Reentrant and focal activations during atrial fibrillation in patients with atrial septal defect.
Adult patients with atrial septal defect frequently experience atrial fibrillation. However, the electrophysiologic mechanism has not been directly examined, and the optimal surgical procedure has not been determined. Ten patients undergoing operations for atrial septal defect and atrial fibrillation underwent intraoperative mapping by use of 253 epicardial electrodes. There were 7 men and 3 women, whose average age was 54 ± 11 years. Eight patients had a secundum defect and 2 a primum defect. There were 4 patients with paroxysmal atrial fibrillation and 6 with long-standing persistent atrial fibrillation. A modified biatrial Maze procedure was performed in 6 patients and pulmonary vein isolation with no other left atrial lesions in 4. The reentrant or focal activations driving atrial fibrillation were confined within the right atrium in all patients with paroxysmal atrial fibrillation, whereas multiple focal activations arising from the pulmonary veins or posterior left atrium and reentrant activations in the left atrium were observed in 5 of 6 patients with long-standing persistent atrial fibrillation. In 9 patients, sinus rhythm was restored postoperatively and 8 of those patients have been free of any atrial fibrillation during a follow-up period of 94 ± 45 months. The pattern of the atrial activation during atrial fibrillation correlated with the type of atrial fibrillation and varied from a simple right atrial reentry to complex reentrant and focal activations in the left atrium.


Management of a Retained Broken Suture Needle During Cerclage Placement.
Broken suture needles with unintentional foreign body retention are an uncommon occurrence during obstetric procedures. Few reports exist in the literature of cases in pregnant patients. We report a case with the pregnancy management of a broken needle during cerclage placement that was retained in the cervix until repeat cesarean delivery. A 36-year-old woman, gravida 12 para 5, presented at 13 weeks of gestation for a history-indicated cerclage. The suture needle broke during the cerclage procedure, leaving a 35-mm needle fragment inside the cervical stroma between the 11 and 2 o'clock position that could not be recovered after multiple attempts. The procedure continued without needle recovery. Intraoperative pelvic X-ray was performed, demonstrating the retained fragment. No further attempts at recovery were made during the pregnancy, and a plan was made to proceed with removal at the patient's repeat cesarean delivery. The patient presented in labor at 32 1/7 weeks of gestation and underwent an uncomplicated cesarean delivery. The retained needle was subsequently removed after manual palpation of the fragment transvaginally. Retained broken suture needles during obstetric procedures require careful management decisions in pregnant patients. Retention of a needle fragment until delivery may be considered if risks of removal outweigh the anticipated benefits.


Strategies and validation for siRNA-based therapeutics for the reversal of multi-drug resistance in cancer.
Resistance of cancer cells to anticancer drugs is the main reason for the failure of traditional cancer treatments. Various cellular components and different loops within the signaling pathways contribute to drug resistance which could be modulated with the aim to restore drug efficacy. Unveiling the molecular mechanisms for cancer drug resistance has now paved the way for the development of novel approaches to regulate the response rates to anticancer drugs at the genetic level. The recent progress on identification and validation of the vital genes directly or indirectly involved in development of cancer drug resistance with the aid of the specific knock down ability of RNA interference technology is discussed in this review.


Toward immunomodulatory and anti-inflammatory properties of statins.
Over the past decade, a large number of studies reported a prominent role of inflammation and immune response in atherosclerosis. Thus, therapeutic strategies to reduce inflammation could exert beneficial effects in the prevention of atherosclerosis progression. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) have demonstrated their capacity to greatly reduce coronary morbidity and mortality in both primary and secondary intervention trials. Furthermore, originally described as the most efficient drugs to reduce serum cholesterol, recent reports suggest that statins also confer cardiovascular benefits by their ability to modulate immuno-inflammatory processes. This review summarizes in vitro and in vivo evidence of immunomodulatory properties of statins.


Combination of vascular endothelial and fibroblast growth factor 2 for induction of neurogenesis and angiogenesis after traumatic brain injury.
Fibroblast growth factor 2 (FGF2) and vascular endothelial growth factor (VEGF) are potent mitogens for endogenous neural stem cells (eNSC) and also induce angiogenesis. We infused the individual factors or their combination into the lateral ventricles of mice for 7 days after traumatic brain injury (TBI) in order to evaluate the effects on functional outcome and on eNSC proliferation and differentiation. The results show that VEGF induced a significant increment in the number of proliferating eNSC in the subventricular zone and in the perilesion cortex and that combination of FGF2 and VEGF did not augment the effects of VEGF alone. Fate analysis showed that most newborn cells differentiated into astrocytes and oligodendroglia while only a few cells differentiated into neurons. Functional outcome was significantly better in mice treated with VEGF, FGF2, or their combination as compared to vehicle. Injury size was significantly reduced only in mice treated with VEGF suggesting additional neuroprotective effects for VEGF. Combination therapy did not have an additive effect on outcome or neuronal differentiation. In conclusion, FGF2-VEGF combination does not augment neurogenesis and angiogenesis or reduce lesion volumes after TBI compared with individual factors. This may suggest the existence of a ceiling effect for brain regeneration.


Prevalence of post-intensive care syndrome in mechanically ventilated patients with COVID-19.
Coronavirus disease 19 (COVID-19) patients usually require long periods of mechanical ventilation and sedation, which added to steroid therapy, favours a predisposition to the development of delirium and subsequent mental health disorders, as well as physical and respiratory sequelae. The aim of this study was to determine the prevalence of post-intensive care syndrome (PICS) at 3 months after hospital discharge, in a cohort of mechanically ventilated patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). An ambispective, observational study was conducted in three hospitals with intensive care unit (ICU) follow-up clinics. We studied adults who survived a critical illness due to SARS-CoV-2 infection requiring invasive mechanical ventilation. A physical (muscle strength and pulmonary function), functional [12-Item Short Form Health Survey (SF-12), and Barthel score], psychological [hospital anxiety and depression (HADS) and posttraumatic stress disorder symptom severity scales], and cognitive [Montreal cognitive assessment (MoCA) test] assessment were performed. A total of 186 patients were evaluated at 88 days (IQR 68-121) after hospital discharge. Mean age was 59 ± 12 years old, 126 (68%) patients were men, and median length of mechanical ventilation was 14 days (IQR 8-31). About 3 out of 4 patients (n = 139, 75%) met PICS criteria. Symptoms of cognitive and psychiatric disorders were found in 59 (32%) and 58 (31%) patients, respectively. Ninety-one (49%) patients had muscle weakness. Pulmonary function tests in patients with no respiratory comorbidities showed a normal pattern in 93 (50%) patients, and a restrictive disorder in 62 (33%) patients. Also, 69 patients (37%) were on sick leave, while 32 (17%) had resumed work at the time of assessment. In conclusion, survivors of critical illness due to SARS-CoV-2 infection requiring mechanical ventilation have a high prevalence of PICS. Physical domain is the most frequently damaged, followed by cognitive and psychiatric disorders. ICU follow-up clinics enable the assistance of this vulnerable population.


Infection after hand surgery.
Postoperative infections are uncommon after hand surgery. Infection can delay recovery and contribute to scarring and stiffness. Measures intended to reduce the risk of infection after hand surgery include hand washing, skin preparation, sterile technique, and prophylactic antibiotics. The role of prophylactic antibiotics for small, clean, elective hand surgery procedures lasting less than 2 hours is debated.


What are the determinants of quality of life in people with cervical dystonia?
Little is known about the quality of life in patients with cervical dystonia, although pain and depression are relatively common. To test the hypothesis that an individual's ability to cope with the disease will modify the association of intrinsic, extrinsic, and disease related factors with quality of life. Patients with cervical dystonia diagnosed by a movement disorder specialist were recruited from seven European countries. Data on quality of life (SF-36), measures of coping, and intrinsic, extrinsic, and disease related factors were collected by a self completed postal questionnaire. 289 patients (101 men and 188 women), mean age 55 years, completed the questionnaire. Both physical and mental quality of life scores were predicted by self esteem and self deprecation, educational level, employment status, social support, response to botulinum toxin, disease severity, social participation, stigma, acceptance of illness, anxiety, and depression. In multivariable analyses, the strongest predictors were anxiety and depression. Severe depression was associated with a 19.1 point decrement in the physical summary score (95% confidence interval, -31.7 to -6.6; p = 0.003); however, disease duration and severity remained predictors. Care for patients with cervical dystonia must not only focus on reducing the severity of the dystonia but also on the psychological wellbeing of the patient. Interventions aimed at treating depression or anxiety, especially of a cognitive nature, may have a large impact on improving quality of life.


Crystal structure of the Z-ring associated cell division protein ZapC from Escherichia coli.
Bacterial cell division involves a contractile ring that organises downstream proteins at the division site and which contains the tubulin homologue FtsZ. ZapC has been discovered as a non-essential regulator of FtsZ. It localises to the septal ring and deletion of zapC leads to a mild phenotype, while overexpression inhibits cell division. Interference with cell division is facilitated by an interaction with FtsZ. Here, we present the 2.9 Å crystal structure of ZapC from Escherichia coli. ZapC forms a dimer and comprises two domains that belong to the Royal superfamily of which many members bind methylated arginines or lysines. ZapC contains an N-terminal chromo-like domain and a Tudor-like C-terminal domain. We show by ITC that ZapC binds the C-terminal tail of FtsZ.


High-dose-rate brachytherapy plus neck dissection for nodal disease.
Regional control for advanced nodal disease has been only marginally affected by concurrent chemoradiation, hyperfractionation, concomitant boost, or accelerated external radiation. Twenty-five necks in 24 patients received brachytherapy treatment (20 Gy in 10 twice-daily fractions) in addition to external radiation, neck dissection +/- chemotherapy. Indications for brachytherapy included initial treatment of bulky disease (n = 12), recurrence of neck disease in a previously treated patient with at least a 3-month disease-free interval (n = 6), persistent disease after a curative efforts (n = 4), inadequate external radiation (ie, <40 Gy) due to either intolerance or noncompliance (n = 3). Overall actuarial regional control was 67% at 2 years. Regional control for those receiving brachytherapy as part of their initial treatment was 82% despite a mean nodal diameter of 8.7 cm (range, 5-15 cm). The 2-year actuarial regional control was 56% for the patients with a disease-free interval of at least 3 years. High-dose-rate brachytherapy produced excellent regional control. (c) 2008 Wiley Periodicals, Inc. Head Neck, 2008.


