A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction.
The solute carrier and presynaptic vesicle protein solute carrier family 10 member 4, or vesicular aminergic-associated transporter (VAAT), was recently proven to have a modulatory role in central cholinergic signalling. It is currently unknown whether VAAT also affects peripheral cholinergic synapses. Here we demonstrated a regulatory role for the presynaptic vesicle protein VAAT in neuromuscular junction (NMJ) development and function. NMJs lacking VAAT had fewer branch points, whereas endplates showed an increased number of islands. Whereas the amplitude of spontaneous miniature endplate potentials in VAAT-deficient NMJs was decreased, the amplitude of evoked endplate potentials and the size of the readily releasable pool of vesicles were both increased. Moreover, VAAT-deficient NMJs displayed aberrant short-term synaptic plasticity with enhanced synaptic depression in response to high-frequency stimulation. Finally, the transcript levels of cholinergic receptor subunits in VAAT-deficient muscles were increased, indicating a compensatory postsynaptic sensitization. Our results suggested that VAAT modulates NMJ transmission efficiency and, as such, may represent a novel target for treatment of disorders affecting motor neurons.


Statins' Effect on Cognitive Outcome After Traumatic Brain Injury: A Systematic Review.
Traumatic brain injury (TBI), also known as the "Silent Epidemic," is a growing devastating global health problem estimated to affect millions of individuals yearly worldwide with little public recognition, leading to many individuals living with a TBI-related disability. TBI has been associated with up to five times increase in the risk of dementia among multiple neurologic complications compared with the general population. Several therapies, including statins, have been tried and showed promising benefits for TBI patients. In this systematic review, we evaluated the recent literature that tested the role of statins on neurological and cognitive outcomes such as Alzheimer's Disease and non-Alzheimer's dementia in survivors of TBI with various severities. We conducted a systematic search on PubMed, PubMed Central, MEDLINE, and Google Scholar. MeSH terms and keywords were used to search for full-text randomized clinical trials (RCTs), cross-sectional, case-control, cohort studies, systematic reviews, and animal studies published in English. Inclusion and exclusion criteria were applied, and the articles were subjected to quality appraisal by two reviewers. Our data search retrieved 4948 nonduplicate records. A total of 18 studies were included - nine human studies, and nine animal laboratory trials - after meeting inclusion, eligibility, and quality assessment criteria. Simvastatin was the most tested statin, and the oral route of administration was the most used. Eight human studies showed a significant neuroprotective effect and improvement in the cognitive outcomes, including dementia. Four randomized clinical trials with 296 patients showed that statins play a neuroprotective role and improve cognitive outcomes through different mechanisms, especially their anti-inflammatory effect; they were shown to lower tumor necrosis factor (TNF)-α and C-reactive protein (CRP) levels. Also, they decreased axonal injury and cortical thickness changes. In addition, four cohort studies compared a total of 867.953 patients. One study showed a decrease in mortality in statin-treated patients (p=0.05). Another study showed a reduction in the incidence of Alzheimer's disease and related dementias (RR, 0.77; 95% CI, 0.73-0.81), while one study showed a decreased risk of dementia after concussions by 6.13% (p=0.001). On the other hand, one cohort study showed no significant difference with the use of statins. In eight animal trials, statins showed a significant neuroprotective effect, improved cognitive outcomes, and neurological functions. Different molecular and cellular mechanisms were suggested, including anti-inflammatory effects, promoting angiogenesis, neurogenesis, increasing cerebral blood flow, neurite outgrowth, promoting the proliferation and differentiation of neural stem cells, and reducing axonal injury. On the contrary, one study showed no benefit and actual adverse effect on the cognitive outcome. Most of the studies showed promising neuroprotective effects of statins in TBI patients. Cognitive outcomes, especially dementia, were improved. However, the optimal therapeutic protocol is still unknown. Thus, statins are candidates for more advanced studies to test their efficacy in preventing cognitive decline in patients with TBI.


HPV genotyping and p16÷Ki-67 dual staining in the detection of high-grade cervical lesion in patients with LSIL on Pap smear.
p16÷Ki-67 dual-stained cytology, either alone or combined with human papillomavirus (HPV) 16÷18 genotyping, could be a useful tool for triage for colposcopy of HPV-positive patients. Based on this background, we aimed at comparing the diagnostic performance of the p16÷Ki-67 dual staining test, and high-risk HPV test for the detection of high-risk cervical intraepithelial neoplasia (CIN2÷3) in patients diagnosed with low-grade squamous intraepithelial lesion (LSIL) on Pap smear. We performed a retrospective study including 184 patients with LSIL cytology on Pap smear, of which 64 were referred for biopsy after colposcopy. Prior biopsy HPV genotyping and dual staining test were performed on all 64 patients. The mean age of the patients selected for conization was 36 years and seven months. The pathological exam showed that 28.13% (18÷64) from the patients LSIL on cytology were actually having CIN2÷3: 12 cases with CIN2, five cases with CIN3 and one case of in situ cervical carcinoma. HPV positive were 56.25% (36÷64) of the patients with LSIL. The p16÷Ki-67 dual staining test was positive in 29.69% (19÷64) of the patients with LSIL. Among women with LSIL cytology, the sensitivity and specificity of the HPV genotyping test for predicting CIN2÷CIN3 were 94.44% (17÷18) and 58.7% (27÷46), respectively. The sensitivity and specificity of the p16÷Ki-67 dual staining test were 66.67% (12÷18) and 84.78% (39÷46), respectively. Our results agree with other data available in literature and suggest that the p16÷Ki-67 dual staining test could be included in the management protocol of patients with modified cytology as a triage test before referring those patients for colposcopy.


Long-term Outcome of Pulmonary Vein Isolation Versus Amiodarone Therapy in Patients with Coexistent Persistent AF and Congestive Heart Failure.
Although pharmacological rhythm control of AF in patients with heart failure with reduced ejection fraction (HFrEF) does not seem to provide any benefit over rate control, catheter ablation of AF has been shown to improve clinical outcomes. These results can be explained with higher success rates of catheter ablation in restoring and maintaining sinus rhythm compared with antiarrhythmic drugs. In addition, pharmacotherapy is not void of side-effects, which are thought to offset its potential antiarrhythmic benefits. Therefore, efforts should be made towards optimisation of ablation techniques for AF in patients with HFrEF.


ChatGPT-4: An assessment of an upgraded artificial intelligence chatbot in the United States Medical Licensing Examination.
Purpose: ChatGPT-4 is an upgraded version of an artificial intelligence chatbot. The performance of ChatGPT-4 on the United States Medical Licensing Examination (USMLE) has not been independently characterized. We aimed to assess the performance of ChatGPT-4 at responding to USMLE Step 1, Step 2CK, and Step 3 practice questions.Method: Practice multiple-choice questions for the USMLE Step 1, Step 2CK, and Step 3 were compiled. Of 376 available questions, 319 (85%) were analyzed by ChatGPT-4 on March 21st, 2023. Our primary outcome was the performance of ChatGPT-4 for the practice USMLE Step 1, Step 2CK, and Step 3 examinations, measured as the proportion of multiple-choice questions answered correctly. Our secondary outcomes were the mean length of questions and responses provided by ChatGPT-4.Results: ChatGPT-4 responded to 319 text-based multiple-choice questions from USMLE practice test material. ChatGPT-4 answered 82 of 93 (88%) questions correctly on USMLE Step 1, 91 of 106 (86%) on Step 2CK, and 108 of 120 (90%) on Step 3. ChatGPT-4 provided explanations for all questions. ChatGPT-4 spent 30.8 ± 11.8 s on average responding to practice questions for USMLE Step 1, 23.0 ± 9.4 s per question for Step 2CK, and 23.1 ± 8.3 s per question for Step 3. The mean length of practice USMLE multiple-choice questions that were answered correctly and incorrectly by ChatGPT-4 was similar (difference = 17.48 characters, SE = 59.75, 95%CI = [-100.09,135.04], t = 0.29, p = 0.77). The mean length of ChatGPT-4's correct responses to practice questions was significantly shorter than the mean length of incorrect responses (difference = 79.58 characters, SE = 35.42, 95%CI = [9.89,149.28], t = 2.25, p = 0.03).Conclusions: ChatGPT-4 answered a remarkably high proportion of practice questions correctly for USMLE examinations. ChatGPT-4 performed substantially better at USMLE practice questions than previous models of the same AI chatbot.


Drug use among young people in Lagos, Nigeria.
This paper presents the results of two studies on drug abuse carried out among young people. One study included a sample of 2,846 pupils from 17 secondary schools in Lagos, the other 300 patients admitted to the Lagos University Teaching Hospital for treatment of drug abuse. Among the secondary school students the major substances used were alcohol, barbiturates, central nervous system stimulants, tobacco, Mandrax and cannabis. The majority of hospital patients treated for drug abuse were cannabis users.


The influence of patients' immigration background and residence permit status on treatment decisions in health care. Results of a factorial survey among general practitioners in Switzerland.
This study examines the influence of patients' immigration background and residence permit status on physicians' willingness to treat patients in due time. A factorial survey was conducted among 352 general practitioners with a background in internal medicine in a German-speaking region in Switzerland. Participants expressed their self-rating (SR) as well as the expected colleague-rating (CR) to provide immediate treatment to 12 fictive vignette patients. The effects of the vignette variables were analysed using random-effects models. The results show that SR as well as CR was not only influenced by the medical condition or the physicians' time pressure, but also by social factors such as the ethnicity and migration history, the residence permit status, and the economic condition of the patients. Our findings can be useful for the development of adequate, practically relevant teaching and training materials with the ultimate aim to reduce unjustified discrimination or social rationing in health care.


Role of exogenous interferons on intrinsic antiviral activity of macrophages from patients affected by neoplasia.
Macrophages derived from in vitro cultured monocytes were infected with herpes simplex virus type 2. A marked impairment in the intrinsic antiviral activity was found in macrophages obtained from patients with breast cancer or melanoma. Moreover, the antiviral activity of macrophages from healthy donors, differentiated in serum from patients with neoplasia, was also impaired. The aim of this work was the evaluation of alpha, beta, gamma exogenous interferon in restoring the intrinsic antiviral activity of macrophages from patients affected by breast cancer or melanoma under different conditions. Pretreatment of macrophages with alpha, beta interferons, but not gamma interferon, restored their impaired intrinsic antiviral activity.


