assay of six polyphenols in S. terebinthifolius Raddi Abbreviations used: RP-HPLC-UV/DAD: Reverse Phase High Performance Liquid Chromatograph with Ultraviolet and Diode Array Detector, HPLC: High Performance Liquid Chromatograph, HPLC-UV: High Performance Liquid Chromatograph with Ultraviolet Detector, ANVISA: Brazilian National Health Surveillance Agency, LOD: Limit of detection, LOQ: Limit of quantitation.


[Vitreolysis with Nd:YAG laser].
From 1985 to 1987, the authors performed Nd:YAG laser vitreolysis in 20 eyes with vitreous membranes. The average power used was 27 mJ, and the maximum was 65 mJ. 18 eyes with vitreous strands were relieved or partially relieved. 2 eyes with floating vitreous membranes were not helped. Vision was improved in 11 eyes, unchanged in 8 eyes, and worsened in 1 eye. The complications included local opacification of the crystalline lens in 2 eyes, retinal hemorrhage in 2 eyes, and retinal hole in 1 eye. It was concluded that YAG laser was useful for lysis of organized vitreous membranes near the optical axis of the eye, and the effect should be good with appropriate contact lenses and proper selection of candidates for the operation.


Machine learning-driven identification of drugs inhibiting cytochrome P450 2C9.
Cytochrome P450 2C9 (CYP2C9) is a major drug-metabolizing enzyme that represents 20% of the hepatic CYPs and is responsible for the metabolism of 15% of drugs. A general concern in drug discovery is to avoid the inhibition of CYP leading to toxic drug accumulation and adverse drug-drug interactions. However, the prediction of CYP inhibition remains challenging due to its complexity. We developed an original machine learning approach for the prediction of drug-like molecules inhibiting CYP2C9. We created new predictive models by integrating CYP2C9 protein structure and dynamics knowledge, an original selection of physicochemical properties of CYP2C9 inhibitors, and machine learning modeling. We tested the machine learning models on publicly available data and demonstrated that our models successfully predicted CYP2C9 inhibitors with an accuracy, sensitivity and specificity of approximately 80%. We experimentally validated the developed approach and provided the first identification of the drugs vatalanib, piriqualone, ticagrelor and cloperidone as strong inhibitors of CYP2C9 with IC values <18 μM and sertindole, asapiprant, duvelisib and dasatinib as moderate inhibitors with IC50 values between 40 and 85 μM. Vatalanib was identified as the strongest inhibitor with an IC50 value of 0.067 μM. Metabolism assays allowed the characterization of specific metabolites of abemaciclib, cloperidone, vatalanib and tarafenacin produced by CYP2C9. The obtained results demonstrate that such a strategy could improve the prediction of drug-drug interactions in clinical practice and could be utilized to prioritize drug candidates in drug discovery pipelines.


Oxygen consumption and sodium pump thermogenesis in a developing mammal.
During development the liver undergoes large changes in its oxygen consumption. The energy requirements of the sodium pump (i.e., ouabain-sensitive respiration) would appear to account for a major part of these changes. In very young rats (birth to 9 days), the sodium pump accounted for approximately 50% of a high weight-specific liver metabolism (LMR). In rats greater than or equal to 20 days of age, the sodium pump accounted for a smaller percentage (33%) of a much lower LMR. These changes scaled with body mass. LMR scaled with an allometric slope of -0.258, ouabain-sensitive respiration with a slope of -0.355, and ouabain-insensitive respiration with a slope of -0.194. It is proposed that changes in LMR of rats during development are due primarily to the changing energy requirements of the sodium pump.