Zona-free hamster ovum penetration assay as a screening procedure for in vitro fertilization.
Twenty couples with primary sterility due to mechanical factors entered our program of IVF. In addition to routine sperm evaluation, an SPA was performed in all cases. Whenever the SPA was pathologic, none of the human ova were fertilized in vitro, while 77% of the patients with a normal SPA had IVF of at least one human ovum. The good correlation between pathologic SPA and failure of IVF stresses the clinical value of this assay. The use of the SPA for patient selection for IVF is suggested.


The prescription pickup lag, an automatic prescription refill program, and community pharmacy operations.
To determine the effect of an automatic prescription refill program on the prescription pickup lag in community pharmacy. A post-only quasi-experimental design comparing automatic and manual refill prescription cohorts for each of the 3 Centers for Medicare and Medicaid medication adherence metrics. A 29-store community pharmacy chain in the Midwest. Community-dwelling patients over the age of 65 years receiving prescription medications included in the statin, renin-angiotensin-aldosterone system antagonist, or non-insulin diabetes adherence metrics. An automatic prescription refill program that initiated prescription refills on a standardized, recurrent basis, eliminating the need for patients to phone in or drop off prescription refills. The prescription pickup lag, defined as the number of days between a prescription being adjudicated in the pharmacy and the prescription being picked up by the patient. A total of 37,207 prescription fills were examined. There were 20.5%, 22.4%, and 23.3% of patients enrolled in the automatic prescription refill program for the statin, renin-angiotensin-aldosterone system antagonist, and diabetes adherence metrics, respectively. Prescriptions in the automatic prescription refill cohorts experienced a median pickup lag of 7 days compared with 1 day for the manual refill prescriptions. 35.2% of all manual refill prescriptions had a pickup lag of 0 days compared with 13% for automatic refills. However, 15.4% of automatic prescription refills had a pickup lag of greater than 14 days, compared with 4.8% of manual refills. Prescriptions in the automatic prescription refill programs were associated with a significantly longer amount of time in the pharmacy before being picked up by the patient. This increased pickup lag may contribute positively by smoothing out workload demands of pharmacy staff, but may contribute negatively owing to an increased amount of rework and greater inventory requirements.


Antibodies to a short synthetic peptide cross-react with human recombinant interleukin 1 alpha.
An antiserum to human interleukin 1 alpha has been prepared by immunizing a sheep with a short synthetic peptide (Mr 1427) conjugated to keyhole limpet haemocyanin using the heterobifunctional cross-linking agent N-succinimidyl bromoacetate. The peptide was selected from a highly hydrophilic region corresponding to residues 169-179 of the cDNA-derived sequence. Two additional peptides corresponding to residues 194-207 and 224-233 failed to elicit cross-reacting antibodies.


Determining accurate costs for genomic sequencing technologies-a necessary prerequisite.
Genome sequencing (GS) is increasingly being translated into clinical practice and is a technology characterized by a complex multi-step workflow. Funding decisions for GS would be aided by formal economic evaluation of GS platforms, but these analyses require detailed costing. This article addresses the importance of and challenges associated with costing GS using a GS microcosting project in autism spectrum disorder as an illustrative example.


Natural antisense transcription of presenilin in the sea urchin for a general control of gene expression during development?
One presenilin gene (PSEN) is expressed in the sea urchin embryo, in the vegetal pole of the gastrula and then mainly in cilia cells located around the digestive system of the pluteus, as we recently have reported. PSEN expression must be accurately regulated for correct execution of these two steps of development. While investigating PSEN expression changes in embryos after expansion of endoderm with LiCl or of ectoderm with Zn2+ by whole-mount in situ hybridization (WISH) and quantitative PCR (qPCR), we detected natural antisense transcription of PSEN. We then found that Endo16 and Wnt5, markers of endo-mesoderm, and of Hnf6 and Gsc, markers of ectoderm, are also sense and antisense transcribed. We discuss that general gene expression could depend on both sense and antisense transcription. This mechanism, together with the PSEN gene, should be included in gene regulatory networks (GRNs) that theorize diverse processes in this species. We suggest that it would also be relevant to investigate natural antisense transcription of PSEN in the field of Alzheimer's disease (AD) where the role of human PSEN1 and PSEN2 is well known.


The interaction of n-alkanols with lipid bilayer membranes: a 2H-NMR study.
The interaction of eight n-alkanols with bilayers of dimyristoylphosphatidylcholine (DMPC) has been studied by deuterium nuclear magnetic resonance (2H-NMR). At comparable temperatures and concentrations of solute in the bilayer, order parameters measured at the 1-methylene segment of the n-alkanols show a maximum for n-dodecanol. For both n-dodecanol and n-tetradecanol, orientational ordering shows a maximum at the C-4 to C-7 methylene segments, with labels at both ends of the n-alkanol exhibiting reduced order. These observations are consistent with earlier findings for n-octanol and n-decanol. Unlike the longer chain n-alkanols, ordering in n-butanol decreases from the hydroxyl group end to the methyl group end of the molecule. Orientational ordering at nine inequivalent sites in DMPC, has also been measured as a function of temperature, for bilayers containing n-butanol, n-octanol, n-dodecanol and n-tetradecanol. At the 3R,S sites on the glycerol backbone, for comparable temperatures and solute concentrations, n-butanol produces a larger disordering than the other n-alkanols. This result probably reflects the greater fraction of time spent by the hydroxyl group of n-butanol in the vicinity of the lipid polar head group compared with the hydroxyl group in longer chain n-alkanols. It was found that n-octanol orders the acyl chains of DMPC, unlike n-butanol which disorders them, and the longer chain n-alkanols which have little effect. Within experimental error, the effect of n-dodecanol on order at all sites in DMPC is the same as n-tetradecanol. The influence of n-alkanols on DMPC ordering at twelve sites has been compared with that of cholesterol which is shown to interact with DMPC bilayers in a distinctly different manner from the n-alkanols.


Efficacy of selamectin against experimentally induced and naturally acquired infections of Toxocara cati and Ancylostoma tubaeforme in cats.
The efficacy of selamectin against experimentally induced and naturally acquired infections of adult ascarids (Toxocara cati) and adult hookworms (Ancylostoma tubaeforme) was evaluated in five controlled studies in cats. Two studies evaluated the efficacy of selamectin against both ascarid (natural or induced) and hookworm (induced) infections; two studies evaluated the efficacy of selamectin against single natural infections of T. cati or A. tubaeforme; and the fifth study evaluated the efficacy of selamectin against induced infections of A. tubaeforme. Cats received selamectin topically in unit doses designed to deliver a minimum of 6mgkg(-1). Treatments were applied to the skin on each animal's back at the base of the neck in front of the scapulae. For experimentally induced infections, cats were inoculated orally with approximately 500 embryonated eggs of T. cati 56 days prior to treatment and/or approximately 150-250 larvae (L(3)) of A. tubaeforme 30 or 42 days prior to treatment. For both induced and naturally acquired infections, cats were allocated randomly to treatments (6-12 cats per treatment) on the basis of fecal egg counts to receive either selamectin or a vehicle containing the inert formulation ingredients. In all studies, adult worm counts were performed at necropsy 14 days after the last treatment administration. Against T. cati, a single application of selamectin provided a 100% reduction in the geometric mean number of adult worms for both experimentally induced and naturally acquired infections. Against A. tubaeforme, a single administration of selamectin provided a 99.4% reduction in the geometric mean number of adult worms in cats with natural infections, and an 84.7-99.7% reduction in adult worms in cats with induced infections. Two doses of selamectin administered at monthly intervals provided a 91.9% reduction in the geometric mean number of adult A. tubaeforme worms in cats with experimentally induced infections. The geometric mean numbers of adult worms (T. cati and A. tubaeforme) from selamectin-treated cats were significantly (P< or =0.0018) lower than for vehicle-treated cats in all studies. Thus, a single topical unit dosage providing a minimum dosage of 6mgkg(-1) selamectin was highly effective in the treatment of naturally acquired and experimentally induced infections of T. cati and A. tubaeforme in cats.


Panel discussion: glomus jugulare tumors of the temporal bone. The surgical management of glomus tumors.
The authors describe the diagnosis and surgical management of 70 glomus tumors seen at the Otology Group in an 8 yr. period. The need for bilateral arteriograms to detect associated tumors (carotid body and intervagale) is stressed. A new surgical technique, the modified intratemporal fossa approach, is described for the removal of large glomus jugulare tumors involving the carotid artery. Complications and results are discussed in detail.


Melanoma recurrence confined to a free flap after isolated limb perfusion.
We present the case of a 72-year-old female presenting to our unit with locally recurrent malignant melanoma of the lower limb almost entirely confined to a fasciocutaneous free flap. The flap (lateral arm donor site) had been used several years previously to reconstruct a wide local excision defect following the excision of recurrent disease. The striking difference about this case is that the recurrence observed after isolated limb perfusion (ILP) was almost entirely confined to the flap rather than the affected limb. Several possible explanations for this phenomenon are discussed--considering factors such as altered flap lymphatics, neuronal factors, and differential flap-versus-normal tissue response to the tumour necrosis factor used in ILP. The case highlights interesting questions about the mechanism of action of ILP--especially with regard to free flap tissue--and unknowns regarding tumour spread across wound scar boundaries.


Pneumolysin as a potential therapeutic target in severe pneumococcal disease.
Acute pulmonary and cardiac injury remain significant causes of morbidity and mortality in those afflicted with severe pneumococcal disease, with the risk for early mortality often persisting several years beyond clinical recovery. Although remaining to be firmly established in the clinical setting, a considerable body of evidence, mostly derived from murine models of experimental infection, has implicated the pneumococcal, cholesterol-binding, pore-forming toxin, pneumolysin (Ply), in the pathogenesis of lung and myocardial dysfunction. Topics covered in this review include the burden of pneumococcal disease, risk factors, virulence determinants of the pneumococcus, complications of severe disease, antibiotic and adjuvant therapies, as well as the structure of Ply and the role of the toxin in disease pathogenesis. Given the increasing recognition of the clinical potential of Ply-neutralisation strategies, the remaining sections of the review are focused on updates of the types, benefits and limitations of currently available therapies which may attenuate, directly and/or indirectly, the injurious actions of Ply. These include recently described experimental therapies such as various phytochemicals and lipids, and a second group of more conventional agents the members of which remain the subject of ongoing clinical evaluation. This latter group, which is covered more extensively, encompasses macrolides, statins, corticosteroids, and platelet-targeted therapies, particularly aspirin.