Immediate TRAM flap breast reconstruction in an obese patient with relapsing benign phyllodes tumor: report of a case.
The authors present a case of relapsing benign phyllodes cystosarcoma of the breast in an obese female treated with a simple mastectomy and an immediate reconstruction using a bipedicled transverse rectus abdominis musculocutaneous (TRAM) flap. After a brief review of treatment options for phyllodes tumors, they discuss the advantages of TRAM flap breast reconstruction, suggesting that it may also be applied in obese patients.


Putting Medical Boots on the Ground: Lessons from the War in Ukraine and Applications for Future Conflict with Near-Peer Adversaries.
In the past 20 years of the Global War on Terror, the US has seen substantial improvements in its system of medical delivery in combat. However, throughout that conflict, enemy forces did not have parity with the weaponry, capability, or personnel of the US and allied forces. War against countries like China and Russia, who are considered near-peer adversaries in terms of capabilities, will challenge battlefield medical care in many different ways. This article reviews the experience of a medical team, Global Surgical and Medical Support Group, that has been providing assistance, training, medical support, and surgical support to Ukraine since the Russian invasion began in February 2022. The team has extensive experience in medicine, surgery, austere environments, conflict zones, and building partner nation capacities. This article compares and contrasts the healthcare systems of this war against the systems used during the Global War on Terror. The lessons learned here could help the US anticipate challenges and successfully plan for the provision of medical care in a future conflict against an adversary with capabilities close to its own.


Creating creativity: reflections from fieldwork.
The present article addresses the question of 'When can we say something is creative?' and, in answering it, takes a critical stand towards past and present scientific definitions of creativity. It challenges an implicit assumption in much psychological theory and research that creativity exists as an 'objective' feature of persons or products, universally recognised and independent of social agreement and cultural systems of norms and beliefs. Focusing on everyday life creative outcomes, the article includes both theoretical accounts and empirical examples from a research exploring creativity evaluations in the context of folk art. In the end, a multi-layered perspective of creativity assessment emerges, integrating dimensions such as newness and originality, value and usefulness, subjective reception and cultural reception of creative products. Implications for how we understand and study creativity are discussed.


Superior mediastinal obstruction with aortic dissection after aortic valve replacement. Diagnosis by computed tomography.
In two patients aortic dissection occurred as a late complication of aortic valve replacement and caused superior vena caval obstruction. The dissection and superior vena caval obstruction were diagnosed by computed tomography.


[Clinical analysis of pacing therapy and treatment of complications during follow-up in children].
Objective: To analyze characteristics of permanent pacemaker implantation in children as well as treatment and prognosis of complications. Method: Clinical data of children who underwent endocardial or epicardial permanent pacemaker implantation between April 2000 and June 2016 in Shanghai Xinhua Hospital and Shanghai Children's Medical Center were analyzed retrospectively. These patients were discharged 5 days after implantation. Electrocardiogram, chest X ray, echocardiography and pacemaker programming were performed during follow-up. Treatment regimes, complication management and prognosis were analyzed retrospectively. Result: Data of a total of 193 cases were collected. One hundred and six patients were male and 87 patients were female.The average age was (5.09±4.05) years(0.4-16 years)and the average weight was (20.47±11.62) kg.133(68.9%); patients were implanted with endocardial pacemakers and 60(31.1%)patients were implanted with epicardial pacemakers; 135(69.9%)patients were single-chamber paced with 87 from RVA and 48 from RVOT. fifty-eight(30.1%)patients were dual chamber paced. These included 122(63.2%)postoperative third degree AV block(Ⅲ-AVB), 38 (19.7%)congenital complete AV block (CCAVB), 3(1.6%)post ventricular septal defect (VSD) interventional therapy AV block, 23 (11.9%)sick sinus syndrome (SSS) and 7(3.6%)Ⅲ-AVB after fulminant myocarditis. One hundred and thirty-seven(71%)patients were followed up for an average duration of 5.32 years(0.3-10 years). Pacemaker exchange were performed in 46 patients due to battery exhaustion.The average life of battery was 5.4 years (1-9 years). Sixteen patients underwent lead exchange due to dislocation or separation.One patient underwent lead extraction due to recovery of AV conduction 21 days after surgery for complete transposition of great arteries (D-TGA/VSD). Skin abrasion, infection or dehiscence occured in 6 patients. Heart failure occurred in 2 patients at 6 and 8 years after implantation whose heart functions improved after switching from VVI to DDD or adding ACEI . One patient died suddenly due to ineffective pacing caused by lead fracture. Another patient under DDD pacing was found to have atrial myocardial perforation with normal sensing and pacing so that no intervention was performed. Conclusion: The pacing mode and path through which leads are implanted for permanent pacemaker implantation in children have their peculiar characteristics.Some complications might occur during follow-up with good prognosis if appropriately treated.


Antiproliferative effect of benzimidazole anthelmintics albendazole, ricobendazole, and flubendazole in intestinal cancer cell lines.
This study aimed to test the antiproliferative effect of three benzimidazole anthelmintics in intestinal cancer cells and to investigate whether these drugs, which inhibit tubulin polymerization, can potentiate the efficacy of the microtubule-stabilizing drug paclitaxel (PTX). Four intestinal cancer cell lines, SW480, SW620, HCT8, and Caco2, with different origins and growth characteristics were used. The antiproliferative effect of albendazole (ABZ), ricobendazole (RBZ), flubendazole (FLU), and their combinations with PTX was tested using three different end-point viability assays, cell cycle distribution analysis, and the x-CELLigence System for real-time cell analysis. ABZ and FLU inhibited cell proliferation significantly in a concentration-dependent and time-dependent manner through cell arrest in the G2/M phase. RBZ was not effective at any concentration tested. The cell lines differed in sensitivity to FLU and ABZ, with HCT8 being the most sensitive, showing IC₅₀ values for ABZ and FLU that reached 0.3 and 0.9 μmol/l, respectively. Combinations of PTX+ABZ and PTX+FLU decreased cell viability more effectively when compared with treatment with individual drugs alone. The anthelmintic benzimidazole drugs ABZ and FLU show a significant cytostatic effect and potentiate the efficacy of PTX in intestinal cancer cells.


Reconnecting flux-rope dynamo.
We develop a model of the fluctuation dynamo in which the magnetic field is confined to thin flux ropes advected by a multiscale model of turbulence. Magnetic dissipation occurs only via reconnection of the flux ropes. This model can be viewed as an implementation of the asymptotic limit R_{m}-->infinity for a continuous magnetic field, where magnetic dissipation is strongly localized to small regions of strong-field gradients. We investigate the kinetic-energy release into heat mediated by the dynamo action, both in our model and by solving the induction equation with the same flow. We find that a flux-rope dynamo is an order of magnitude more efficient at converting mechanical energy into heat. The probability density of the magnetic energy release in reconnections has a power-law form with the slope -3 , consistent with the solar corona heating by nanoflares.


Aripiprazole reversed gastroparesis in a child with 1q21.1-q21.2 microdeletion.
An 11-year-old Caucasian boy, with a microdeletion in the 1q21.1-q21.2 region, had multiple medical conditions including gastroparesis documented initially at the age of 5. The patient had a history of poor feeding since infancy and had been treated for gastro-oesophageal reflux disease (GERD), constipation and multiple food allergies. As a consequence of the GERD and his concurrent immunoglobulin (IgG) subclass deficiency, the patient had multiple otolaryngologic (ENT) infections and required two sinus surgeries. The patient had poor weight gain (below the third percentile for weight-for-age) and required a short course of parenteral nutrition and eventually a gastrostomy tube. He was started on metoclopramide as treatment for gastroparesis with an increase in his appetite, oral intake and weight gain. However, severe headaches and worsening in his behaviour caused the agent to be discontinued. He had little weight gain and after a course of parenteral nutrition he was converted to a transpyloric feeding tube. Because of ongoing behavioural problems that interfered with his school performance, a psychiatrist started him on aripiprazole. After aripiprazole was prescribed at age 11, his appetite and oral intake dramatically increased and a repeat gastric emptying study was normal. The increased oral intake and weight gain continued, allowing removal of the feeding tube. More than 2 years later, on aripiprazole, he continues to gain weight without any supplemental feedings.


Bilateral Optic Pathway Ganglioglioma: The Fifth Case in the Literature.
Gangliogliomas are mixed tumors which contain both glial and neuronal elements. The optic pathway is a very rare location for gangliogliomas, with less than 23 cases reported in the literature. Bilateral involvement of the entire optic pathway was reported in only 4 cases before. Because of similar radiological appearance of other pathological entities such as gliomas and craniopharyngiomas, histopathological diagnosis is essential. We report a ganglioglioma case that involved both optic pathways. A 12-year-old patient suffering from visual deterioration for 6 months was evaluated. After a visual field test and radiological examinations, a microsurgical biopsy procedure was performed. Pathological examination revealed dysplastic/neoplastic ganglion cells and neoplastic glial cells, and the diagnosis was a World Health Organization (WHO) grade 1 ganglioglioma. The patient is scheduled for adjuvant radiotherapy with the hope of prevention of progression.


Sugar-linked dithiocarbamates as modulators of metabolic and genotoxic properties of N-nitroso compounds.
A series of putative anticarcinogenic and antimutagenic compounds was synthesized on the basis of tetraethylthiuram disulfide (disulfiram) and its metabolite, diethyldithiocarbamate (DDTC). Diallyldithiocarbamate was synthesized in order to combine the anticarcinogenic properties of diallyl sulfide, a known inhibitor of chemical carcinogenesis from Allium species, and those of DDTC. Several sugar-linked dithiocarbamates (SDTCs) were prepared using glucose, cellobiose, and lactose as glycosyl donors and DDTC and diallyldithiocarbamate as acceptors. All the S--glycoside bonds of SDTCs were very stable under physiological conditions in vitro. At low nitrosamine concentrations, glucose-DDTC inhibited microsomal nitrosamine dealkylases in vitro. In vivo these enzymes were also inhibited 4 h after i.p. administration of glucose-DDTC or lactose-DDTC to rats (1.7 mmol/kg); after 24 h, the values had returned to control levels. Glucose-DDTC induced the activity of glutathione-related enzymes. Concomitant treatment of rats with glucose-DDTC and N-nitrosodiethylamine (NDEA) led to a depression of the oxidative metabolism of [14C]NDEA to 14CO2 but increased the elimination of unchanged [14C]NDEA in the urine. Furthermore, glucose-DDTC totally inhibited the formation of DNA single-strand breaks induced by NDEA. All these effects may contribute to possible antimutagenic and anticarcinogenic actions of the dithiocarbamates investigated.


