Immunohistochemical distribution of cyclic GMP-dependent protein kinase-1 in human prostate tissue.
Phosphodiesterase 5 (PDE5) inhibitors improve smooth muscle relaxation and therefore are considered for pharmacotherapy of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). Cyclic guanosine monophosphate (cGMP)-dependent protein kinase-1 (cGKI) has been identified as one of the downstream targets for cGMP. The aim of the present study was to evaluate, by means of immunohistochemistry and Western blot analysis, the expression and localization of cGKI isoforms in relation to smooth muscle alpha-actin and cGMP in the human prostate. Cryostat sections of tissue segments excised from the transition zone of human prostates from 11 patients (aged 54-68 yr) were incubated with primary antibodies directed against smooth muscle alpha-actin, cGMP, cGKI, cGKIalpha, and cGKIbeta. Visualization of double-labelled immunofluorescent staining was achieved by laser microscopy. Western blot analysis was performed to confirm the expression of cGKI isoforms. Immunoreactivities specific for cGKI, cGKIalpha, and cGKIbeta were observed in the smooth musculature of the transition zone. Double-staining revealed the colocalization of smooth muscle alpha-actin, cGMP, and cGKI isoforms in smooth muscle cells of the fibromuscular stroma. The expression of cGKI isoforms was confirmed by Western blot analysis. Our results confirm the presence of cGKI isoforms alpha and beta in the transition zone of human prostate tissue. In addition, the colocalization of alpha-actin, cGMP, and cGKI isoforms provides further evidence for a significant role of the nitric oxide/cGMP pathway in the regulation of smooth muscle contractility in human prostate tissue and therefore could provide additional targets for pharmacotherapy of BPH and LUTS.


Do recruitment SWAT interventions have an impact on participant retention in randomised controlled trials? A systematic review.
Evidence-based methods for randomised controlled trial recruitment and retention are extremely valuable. Despite increased testing of these through studies within a trial, there remains limited high-certainty evidence for effective strategies. In addition, there has been little consideration as to whether recruitment interventions also have an impact on participant retention. A systematic review was conducted. Studies were eligible if they were randomised controlled trials using a recruitment intervention and which also assessed the impact of this on retention at any time point. Searches were conducted through MEDLINE, EMBASE, Cochrane Library, and the Northern Ireland Hub for Trials Methodology Research SWAT Repository. Two independent reviewers screened the search results and extracted data for eligible studies using a piloted extraction form. A total of 7815 records were identified, resulting in 10 studies being included in the review. Most studies (n = 6, 60%) focussed on the information given to participants (n = 6, 60%), with two (20%) focussing on incentives, and two focussing on trial design and recruiter interventions. Due to intervention heterogeneity, none of the interventions could be meta-analysed. Only one study found any statistically significant effect of letters including a photograph (odds ratio: 5.40, 95% CI 1.12-26.15, p = 0.04). Assessment of the impacts of recruitment strategies, evaluated in a SWAT, on retention of participants in the host trial remains limited. Assessment of the impact of recruitment interventions on retention is recommended to minimise future research costs and waste.


Patterns of patient presentation to a Dublin urban emergency department with assault related injuries.
After perceiving an increase in the number of patients attending a large urban Irish Emergency Department (ED) with injuries sustained in assaults, the authors sought to examine the issue. A prospective observational study was conducted to look at the demographic profiles of victim and perpetrator, at rates of crime reporting and at the level of follow-up care arranged in the ED. Those most commonly assaulted were young Irish males who usually sustained head or facial injuries during weekend nights. Glass was the weapon most often used. Less than two-thirds of all victims planned to report the incident to the Garda Siochana (the Irish national police force). Women assaulted by their partners were least likely to involve the police. One fifth of patients required admission. Violence in Dublin's inner city is now a major health issue.