Calcium transients in frog skeletal muscle fibres following conditioning stimuli.
1. Intracellular Ca(2+) transients were recorded from frog twitch muscle fibres, using arsenazo III as a Ca(2+) monitor. When fibres were stimulated by two action potentials, the arsenazo signal to the second stimulus was smaller than the first, for stimulus intervals of up to several seconds.2. The recovery of the amplitude of the second response followed two exponential time courses; a fast one with a time constant of about 70 msec giving recovery to about 90% of the control value, followed by a slow recovery to 100%, with a time constant of about 12 sec (at 10 degrees C).3. The time constant of the fast recovery component was strongly temperature-dependent, with a Q(10) of approximately 2.7, whilst the Q(10) of the slow component was about 1.4.4. Removal of Ca(2+) in the bathing medium lengthened the time constant of the slow recovery component by a factor of three, but had little effect on the fast recovery component. The lengthening of the slow component was not reversed by addition of Mg(2+), but Sr(2+) ions could substitute for Ca(2+).5. The influence of membrane potential on the recovery time-course was investigated after blocking action potentials with tetrodotoxin, using a voltage clamp to control membrane potential. Paired depolarizing stimuli were used, with the potential held to either low (-60 or -80 mV) or high (-110 or -140 mV) potentials between stimuli. No differences were apparent in either the fast or slow recovery components at these holding potentials.6. The arsenazo response elicited by an action potential following a conditioning tetanus was reduced in size even more strongly than following a single action potential. The time course of recovery of the response following a tetanus again comprised two exponential components. After a 20 Hz tetanus for 0.5 sec, the fast component had a time constant of about 400 msec, and gave a recovery to about 60% of the control value. Subsequent recovery to 100% occurred with a time constant of about 12 sec.7. The time constant of the fast recovery component increased markedly with increasing frequency or duration of the conditioning tetanus. The time constant of the slow component was not appreciably altered by conditioning tetani varying between one impulse and sixty impulses. However, the reduction in response size due to the slow component, extrapolated to zero stimulus interval, increased with increasing number of impulses in the tetanus.8. The time constant of the fast recovery component corresponded closely with the decay time constant of the arsenazo response to the conditioning stimulus. This correspondence held over a nearly fifty-fold range of time constants, and for two different conditions which affected the decay time constant (temperature, and frequency of tetanic stimulation).9. The decay time constant of the arsenazo response elicited by an action potential was slowed by a preceding impulse or tetanus. Following a 20 Hz tetanus for 0.5 sec, recovery of the half decay time appeared to follow an exponential time course, with a time constant of about 12 sec.10. These results suggest that the fast recovery component reflects the re-filling of release stores in the sarcoplasmic reticulum by Ca(2+) ions taken up from the cytoplasm. The origin of the slow component is less clear, but it may arise from inactivation of the excitation-contraction (e-c) coupling process between T-tubule depolarization and Ca(2+) release from the sarcoplasmic reticulum.


Characterization and comparison of two newly established Epstein-Barr virus-negative lymphoma B-cell lines. Surface markers, growth characteristics, cytogenetics, and transplantability.
Two Epstein-Barr virus (EBV)-negative lymphoma B-cell lines, HBL-1 and HBL-2, were established from a pleural effusion and a lymph node biopsy of two patients with diffuse large cell lymphoma. HBL-1 and HBL-2 showed the characteristics of activated B-cells in B-cell lineage, as did original lymphoma cells. Chromosome analyses revealed that HBL-1 exhibiting 14q+ marker-positive lymphoid cancer showed a new subclass of 14q32 translocation resulting from a translocation between chromosomes 14 and 16, which had been masked in a complex translocation involving five chromosomes, and that HBL-2 had a 14q+ marker chromosome, the result of an 11;14 translocation [t(11;14)(q13;32)]. Successful heterotransplantation into athymic nude mice demonstrated tumorigenicity of HBL-1 and HBL-2. The transplantability and tumor growth rate of HBL-2 were higher and more rapid than those of HBL-1. HBL-1 and HBL-2 appear useful for facilitating therapeutic investigations as well as immunologic and oncogenic studies in B-cell lymphomas.


Visibility of speech articulation enhances auditory phonetic convergence.
Talkers automatically imitate aspects of perceived speech, a phenomenon known as phonetic convergence. Talkers have previously been found to converge to auditory and visual speech information. Furthermore, talkers converge more to the speech of a conversational partner who is seen and heard, relative to one who is just heard (Dias & Rosenblum Perception, 40, 1457-1466, 2011). A question raised by this finding is what visual information facilitates the enhancement effect. In the following experiments, we investigated the possible contributions of visible speech articulation to visual enhancement of phonetic convergence within the noninteractive context of a shadowing task. In Experiment 1, we examined the influence of the visibility of a talker on phonetic convergence when shadowing auditory speech either in the clear or in low-level auditory noise. The results suggest that visual speech can compensate for convergence that is reduced by auditory noise masking. Experiment 2 further established the visibility of articulatory mouth movements as being important to the visual enhancement of phonetic convergence. Furthermore, the word frequency and phonological neighborhood density characteristics of the words shadowed were found to significantly predict phonetic convergence in both experiments. Consistent with previous findings (e.g., Goldinger Psychological Review, 105, 251-279, 1998), phonetic convergence was greater when shadowing low-frequency words. Convergence was also found to be greater for low-density words, contrasting with previous predictions of the effect of phonological neighborhood density on auditory phonetic convergence (e.g., Pardo, Jordan, Mallari, Scanlon, & Lewandowski Journal of Memory and Language, 69, 183-195, 2013). Implications of the results for a gestural account of phonetic convergence are discussed.


The high-throughput atomization of polymer solutions for fiber synthesis in a single step aided with corona ionizers.
Polymer microfibers are ubiquitous structures across virtually all technological fields. Their applications include, for instance, filter media, tissue regeneration, wound healing and dressing, and reinforcement materials. The most effective methods for fabrication of fibrous micro and nanomaterials rely on electric fields to spin a liquid jet into an ultrafine thread that rapidly dries up forming a fiber. Continuous spinning and collection leads to formation of fiber mats. Here we report a robust yet simple approach for the massive production of liquid threads, which upon acquiring electrical charges in-flight are collected downstream in the form of fibers. The entire process takes place on-line in a single step. The liquid threads are produced through the fragmentation of a polymer solution bulk due to a turbulent interaction of a gas-liquid interface in the interior of an engineered device, a so-called Flow Blurring atomizer. The particularity of this approach consists precisely in such vigorous interaction, at the micrometer scale, which triggers a bubbly motion in the interior of the device, that is a "micro-mixing". Subsequently, the threads are passed through ionized air currents, at ambient conditions, and then stretched to sub-micrometer dimensions by electric fields. Polyvinylpyrrolidone (PVP) as well as carbon nanotubes (CNTs) or graphene oxide sheets (GOSs)-containing PVP fibers, with diameters in the range 100-900 nm, were synthesized via this approach. In the cases studied herein the method was operated at liquid flow rates (i.e. production rates) of 0.2 mL/min but it could be readily increased up to a few tens of mL/min. The method requires further improvement and optimization, nevertheless it is a promising alternative for mass production of polymer fibers.


Percutaneous renal cryoablation of renal tumors in patients with von Hippel-Lindau disease.
We determine the feasibility and safety of performing percutaneous cryoablation of renal tumors in patients with von Hippel-Lindau disease. We selected 2 men and 2 women with von Hippel-Lindau disease and radiographic determined solid renal tumors were selected to undergo percutaneous cryoablation. All patients underwent standard preoperative evaluation. An interventional magnetic resonance imaging unit was used for probe guidance and ice ball monitoring. The cryoablation procedure was performed with a 2 or 3 mm. cryoprobe using a pressurized argon gas system for ice ball formation. The patients were hospitalized overnight for observation and discharged home the following day. A followup computerized tomogram or magnetic resonance imaging scan was performed at 1 week, 1, 3, 6 and 12 months and every 6 months thereafter, along with physical examination, urinalysis, serum blood urea nitrogen and creatinine. A total of 5 tumors were treated ranging from 2.8 to 5.0 cm. in diameter. All patients underwent the procedure without difficulty with 2 requiring re-treatment due to residual tumor for a total of 7 treatments. At followup from 2 to 23 months there has been no radiographic evidence of recurrence at the cryoablated areas. Percutaneous cryoablation of renal tumors in patients with von Hippel-Lindau disease proved to be successful in this initial series. Although 2 patients had residual tumor after the initial cryoablation procedure re-treatment was performed with no adverse sequela. This minimally invasive therapy may allow patients with von Hippel-Lindau disease to avoid the necessity of multiple open surgical procedures.


Impact of the right ventricular lead position on clinical outcome and on the incidence of ventricular tachyarrhythmias in patients with CRT-D.
Data on the impact of right ventricular (RV) lead location on clinical outcome and ventricular tachyarrhythmias in cardiac resynchronization therapy with defibrillator (CRT-D) patients are limited. To evaluate the impact of different RV lead locations on clinical outcome in CRT-D patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial. We investigated 742 of 1089 CRT-D patients (68%) with adjudicated RV lead location enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial to evaluate the impact of RV lead location on cardiac events. The primary end point was heart failure or death; secondary end points included ventricular tachycardia (VT), ventricular fibrillation (VF), or death and VT or VF alone. Eighty-six patients had the RV lead positioned at the RV septal or right ventricular outflow tract region, combined as nonapical RV group, and 656 patients had apical RV lead location. There was no difference in the primary end point in patients with nonapical RV lead location versus those with apical RV lead location (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.54-1.80; P = .983). Echocardiographic response to CRT-D was comparable across RV lead location groups (P > .05 for left ventricular end-diastolic volume, left ventricular end-systolic volume, and left atrial volume percent change). However, nonapical RV lead location was associated with significantly higher risk of VT/VF/death (HR 2.45; 95% CI 1.36-4.41; P = .003) and VT/VF alone (HR 2.52; 95% CI 1.36-4.65; P = .002), predominantly in the first year after device implantation. Results were consistent in patients with left bundle branch block. In CRT-D patients, there is no benefit of nonapical RV lead location in clinical outcome or echocardiographic response. Moreover, nonapical RV lead location is associated with an increased risk of ventricular tachyarrhythmias, particularly in the first year after device implantation.