Closed field unbalanced magnetron sputtering ion plating of Ni/Al thin films: influence of the magnetron power.
In this study NiAl thin films have been deposited using closed field unbalanced magnetron sputtering Ion plating (CFUBMSIP). The influence of magnetron power has been investigated using dense and humongous NiAl compound targets onto stainless steel and glass substrates. Potential applications include tribological, electronic media and bond coatings in thermal barrier coatings system. Several techniques has been used to characterise the films including surface stylus profilometry, energy dispersive spectroscopy (EDAX), X-Ray diffraction (XRD) Composition analysis of the samples was carried out using VGTOF SIMS (IX23LS) and Atomic force microscopy (AFM). Scratch tester (CSM) combined with acoustic emission singles during loading in order to compare the coating adhesion. The acoustic emission signals emitted during the indentation process were used to determine the critical load, under which the film begins to crack and/or break off the substrate. The average thickness of the films was approximately 1 um. EDAX results of NiAl thin films coating with various magnetron power exhibited the near equal atomic% Ni:Al. The best result being obtained using 300 W and 400 W DC power for Ni and Al targets respectively. XRD revealed the presence of beta NiAl phase for all the films coatings. AFM analysis of the films deposited on glass substrates exhibited quite a smooth surface with surface roughness values in the nanometre range. CSM results indicate that best adhesion was achieved at 300 W for Ni, and 400 W for Al targets compared to sample other power values. SIMS depth profile showed a uniform distribution of the Ni and Al component from the surface of the film to the interface.


Experimental and Numerical Design and Evaluation of a Vibration Bioreactor using Piezoelectric Patches.
In this present study, we propose a method for exposing biological cells to mechanical vibration. The motive for our research was to design a bioreactor prototype in which in-depth in vitro studies about the influence of vibration on cells and their metabolism can be performed. The therapy of cancer or antibacterial measures are applications of interest. In addition, questions about the reaction of neurons to vibration are still largely unanswered. In our methodology, we used a piezoelectric patch (PZTp) for inducing mechanical vibration to the structure. To control the vibration amplitude, the structure could be excited at different frequency ranges, including resonance and non-resonance conditions. Experimental results show the vibration amplitudes expected for every frequency range tested, as well as the vibration pattern of those excitations. These are essential parameters to quantify the effect of vibration on cell behavior. Furthermore, a numerical model was validated with the experimental results presenting accurate results for the prediction of those parameters. With the calibrated numerical model, we will study in greater depth the effects of different vibration patterns for the abovementioned cell types.


Prevalence and determinants of HPV infection among Colombian women with normal cytology.
Human papillomavirus is the principal risk factor associated with cervical cancer, the most common malignancy among women in Colombia. We conducted a survey, aiming to report type specific prevalence and determinants of human papillomavirus infection in women with normal cytology. A total of 1859 women from Bogota, Colombia were interviewed and tested for human papillomavirus using a general primer GP5+/GP6+ mediated PCR-EIA. The overall HPV DNA prevalence was 14.8%; 9% of the women were infected by high risk types, 3.1% by low risk types, 2.3% by both high risk/low risk types and 0.4% by uncharacterized types (human papillomavirus X). Thirty-two different human papillomavirus types were detected, being human papillomavirus 16, 58, 56, 81(CP8304) and 18 the most common types. The human papillomavirus prevalence was 26.1% among women younger than 20 years, 2.3% in women aged 45-54 years, and 13.2% in women aged 55 years or more. For low risk types the highest peak of prevalence was observed in women aged 55 years or more. Compared to women aged 35-44 years, women aged less than 20 years had a 10-fold increased risk of having multiple infections. Besides age, there was a positive association between the risk of human papillomavirus infection and number of regular sexual partners and oral contraceptive use. In women aged below 25 years, high educational level and having had casual sexual partners predicted infection risk. In conclusion, there was a broad diversity of human papillomavirus infections with high risk types being the most common types detected. In this population multiplicity of sexual partners and, among young women, high educational level and casual sexual partners seem to determine risk.


p53 protein-mediated up-regulation of MAP kinase phosphatase 3 (MKP-3) contributes to the establishment of the cellular senescent phenotype through dephosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2).
Growth arrest is one of the essential features of cellular senescence. At present, the precise mechanisms responsible for the establishment of the senescence-associated arrested phenotype are still incompletely understood. Given that ERK1/2 is one of the major kinases controlling cell growth and proliferation, we examined the possible implication of ERK1/2. Exposure of normal rat epithelial cells to etoposide caused cellular senescence, as manifested by enlarged cell size, a flattened cell body, reduced cell proliferation, enhanced β-galactosidase activity, and elevated p53 and p21. Senescent cells displayed a blunted response to growth factor-induced cell proliferation, which was preceded by impaired ERK1/2 activation. Further analysis revealed that senescent cells expressed a significantly higher level of mitogen-activated protein phosphatase 3 (MKP-3, a cytosolic ERK1/2-targeted phosphatase), which was suppressed by blocking the transcriptional activity of the tumor suppressor p53 with pifithrin-α. Inhibition of MKP-3 activity with a specific inhibitor or siRNA enhanced basal ERK1/2 phosphorylation and promoted cell proliferation. Apart from its role in growth arrest, impairment of ERK1/2 also contributed to the resistance of senescent cells to oxidant-elicited cell injury. These results therefore indicate that p53-mediated up-regulation of MKP-3 contributes to the establishment of the senescent cellular phenotype through dephosphorylating ERK1/2. Impairment of ERK1/2 activation could be an important mechanism by which p53 controls cellular senescence.


Personalized Prognostic Risk Score for Long-Term Survival for Children with Acute Leukemia after Allogeneic Transplantation.
We studied leukemia-free (LFS) and overall survival (OS) in children with acute myeloid (AML, n = 790) and acute lymphoblastic leukemia (ALL, n = 1096) who underwent transplantation between 2000 and 2010 and who survived for at least 1 year in remission after related or unrelated donor transplantation. Analysis of patient-, disease-, and transplantation characteristics and acute and chronic graft-versus-host disease (GVHD) was performed to identify factors with adverse effects on LFS and OS. These data were used to develop risk scores for survival. We did not identify any prognostic factors beyond 4 years after transplantation for AML and beyond 3 years for ALL. Risk score for survival for AML includes age, disease status at transplantation, cytogenetic risk group, and chronic GVHD. For ALL, the risk score includes age at transplantation and chronic GVHD. The 10-year probabilities of OS for AML with good (score 0, 1, or 2), intermediate (score 3), and poor risk (score 4, 5, 6, or 7) were 94%, 87%, and 68%, respectively. The 10-year probabilities of OS for ALL were 89% and 80% for good (score 0 or 1) and poor risk (score 2), respectively. Identifying children at risk for late mortality with early intervention may mitigate some excess late mortality.


Understanding the motion of hard-shell capsules in dry powder inhalers.
The delivery of small drug particles from a dry powder inhaler (DPI) into the patient's peripheral airways requires the dispersion of the powder. In DPIs that contain a rotating pierced capsule, the capsule's motion is paramount to powder dispersion. Previous studies have simplified the capsule motion in an Aerolizer® inhaler as a constant rotation around a fixed center. The present work examines deviations from this simplified motion and describes the capsule collisions with the surrounding inhaler walls. High-speed photography was employed to analyze the motion of a size 3 capsule in an Aerolizer® inhaler at various flow rates ranging from 30 to 100 L/min. Frequent collisions of the capsule with the surrounding inhaler walls were observed. Computational fluid dynamics (CFD) simulations indicated that the air flow through the capsule governs the behavior of small drug particles, while inertial forces are the dominant influence on large carrier particles in the capsule. Discrete element method (DEM) simulations were employed to study the effect of the capsule-inhaler collisions on the powder discharge from a rotating capsule. The collisions vastly improved the discharge of a polydisperse model carrier powder from the capsule over a wide range of cohesiveness.


Handmade somatic cell cloning in cattle.
Apart from the biological and ethical problems, technical difficulties also hamper the improvement and widespread application of somatic cell nuclear transfer (NT). Recently introduced zona-free procedures may offer a solution for the latter problem. The most radical approach of these techniques is the so-called handmade cloning (HMC). It does not require micromanipulators because the manipulations required for both enucleation and nucleus transfer are performed by hand. The HMC technique includes manual bisection of zona-free oocytes, selection of cytoplasts by staining, and the simultaneous fusion of the somatic cell with two cytoplasts to produce a cloned embryo. HMC is a rapid and efficient technique that suits large-scale NT programs. It requires less expertise and time than traditional NT methods and the cost of equipment is significantly less. Production efficiency is high and embryo quality, in terms of pregnancy rates and live births, is not compromised. Although HMC has been developed particularly for bovine NT, the technique is applicable to other species. The method may become a useful tool for both experimental and commercial somatic cell cloning because it allows for standardization of procedures and provides the possibility of automation.


Nonspastic hemifacial spasm confirmed by abnormal muscle responses.
Hemifacial spasm is usually diagnosed by inspection which mainly identifies involuntary movements of orbicularis oculi. Assessing abnormal muscle responses (AMR) is another diagnostic method. We report a case of left hemifacial spasm without detectable involuntary facial movements. The patient was a 48-year-old man with a long history of subjective left facial twitching. On magnetic resonance imaging (MRI), the left VIIth cranial nerve was compressed by the left anterior inferior cerebellar artery (AICA), which was in turn compressed by the left vertebral artery. We initially treated him with botulinum toxin. We were able to record AMR, and hemifacial spasm occurred after AMR stimulation, although no spasm was detectable by inspection. Subsequently, we performed microvascular decompression with transposition of the AICA that compressed the VIIth cranial nerve. His hemifacial spasm resolved by 5 weeks after surgery and was not induced by AMR stimulation. Hemifacial spasm can sometimes be diagnosed by detecting AMR rather than by visual inspection. We propose that such hemifacial spasm should be termed nonspastic hemifacial spasm.