Cigarette smoke exposure inhibits contact hypersensitivity via the generation of platelet-activating factor agonists.
Previous studies have established that pro-oxidative stressors suppress host immunity because of their ability to generate oxidized lipids with platelet-activating factor receptor (PAF-R) agonist activity. Although exposure to the pro-oxidative stressor cigarette smoke (CS) is known to exert immunomodulatory effects, little is known regarding the role of PAF in these events. The current studies sought to determine the role of PAF-R signaling in CS-mediated immunomodulatory effects. We demonstrate that CS exposure induces the generation of a transient PAF-R agonistic activity in the blood of mice. CS exposure inhibits contact hypersensitivity in a PAF-R-dependent manner as PAF-R-deficient mice were resistant to these effects. Blocking PAF-R agonist production either by systemic antioxidants or treatment with serum PAF-acetyl hydrolase enzyme blocked both the CS-mediated generation of PAF-R agonists and PAF-R-dependent inhibition of contact hypersensitivity (CHS) reactions, indicating a role for oxidized glycerophosphocholines with PAF-R agonistic activity in this process. In addition, cyclooxygenase-2 inhibition did not block PAF-R agonist production but prevented CS-induced inhibition of CHS. This suggests that cyclooxygenase-2 acts downstream of the PAF-R in mediating CS-induced systemic immunosuppression. Moreover, CS exposure induced a significant increase in the expression of the regulatory T cell reporter gene in Foxp3(EGFP) mice but not in Foxp3(EGFP) mice on a PAF-R-deficient background. Finally, regulatory T cell depletion via anti-CD25 Abs blocked CS-mediated inhibition of CHS, indicating the potential involvement of regulatory T cells in CS-mediated systemic immunosuppression. These studies provide the first evidence, to our knowledge, that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF-R agonists produced through lipid oxidation.


The N terminus of the cardiac L-type Ca(2+) channel alpha(1C) subunit. The initial segment is ubiquitous and crucial for protein kinase C modulation, but is not directly phosphorylated.
The first 46 amino acids (aa) of the N terminus of the rabbit heart (RH) L-type cardiac Ca(2+) channel alpha(1C) subunit are crucial for the stimulating action of protein kinase C (PKC) and also hinder channel gating (Shistik, E., Ivanina, T., Blumenstein, Y., and Dascal, N. (1998) J. Biol. Chem. 273, 17901-17909). The mechanism of PKC action and the location of the PKC target site are not known. Moreover, uncertainties in the genomic sequence of the N-terminal region of alpha(1C) leave open the question of the presence of RH-type N terminus in L-type channels in mammalian tissues. Here, we demonstrate the presence of alpha(1C) protein containing an RH-type initial N-terminal segment in rat heart and brain by using a newly prepared polyclonal antibody. Using deletion mutants of alpha(1C) expressed in Xenopus oocytes, we further narrowed down the part of the N terminus crucial for both inhibitory gating and for PKC effect to the first 20 amino acid residues, and we identify the first 5 aa as an important determinant of PKC action and of N-terminal effect on gating. The absence of serines and threonines in the first 5 aa and the absence of phosphorylation by PKC of a glutathione S-transferase-fusion protein containing the initial segment suggest that the effect of PKC does not arise through a direct phosphorylation of this segment. We propose that PKC acts by attenuating the inhibitory action of the N terminus via phosphorylation of a remote site, in the channel or in an auxiliary protein, that interacts with the initial segment of the N terminus.


Rehabilitation Exergames: Use of Motion Sensing and Machine Learning to Quantify Exercise Performance in Healthy Volunteers.
Performing physiotherapy exercises in front of a physiotherapist yields qualitative assessment notes and immediate feedback. However, practicing the exercises at home lacks feedback on how well patients are performing the prescribed tasks. The absence of proper feedback might result in patients performing the exercises incorrectly, which could worsen their condition. We present an approach to generate performance scores to enable tracking the progress by both the patient at home and the physiotherapist in the clinic. This study aims to propose the use of 2 machine learning algorithms, dynamic time warping (DTW) and hidden Markov model (HMM), to quantitatively assess the patient's performance with respect to a reference. Movement data were recorded using a motion sensor (Kinect V2), capable of detecting 25 joints in the human skeleton model, and were compared with those of a reference. A total of 16 participants were recruited to perform 4 different exercises: shoulder abduction, hip abduction, lunge, and sit-to-stand exercises. Their performance was compared with that of a physiotherapist as a reference. Both algorithms showed a similar trend in assessing participant performance. However, their sensitivity levels were different. Although DTW was more sensitive to small changes, HMM captured a general view of the performance, being less sensitive to the details. The chosen algorithms demonstrated their capacity to objectively assess the performance of physical therapy. HMM may be more suitable in the early stages of a physiotherapy program to capture and report general performance, whereas DTW could be used later to focus on the details. The scores enable the patient to monitor their daily performance. They can also be reported back to the physiotherapist to track and assess patient progress, provide feedback, and adjust the exercise program if needed.