Detecting Rumors Through Modeling Information Propagation Networks in a Social Media Environment.
In the midst of today's pervasive influence of social media content and activities, information credibility has increasingly become a major issue. Accordingly, identifying false information, e.g. rumors circulated in social media environments, attracts expanding research attention and growing interests. Many previous studies have exploited user-independent features for rumor detection. These prior investigations uniformly treat all users relevant to the propagation of a social media message as instances of a generic entity. Such a modeling approach usually adopts a homogeneous network to represent all users, the practice of which ignores the variety across an entire user population in a social media environment. Recognizing this limitation of modeling methodologies, this study explores user-specific features in a social media environment for rumor detection. The new approach hypothesizes that whether a user tends to spread a rumor is dependent upon specific attributes of the user in addition to content characteristics of the message itself. Under this hypothesis, information propagation patterns of rumors versus those of credible messages in a social media environment are systematically differentiable. To explore and exploit this hypothesis, we develop a new information propagation model based on a heterogeneous user representation for rumor recognition. The new approach is capable of differentiating rumors from credible messages through observing distinctions in their respective propagation patterns in social media. Experimental results show that the new information propagation model based on heterogeneous user representation can effectively distinguish rumors from credible social media content.


Effect of acute tensile loading on gender-specific tendon structural and mechanical properties.
Stretching is commonly used prior to exercise, as it is thought to reduce the risk of injury, and it is also used in the preconditioning of tendon grafts. As tendon properties have been shown to be different between genders, it is proposed that stretching will differentially affect the structure. Here we examine the effect of acute stretch on the mechanical properties of both male and female medial gastrocnemius tendon. Female [20 years +/- 1 (SEM), n = 17] and male (22 years +/- 1, n = 18) subjects underwent a 5-min passive dorsiflexion stretch. Prior to and post stretch medial gastrocnemius tendon stiffness (K), length (l) and cross-sectional area (csa) were measured using ultrasonography and dynamometry. Stiffness and Young's modulus (epsilon) were significantly reduced with stretch for both genders (p < 0.05). Females showed significantly (p < 0.05) greater pre- to poststretch decreases in K (22.4 vs. 8.8%) and epsilon (20.5 vs. 8.4%) in comparison to males. The present results show that stretching acutely reduces stiffness of the medial gastrocnemius tendon in females and males, with females showing significantly greater change. The observed disparity between genders may be due in part to variations in tendon moment arm and intrinsic differences in tendon composition. These differential changes in tendon mechanical properties have functional, motor control, and injury risk implications, as well as possible implications for preconditioning of tendon grafts.


Towards optimizing single pulse electrical stimulation: High current intensity, short pulse width stimulation most effectively elicits evoked potentials.
While single pulse electrical stimulation (SPES) is increasingly used to study effective connectivity, the effects of varying stimulation parameters on the resulting cortico-cortical evoked potentials (CCEPs) have not been systematically explored. We sought to understand the interacting effects of stimulation pulse width, current intensity, and charge on CCEPs through an extensive testing of this parameter space and analysis of several response metrics. We conducted SPES in 11 patients undergoing intracranial EEG monitoring using five combinations of current intensity (1.5, 2.0, 3.0, 5.0, and 7.5 mA) and pulse width at each of three charges (0.750, 1.125, and 1.500 μC/phase) to study how CCEP amplitude, distribution, latency, morphology, and stimulus artifact amplitude vary with each parameter. Stimulations with a greater charge or a greater current intensity and shorter pulse width at a given charge generally resulted in greater CCEP amplitudes and spatial distributions, shorter latencies, and increased waveform correlation. These effects interacted such that stimulations with the lowest charge and highest current intensities resulted in greater response amplitudes and spatial distributions than stimulations with the highest charge and lowest current intensities. Stimulus artifact amplitude increased with charge, but this could be mitigated by using shorter pulse widths. Our results indicate that individual combinations of current intensity and pulse width, in addition to charge, are important determinants of CCEP magnitude, morphology, and spatial extent. Together, these findings suggest that high current intensity, short pulse width stimulations are optimal SPES settings for eliciting strong and consistent responses while minimizing charge.


The effects of a video-based randomized controlled trial intervention on depression stigma and help-seeking attitudes in university students.
University students are a risk group for developing mental illness, but they do not receive the care they need because of hampered help-seeking induced by stigma. This study evaluates the effects of a video-based stigma reduction intervention and help-seeking attitudes promotion in university students. We randomly distributed a sample of university students among one control group (CG, n = 188) and two intervention groups (IG-1, n = 222 and IG-2, n = 216): IG-1 watched a contact-based video and IG-2 the same video plus a psychoeducational video. The study followed an experimental single-blind randomized control trial design with a pre-test before the intervention (M0), a post-test, and a follow-up test. We evaluated participants using a sociodemographic questionnaire, the Attitudes Toward Seeking Professional Psychological Help Questionnaire, the Depression Stigma Scale, the 9-item Patient Health Questionnaire, and the 7-item Generalized Anxiety Disorder. A total of 626 participants with a mean age of 19.85 (SD=1.48) responded to all evaluation moments. At M0, there were no differences between groups on stigma or help-seeking attitudes. Immediately after the intervention, stigma levels significantly decreased, and help-seeking attitudes significantly improved. These effects persisted for the next five months. Video-based depression stigma reduction intervention can be an essential tool to reduce depression stigma and improve help-seeking attitudes.


Shedding of proangiogenic microvesicles from hypertrophic scar myofibroblasts.
Hypertrophic scars are a common complication of burn injuries and represent a major challenge in terms of prevention and treatment. These scars are characterized by a supraphysiological vascular density and by the presence of pathological myofibroblasts (Hmyos) displaying a low apoptosis propensity. However, the nature of the association between these two hallmarks of hypertrophic scarring remains largely unexplored. Here, we show that Hmyos produce signalling entities known as microvesicles that significantly increase the three cellular processes underlying blood vessel formation: endothelial cell proliferation, migration and assembly into capillary-like structures. The release of microvesicles from Hmyos was dose-dependently induced by the serum protein α-2-macroglobulin. Using flow cytometry, we revealed the presence of the α-2-macroglobulin receptor-low-density lipoprotein receptor-related protein 1-on the surface of Hmyos. The inhibition of the binding of α-2-macroglobulin to its receptor abolished the shedding of proangiogenic microvesicles from Hmyos. These findings suggest that the production of microvesicles by Hmyos contributes to the excessive vascularization of hypertrophic scars. α-2-Macroglobulin modulates the release of these microvesicles through interaction with low-density lipoprotein receptor-related protein 1.


Meiosis-specific yeast Hop1 protein promotes pairing of double-stranded DNA helices via G/C isochores.
In eukaryotes, genetic exchange between homologs is facilitated by a tripartite proteinaceous structure called the synaptonemal complex (SC). Several lines of evidence indicate that the genes that encode components of SC are essential for meiotic chromosome pairing and recombination. However, the molecular mechanism by which SC proteins promote these processes is obscure. Here, we report that Saccharomyces cerevisiae Hop1 protein, a component of SC, promotes pairing between two double-stranded DNA helices containing a centrally located G/C isochore. Significantly, pairing was rapid and robust, and required four contiguous G/C base pairs. Using a series of truncated DNA double helices we show that 20 bp on either side of 8 bp target G/C sequence is essential for pairing. To our knowledge, Hop1 is the first protein shown to do so from yeast or any other organism. These results indicate that Hop1 protein is likely to play a direct role in meiotic chromosome pairing and recombination.


Genetic inactivation of adenosine A2A receptors attenuates acute traumatic brain injury in the mouse cortical impact model.
The inactivation of the A(2A) receptor (A(2A)R) has been shown to neuroprotect against brain injury in several animal models of neurological disorders including stroke and Parkinson's disease. However, despite marked elevation of adenosine level, the role of the A(2A) in traumatic brain injury (TBI) remains unclear. In the present study, we investigated the effects of genetic inactivation of A(2A)Rs in the acute stage. The A(2A)R knock-out (KO) mice and their wild-type (WT) littermates were subjected to cortical impact injury by a dropping weight. The control group was only craniotomized without TBI. At 24 h post-TBI, the neurological deficit scores of the KO mice were significantly lower than that of WT littermates. Consistent with the behavioral changes, the brain water contents as well as histological changes and the TUNEL-positive cells of the injured cortex of the KO mice were significantly lower than that of WT littermates. Furthermore, the glutamate level in the cerebral spinal fluid (CSF) of the KO mice was also significantly lower than that of WT littermates. In addition, we found that at 12 h post-TBI the mRNA and protein levels of TNF-alpha and IL-1beta were higher in the KO mice than that in the WT littermates. However, at 24 h post-TBI, the level of TNF-alpha and IL-1beta continually increased in the WT mice but largely declined in the KO mice. These results suggest that the genetic inactivation of A(2A)R protects against TBI, which is mainly associated with the suppression of glutamate level.


Editor's Choice - Endurant Stent Graft in Patients with Challenging Neck Anatomy "One Step Outside Instructions for Use": Early and Midterm Results from the EAGLE Registry.
The aim of the Endurant for Challenging Anatomy: Global Experience (EAGLE) registry is to evaluate prospectively the technical and clinical success rate of a stentgraft used in patients with challenging neck anatomy outside the instructions for use (IFU) but within objective anatomical limits. This was a prospective, international, multicentre, observational study. From 1 February 2012 to 1 September 2017, patients with an abdominal aortic aneurysm with a challenging infrarenal neck that were deemed suitable for endovascular aneurysm repair were included prospectively at 23 European centres. Patients were distributed by anatomy into three groups: short neck (SN; infrarenal neck 5 - 10 mm in combination with suprarenal angulation [α] ≤ 45° and infrarenal angulation [β] ≤ 60°); medium neck (MN; infrarenal neck 10 - 15 mm with α ≤ 60° and β 60° - 75° or α 45°- 60° and β ≤ 75°; and long angulated neck (LN; infrarenal neck ≥ 15 mm with α ≤ 75° and β 75°- 90° or α 60°- 75° and β ≤ 90°. All computed tomography scans were reviewed by an independent core laboratory. Primary outcomes were technical and clinical success. Secondary endpoints were peri-operative major adverse events, all cause mortality, aneurysm related mortality, endoleaks, migration, and secondary intervention. One hundred and fifty patients (81.3% male) were included (SN = 55, MN = 16, LN = 79). The median follow up was 36 ± 12.6 months. In the overall cohort, the technical success rate was 93.3%. Estimated freedom from aneurysm related death was 97.3% at three years. Freedom from secondary interventions was 84.7% at three years. Estimated clinical success was 96.0%, 90.8%, and 83.2% at 30 days, one year, and three years, respectively. Estimated freedom from all cause mortality, late type IA endoleak, and migration at three years was 75.1%, 93.7%, and 99.3%, respectively. The early and midterm results of the EAGLE registry show that endovascular repair with the Endurant stentgraft in selected patients with challenging infrarenal neck anatomy yields results in line with large "real world" registries. Long term results are awaited for more definitive conclusions.