Anti-p200 pemphigoid: diagnosis and treatment of a case presenting as an inflammatory subepidermal blistering disease.
Anti-p200 pemphigoid is a recently defined subepidermal immunobullous disease. It is characterized by the binding of circulating IgG autoantibodies to the dermal side of 1 M NaCl split skin and by reactivity of these autoantibodies to a unique 200-kd antigen on immunoblot of dermal extract. On immunoelectron microscopic examination, these autoantibodies deposit at the lamina lucida-lamina densa interface. We describe the clinical, histologic, and immunopathologic features in a patient with anti-p200 pemphigoid, as well as his favorable response to treatment with systemic glucocorticosteroids and dapsone.


Targeting the programmed cell death 1: programmed cell death ligand 1 pathway reverses T cell exhaustion in patients with sepsis.
A major pathophysiologic mechanism in sepsis is impaired host immunity which results in failure to eradicate invading pathogens and increased susceptibility to secondary infections. Although many immunosuppressive mechanisms exist, increased expression of the inhibitory receptor programmed cell death 1 (PD-1) and its ligand (PD-L1) are thought to play key roles. The newly recognized phenomenon of T cell exhaustion is mediated in part by PD-1 effects on T cells. This study tested the ability of anti-PD-1 and anti-PD-L1 antibodies to prevent apoptosis and improve lymphocyte function in septic patients. Blood was obtained from 43 septic and 15 non-septic critically-ill patients. Effects of anti-PD-1, anti-PD-L1, or isotype-control antibody on lymphocyte apoptosis and interferon gamma (IFN-γ) and interleukin-2 (IL-2) production were quantitated by flow cytometry. Lymphocytes from septic patients produced decreased IFN-γ and IL-2 and had increased CD8 T cell expression of PD-1 and decreased PD-L1 expression compared to non-septic patients (P<0.05). Monocytes from septic patients had increased PD-L1 and decreased HLA-DR expression compared to non-septic patients (P<0.01). CD8 T cell expression of PD-1 increased over time in ICU as PD-L1, IFN-γ, and IL2 decreased. In addition, donors with the highest CD8 PD-1 expression together with the lowest CD8 PD-L1 expression also had lower levels of HLA-DR expression in monocytes, and an increased rate of secondary infections, suggestive of a more immune exhausted phenotype. Treatment of cells from septic patients with anti-PD-1 or anti-PD-L1 antibody decreased apoptosis and increased IFN-γ and IL-2 production in septic patients; (P<0.01). The percentage of CD4 T cells that were PD-1 positive correlated with the degree of cellular apoptosis (P<0.01). In vitro blockade of the PD-1:PD-L1 pathway decreases apoptosis and improves immune cell function in septic patients. The current results together with multiple positive studies of anti-PD-1 and anti-PD-L1 in animal models of bacterial and fungal infections and the relative safety profile of anti-PD-1/anti-PD-L1 in human oncology trials to date strongly support the initiation of clinical trials testing these antibodies in sepsis, a disorder with a high mortality.


Thermal expansion of diamond at low temperatures.
Temperature variation of a lattice parameter of a synthetic diamond crystal (type IIa) was measured using high-energy-resolution x-ray Bragg diffraction in backscattering. A 2 order of magnitude improvement in the measurement accuracy allowed us to directly probe the linear thermal expansion coefficient at temperatures below 100 K. The lowest value measured was 2x10{-9} K-1. It was found that the coefficient deviates from the expected Debye law (T3) while no negative thermal expansion was observed. The anomalous behavior might be attributed to tunneling states due to low concentration impurities.


Harnessing region-specific neurovascular signaling to promote germinal matrix vessel maturation and hemorrhage prevention.
Germinal matrix hemorrhage (GMH), affecting about 1 in 300 births, is a major perinatal disease with lifelong neurological consequences. Yet despite advances in neonatal medicine, there is no effective intervention. GMH is characterized by localized bleeding in the germinal matrix (GM), due to inherent vessel fragility unique to this developing brain region. Studies have shown that reduced TGFβ signaling contributes to this vascular immaturity. We have previously shown that a region-specific G-protein-coupled receptor pathway in GM neural progenitor cells regulates integrin β8, a limiting activator of pro-TGFβ. In this study, we use mice to test whether this regional pathway can be harnessed for GMH intervention. We first examined the endogenous dynamics of this pathway and found that it displays specific patterns of activation. We then investigated the functional effects of altering these dynamics by chemogenetics and found that there is a narrow developmental window during which this pathway is amenable to manipulation. Although high-level activity in this time window interferes with vessel growth, moderate enhancement promotes vessel maturation without compromising growth. Furthermore, we found that enhancing the activity of this pathway in a mouse model rescues all GMH phenotypes. Altogether, these results demonstrate that enhancing neurovascular signaling through pharmacological targeting of this pathway may be a viable approach for tissue-specific GMH intervention. They also demonstrate that timing and level are likely two major factors crucial for success. These findings thus provide critical new insights into both brain neurovascular biology and the intervention of GMH.


[A Cinematographic study of embryonic developmentin vitro of the viviparous, paedogenetic gall midgeHeteropeza pygmaea].
1. In the paedogenetic gall midgeHeteropeza pygmaea, embryonic growth is at the expense of maternal tissues. The possibility of culturing egg folliclesin vitro throughout the entire period of embryonic development allowed the filming of embryogenesis. In the present paper development, growth and degeneration of egg folliclesin vitro (at 25° C) are analysed by time-lapse film. 2. During development of the mature egg follicle up to germ band formation, the yolk globules undergo alternative periods of oscillation and rest within the yolk syncytium. During the periods of time in which the yolk globules are at rest, cleavage divisions take place. All egg follicles analysed showed 13 resting periods which corresponded to the 13 cleavage divisions. A comparison with other investigations indicates, that oscillation of the yolk globules is not required for the migration of the nuclei, but is connected with a special function of the yolk syncytium in paedogenetic gall midges. 3. From the 1st until the 6th cleavage division the average duration of the mitotic cycle decreases from 75 to 50 minutes; from the 6th until the 13th cleavage division it increases to more than 3 hours. 4. Blastokinesis, i. e. germ band extension and germ band retraction, in all probability is the consequence of autonomous movements of the germ band and not of a morphogenetic effect of the yolk syncytium. 5. Egg follicles from different preparations show varying rates of development and growth whereas egg follicles within one culture drop develop and grow with the same rate although they may not be at exactly the same stage of development. 6. In certain stages of development (cleavage, germ band retraction and dorsal closure) the increase in length of the egg follicle is discontinuous. During germ band retraction many egg follicles show up to 7 elongations and contractions, which may amount to as much as one fifth of the egg follicle length. The period of time of one elongation-contraction cycle is between 1 1/4 and 2 3/4 hours and increases by 1/4 hour with each new cycle. At the same time as the egg follicle length increases, its width decreases and vice-versa, suggesting that the increase in volume is continuous. 7. Measurements of two egg follicles at the blastoderm stage revealed rhythmic fluctuations in length which amounted to no more than one fiftieth of the total egg follicle length. There may be as many as 60 such fluctuation cycles, each of which has a constant period of about 15 minutes. The endogenous process underlying these fluctuations is obscure. 8. The egg follicles which degenerate in culture are generally the smaller and less developed ones in any given preparation; however, until their sudden degeneration, they show the same rate of growth and development as the non degenerating egg follicles. 9. The extraordinary mode of paedogenetic egg development ofHeteropeza is interpreted as a displacement of embryogenesis into oogenesis.


Squamous-cell carcinoma of the pleura.
There are few reports of primary malignant tumours of the pleura other than mesothelioma. Reports of squamous-cell carcinoma of the pleura are especially rare. Epidermoid carcinoma of the pleura may occur in connection with persistent empyema drained by a pleurocutaneous fistula or long-standing extrapleural pneumothorax without fistula.


Posterior cervical fixation using a new polyaxial screw and rod system: technique and surgical results.
Standard lateral mass plate and screw systems are of limited use in patients with abnormal cervical anatomy and do not easily allow for extension to either the occipit or the thoracic spine. The objective of this study was to demonstrate the safety, surgical efficacy, and advantages of a new cervical polyaxial screw and rod system for posterior occipitocervicothoracic arthrodesis. The authors reviewed a multicenter series of patients who underwent surgery in which they used a new posterior cervical polyaxial screw and rod system. The system was implanted in 32 (20 women and 12 men) adult patients (mean age 56.9 years, range 23-84 years). Twenty-three of the patients were treated for spondylostenosis; four for cervical fracture/dislocations; four for kyphosis; and one patient was treated for pseudarthrosis that developed after prior surgery. The system was successfully implanted in all patients despite the presence of anatomical lateral mass anomalies in the majority of cases. The mean number of levels fused was 3.9 (range one-eight levels). This dynamic system allowed for screw placement into the occiput, C-1 lateral masses, C-2 pars, C3-7 lateral masses, and low cervical as well as upper thoracic pedicles. Selective application of compressive or distractive forces was possible in adjacent segments. Surgery-related complications included one dural tear and one malpositioned screw. There were two cases of wound infection. Unlike standard lateral mass plate and screw systems, the new cervical polyaxial screw and rod system easily accommodates severe degenerative cervical spondylosis and curvatures. This instrumentation system allows for polyaxial screw placement with subsequent multiplanar rod contouring and offset attachment. The authors have used this system successfully, and without significant complications, to achieve posterior cervical arthrodesis.


Brain-based limitations in attention and secondary task engagement during high-fidelity driving simulation among young adults.
Distracted driving remains a leading factor in fatal motor vehicle crashes, particularly in young drivers. Due to ongoing neuromaturation, attention capabilities are changing and improving throughout young adulthood. Here, we sought to bridge neuroscience with driving simulation by evaluating the effects of driving on attention processing through a selective auditory attention task. Participants (18-25 years old) engaged in an auditory attention task during LOAD (driving a high-fidelity simulator) and No-LOAD conditions (sitting in the parked simulator). For the auditory task, participants responded to a target auditory tone in a target ear. The event-related potential components, collected from frontal and posterior regions, P2 and P3, were used to evaluate attention processing across LOAD and No-LOAD conditions for attended and unattended stimuli. Data from 24 participants were evaluated in repeated measures ANOVAs, considering interactions between load and attention conditions for the P2 and P3 components of the cortical region. We observed a significant difference between response to attended and unattended stimuli for posterior P2 and P3 responses at the frontal and posterior midline sites. Comparing LOAD and No-LOAD conditions, there was a significant difference for P2 response at the posterior site and P3 response at the frontal site. A significant interaction between load and attended stimuli was found for P3 response at the posterior site. These data document differences in neural processing of auditory stimuli during high-fidelity simulated driving versus sitting parked in the simulator. Findings suggest the cognitive load of driving affects auditory attention.