BIBF 1120/ nintedanib : a new triple angiokinase inhibitor-directed therapy in patients with non-small cell lung cancer.
Several new targeted agents with anti-angiogenic properties have been developed recently, including vandetanib, sunitinib, sorafenib, bevacizumab and others. Tumor development, progression, metastasis are strongly linked to angiogenesis. Targeted agents like bevacizumab, a monoclonal antibody which targets VEGF, have been fully developed in several solid tumors. These new agents strongly advocate that targeting angiogenesis is one of the best approaches for cancer therapy. Those agents that target additional pro-angiogenic intracellular signaling pathways beyond VEGF signaling have also the potential to contribute to anticancer therapies. The authors present here nintedanib (BIBF 1120), a triple angiokinase inhibitor. It targets not only VEGFRs, but also FGFR and PDGFR. All the available clinical information regarding Phase I - II trials and the toxicity and efficacy of BIBF 1120 both as single agent and in combination with cytotoxic agents in non-small cell lung cancer (NSCLC) is reviewed and discussed here. Up till now, Phase I and II trials with nintedanib showed an improvement for survival of advanced NSCLC patients. Tolerability profile seems to be acceptable in these clinical trials. However, Phase III trials are mandatory to translate these findings into clinical practice. The research for predictive biomarkers could improve the success of these anti-angiogenic agents.


Why two heads apart are better than two heads together: multiple mechanisms underlie the collaborative inhibition effect in memory.
Although a group of people working together remembers more than any one individual, they recall less than their predicted potential. This finding is known as collaborative inhibition and is generally thought to arise due to retrieval disruption. However, there is growing evidence that is inconsistent with the retrieval disruption account, suggesting that additional mechanisms also contribute to collaborative inhibition. In the current studies, we examined 2 alternate mechanisms: retrieval inhibition and retrieval blocking. To identify the contributions of retrieval disruption, retrieval inhibition, and retrieval blocking, we tested how collaborative recall of entirely unshared information influences subsequent individual recall and individual recognition memory. If collaborative inhibition is due solely to retrieval disruption, then there should be a release from the negative effects of collaboration on subsequent individual recall and recognition tests. If it is due to retrieval inhibition, then the negative effects of collaboration should persist on both individual recall and recognition memory tests. Finally, if it is due to retrieval blocking, then the impairment should persist on subsequent individual free recall, but not recognition, tests. Novel to the current study, results suggest that retrieval inhibition plays a role in the collaborative inhibition effect. The negative effects of collaboration persisted on a subsequent, always-individual, free-recall test (Experiment 1) and also on a subsequent, always-individual, recognition test (Experiment 2). However, consistent with the retrieval disruption account, this deficit was attenuated (Experiment 1). Together, these results suggest that, in addition to retrieval disruption, multiple mechanisms play a role in collaborative inhibition. (PsycINFO Database Record (c) 2015 APA, all rights reserved).


The unusually slow unfolding rate causes the high stability of pyrrolidone carboxyl peptidase from a hyperthermophile, Pyrococcus furiosus: equilibrium and kinetic studies of guanidine hydrochloride-induced unfolding and refolding.
To elucidate the energetic features of the anomalously high-level stabilization of a hyperthermophile pyrrolidone carboxyl peptidase (PfPCP) from a hyperthermophilic archaeon, Pyrococcus furiosus, equilibrium and kinetic studies of the guanidine hydrochloride (GuHCl)-induced unfolding and refolding were carried out with CD measurements at 220 nm in comparison with those from the mesophile homologue (BaPCP) from Bacillus amyloliquefaciens. The mutant protein of PfPCP substituted with Ser at both Cys142 and Cys188 (PfC142/188S) was used. The GuHCl unfolding for PfC142/188S and BaPCP was reversible. It was difficult to obtain the equilibrated unfolding curve of the hyperthermophile proteins at temperatures below 50 degreesC and pH 7, because of the remarkably slow rate of the unfolding. The unfolding for PfC142/188S attained equilibrium after 7 days at 60 degreesC, resulting in the coincidence between the unfolding and refolding curves. The Gibbs energy change of unfolding, DeltaGH2O (56.6 kJ/mol), for PfC142/188S at 60 degreesC and pH 7 was dramatically higher than that (7.6 kJ/mol) for BaPCP at 40 degreesC and pH 7. The unfolding and refolding kinetics for PfC142/188S and BaPCP at both 25 and 60 degreesC at pH 7 were approximated as a single exponential. The rate constant in water (kuH2O) of the unfolding reaction for PfC142/188S (1.6 x 10(-)15 s-1) at 25 degreesC and pH 7 was drastically reduced by 7 orders of magnitude compared to that (1.5 x 10(-)8 s-1) for BaPCP, whereas the refolding rates (krH2O) in water for PfC142/188S (9.3 x 10(-)2 s-1) and BaPCP (3.6 x 10(-)1 s-1) at 25 degreesC and pH 7 were similar. These results indicate that the greater stability of the hyperthermophile PCP was characterized by the drastically slow unfolding rate.