Influence of age, gender, and race on nitric oxide release over acupuncture points-meridians.
This study examined the influence of age, gender and race on nitric oxide (NO) release over acupuncture points, meridian without acupoint, and non-meridian regions of the Pericardium (PC) and Bladder (BL) meridian as well as aging on LU meridian in 61 healthy subjects. Biocapture tubes were attached to the skin surface, and total nitrite and nitrate was biocaptured and quantified using chemiluminescence. In elder ages compared to adults, NO levels over the ventral forearm were significantly decreased over LU on radial regions but not altered over PC on medial regions. Conversely, NO content was elevated over BL regions only in overweight/obesity of elder ages. NO levels over PC regions were marginally elevated in overweight/obese males compared to females but did not alter between races. These results suggest a selective reduction of NO release over LU meridian with aging, which is consistent with a progressive decline in lung function and increase in chronic respiratory disease in elder ages. Increased NO levels along the BL meridian in older obese subjects may reflect a modified NO level along somatic-bladder pathway for counteracting bladder dysfunctions with aging. Both of them support somatic-organ connections in the meridian system associated with potential pathophysiological changes with aging.


Prevalence of latex sensitivity and allergy among physicians of a residency program in a children´s hospital of Buenos Aires.
International publications estimate a 7 %-17 % latex sensitization (LS) prevalence among health care workers, but values in Argentina are unknown. To estimate the prevalence of latex sensitization and allergy among residents of a children's hospital using the immediate-reading prick test and to assess associated risk factors in this population. Cross-sectional study. Residents, trainers, and Chief residents of the Departments of Pediatrics, Orthopedics, Surgery and Intensive Care were included between June and October 2017. All of them were administered a questionnaire (assessing atopic diseases and other risk factors) and underwent the immediatereading prick test. Total and latex-specific immunoglobulin E levels were determined in a subgroup of individuals (first- and fourth-year residents, surgical specialties, and intensive care). A total of 113 participants were included. LS prevalence was 7.96 % (95 % confidence interval: 3.70-14.58); 4 participants were allergic to latex. A history of latex-related symptoms (LRS) was significantly associated with a positive result in the immediate-reading prick test (p = 0.0196; odds ratio: 6.13; 95 % confidence interval: 1.44-26.04). There was no association between LS and the year of the residency program. The observed LS prevalence was 7.9 %. There was a significant relation between a history of LRS and a positive result in the immediate-reading prick test.


Quality control in laparoscopic cholecystectomy: operation notes, video or photo print?
In 1995 the concept of a 'critical view of safety' (CVS) in Calot's triangle was introduced to prevent bile duct injury in laparoscopic cholecystectomy. The aim of this study was to determine the most reliable method for recording CVS. Operation notes, video images and photo prints from 50 consecutive elective non-converted laparoscopic cholecystectomies were analysed. Operation notes alone did not suffice to record CVS. As an adjunct, video proved superior to photo print with regard to quality. Nevertheless, photo prints were practically and logistically much easier to produce than video. Moreover, when good quality images were achieved, photo print recorded CVS more conclusively than video. Operation notes,video and photo print are complementary, and the combination records CVS conclusively in nearly every case.


Characterization of GTP-dependent Met-tRNAf binding protein.
Purified GTP-dependent Met-tRNAf binding protein (EIF2) prepared from the 0.5 M KCl eluate of reticulocyte polyribosomes was successfully resolved into its three-component subunits by isoelectric focusing in the presence of urea. The 37,000-dalton subunit focused at a pH of 5.8 and was resolved into two spots; the 48,000-dalton subunit focused at a pH of 6.6 and was resolved into three spots; and the 52,000-dalton subunit exhibited an isoelectric point of 8.9 and migrated as a single spot. When isolated 37,000- and 48,000-dalton subunit was found to possess Met-tRNAf and mRNA binding activities while the 37,000-dalton subunit was found to possess GDP binding activity. Phosphorylation of EIF2 by protein kinases present in reticulocyte lysates was demonstrated using [gamma-32P]GTP or [gamma-32P]ATP as the phosphate donor. The 37,000-dalton subunit was preferentially phosphorylated when [gamma-32P]ATP was used as substrate; the 48,000-dalton subunit was preferentially phosphorylated when the [gamma-52P]GTP was used as phosphate donor, although some phosphorylation of the 37,000-dalton subunit was also observed. The 37,000-dalton subunit of ribosome-associated EIF2 was present predominantly in a dephosphorylated form following purification.


Major Pathologic Response after Induction Therapy Has a Long-Term Impact on Survival and Tumor Recurrence in Stage IIIA/B Locally Advanced NSCLC.
Major pathologic response (MPR) determines favorable outcome in locally advanced non-small cell lung cancer after induction therapy (IT) followed by lung resection. The aim of this retrospective study was to identify the prognostic relevance of MPR in long-term interval. In 55 patients, the survival rate according to MPR and non-MPR was estimated by Kaplan-Meier method and compared using log-rank, Breslow, and Tarone-Ware tests. The IT included chemoradiation with 50.4 Gy (range: 45-56.4 Gy) combined with platinum-based chemotherapy in 52 patients (94.5%) and platinum-based chemotherapy in 3 patients (5.5%). Perioperative morbidity and 30-day mortality were 36 and 3.6%, respectively. The estimated 5-year postoperative and progressive-free survivals were statistically significantly improved in MPR versus non-MPR with 53.5 versus 18% and 49.4 versus 18.5%, respectively. According to the log-rank, Breslow, and Tarone-Ware tests, the MPR demonstrates prognostic significance in early, long-term, and whole postoperative interval. MPR is associated with a robust correlation to long-term postoperative and recurrence-free survival improvement, and can potentially simplify the multidisciplinary debate and allow further stratification of adjuvant treatment in multimodality therapy.


Efficacy and safety of poly (ADP-ribose) polymerase inhibitors therapy for BRCA-mutated breast cancer: A systematic review and meta-analysis.
To evaluate the efficacy, safety, and potential advantages of Poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA-mutated breast cancer, we performed a meta-analysis of published studies. Four randomized controlled trials (RCTs) were included in the meta-analysis. Data analysis was conducted in Review Manager 5.4. The progression-free survival (PFS) of the patients with triple-negative (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.74-0.88; P < 0.00001) or hormone receptor-positive (HR 0.83; 95% CI 0.77-0.91; P < 0.0001) BRCA-mutated breast cancer was significantly extended in the containing PARPi therapy arm versus the chemotherapy arm. PFS of the patients who did not receive platinum-based therapy (HR 0.78; 95% CI 0.70-0.86; P < 0.0001) was significantly extended in the PARPi monotherapy arm versus the chemotherapy arm. The objective response rate of patients treated by PARPi monotherapy (risk ratio [RR] 2.51; 95% CI 1.81-3.47; P < 0.00001) was significantly higher than that of patients treated by chemotherapy. The incidence of thrombocytopenia in patients received PARPi combined therapy was obviously increased compared with chemotherapy group (RR 1.36; 95% CI 1.07-1.72; P = 0.01). PARPi monotherapy markedly increased the incidence of anemia (RR 5.83; 95% CI 2.64-12.88; P < 0.0001) versus chemotherapy. However, the risk of neutropenia (RR 0.48; 95% CI 0.29-0.81; P = 0.006) was reduced in the PARPi monotherapy arm. There were no statistical differences in other adverse events among these three groups. PARPi combined therapy and monotherapy improved PFS of patients with BRCA-mutated breast cancer compared with standard chemotherapy, which was unrelated to type of BRCA mutation and status of hormone receptor. PARPi therapy has slightly higher hematological toxicity and better overall safety and tolerance. CRD42020204385.


Cellulose sulfate: tolerance and acceptability of penile application.
Sodium cellulose sulfate (CS) is under development as a vaginal microbicide and spermicide. This was a Phase I, randomized, double-blind study of men to assess acceptability, safety, and degree of penile irritation of seven consecutive daily doses of CS compared to an active control containing nonoxynol-9 (Conceptrol). The data suggest that CS gel is not more irritating to the male genitalia than Conceptrol. This, along with the minimal irritation seen in a Phase I safety study in women following 6 consecutive days of vaginal administration, suggests that CS could be used in future studies, without undue risk, where couples engage in vaginal intercourse. Male volunteers in future studies should be informed that 1 out of 24 participants in the CS group in this study experienced tingling and slight stinging for a brief time after exposure compared with 3 out of 12 in the Conceptrol group who reported similar symptoms.


Schizophrenia-associated differential DNA methylation in brain is distributed across the genome and annotated to MAD1L1, a locus at which DNA methylation and transcription phenotypes share genetic variation with schizophrenia risk.
DNA methylation (DNAm), the addition of a methyl group to a cytosine in DNA, plays an important role in the regulation of gene expression. Single-nucleotide polymorphisms (SNPs) associated with schizophrenia (SZ) by genome-wide association studies (GWAS) often influence local DNAm levels. Thus, DNAm alterations, acting through effects on gene expression, represent one potential mechanism by which SZ-associated SNPs confer risk. In this study, we investigated genome-wide DNAm in postmortem superior temporal gyrus from 44 subjects with SZ and 44 non-psychiatric comparison subjects using Illumina Infinium MethylationEPIC BeadChip microarrays, and extracted cell-type-specific methylation signals by applying tensor composition analysis. We identified SZ-associated differential methylation at 242 sites, and 44 regions containing two or more sites (FDR cutoff of q = 0.1) and determined a subset of these were cell-type specific. We found mitotic arrest deficient 1-like 1 (MAD1L1), a gene within an established GWAS risk locus, harbored robust SZ-associated differential methylation. We investigated the potential role of MAD1L1 DNAm in conferring SZ risk by assessing for colocalization among quantitative trait loci for methylation and gene transcripts (mQTLs and tQTLs) in brain tissue and GWAS signal at the locus using multiple-trait-colocalization analysis. We found that mQTLs and tQTLs colocalized with the GWAS signal (posterior probability >0.8). Our findings suggest that alterations in MAD1L1 methylation and transcription may mediate risk for SZ at the MAD1L1-containing locus. Future studies to identify how SZ-associated differential methylation affects MAD1L1 biological function are indicated.