A C20 fullerene-based sheet with ultrahigh thermal conductivity.
A new two-dimensional (2D) carbon allotrope, Hexa-C20, composed of C20 fullerene is proposed. State-of-the-art first principles calculations combined with solving the linearized phonon Boltzmann transport equation confirm that the new carbon structure is not only dynamically and thermally stable, but also can withstand temperatures as high as 1500 K. Hexa-C20 possesses a quasi-direct band gap of 3.28 eV, close to that of bulk ZnO and GaN. The intrinsic lattice thermal conductivity κlat of Hexa-C20 is 1132 W m-1 K-1 at room temperature, which is much larger than those of most carbon materials such as graphyne (82.3 W m-1 K-1) and penta-graphene (533 W m-1 K-1). Further analysis of its phonons uncovers that the main contribution to κlat is from the three-phonon scattering, while the three acoustic branches are the main heat carriers, and strongly coupled with optical phonon branches via an absorption process. The ultrahigh lattice thermal conductivity and an intrinsic wide band gap make the Hexa-C20 sheet attractive for potential thermal management applications.


Estimation of sex-age specific clinical reference ranges by nonlinear optimization method.
Most reference ranges are not considered sex-age specific differences. We collected about 700,000 health examination data with 24 items to estimate sex-age specific clinical reference ranges. We proposed nonlinear optimization method as a new method compatible with NCCLS guideline. All items showed sex-age specific differences of reference ranges. Especially, hepatic functions in young aged men and all aged women, diabetic functions in young aged people, blood pressures in older people, and total cholesterol in all aged people might have serious problems. Some abnormal individuals might not be detected using established reference ranges, on the other hand, some normal individuals might be treated excessively.


Effect of immersion in low-pH solution on physicochemical properties of high-pH venison.
The color of venison observed at a high-pH is not preferred by consumers. However, the physicochemical properties of venison soaked in a low-pH solution to lower its high-pH are unknown. We investigated the effect of immersion in a low-pH solution on the physicochemical properties of a high-pH venison. The pH of M. longissimus thoracis from seven female wild deer (Cervus nippon) was measured and divided into normal-pH venison and high-pH venison groups. The a* and b* values for high-pH venison were lower than those for normal-pH venison before storage. There was no significant difference in the pH between high-pH venison immersed in a pH 4 solution and normal-pH venison stored. The drip loss of immersed high-pH venison was significantly lower than that of normal-pH venison and high-pH venison. Cooking loss and total loss were the lowest for normal-pH venison and the highest for immersed high-pH venison. The maximum load between normal-pH venison, high-pH venison, and immersed high-pH venison did not differ significantly. Our work showed that meat color became favorable by immersing high-pH venison in a solution of pH 4, followed by heating.


The investigation of association between IL-1Ra and ACE I/D polymorphisms in carpal tunnel syndrome.
Carpal tunnel syndrome (CTS) is a common neurologic impairment caused by injury on the median nerve in the wrist, characterized by pain and loss of sensory. CTS usually occurs through three factors, such as a mechanical pressure on median nerve, immunologic changes, and oxidative stress. The aim of this study was to evaluate the influence of interleukin-1 receptor antagonist (IL-1Ra) and angiotensin-converting enzyme (ACE) I/D polymorphisms on the susceptibility of patients to the CTS. One hundred fifty-eight patients with CTS and 151 healthy controls were enrolled in this study. Each patient was analyzed according to diseases symptoms, such as gender, a positive Tinel's sign, a positive Phalen maneuver, disease sides, EMG findings, and clinical stage. We applied the polymerase chain reaction (PCR) to determine the polymorphisms of IL-1Ra and ACE I/D. The statistically significant relation was not found between IL-1Ra, ACE I/D polymorphisms and CTS (respectively, P>.05; P>.05, OR: 1.51, CI: 0.82-1.61). Additionally, in the result of the statistical analysis compared with gene polymorphisms and clinical characteristics, we did not find any correlation (P>.05). Our findings showed that there are no associations of IL-1Ra and ACE I/D polymorphisms with susceptibility of a person for the development of CTS. So, it means that these polymorphisms do not create a risk for the development of CTS. Further studies with larger populations will be required to confirm these findings in different study populations.


Unilateral and bilateral MRI-targeted repetitive transcranial magnetic stimulation for treatment-resistant depression: a randomized controlled study.
Several factors may mitigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) over sham rTMS in patients with treatment-resistant depression (TRD). These factors include unilateral stimulation (i.e., treatment of only the left dorsolateral prefrontal cortex [DLPFC]), suboptimal methods of targeting the DLPFC and insufficient stimulation intensity (based on coil-to-cortex distance). We recruited patients with TRD between the ages of 18 and 85 years from a university hospital, and participants were randomized to receive sequential bilateral rTMS (600 pulses at 1 Hz followed by 1500 pulses at 10 Hz), unilateral high-frequency left (HFL)-rTMS (2100 pulses at 10 Hz) or sham rTMS for 3 or 6 weeks depending on treatment response. Stimulation was targeted with MRI localization over the junction of the middle and anterior thirds of the middle frontal gyrus, using 120% of the coil-to-cortex adjusted motor threshold. Our primary outcome of interest was the remission rate. A total of 121 patients participated in this study. The remission rate was significantly higher in the bilateral group than the sham group. The remission rate in the HFL-rTMS group was intermediate and did not differ statistically from the rate in the 2 other groups. There were no significant differences in reduction of depression scores among the 3 groups. The number of pulses used per session in the unilateral group was somewhat lower in our trial than in more recent trials, and the sham condition did not involve active stimulation. Our findings suggest that sequential bilateral rTMS is superior to sham rTMS; however, adjusting for coil-to-cortex distance did not yield enhanced efficacy rates.


Biology and potential clinical implications of tissue inhibitor of metalloproteinases-1 in colorectal cancer treatment.
Colorectal cancer (CRC) is the second leading cause of cancer-related death in the industrialized world. About half of "curatively" resected patients develop recurrent disease within the next 3-5 years despite the lack of clinical, histological and biochemical evidence of remaining overt disease after resection of the primary tumour. Availability of validated biological markers for early detection, selection for adjuvant therapy, prediction of treatment efficacy and monitoring of treatment efficacy would most probably increase survival. Tissue inhibitor of metalloproteinases-1 (TIMP-1) may be such a marker. TIMP-1 inhibits the proteolytic activity of metalloproteinases, which are centrally involved in tumour invasion and metastases. However, in clinical investigations high tumour tissue or plasma levels of TIMP-1 have shown a strong and independent association with a shorter survival time in CRC patients, suggesting that TIMP-1 could have a tumour-promoting function. Furthermore, measurement of plasma TIMP-1 has been shown to be useful for disease detection, with a high sensitivity and high specificity for early-stage colon cancer. This review describes some basic information on the current knowledge of the biology of TIMP-1 as well as the potential use of TIMP-1 as a biological marker in the management of CRC patients.


On the maintenance of bird song dialects.
Many bird species, especially song birds but also for instance some hummingbirds and parrots, have noted dialects. By this we mean that locally a particular song is sung by the majority of the birds, but that neighbouring patches may feature different song types. Behavioural ecologists have been interested in how such dialects come about and how they are maintained for over 45 years. As a result, a great deal is known about different mechanisms at play, such as dispersal, assortative mating and learning of songs, and there are several competing hypotheses to explain the dialect patterns known in nature. There is, however, surprisingly little theoretical work testing these different hypotheses at present. We analyse the simplest kind of model that takes into account the most important biological mechanisms, and in which one may speak of dialects: a model in which there are but two patches, and two song types. It teaches us that a combination of little dispersal and strong assortative mating ensures dialects are maintained. Assuming a simple, linear frequency-dependent learning rule has little effect on the maintenance of dialects. A nonlinear learning rule, however, has dramatic consequences and greatly facilitates dialect maintenance. Adding fitness benefits for singing particular songs in a given patch also has a great impact. Now rare song types may invade and remain in the population.


Numerical simulation of high-temperature thermal contact resistance and its reduction mechanism.
High-temperature thermal contact resistance (TCR) plays an important role in heat-pipe-cooled thermal protection structures due to the existence of contact interface between the embedded heat pipe and the heat resistive structure, and the reduction mechanism of thermal contact resistance is of special interests in the design of such structures. The present paper proposed a finite element model of the high-temperature thermal contact resistance based on the multi-point contact model with the consideration of temperature-dependent material properties, heat radiation through the cavities at the interface and the effect of thermal interface material (TIM), and the geometry parameters of the finite element model are determined by simple surface roughness test and experimental data fitting. The experimental results of high-temperature thermal contact resistance between superalloy GH600 and C/C composite material are employed to validate the present finite element model. The effect of the crucial parameters on the thermal contact resistance with and without TIM are also investigated with the proposed finite element model.


In Vivo Reflectance Confocal Microscopy in General Dermatology: How to Choose the Right Indication.
Reflectance confocal microscopy (RCM) is a high-resolution, noninvasive imaging technique being increasingly used as an aid to diagnosis in the dermatology setting. RCM is applied in the diagnosis of both melanoma and nonmelanoma skin tumors, but also in the interpretation and management of inflammatory skin diseases. Two different devices with different designs for specific indications are available in the market: a static and a handheld probe. Several clinical presentations of the lesion could affect the examination, such as the presence of ulceration or hyperkeratosis; moreover, the anatomical site can drive the probe selection as well as the effective indication to RCM examination. In this review article, indications for the use of RCM are described in detail with a schematic approach for practical purposes.


[Statistical studies on thrombotic complications and the incidence of endocarditis neoplastic diseases].
On the basis of data gained by autopsy the frequency of thrombotic and thromboembolic complications (TTK) was investigated by correlation analysis in unselected malignant tumour diseases and in malignant tumour diseases with tumour endocarditis (TE). The following things could be detected: 1. No increase of TTK in malignant tumour diseases compared with the total material, 2. A significant increase of TTK in tumours with TE, 3. A significant increase of TTK with an increasing histological tumour differentiation and an increasing inflammatory current reaction of the tumour, and 4. Parallel behaviour of tumours with TTK and those with TE concerning primary tumours. TTK was interpreted as the cause of an abnormally enhanced tendency of blood coagulation on the basis of an immunocomplex disease, because: 1. The coagulation system is being activated by circulating immunocomplexes, 2. Circulating immunocomplexes will increase with tumour parameters, differentiation, and current reaction, and 3. Frequency of TTK and TE will increase with the same parameters.