Supernumerary tooth in nasopalatine canal: a rare cause of septal cartilage collapse.
Mesiodens is the most common type of supernumerary tooth, located between the maxillary central incisors in close relation to the nasopalatine canal. A 20-year-old man presented with right-sided nasal blockage, nasal discharge and collapsed nose without history of trauma. Imaging revealed a calcified mass in the inferior meatus extending into dilated nasopalatine canal. Endoscopic removal of the mass revealed tuberculate appearance of an incompletely developed tooth, consistent with mesiodens. Based on the history of septal cartilage collapse with right-sided mucopurulent discharge, endoscopic findings of the right inferior turbinate being adherent to the septal cartilage and the underlying mesiodens, we believe that the patient developed a septal abscess secondary to infection in nasal mucosa surrounding the mesiodens causing collapse of septal cartilage. While a tooth or tooth-like mass causing nasal passage air-flow obstruction is uncommon, we believe that this is the first reported case of mesiodens presenting with septal cartilage collapse.


Molecular markers of cancer in cartilaginous fish: immunocytochemical study of PCNA, p-53, myc and ras expression in neoplastic and hyperplastic tissues from free ranging blue sharks, Prionace glauca (L.).
Archival formalin-fixed tissues from wild-caught adult blue sharks, Prionace glauca (L.), were used for immunocytochemical detection of proliferating cell nuclear antigen (PCNA), two oncoproteins from the oncogenes c-myc and pan-ras, and a protein product from the tumour suppressor gene p-53. All sharks were caught during summer months between 2000 and 2006 by recreational fishermen off the USA coast in the northwestern Atlantic. The sharks were necropsied on landing and selected organ samples were collected into elasmobranch formalin and processed for paraffin embedding and light microscopy. Paraffin-embedded sections from collected tissue were both stained with haematoxylin and eosin and processed by immunocytochemical techniques using antibodies raised against the PCNA, p-ras, c-myc and p-53 proteins. The lesions examined in this study included two well differentiated adenomatous gastric polyps, a testicular capsular mesothelioma, a gingival fibropapilloma with elements of ameloblastoma, three liver tumours, two pericardial fibropapillomas and six cases of proliferative serositis (pericarditis and peritonitis). Normal and hyperplastic tissues from blue sharks, and human neoplastic tissues served as negative and positive controls, respectively. We detected upregulation of PCNA in many neoplastic, one dysplastic and in some hyperplastic lesions, and positive p-ras and c-myc signals in some of the neoplastic lesions. None of the examined tissues showed positive p-53 signalling. This is the first literature report on immunocytochemical detection of molecular markers of cancer in sharks and in fish of the class Chondrichthyes.