The VASP-profilin1 (Pfn1) interaction is critical for efficient cell migration and is regulated by cell-substrate adhesion in a PKA-dependent manner.
Dynamic regulation of the actin cytoskeleton is an essential feature of cell motility. Action of Enabled (Ena)/vasodilator-stimulated phosphoprotein (VASP), a family of conserved actin-elongating proteins, is an important aspect of regulation of the actin cytoskeletal architecture at the leading edge that controls membrane protrusion and cell motility. In this study, we performed mutagenesis experiments in overexpression and knockdown-rescue settings to provide, for the first time, direct evidence of the role of the actin-binding protein profilin1 (Pfn1) in VASP-mediated regulation of cell motility. We found that VASP's interaction with Pfn1 is promoted by cell-substrate adhesion and requires down-regulation of PKA activity. Our experimental data further suggest that PKA-mediated Ser137 phosphorylation of Pfn1 potentially negatively regulates the Pfn1-VASP interaction. Finally, Pfn1's ability to be phosphorylated on Ser137 was partly responsible for the anti-migratory action elicited by exposing cells to a cAMP/PKA agonist. On the basis of these findings, we propose a mechanism of adhesion-protrusion coupling in cell motility that involves dynamic regulation of Pfn1 by PKA activity.


Clinical and aortographic assessment of the complications of arterial catheterization.
Catheterization of the umbilical artery for the treatment of critically ill neonates provides a convenient method for monitoring blood gas tension and chemistry. The most important complications are thrombotic. Thirty eight aortographs were carried out in infants who underwent umbilical artery catheterization. 17/38 of the aortographs were pathological. Bacterial cultures were positive in 11/17, but only 4 coincided with pathological aortographs. Clinical signs indicating complications due to the presence of the catheter wwere observed in 10 cases. Post-mortem examination of eight subjects--three of whom had pathological aortographs--during the course of the investigation revealed only one case of thrombosis. This baby was considered to have died as a direct result of a thrombotic complication. In our experience the clinical signs of vascular complications and evaluation of the peripheral circulation in the ipsilateral leg remain the most important ways of assessing the indication for catheter-withdrawal.


Network analysis dataset of system dynamics models.
This paper presents a tool developed for the analysis of networks extracted from system dynamics models. The developed tool and the collected models were used and analyzed in the research paper, Review and structural analysis of system dynamics models in sustainability science [1]. The models developed in Vensim, Stella, and InsightMaker are converted into networks of state-variables, flows, and parameters by the developed Python program that also performs model reduction, modularity analysis and calculates the structural properties of the models and its main variables. The dataset covers the results of the analysis of nine models in sustainability science used for policy testing, prediction and simulation.


Prediagnostic presentations of glioma in primary care: a case-control study.
Aim: This study aimed to assess the prevalence of symptoms glioma patients may present with to the general practitioner, and whether these can be distinguished from patients with other CNS disorders or any other condition. Methods: Glioma patients were matched to CNS patients and 'other controls' using anonymized general practitioner registries. Prevalences were evaluated in the 5 years prior to diagnosis. Result: CNS patients reported significantly more motor symptoms in the period 60-24 months, (p = 0.039). Moreover, <6 months before diagnosis CNS patients differed significantly in mood disorders/fear compared with 'other controls' (p = 0.012) but not glioma patients (p = 0.816). Conclusion: Glioma patients could not be distinguished from both control groups with respect to the number or type of prediagnostic symptoms.


[Imagined exposure as treatment of catastrophizing in fibromyalgia: a pilot study].
We want to assess the effectiveness of a new approach (imagined exposure) for the Cognitive Behavioural Treatment (CBT) in fibromyalgia. Quasi-experimental design of a temporary nature in a single group with pre and post and with/without treatment. Fibromyalgia (FM) patients, who met the American College of Rheumatology's criteria for FM. In this study eight people took part, seven females and one male, selected from FM Cantabria Association. The CBT consisted of 11 group sessions and lasted 15 weeks. All patients were evaluated before and after the program. The data were based on the following scales: visual-analog scale (VAS) for pain intensity, the Fibromyalgia Impact Questionnaire (FIQ), the Pain Catastrophizing Scale (PCS) and the Hospital Anxiety and Depression Scale (HADS). Despite finding improvements in every variable, no significant differences were found between pre and postreatment in VAS, HADS and FIQ. However, after treatment, significant differences were found in PCS (p 0.05), and its three subscales. Moreover, rate decrease in rumination was higher after imagined exposure. These results suggest that CBT is effective either in catastrophizing decreasing or in rumination. Imagined exposure may enhance the results in particular cases. Further studies with larger samples are needed to confirm these results.


Urgent Neurosurgical Interventions in the COVID-19-Positive Pediatric Population.
Urgent neurosurgical interventions for pediatric patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are rare. These cases pose additional stress on a potentially vulnerable dysregulated inflammatory response that can place the child at risk of further clinical deterioration. Our aim was to describe the perioperative course of SARS-CoV-2-positive pediatric patients who had required an urgent neurosurgical intervention. We retrospectively analyzed pediatric patients aged ≤18 years who had been admitted to a quaternary children's hospital with a positive polymerase chain reaction test result for SARS-CoV-2 virus from March 2020 to October 2021. The clinical characteristics, anesthetic and neurosurgical operative details, surgical outcomes, and non-neurological symptoms were collected and analyzed. We identified 8 SARS-CoV-2-positive patients with a mean age of 8.83 years (median, 8.5 years; range, 0.58-18 years). Of the 8 patients, 6 were male. All children had had mild or asymptomatic coronavirus disease 2109. The anesthetic and surgical courses for these patients were, overall, uncomplicated. All the patients had been admitted to a specialized isolation unit in the pediatric intensive care unit for cardiopulmonary and neurological monitoring. The use of increased protective personal equipment during anesthesia and surgery did not impede a successful neurosurgical operation. SARS-CoV-2-positive pediatric patients with minimal coronavirus disease 2019-related symptoms who require urgent neurosurgical interventions face unique challenges regarding their anesthetic status, operative delays due to SARS-CoV-2 polymerase chain reaction testing, and requirements for additional protective personal equipment. Despite these clinical challenges, the patients in our study had not experienced adverse postoperative consequences, and no healthcare professional involved in their care had contracted the virus.


Androgens, health and sexuality in women and men.
The importance of good sexual function for individuals is well recognised. Testosterone is contributory to a healthy sex life for both women and men. The British Society for Sexual Medicine (BSSM) has initiated and led the development of these guidelines for the assessment of testosterone deficiency in both women and men, for use within the UK and beyond. Clinical awareness of the possibility of testosterone deficiency and the impact this may have on an individual's sexual and somatic function and the need to make sufficient enquiry about the sex life of patients attending a broad spectrum of clinical services is emphasised. The management of testosterone deficiency is outlined in detail for both women and men.


Read-Based Phasing and Analysis of Phased Variants with WhatsHap.
WhatsHap is a command-line tool for phasing and phasing-related tasks. It allows to infer haplotypes in diploid and polyploid samples based on (preferably long) reads covering at least two heterozygous variants. It offers additional tools for working with phased variant calls such as computing statistics, comparing different phasings and assigning reads in alignment files to their haplotype.


Blastocyst development after fertilization with in vitro spermatids derived from nonhuman primate embryonic stem cells.
To demonstrate that functional spermatids can be derived in vitro from nonhuman primate pluripotent stem cells. Green fluorescent protein-labeled, rhesus macaque nonhuman primate embryonic stem cells (nhpESCs) were differentiated into advanced male germ cell lineages using a modified serum-free spermatogonial stem cell culture medium. In vitro-derived round spermatid-like cells (rSLCs) from differentiated nhpESCs were assessed for their ability to fertilize rhesus oocytes by intracytoplasmic sperm(atid) injection. Multiple academic laboratory settings. Not applicable. Intracytoplasmic sperm(atid) injection of in vitro-derived spermatids from nhpESCs into rhesus macaque oocytes. Differentiation into spermatogenic cell lineages was measured through multiple assessments including ribonucleic acid sequencing and immunocytochemistry for various spermatogenic markers. In vitro spermatids were assessed for their ability to fertilize oocytes by intracytoplasmic sperm(atid) injection by assessing early fertilization events such as spermatid deoxyribonucleic acid decondensation and pronucleus formation/apposition. Preimplantation embryo development from the one-cell zygote stage to the blastocyst stage was also assessed. Nonhuman primate embryonic stem cells can be differentiated into advanced germ cell lineages, including haploid rSLCs. These rSLCs undergo deoxyribonucleic acid decondensation and pronucleus formation/apposition when microinjected into rhesus macaque mature oocytes, which, after artificial activation and coinjection of ten-eleven translocation 3 protein, undergo embryonic divisions with approximately 12% developing successfully into expanded blastocysts. This work demonstrates that rSLCs, generated in vitro from primate pluripotent stem cells, mimic many of the capabilities of in vivo round spermatids and perform events essential for preimplantation development. To our knowledge, this work represents, for the first time, that functional spermatid-like cells can be derived in vitro from primate pluripotent stem cells.


A Simple and Rapid Fluorescent Probe for Detection of Cr3+ Based on a Coumarin Schiff Base in Aqueous Solution.
A new Cr3+ probe was synthesized using simple Schiff base reaction, which showed prominent fluorescence increasing switch before and after addition Cr3+. The probe proved to have excellent properties, based on both UV-vis absorption and fluorescence spectra. Those properties included high switching performance, good selectivity, and small interference with other metal ions. The fluorescent change mechanism of the probe was attributed to the combined action between the restricted C=N isomerization and the suppression of highly efficient photo-induced electron transfer (PET) process. Moreover, this fluorescence probe for Cr3+ detection also has great potential for bioimaging of cancer cells.


Efficacy of Andrographis paniculata extract treatment in mild to moderate COVID-19 patients being treated with favipiravir: A double-blind, randomized, placebo-controlled study (APFaVi trial).
While favipiravir had been the standard anti-SARS-CoV-3 drug for COVID-19 treatment in Thailand, the efficacy of favipiravir treatment is controversial. Andrographis paniculata extract (APE) inhibits viral entry, exhibits immunomodulatory effects, and proposes to have the potential for early-stage COVID-19 treatment. A randomized, double-blind, placebo-controlled trial was performed in Thailand during June - September 2021. Non-severe COVID-19 patients were randomized 1:1 to groups receiving 180 mg/day of APE plus favipiravir (APE-FPV group) or placebo plus favipiravir (placebo-FPV group). Efficacy in preventing disease progression to severe COVID-19 was assessed on day 4, using World Health Organization Clinical Progression Scale (WHOCPS) score and visual analog scale (VAS) for acute respiratory tract infection symptoms. Of 146 patients, there were 73 patients in each group. Non-deterioration of WHOCPS scores on day 4 was 98.63% versus 97.26% of patients in the APE-FPV and placebo-FPV groups (p = 1.000). No difference in supplemental oxygen, hospitalization, and death was shown in both groups. The oxygen supplemental was 4.11% in the placebo-FPV group. The interleukin (IL)-1β was significantly lower in the APE than in the placebo-FPV group throughout the study. We found no difference in virologic outcomes between groups and no substantial adverse events. APE treatment did not demonstrate additional clinical and virological benefits in patients with mild to moderate COVID-19 being treated with favipiravir. Early reduction of IL-1β with APE may be advantageous in preventing cytokine storms in severe COVID-19 and requires further study.