Neuropathies associated with conduction block.
Two disorders, Lewis-Sumner syndrome and multifocal motor neuropathy, are defined by the demonstration of conduction block. These two entities have been intertwined since their description but there are important distinctions between them. It is therefore timely to reconsider these disorders and the physiologic process that defines them. Understanding of the pathophysiology of conduction block has evolved with better understanding of the structure of the node of Ranvier and surrounding apparatus. Axonal excitability studies have begun to give insights into why multifocal motor neuropathy has only motor conduction block. The many published criteria for conduction block vary in sensitivity and specificity and the electromyographer must be aware of the difficulties in determining physiologic block. The distinctions between Lewis-Sumner syndrome and multifocal motor neuropathy have become increasingly clear. Evidence suggests that Lewis-Sumner syndrome is a multifocal variant of chronic inflammatory demyelinating polyneuropathy but that multifocal motor neuropathy is distinct. It is important to recognize the distinctions between these disorders, not only because there are important therapeutic issues, but also because a true understanding of the nature of these illnesses will only be accomplished if the overlaps and differences are carefully considered.


Cyclodiphosphazanes with hemilabile ponytails: synthesis, transition metal chemistry (Ru(II), Rh(I), Pd(II), Pt(II)), and crystal and molecular structures of mononuclear (Pd(II), Rh(I)) and bi- and tetranuclear rhodium(I) complexes.
Cyclodiphosphazanes having hemilabile ponytails such as cis-[(t)()BuNP(OC(6)H(4)OMe-o)](2) (2), cis-[(t)()BuNP(OCH(2)CH(2)OMe)](2) (3), cis-[(t)BuNP(OCH(2)CH(2)SMe)](2) (4), and cis-[(t)BuNP(OCH(2)CH(2)NMe(2))](2) (5) were synthesized by reacting cis-[(t)()BuNPCl](2) (1) with corresponding nucleophiles. The reaction of 2 with [M(COD)Cl(2)] afforded cis-[MCl(2)(2)(2)] derivatives (M = Pd (6), Pt (7)), whereas, with [Pd(NCPh)(2)Cl(2)], trans-[MCl(2)(2)(2)] (8) was obtained. The reaction of 2 with [Pd(PEt(3))Cl(2)](2), [{Ru(eta(6)-p-cymene)Cl(2)](2), and [M(COD)Cl](2) (M = Rh, Ir) afforded mononuclear complexes of Pd(II) (9), Ru(II) (11), Rh(I) (12), and Ir(I) (13) irrespective of the stoichiometry of the reactants and the reaction condition. In the above complexes the cyclodiphosphazane acts as a monodentate ligand. The reaction of 2 with [PdCl(eta(3)-C(3)H(5))](2) afforded binuclear complex [(PdCl(eta(3)-C(3)H(5)))(2){((t)BuNP(OC(6)H(4)OMe-o))(2)-kappaP}] (10). The reaction of ligand 3 with [Rh(CO)(2)Cl](2) in 1:1 ratio in CH(3)CN under reflux condition afforded tetranuclear rhodium(I) metallamacrocycle (14), whereas the ligands 4 and 5 afforded bischelated binuclear complexes 15 and 16, respectively. The crystal structures of 8, 9, 12, 14, and 16 are reported.


Effects on strength, power, and flexibility in adolescents of nonperiodized vs. daily nonlinear periodized weight training.
The aim of this study was to compare 2 models of resistance training (RT) programs, nonperiodized (NP) training and daily nonlinear periodized (DNLP) training, on strength, power, and flexibility in untrained adolescents. Thirty-eight untrained male adolescents were randomly assigned to 1 of 3 groups: a control group, NP RT program, and DNLP program. The subjects were tested pretraining and after 4, 8, and 12 weeks for 1 repetition maximum (1RM) resistances in the bench press and 45° leg press, sit and reach test, countermovement vertical jump (CMVJ), and standing long jump (SLJ). Both training groups performed the same sequence of exercises 3 times a week for a total of 36 sessions. The NP RT consisted of 3 sets of 10-12RM throughout the training period. The DNLP training consisted of 3 sets using different training intensities for each of the 3 training sessions per week. The total volume of the training programs was not significantly different. Both the NP and DNLP groups exhibited a significant increase in the 1RM for the bench press and 45° leg press posttraining compared with that pretraining, but there were no significant differences between groups (p ≤ 0.05). The DNLP group's 1RM changes showed greater percentage improvements and effect sizes. Training intensity for the bench press and 45° leg press did not significantly change during the training. In the CMVJ and SLJ tests, NP and DNLP training showed no significant change. The DNLP group showed a significant increase in the sit and reach test after 8 and 12 weeks of training compared with pretraining; this did not occur with NP training. In summary, in untrained adolescents during a 12-week training period, a DNLP program can be used to elicit similar and possible superior maximal strength and flexibility gains compared with an NP multiset training model.


Antioxidative potential, nutritional value and sensory profiles of confectionery fortified with green and yellow tea leaves (Camellia sinensis).
This paper presents a study on development of functional food products containing green and yellow tea leaves. The results indicated that green and yellow tea are significant tools in the creation of the nutritional value, antioxidative potential and stability of the lipid fraction of cookies. Tea-fortified cookies showed considerably higher contents of dietary fiber, especially hemicellulose and insoluble fractions, and were characterized by significantly higher antioxidant potential associated with their phenolics content. Results of ABTS, DPPH, ORACFL and PCL assay showed significantly higher antioxidant potential of tea cookies, highest for yellow tea. The antioxidative potential of applied teas was significant in terms of the inhibition of hydroperoxide content, while formation of secondary lipid oxidation products was less spectacular. It is concluded that tea leaves could be widely used as a source of polyphenols with high antioxidative potential, as well as fiber; thus introducing numerous health benefits for the consumer.


The relationship between glucagon receptors and metabolic profile in two strains of rats: Wistar-Furth and Sprague-Dawley.
We studied glucagon and insulin binding to isolated hepatocyte receptors in Wistar-Furth (WF) and Sprague-Dawley (SD) rats, using 125I-labeled hormones. Hepatocytes from WF rats bound more glucagon than hepatocytes from SD rats. There were no differences in insulin binding. These observations prompted us to investigate other strain differences. Fasting and nonfasting serum glucose, glucagon, insulin, and growth hormone were measured. WF animals had a lower fasting glucose and higher fasting glucagon than SD animals, while SD rats had higher nonfasting insulin levels and a higher hepatic glycogen content. Total hepatic glucose production in response to glucagon (10(-8) M) was greater in WF than in SD rats, while glucagon-stimulated gluconeogenesis from alanine was the same in the two groups of animals. We concluded that the decreased glucagon binding does not play a significant role in the maintenance of serum glucose or in the gluconeogenetic response glucagon, and that neither these responses nor the serum glucagon levels appears to be correlated with the number of glucagon receptors. We conclude further that different animal strains of the same species may differ in their biologic responses.


Anti-CD28-induced co-stimulation and TCR avidity regulates the differential effect of TGF-beta1 on CD4+ and CD8+ naïve human T-cells.
TGF-beta1 is a powerful regulator of various T-cell functions. However, it has been unclear how the T-cell responsiveness towards TGF-beta1 is affected by its phenotype or signaling intensity. In the present study, we demonstrate that the phenotype and the TCR-signaling intensity of the responding T-cell as well as the presence of anti-CD28 co-stimulation markedly affects how naïve human cord blood T-cells respond to TGF-beta1. In this report we demonstrate that the strength of the stimulatory signal modifies the T-cell response towards TGF-beta1. Thus, the greatest anti-proliferative effect of TGF-beta1 was observed during weak stimulatory conditions (low dose of anti-CD3 with no co-stimulatory signal). However, such anti-proliferative effect was reduced during strong stimulatory signal (high dose of anti-CD3 with a CD28-directed co-stimulatory signal). In addition, our results indicate that CD8+ T-cells are generally more responsive towards TGF-beta1 than CD4+ T-cells. To our surprise, naïve T-cells had a skewed Th1/Tc1 cytokine secretion pattern with high amounts of IL-2, IFNgamma and TNFalpha, but low amounts of IL-4, IL-5 and IL-10. TGFbeta1 significantly reduced the secretion of IL-2 and IFNgamma, but such suppression was partially prevented by anti-CD28-induced co-stimulation. In contrast, the inhibitory effect on IL-5 secretion was unaffected by anti-CD28 co-stimulation. Interestingly, TGF-beta1 induced IL-10 and TNFalpha secretion. However, the induction of IL-10 secretion was reduced during optimal stimulatory conditions while TGF-beta1 further induced TNFalpha secretion. These data demonstrate that the duration, intensity and type of signaling alters the sensitivity of T-cells to powerful immunological modifying agents like TGF-beta1.


Effects of an integrated clinical information system on medication safety in a multi-hospital setting.
The implementation of vendor-based integrated clinical information technology was studied, and its effect on medication errors throughout the medication-use process in a health care system was evaluated. The integrated systems selected for implementation included computerized physician order entry, pharmacy and laboratory information systems, clinical decision-support systems (CDSSs), electronic drug dispensing systems (EDDSs), and a bar-code point-of-care medication administration system. The primary endpoint was the reduction in related medication errors. Secondary endpoints included the reductions in medication order turnaround time and EDDS override transactions. Integrated clinical information system technology was implemented in a multihospital health care system with a phased-in approach. A positive effect of this integration on medication errors throughout the medication-use process was demonstrated. Most prescribing errors decreased significantly in the selected categories monitored, specifically drug allergy detection, excessive dosing, and incomplete or unclear orders. Pharmacists were also twice as likely to identify dosages requiring adjustment for renal insufficiency when the integrated technology was in place and more than six times as likely for drug levels outside of the therapeutic range. A positive effect on medication administration safety was also demonstrated: 73 administration-related errors were intercepted through electronic bar-code scanning for every 100,000 doses charted. Integration of clinical information system technology decreased selected types of medication errors throughout the medication-use process in a health care system and improved therapeutic drug monitoring in patients with renal insufficiency and in patients receiving drugs with narrow therapeutic ranges through the use of CDSS alerts.