Association of interferon lambda polymorphisms with elevated baseline viral loads in chronic hepatitis C virus genotype 6 infection.
Globally, hepatitis C virus (HCV) is one of the major causes of hepatocellular carcinoma and liver cirrhosis. For clinical decision making, genetic variation in the interferon-λ (IFNL) cluster has been utilised as a baseline predictor of natural and interferon-based treatment-induced viral clearance. In Vietnam, where HCV genotypes 1 (g1) and g6 predominate, no prior studies have been conducted investigating associations of IFNL3/4 polymorphisms with spontaneous clearance (SC) or HCV viral load (VL) in chronic infection. In this study, we have investigated the host genetic variations in IFNL loci to determine the association of IFNL3/4 polymorphisms with HCV SC and baseline VLs in a Vietnamese HCV-seropositive cohort. The majority of the cohort harboured major homozygous polymorphisms in IFNL3/4 cluster (i.e. rs12979860-CC: 82.7%; rs8099917-TT: 84.8% and rs368234815-TT/TT: 85.5%) and the SC rates in these groups were 15.8%, 16.3% and 15.7%, respectively. In the minor allele groups, the resolution rates were lower (12% in rs12979860 non-CC, 9.1% in rs8099917 non-TT and 9.5% in rs368234815 non-TT/TT). Furthermore, in individuals harbouring minor alleles, females achieved higher SC rates than males. HCV g6-infected rs12979860 major homozygous individuals had significantly higher viral loads than individuals with minor alleles (CC: 6.56 log IU/ml vs. non-CC: 5.66 log IU/ml; P = 0.021). The association between IFNL3/4 genotypes with elevated HCV VL observed in HCV g6-infected individuals may have implications for the progression of liver disease in Southeast Asian countries where this viral genotype predominates and therefore warrants further studies.


The unfolded protein response and programmed cell death are induced by expression of Garlic virus X p11 in Nicotiana benthamiana.
Garlic virus X (GarVX) ORF3 encodes a p11 protein, which contributes to virus cell-to-cell movement and forms granules on the endoplasmic reticulum (ER) in Nicotiana benthamiana. Expression of p11 either from a binary vector, PVX or TMV induced ER stress and the unfolded protein response (UPR), as demonstrated by an increase in transcription of the ER luminal binding protein (BiP) and bZIP60 genes. UPR-related programmed cell death (PCD) was elicited by PVX : p11 or TMV : p11 in systemic infected leaves. Examination of p11 mutants with deletions of two transmembrane domains (TM) revealed that both were required for generating granules and for inducing necrosis. TRV-based VIGS was used to investigate the correlation between bZIP60 expression and p11-induced UPR-related PCD. Less necrosis was observed on local and systemic leaves of bZIP60 knockdown plants when infected with PVXp11, suggesting that bZIP60 plays an important role in the UPR-related PCD response to p11 in N. benthamiana.


Unconventional Perfusion Flaps in the Experimental Setting: A Systematic Review and Meta-Analysis.
Unconventional perfusion flaps offer multiple potential advantages compared with traditional flaps. Although there are numerous experimental articles on unconventional perfusion flaps, the multiple animal species involved, the myriad vascular constructions used, and the frequently conflicting data reported make synthesis of this information challenging. The main aim of this study was to perform a systematic review and meta-analysis of the literature on the experimental use of unconventional perfusion flaps, to identify the best experimental models proposed and to estimate their global survival rate. The authors performed a systematic review and meta-analysis of all articles written in English, French, Italian, Spanish, and Portuguese on the experimental use of unconventional perfusion flaps and indexed to PubMed from 1981 until February 1, 2017. A total of 68 studies were found, corresponding to 86 optimized experimental models and 1073 unconventional perfusion flaps. The overall unconventional perfusion flap survival rate was 90.8 percent (95 percent CI, 86.9 to 93.6 percent; p < 0.001). The estimated proportion of experimental unconventional perfusion flaps presenting complete survival or nearly complete survival was 74.4 percent (95 percent CI, 62.1 to 83.7 percent; p < 0.001). The most commonly reported animal species in the literature were the rabbit (57.1 percent), the rat (26.4 percent), and the dog (14.3 percent). No significant differences were found in survival rates among these species, or among the diverse vascular patterns used. These data do not differ significantly from those reported regarding the use of unconventional perfusion flaps in human medicine, suggesting that rabbit, rat, and canine experimental unconventional perfusion flap models may adequately mimic the clinical application of unconventional perfusion flaps.