Phase II study of 4'-(9-acridinylamino) methanesulfon-m- anisidide (AMSA) in metastatic melanoma.
A phase II study of AMSA in previously treated patients with metastatic malignant melanoma was conducted. The dose schedule of AMSA was 40 mg/m2/day for 3 days repeated at 3-week intervals. Among the 30 evaluable patients, one achieved a complete response, one a partial response, and four had minor responses. Side effects included mild nausea and vomiting and moderate degree of myelosuppression. AMSA has poor activity against previously treated metastatic melanoma.


Differential constitutive expression of interferon genes in early mouse embryos.
Recent evidence suggests that several processes during mammalian embryogenesis may be regulated by IFNs or IFN-like molecules. With the use of MAPPing, the simultaneous presence of transcripts homologous to IFN-alpha, IFN-beta, IRF-1, and IRF-2 was examined in mouse embryos and in embryonal carcinoma (EC) P19 cells, which are equivalent to epiblast cells of the early postimplantation blastocysts. Transcripts for IFN-alpha, but not for IFN-beta, were detected as maternal transcripts in the ovulated oocyte and persisted over early embryogenesis. IRF-1 transcripts appeared only after the first cell cleavage in the two-cell stage embryo. IRF-2 transcripts were analyzed only in EC P19 cells and were found in both undifferentiated (D-) and differentiated (D+) cells. The IFN-alpha transcripts present in (D-) P19 cells were cloned and the partial cDNA sequences determined. Mu IFN-alpha A and a new Mu IFN-alpha species (Mu IFN-alpha 12) were isolated from (D-) P19 cells. The presence of constitutive IFN-alpha transcripts in early mouse embryos suggests a role for these molecules during embryogenesis.


Clopidogrel Resistance Increases Rate of Recurrent Stroke and Other Vascular Events in Chinese Population.
Research regarding clopidogrel resistance (CR) and ischemic stroke (IS) recurrence related to IS is scanty. The aim of the present study was to determine the incidence of CR and the association between CR and IS recurrence and other vascular events in patients with IS receiving clopidogrel. CR was assessed by platelet aggregation assay in 535 IS patients receiving clopidogrel. All patients continued taking clopidogrel after discharge and were followed up for 6 months. The primary outcome was a composite of recurrent ischemic stroke (RIS), myocardial infarction, and death. The secondary outcome was the degree of disability as measured by modified Rankin Scale (mRS). Out of 535 IS patients, 208 (38.88%) were CR and 327 (61.12%) were clopidogrel sensitive (CS). Diabetes was independently associated with risk of CR (odds ratio: 2.42, 95% confidence interval [CI], 1.22-4.97, P <.01). During the follow-up period, the incidence of ischemic vascular events was higher in the CR group than in the CS group; the proportion of patients with mRS score of 0-2 points at 6 months was significantly lower in CR group than in CS group. CR (hazard ratio [HR]: 2.82, 95% CI, 1.23-6.94, P <.01), diabetes (HR: 1.61, 95% CI, 1.01-3.49, P = .02), and hypertension (HR: 1.84, 95% CI, 1.12-4.72, P = .03) were independent risk factors for ischemic vascular events. The incidence of CR in IS patients taking clopidogrel is relatively high in the Chinese population. CR is associated with ischemic vascular events, including RIS, and poor neurological recovery.


Tear fluid electrolytes and albumin in persons under environmental stress.
Sixty-two subjects selected among 287 persons with indoor air complaints were exposed to a standard mixture of 22 different organic gases and vapors normally found in Danish houses. Persons were randomly assigned to one of four exposure groups, and each subject stayed during the test day from 10:00 AM to 4:00 PM under standardized conditions in a climate chamber. During exposure the blink frequency was recorded, and after exposure the tear fluid contents of serum albumin, potassium, and sodium were measured. It was found that the persons had an increased concentration of serum albumin in the tear fluid, and that exposure to high concentrations of organic gases and vapors induced a tear reflex-mediated dilution of the tears.


Expression of an anti apoptotic recombinant short peptide in mammalian cells.
Understanding the mechanisms of the apoptotic and anti apoptotic processes may lead to a better way to control these cascades. Here we demonstrated for the first time the feasibility to express a short functional peptide in mammalian cells that abrogates the apoptosis cascade through interference with the proteolytic activity of the initiator caspase 9 and the executing caspase 3 enzymes. The expression of a short peptide that includes the pseudo-substrate motif of the apoptosis inhibitor protein P35 (Asp-Gln-Met-Asp) leads to the abrogation of cell death induced through either the mitochondrial or the death receptors pathways. Short open reading frames have been detected in several mammalian mRNAs, primarily upstream of the main long reading frame (uORFs), however, direct evidence for de-novo peptides translation has not been provided. Utilizing biochemical and imaging techniques we demonstrate here that the functional recombinant peptide was localized to the cytpoplasmic fraction of the cell. In conclusion, this work demonstrates that ribosomes recognize short ORFs to translate stable short recombinant peptides in mammalian cells. Expression of these intracellular peptides results in the knock down of apoptotic processes to generate apoptosis resistant stable cells.


Topological data analysis to identify cardiac resynchronization therapy patients exhibiting benefit from an implantable cardioverter-defibrillator.
Current guidelines recommend considering multiple factors while deciding between cardiac resynchronization therapy with a defibrillator (CRT-D) or a pacemaker (CRT-P). Nevertheless, it is still challenging to pinpoint those candidates who will benefit from choosing a CRT-D device in terms of survival. We aimed to use topological data analysis (TDA) to identify phenogroups of CRT patients in whom CRT-D is associated with better survival than CRT-P. We included 2603 patients who underwent CRT-D (54%) or CRT-P (46%) implantation at Semmelweis University between 2000 and 2018. The primary endpoint was all-cause mortality. We applied TDA to create a patient similarity network using 25 clinical features. Then, we identified multiple phenogroups in the generated network and compared the groups' clinical characteristics and survival. Five- and 10-year mortality were 43 (40-46)% and 71 (67-74)% in patients with CRT-D and 48 (45-50)% and 71 (68-74)% in those with CRT-P, respectively. TDA created a circular network in which we could delineate five phenogroups showing distinct patterns of clinical characteristics and outcomes. Three phenogroups (1, 2, and 3) included almost exclusively patients with non-ischemic etiology, whereas the other two phenogroups (4 and 5) predominantly comprised ischemic patients. Interestingly, only in phenogroups 2 and 5 were CRT-D associated with better survival than CRT-P (adjusted hazard ratio 0.61 [0.47-0.80], p < 0.001 and adjusted hazard ratio 0.84 [0.71-0.99], p = 0.033, respectively). By simultaneously evaluating various clinical features, TDA may identify patients with either ischemic or non-ischemic etiology who will most likely benefit from the implantation of a CRT-D instead of a CRT-P. Topological data analysis to identify phenogroups of CRT patients in whom CRT-D is associated with better survival than CRT-P. AF atrial fibrillation, CRT cardiac resynchronization therapy, CRT-D cardiac resynchronization therapy defibrillator, CRT-P cardiac resynchronization therapy pacemaker, DM diabetes mellitus, HTN hypertension, LBBB left bundle branch block, LVEF left ventricular ejection fraction, MDS multidimensional scaling, MRA mineralocorticoid receptor antagonist, NYHA New York Heart Association.


Generation of hiPSC line TCIERi001-A from normal human epidermal keratinocytes.
Human induced pluripotent stem cell (hiPSC) line TCIERi001-A was generated from normal human epidermal keratinocytes (NHEK) primary cell line with the nonintegrating system using Sendai reprogramming kit. Sendai particles were used to deliver the defined transcription factors that included three vector preparations, such as polycistronic KLF4-OCT3/4-SOX2, cMYC, and KLF4.


Willingness to quit alcohol use and its associated factors among male outpatients attending urban primary health centers in Delhi.
Harmful use of alcohol has led to 1.7 million deaths from noncommunicable diseases and 1 million injury deaths including road traffic accidents, self-harm, and interpersonal violence. The opportunistic screening can be used to screen for substance abuse in outpatient department (OPD) attendees of primary health-care (PHC) settings in India. This study was conducted to determine the prevalence of willingness to quit alcohol use among alcohol users and factors associated with it. A facility-based cross-sectional study was conducted in urban PHCs and willingness to quit alcohol was assessed among the alcohol users. Alcohol Use Disorder Identification Test (AUDIT) scale was used to assess the alcohol use disorder score. Data were entered using Epidata version 3.1 and analyzed using STATA version 14. It is found that two-third of the male OPD patients are using alcohol and 59% of the alcohol users were willing to quit alcohol. Education (adjusted prevalence rate ratio [aPR] = 1.9; 95% confidence interval [CI]: 1.2-2.9), occupation (aPR = 1.4; 95% CI: 1.1-1.8), higher AUDIT scores (aPR = 2.7; 95% CI: 2.2-3.5), frequency of alcohol use (aPR = 1.6; 95% CI: 1.2-2.0), and positive family history of alcohol-related illness times (aPR = 1.6; 95% CI: 1.3-2.0) were significantly associated with willingness to quit alcohol. Two-third of the male OPD patients are using alcohol and 59% of the alcohol users were willing to quit alcohol. Education, occupation, higher AUDIT scores, frequency of alcohol use, and positive family history of alcohol-related illness were significantly associated with willingness to quit alcohol.


The risk of overestimating cost savings from hospital-at-home schemes: A literature review.
The concept of hospital-at-home means that home treatment is provided to patients who would otherwise have been treated in the hospital. This may lead to lower costs, but estimates of savings may be overstated if inpatient hospital costs are priced incorrectly. The objective of this study was to evaluate the quality of cost analyses of hospital-at-home studies for acute conditions published from 1996 through 2019 and to present an overview of evidence. Literature review DATA SOURCES: The PubMed and NHS EED databases were searched. The overall quality of studies was evaluated based on Quality of Health Economic Studies (QHES) score, design, sample size, alignment of cost calculation with study perspective, time horizon, use of tariffs or real resource use and clarity of calculations. Furthermore, we systematically assessed whether cost savings were likely to be overestimated, based on criteria about the costing of inpatient hospital days, informal care costs and bias. We identified 48 studies. The average QHES score was 60 out of a maximum of 100 points. Almost all studies violated one or more criteria for the risk of overestimation of cost savings. The most frequent problems were the use of average unit prices per inpatient day (not taking into account the decreasing intensity of care) and biased designs. Most studies found cost differences in favour of hospital-at-home; the range varied from savings of €8773 to a cost increase of €2316 per patient. Overall quality of studies was not good, with some exceptions. Many cost savings were probably overestimated.