A glance at Appalachia.
Appalachia is usually written about in romantic terms; rarely are the citizens of Appalachia portrayed as contributors to society. Appalachia is made up of many cultures--African American, European American, Melungeon, Native American and others. Appalachian cultures are not locked in a fixed state; one needs only to review the history of Appalachia to understand this concept (Tice & Billings, 1991). Appalachian cultures are fluid and ever-changing. The cultures are expressed in literature, oral histories, music and regional history.


Single-molecule nanoscale electrocatalysis.
Nanoscale catalysts are important for electrocatalysis, especially in energy conversion as in photoelectrochemical cells and fuel cells. Understanding their reactivity is essential for improving their performances and designing new ones, but challenging due to their inherent structural heterogeneity. This article reviews recent developments in using single-molecule fluorescence microscopy to overcome this challenge and interrogate directly the individuality of nanoscale catalysts. Using electrocatalysis by single-walled carbon nanotubes (SWNTs) as an example, this article discusses how the single-molecule approach dissects the reaction kinetics at single-reaction resolution, unravels the reaction mechanism, and quantifies the reactivity and inhomogeneity of individual SWNT reactive sites, which are imaged to nanometre precision via super-resolution optical imaging. New scientific questions and opportunities are also discussed, as well as the related optical studies of single-molecule and single-nanoparticle electrochemistry.


BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression.
BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC-derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC-derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression.


Acetylcholine and calcium on membrane permeability and contraction of intestinal smooth muscle.
Acetylcholine elicited a sustained contraction and an increase in potassium efflux in longitudinal muscle isolated from the guinea pig ileum. Stepwise increases in the calcium concentration of the bathing medium, from 0.06 to 36 mM generally reduced the increase in potassium efflux, but had a complex effect on the mechanical response. Contractions produced by high levels of acetylcholine became progressively larger or remained at a high magnitude as the calcium concentration was increased. Contractions produced by low levels of acetylcholine also improved initially, but were depressed again by the highest concentration of calcium introduced. Ethanol, in the appropriate concentration, inhibited completely the acetylcholine-induced contraction without reducing the increase in potassium efflux. Calcium reversed this effect. Both extracellular calcium and ethanol depressed the large, transient increase in muscle tone developed by fibers that were preincubated in a high calcium medium and then exposed to a calcium-free medium. These findings suggested that extracellular calcium ions react with two different sites in the membrane, a stabilizing site and a storage site. A muscle contraction is activated by calcium ions which diffuse from the storage site to the myoplasm. Calcium ions reacting with the stabilizing site impede this diffusion process. Part of the stimulatory effect of acetylcholine is derived from its capacity to counteract the action of calcium at the stabilizing site.


Utility of microfluidic devices to study the platelet-endothelium interface.
The integration of biomaterials and understanding of vascular biology has led to the development of perfusable endothelialized flow models, which have been used as valuable tools to study the platelet-endothelium interface under shear. In these models, the parameters of geometry, compliance, biorheology, and cellular complexity are varied to recapitulate the physical biology of platelet recruitment and activation under physiologically relevant conditions of blood flow. In this review, we summarize the mechanistic insights learned from perfusable microvessel models and discuss the potential utility as well as challenges of endothelialized microfluidic devices to study platelet function in the bloodstream in vitro.


Spectral and polarographic determination of eprosartan. Kinetic studies of the oxidation of eprosartan using a platinum electrode.
Two simple and sensitive methods are presented for the determination of eprosartan in pharmaceutical preparations. The first method, spectrophotometry, was based on the oxidation of this drug by ammonium cerium (IV) nitrate in the presence of perchloric acid with subsequent measurement of the absorbance at 326 nm; this principle was adopted to develop a kinetic method for the determination of eprosartan in dosage forms. The second method, differential pulse polarography, was based on measuring the peak height at -1300 mV, corresponding to the reduction of the drug in Britton-Robinson buffer (pH 3). The proposed methods proved to be accurate and precise and can be applied for the routine analysis of this drug in commercial dosage forms, without interference from the excipients. The work was extended to study the electrochemical oxidation of eprosartan at different electrolysis currents (10-40 mA). The electrochemical decomposition products were characterized by UV/visible spectroscopy; the decomposition rates follow first order reactions and increase with raising the current. The degradation was found to be faster in basic than acidic medium. The thermodynamics for electrochemical decomposition were also evaluated at different pH values.


Mapping of multiple B cell epitopes on the 70-kilodalton autoantigen of the U1 ribonucleoprotein complex.
High titer IgG autoantibodies to the 70-kDa polypeptide component (p70) of the U1 ribonucleoprotein (RNP) complex occur in the sera of patients with mixed connective tissue disease, SLE, and related rheumatic diseases. To gain insight into the pathogenesis and diversity of this antibody response we have used recombinant DNA technology to map the linear B cell epitopes on p70. A full length 1.7-kb cDNA clone encoding p70 was isolated from a human placental library and restriction fragments or polymerase chain reaction-generated fragments of the gene subcloned into the bacterial expression vector pGEX. Purified fusion proteins representing specific regions of p70 were immunoblotted with a panel of 70 anti-(U1)RNP+ sera containing anti-p70 antibodies. Six epitopes, four major (A, B, C, and F) and two minor (D and E) were mapped and were located throughout the molecule. The anti-(U1)RNP sera displayed heterogeneity in their pattern of reactivity to the six epitopes although reactivity to epitope C was more frequently associated with SLE rather than mixed connective tissue disease. The identification of multiple B cell epitopes on p70 is consistent with the concept that this self Ag drives the autoantibody response.


The Source of Palm Orientation Errors in the Signing of Children with ASD: Imitative, Motoric, or Both?
Palm orientation reversal errors (e.g., producing the 'bye-bye' gesture with palm facing inward rather than outward as is customary in American culture) have been documented in the signing of deaf and hearing children with autism spectrum disorder (ASD) and in the imitation of gestures by signing and non-signing children with ASD. However the source of these unusual errors remains opaque. Given that children with ASD have documented difficulties with both imitation and motor skills, it is important to clarify the nature of these errors. Here we present a longitudinal case study of a single child with ASD, a hearing, signing child of Deaf parents. Samples of the child's signing were analyzed at ages 4;11, 6;2, 10;2, and 14;11. Lexical signs and fingerspelled letters were coded for the four parameters of sign articulation (handshape, location, movement, and palm orientation). Errors decreased for handshape, location, and movement after age 4;11, but increased on palm orientation from 4;11 and remained high, exceeding 55% of signs by 14;11. Fingerspelled letters contained a large proportion of 180-degree reversals, which suggest an origin in imitation differences, as well as midline-facing errors, suggestive of a motor origin. These longitudinal data suggest that palm orientation errors could be rooted in both imitation differences and motoric difficulties.


Assessing the case for mandatory folate fortification: policy-making in the face of scientific uncertainties.
This paper presents the view that policy-makers face scientific uncertainties in assessing the case for mandatory folate fortification as a policy response to epidemiological evidence of the relationship between folate and neural tube defects. Moreover, the resolution of these uncertainties is confounded by the under-resourced state of nutrition information systems in Australia and New Zealand. The uncertainties relate to potential risks and benefits associated with the intervention for the target group and the population in general. These risks and benefits reflect the mismatch between evidence and policy that arises when addressing a presumed genetic abnormality in at-risk individuals with an intervention that is population-wide in its scope. There is an urgent need to conduct ongoing national nutrition surveys and monitor and evaluate policy interventions to strengthen the capacity of nutrition information systems to inform decision-making for this current, and future, public health nutrition policy.


Symptoms of delirium predict incident delirium in older long-term care residents.
Detection of long-term care (LTC) residents at risk of delirium may lead to prevention of this disorder. The primary objective of this study was to determine if the presence of one or more Confusion Assessment Method (CAM) core symptoms of delirium at baseline assessment predicts incident delirium. Secondary objectives were to determine if the number or the type of symptoms predict incident delirium. The study was a secondary analysis of data collected for a prospective study of delirium among older residents of seven LTC facilities in Montreal and Quebec City, Canada. The Mini-Mental State Exam (MMSE), CAM, Delirium Index (DI), Hierarchic Dementia Scale, Barthel Index, and Cornell Scale for Depression were completed at baseline. The MMSE, CAM, and DI were repeated weekly for six months. Multivariate Cox regression models were used to determine if baseline symptoms predict incident delirium. Of 273 residents, 40 (14.7%) developed incident delirium. Mean (SD) time to onset of delirium was 10.8 (7.4) weeks. When one or more CAM core symptoms were present at baseline, the Hazard Ratio (HR) for incident delirium was 3.5 (95% CI = 1.4, 8.9). The HRs for number of symptoms present ranged from 2.9 (95% CI = 1.0, 8.3) for one symptom to 3.8 (95% CI = 1.3, 11.0) for three symptoms. The HR for one type of symptom, fluctuation, was 2.2 (95% CI = 1.2, 4.2). The presence of CAM core symptoms at baseline assessment predicts incident delirium in older LTC residents. These findings have potentially important implications for clinical practice and research in LTC settings.


Bronchoesophageal fistula: An unusual manifestation of lung cancer.
Bronchoesophageal fistula (BEF) is a rare condition caused by a fistulous connection between the bronchus and the esophagus. BEF can be acquired or congenital; congenital BEFs are rarely encountered in adults. Acquired BEF can be due to either a benign or a malignant process. Acquired BEF due to primary lung cancer is a life-threatening and usually a terminal complication. Unlike tracheoesophageal fistula, this condition is much rarer. Patients usually present with symptoms related to recurrent aspiration. Barium esophagogram is the initial diagnostic modality of choice. Treatment is primarily palliative. We are presenting a case of a bronchoesophageal fistula caused by non-small cell lung cancer that was successfully treated with concurrent chemoradiation therapy.


Characterization of a novel picornavirus isolate from a diseased European eel (Anguilla anguilla).
A novel picornavirus was isolated from specimens of a diseased European eel (Anguilla anguilla). This virus induced a cytopathic effect in eel embryonic kidney cells and high mortality in a controlled transmission study using elvers. Eel picornavirus has a genome of 7,496 nucleotides that encodes a polyprotein of 2,259 amino acids. It has a typical picornavirus genome layout, but its low similarity to known viral proteins suggests a novel species in the family Picornaviridae.


Two new piperidine alkaloids from the leaves of Microcos paniculata.
Two new piperidine alkaloids, microcosamines A (1) and B (2), were isolated from the leaves of Microcos paniculata. Their structures were elucidated by spectroscopic analysis. Both new compounds showed significant larvicidal activity against Culex quinquefasciatus.