Phonological acquisition of Brazilian Portuguese: Ages of customary production, acquisition and mastery.
AIMS: To describe typical phonological development of Brazilian Portuguese (BP)-speaking children, considering the following parameters: age of customary production, acquisition and mastery. Data were collected from 857 children aged between 3 years and 8 years 11 months with typical language and speech development. The sample was grouped into 6-month age bands. The data were analysed using one-way analysis of variance (ANOVA) followed by Games-Howell post-hoc tests. Stops (/p, b, t, d, k, g/), nasals (/m, n, ɲ/) and some fricatives (/f, v, s, z/) were mastered before the age of 3 years (age of mastery). The age of acquisition for phonemes /ʃ, ʒ/ was 3;6, though both were only mastered at 4;0 years. The liquid /l/ was acquired at 3;0 and mastered at age 3;6, while /x/ was acquired and mastered at age 3;6. The phoneme /ʎ/ was acquired at 7;0 and mastered at age 8;6. The tap /ɾ/ was acquired between the ages of 4;0 and 4;6, and mastered at 4;6. In coda position, /n, l/ were acquired at 3;0, while /s/ was mastered at 4;6 and /ɾ/ between 4;6 and 5;0 years. Clusters involving /ɾ/ were acquired at 6;0, while those with /l/ were acquired between the ages of 6;6 and 7;0. This study presented acquisition for consonants in BP and can be used as a reference for the assessment of developmental speech disorders. In this study, stops and nasals were acquired first, followed by fricatives and, lastly, liquids. This finding is corroborated by previous studies in BP and other languages. What is already known on the subject What this paper adds to existing knowledge What are the potential or actual clinical implications of this work?


Trunk Control Test as a Main Predictor of the Modified Barthel Index Score at Discharge From Intensive Post-acute Stroke Rehabilitation: Results From a Multicenter Italian Study.
To verify whether trunk control test (TCT) upon admission to intensive inpatient post-stroke rehabilitation, combined with other confounding variables, is independently associated with discharge mBI. Multicentric retrospective observational cohort study. Two Italian inpatient rehabilitation units. A total of 220 post-stroke adult patients, within 30 days from the acute event, were consecutively enrolled. Not applicable. The outcome measure considered was the modified Barthel Index (mBI), one of the most widely recommended tools for assessing stroke rehabilitation functional outcomes. All variables collected at admission and significantly associated with mBI at discharge in the univariate analysis (TCT, mBI at admission, pre-stroke modified Rankin Scale [mRS], sex, age, communication ability, time from the event, Cumulative Illness Rating Scale, bladder catheter, and pressure ulcers) entered the multivariate analysis. TCT, mBI at admission, premorbid disability (mRS), communication ability and pressure ulcers (P<.001) independently predicted discharge mBI (adjusted R2=68.5%). Concerning the role of TCT, the model with all covariates and without TCT presented an R2 of 65.1%. On the other side, the model with the TCT only presented an R2 of 53.1%. Finally, with the inclusion of both TCT and all covariates, the model showed an R2 increase up to 68.5%. TCT, with other features suggesting functional/clinical complexity, collected upon admission to post-acute intensive inpatient stroke rehabilitation, independently predicted discharge mBI.


TNF inhibits insulin induced STAT5 activation in differentiated mouse muscle cells pmi28.
Tumor necrosis factor (TNF) plays a central role in the state of insulin resistance leading to type II diabetes. We here describe the crosstalk of TNF with insulin signaling cascades in the mouse muscle cell line pmi28. TNF downregulated insulin induced insulin receptor kinase activity and insulin induced activation of the transcription factor STAT5. Our results provide evidence that the inhibitory crosstalk between TNF and insulin in skeletal muscle cells comprises an interference with the expression of STAT5 regulated genes which may play an important role in the manifestation and/or progression of insulin resistance in muscle cells.


Segmental stiff skin syndrome (SSS): A distinct clinical entity.
Stiff skin syndrome (SSS) is a noninflammatory, fibrosing condition of the skin, often affecting the limb girdles. We present 4 new patients with SSS with largely unilateral, segmental distribution. To date, reported cases of SSS have been grouped based on generally accepted clinical and histopathologic findings. The purpose of this study was to analyze differences in clinical and histopathologic findings between previously reported SSS cases. This is a retrospective review of 4 new cases and 48 previously published cases of SSS obtained from PubMed search. Of 52 total cases, 18 (35%) were segmentally distributed and 34 (65%) were widespread. The average age of onset was 4.1 years versus 1.6 years for segmental versus widespread SSS, respectively. Limitation in joint mobility affected 44% of patients with segmental SSS and 97% of patients with widespread SSS. Histopathologic findings were common between the 2 groups. This was a retrospective study of previously published cases limited by the completeness and accuracy of the reviewed cases. We propose a distinct clinical entity, segmental SSS, characterized by a segmental distribution, later age of onset, and less severe functional limitation. Both segmental SSS and widespread SSS share common diagnostic histopathologic features.


Bidirectional association between diabetic peripheral neuropathy and vitamin B12 deficiency: Two longitudinal 9-year follow-up studies using a national sample cohort.
This study aims to investigate the association among metformin use, vit B12 deficiency, and DPN occurrence in diabetes. This retrospective, propensity-matched cohort study was performed using National Health Insurance Service database - National Sample Cohort in South Korea. Study 1 analyzed DPN incidence according to vit B12 deficiency and study 2 analyzed vit B12 deficiency incidence according to the presence/absence of DPN. Moreover, we compared the results with respect to metformin use. In study 1, DPN incidence per 10000 person-year (PY) was 179.7 and 76.6 in the vit B12 and non-vit B12 deficiency groups, respectively. The adjusted HR was 1.32 (95% CI; 1.21-1.44, P < 0.05) and metformin use elicited a more significant effect of DPN occurrence in patient with vit B12 deficiency (HR: 5.76 (95% CI; 5.28-6.29). In study 2, vit B12 deficiency incidence per 10000 PY was 250.6 and 129.4 in the DPN and non-DPN groups, respectively. The adjusted HR was 2.44 (95% CI; 2.24-2.66, P < 0.05), however, metformin prescription was associated with the reduced incidence of vit B12 deficiency in DPN patients (HR 0.68 (95% CI; 0.62-0.74, P < 0.05). DPN occurrence increased in diabetes with vit B12 deficiency and the incidence of vit B12 deficiency was also high in DPN patients. However, metformin showed opposite effects in both cohorts. Further studies clarifying the causal relationship among DPN occurrence, vit B12 deficiency, and metformin use are warranted.


Pathology of myxomatous mitral valve disease in the dog.
Mitral valve competence requires complex interplay between structures that comprise the mitral apparatus - the mitral annulus, mitral valve leaflets, chordae tendineae, papillary muscles, and left atrial and left ventricular myocardium. Myxomatous mitral valve degeneration is prevalent in the canine, and most adult dogs develop some degree of mitral valve disease as they age, highlighting the apparent vulnerability of canine heart valves to injury. Myxomatous valvular remodeling is associated with characteristic histopathologic features. Changes include expansion of extracellular matrix with glycosaminoglycans and proteoglycans; valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fibrosa layer. These lead to malformation of the mitral apparatus, biomechanical dysfunction, and mitral incompetence. Mitral regurgitation is the most common manifestation of myxomatous valve disease and in advanced stages, associated volume overload promotes progressive valvular regurgitation, left atrial and left ventricular remodeling, atrial tears, chordal rupture, and congestive heart failure. Future studies are necessary to identify clinical-pathologic correlates that track disease severity and progression, detect valve dysfunction, and facilitate risk stratification. It remains unresolved whether, or to what extent, the pathobiology of myxomatous mitral valve degeneration is the same between breeds of dogs, between canines and humans, and how these features are related to aging and genetics.


Quantitative assessment data of PAHs and N-PAHs in core sediments from the Niger Delta, Nigeria.
Polycyclic aromatic compounds (PACs) pollution has been the focus of environmental research, mostly due to their mutagenicity, carcinogenicity, teratogenicity and genotoxicity. Concentrations of polycyclic aromatic hydrocarbons (PAHs) and the nitrogen-containing analogues (N-PAHs) (which tend to accumulate in sediments rather than water) was measured in 2 cm intervals segments from Bonny Estuary, Niger Delta using GC-MS. Data showed that PAHs/N-PAHs levels ranged from 8699 to 22,528 µg/kg and 503-2020 µg/kg, respectively. Furthermore, the data revealed that ƩPAHs level in the estuarine segments was > 45% higher than DPR/EGASPIN intervention limit. This gives insight on PAHs/N-PAHs contamination in the oil rich region.


Surgical bypass for subclavian vein occlusion in hemodialysis patients.
The majority of patients with end-stage renal disease are dependent on hemodialysis. Significant stenosis or occlusion of the subclavian vein is known to occur in 20% to 50% of patients who have had central venous catheters inserted into the subclavian vein or the internal jugular vein. Surgical bypass of the obstructed venous segment proximal to a functioning dialysis access site is an established treatment to relieve symptoms and salvage the functional dialysis access. A retrospective review of all subclavian venous bypass procedures performed at St Louis University Hospital from May 1987 to May 2000 was undertaken. Twelve procedures were performed during this time. The mean age of the patient was 55.5 years (range 17 to 72 years). There were 11 men and 1 woman. Before surgical bypass, all patients underwent bilateral venograms to evaluate their central venous systems. An extraanatomic surgical bypass was performed in all patients. Patients were followed for a mean of 16 months (range 1 to 79 months). At 1 month, 100% of hemodialysis access sites remained functional. At 1 year, 80%; 2 years, 60%; and 3 years, 25% of the salvaged arteriovenous hemodialysis access sites provided for functional dialysis. One patient required thrombectomy of the bypass graft at 14 months. Surgical bypass of an occluded or stenotic subclavian vein segment is successful in providing both symptomatic relief and salvage of a functioning dialysis access in the hemodialysis patient population. Study of the central venous system is essential in selecting an appropriate bypass procedure in individual patients.