Epiretinal membrane formation associated with idiopathic macular telangiectasia: case report.
A 46-year-old woman complained of blurred and distorted vision in both eyes. Ophthalmic examination showed that visual acuity was 20/200 for the right eye and counting fingers left eye. Fundoscopy revealed perimacular hemorrhages, aneurismal dilatation of the vessels in the posterior pole, and a white and elevated lesion adjacent to vascular changes. We report a case of idiopathic macular telangiectasia and epiretinal membrane that occurs concomitantly. To our knowledge, this is the first report that describes an association between idiopathic macular telangiectasia and epiretinal membrane formation.


Immunological tolerance: transmission from mother to offspring.
Mice born and raised by mothers made specifically unresponsive to heterologous erythrocytes by prior treatment with soluble extracts of these cells become themselves tolerant. Tolerance is achieved through nursing since normal neonates fostered by tolerant animals become tolerant, while animals born to tolerant mothers but nursed by normal mice are fully responsive.


Microfluidic device for studying cell migration in single or co-existing chemical gradients and electric fields.
Cell migration is involved in physiological processes such as wound healing, host defense, and cancer metastasis. The movement of various cell types can be directed by chemical gradients (i.e., chemotaxis). In addition to chemotaxis, many cell types can respond to direct current electric fields (dcEF) by migrating to either the cathode or the anode of the field (i.e., electrotaxis). In tissues, physiological chemical gradients and dcEF can potentially co-exist and the two guiding mechanisms may direct cell migration in a coordinated manner. Recently, microfluidic devices that can precisely configure chemical gradients or dcEF have been increasingly developed and used for chemotaxis and electrotaxis studies. However, a microfluidic device that can configure controlled co-existing chemical gradients and dcEF that would allow quantitative cell migration analysis in complex electrochemical guiding environments is not available. In this study, we developed a polydimethylsiloxane-based microfluidic device that can generate better controlled single or co-existing chemical gradients and dcEF. Using this device, we showed chemotactic migration of T cells toward a chemokine CCL19 gradient or electrotactic migration toward the cathode of an applied dcEF. Furthermore, T cells migrated more strongly toward the cathode of a dcEF in the presence of a competing CCL19 gradient, suggesting the higher electrotactic attraction. Taken together, the developed microfluidic device offers a new experimental tool for studying chemical and electrical guidance for cell migration, and our current results with T cells provide interesting new insights of immune cell migration in complex guiding environments.


Difference in the toxicity mechanism between ion and nanoparticle forms of silver in the mouse lung and in macrophages.
The health effects of silver nanoparticles (AgNPs) have not been well investigated, despite AgNPs now being widely used in consumer products. We investigated the metabolic behavior and toxicity of AgNPs in comparison to silver nitrate (AgNO3) both in vivo and in vitro. AgNPs (20 nm diameter) suspended in 1% albumin solution or AgNO3 solution was injected into the mouse lung. Less than 1% of the initial dose of AgNPs and more than 7% of the initial dose of AgNO3 was recovered in the liver 4h after administration, suggesting that the ionic form of silver was absorbed by the lung tissue and entered the systemic circulation more efficiently than AgNPs. The pro-inflammatory cytokine, IL-1β, and neutrophils in bronchoalveolar lavage fluid (BALF) increased following intratracheal instillation of AgNPs or AgNO3. AgNO3 recruited more neutrophils in the alveolar space than did AgNPs. In the in vitro study, AgNO3 was more cytotoxic than 20, 60, or 100 nm diameter AgNPs in a mouse macrophage cell line (J774.1). To investigate the intracellular distribution of Ag in detail, J774.1 cells were exposed to AgNO3 or 20 nm AgNPs and the distribution of Ag to cytosolic proteins was investigated using HPLC-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS). Ag was mainly distributed to metallothioneins (MT) and to high molecular weight proteins in AgNO3- and AgNPs-exposed cells, respectively. Confocal laser microscopic examination of LysoTracker(®)-labeled cells indicated that AgNPs were colocalized with lysosomes in J774.1 cells. These results suggest that AgNPs were transported to lysosomes and only gradually dissolved in the macrophages, causing milder inflammatory stimulation in the mouse lung compared to AgNO3.


Pancreatic fibrosis in chronic alcoholics and nonalcoholics without clinical pancreatitis.
A postmortem study was undertaken to determine the prevalence and nature of pancreatic injury in chronic alcoholics with no clinical pancreatitis. The material for this postmortem study was obtained from 101 entire pancreata. From five sites in each of the pancreata, sections were obtained and evaluated by two pathologists who used a 0-3 numerical grading of fibrosis. Forty-seven percent of the alcoholics had diffuse fibrosis of all five segments, in contrast to only 29% of the nonalcoholics. No fibrosis was present in 32% of the alcoholics and 56% of the nonalcoholics (p less than 0.05). The nonalcoholics tended to show an increase with age in the proportion of cases having fibrosis. The data suggest that there is ongoing pancreatic damage in chronic alcoholics before the onset of clinical pancreatitis.


Association between birth weight in preterm neonates and the BclI polymorphism of the glucocorticoid receptor gene.
Endogenous and exogenous glucocorticoids influence fetal growth and development, and maternal administration of synthetic glucocorticoids may decrease the risk of perinatal morbidity including lung disease in preterm neonates. Because polymorphisms of the glucocorticoid receptor gene are known to influence the sensitivity to glucocorticoids, in the present study we examined whether any associations could exist among the BclI, N363S and ER22/23EK polymorphisms of the glucocorticoid receptor gene and gestational age, birth weight and/or perinatal morbidity of 125 preterm neonates born at 28-35 weeks' gestation with (n=57) or without maternal dexamethasone treatment (n=68). The prevalence of the three polymorphisms in the whole group of preterm infants was similar to that reported in healthy adult Hungarian population. However, we found that the BclI polymorphism significantly associated with higher birth weight adjusted for the gestational age (p=0.004, ANOVA analysis). None of the three polymorphisms showed an association with perinatal morbidities, including necrotizing enterocolitis, intraventricular hemorrhagia, patent ductus arteriosus, respiratory distress syndrome, bronchopulmonary dysplasia and sepsis in the two groups of preterm neonates with and without maternal dexamethasone treatment. These results suggest that the BclI polymorphism of the glucocorticoid receptor gene may have an impact on gestational age-adjusted birth weight, but it does not influence perinatal morbidities of preterm neonates.


Endocannabinoids Have Opposing Effects On Behavioral Responses To Nociceptive And Non-nociceptive Stimuli.
The endocannabinoid system is thought to modulate nociceptive signaling making it a potential therapeutic target for treating pain. However, there is evidence that endocannabinoids have both pro- and anti-nociceptive effects. In previous studies using Hirudo verbana (the medicinal leech), endocannabinoids were found to depress nociceptive synapses, but enhance non-nociceptive synapses. Here we examined whether endocannabinoids have similar bidirectional effects on behavioral responses to nociceptive vs. non-nociceptive stimuli in vivo. Hirudo were injected with either the 2-arachidonoylglycerol (2-AG) or anandamide and tested for changes in response to nociceptive and non-nociceptive stimuli. Both endocannabinoids enhanced responses to non-nociceptive stimuli and reduced responses to nociceptive stimuli. These pro- and anti-nociceptive effects were blocked by co-injection of a TRPV channel inhibitor, which are thought to function as an endocannabinoid receptor. In experiments to determine the effects of endocannabinoids on animals that had undergone injury-induced sensitization, 2-AG and anandamide diminished sensitization to nociceptive stimuli although the effects of 2-AG were longer lasting. Sensitized responses to non-nociceptive stimuli were unaffected 2-AG or anandamide. These results provide evidence that endocannabinoids can have opposing effects on nociceptive vs. non-nociceptive pathways and suggest that cannabinoid-based therapies may be more appropriate for treating pain disorders in which hyperalgesia and not allodynia is the primary symptom.


Bronchiolitis: Recommendations for diagnosis, monitoring and management of children one to 24 months of age.
Bronchiolitis is the most common reason for admission to hospital in the first year of life. There is tremendous variation in the clinical management of this condition across Canada and around the world, including significant use of unnecessary tests and ineffective therapies. This statement pertains to generally healthy children ≤2 years of age with bronchiolitis. The diagnosis of bronchiolitis is based primarily on the history of illness and physical examination findings. Laboratory investigations are generally unhelpful. Bronchiolitis is a self-limiting disease, usually managed with supportive care at home. Groups at high risk for severe disease are described and guidelines for admission to hospital are presented. Evidence for the efficacy of various therapies is discussed and recommendations are made for management. Monitoring requirements and discharge readiness from hospital are also discussed.


Interplay of biomaterials and micro-scale technologies for advancing biomedical applications.
Micro-scale technologies have already dramatically changed our society through their use in the microelectronics and telecommunications industries. Today these engineering tools are also useful for many biological applications ranging from drug delivery to DNA sequencing, since they can be used to fabricate small features at a low cost and in a reproducible manner. The discovery and development of new biomaterials aid in the advancement of these micro-scale technologies, which in turn contribute to the engineering and generation of new, custom-designed biomaterials with desired properties. This review aims to present an overview of the merger of micro-scale technologies and biomaterials in two-dimensional (2D) surface patterning, device fabrication and three-dimensional (3D) tissue-engineering applications.


Primary pulmonary hypertension and coronary artery bypass surgery.
Coronary artery bypass surgery in patients with primary pulmonary hypertension is extremely rare. Right ventricular failure due to persistent elevation of pulmonary pressure is the most important complication in the postoperative period. Creation of an interatrial septal defect and reducing postoperative supraventricular arrhythmia by amiadarone infusion and continuous nasal oxygen therapy can reduce postoperative mortality and morbidity.


Use of botulinum toxin for movement disorders.
The term movement disorders encompasses all disorders hypokinetic and hyperkinetic, which were previously known as extrapyramidal syndromes. With the definition of movement disorders and their diagnostic criteria and classifications, new studies for therapeutics could be performed. New drugs were launched, functional neurosurgery was developed, and the introduction of botulinum toxin (BoNT) for hyperkinesias was introduced. BoNT is an important therapy for dystonia, tics, myoclonus, and tremors. The aim of this review is to present the new and well-established uses of BoNT for movement disorders.