Immunogenic chemotherapy with cyclophosphamide and doxorubicin against established murine carcinoma.
Mitigation of regulatory T cell-mediated immunosuppression and elicitation of immunogenic tumor cell death are crucial events for optimal anti-tumor immune activity in vivo. This study was designed to investigate the potential synergistic activity of the combined use of cyclophosphamide (CP) and doxorubicin (DR), both of which are known to resolve these two issues. BALB/c mice were inoculated subcutaneously with CT-26 carcinoma cells in the bilateral flank and treated with an intraperitoneal injection of a low dose of CP followed by an intratumoral injection of DR into one side of the tumor. We found that, in addition to a significant suppression of growth on the DR-treated side of the tumor, combination therapy suppressed the growth of DR-untreated remote tumors in both tumor-specific and T cell-dependent manners. Mitomycin C showed no such synergistic anti-tumor activity with CP treatment. Combination therapy increased the frequency of interferon (IFN)-gamma-producing T lymphocytes specific to a CT-26-associated class I-binding tumor peptide in the tumor-draining lymph nodes. Real-time PCR analysis revealed that combination therapy led to an increase in IFN-gamma and tumor necrosis factor-alpha mRNA expression; however, levels of Foxp3 and transforming growth factor-beta within the remote tumor tissues were decreased. In addition, knock down of calreticulin expression in CT-26 cells using small interfering RNA attenuated anti-tumor vaccine effects induced by DR-treated CT-26 cells. These results provide an immunological rationale for the combined use of chemotherapeutic drugs, i.e., CP and DR, and further recommend their use with current cancer vaccines.


Bubbling cell death: A hot air balloon released from the nucleus in the cold.
Cell death emanating from the nucleus is largely unknown. In our recent study, we determined that when temperature is lowered in the surrounding environment, apoptosis stops and bubbling cell death (BCD) occurs. The study concerns the severity of frostbite. When exposed to severe cold and strong ultraviolet (UV) irradiation, people may suffer serious damages to the skin and internal organs. This ultimately leads to limb amputations, organ failure, and death. BCD is defined as "formation of a single bubble from the nucleus per cell and release of this swelling bubble from the cell surface to extracellular space that causes cell death." When cells are subjected to UV irradiation and/or brief cold shock (4℃ for 5 min) and then incubated at room temperature or 4℃ for time-lapse microscopy, each cell releases an enlarging nuclear gas bubble containing nitric oxide. Certain cells may simultaneously eject hundreds or thousands of exosome-like particles. Unlike apoptosis, no phosphatidylserine flip-over, mitochondrial apoptosis, damage to Golgi complex, and chromosomal DNA fragmentation are shown in BCD. When the temperature is increased back at 37℃, bubble formation stops and apoptosis restarts. Mechanistically, proapoptotic WW domain-containing oxidoreductase and p53 block the protective TNF receptor adaptor factor 2 that allows nitric oxide synthase 2 to synthesize nitric oxide and bubble formation. In this mini-review, updated knowledge in cell death and the proposed molecular mechanism for BCD are provided.


Pancreatic involvement in chronic viral hepatitis.
To elucidate the frequency and characteristics of pancreatic disorders in the course of chronic viral hepatitis. We prospectively assessed the serum pancreatic enzyme levels and imaging findings in patients with chronic viral hepatitis and healthy control subjects. Serum amylase (t-Amy), salivary amylase (s-Amy), pancreatic amylase (p-Amy) and serum lipase levels were higher in hepatitis patients in comparison to control subjects. However, in asymptomatic viral carriers, only the serum t-Amy levels were higher than those of the controls. The levels of each enzyme rose with the progression of liver disease in patients with hepatitis B or C; whereas the levels of each enzyme within the same clinical stage of the disease did not differ between patients diagnosed with either hepatitis B or hepatitis C virus. Imaging findings demonstrated chronic pancreatitis in only 1 out of 202 patients (0.5%). Our data suggest that serum levels of pancreatic enzymes increase with the progression of liver disease in patients diagnosed with viral hepatitis. Pancreatic disease, asymptomatic in most cases, may represent an extrahepatic manifestation of chronic viral hepatitis.


The impact of modal interference on the beam quality of high-power fiber amplifiers.
Recent work on high-power fiber amplifiers report on a degradation of the output beam quality or even on the appearance of mode instabilities. By combining the transversally resolved rate equations with a 3D Beam propagation method we have managed to create a model able to provide an explanation of what we believe is at the root of this effect. Even though this beam quality degradation is conventionally linked to transversal hole burning, our simulations show that this alone cannot explain the effect in very large mode area fibers. According to the model presented in this paper, the most likely cause for the beam quality degradation is an inversion-induced grating created by the interplay between modal interference along the fiber and transversal hole burning.


Outbreak of African tick-bite fever in six Italian tourists returning from South Africa.
In May 1999, a cluster of cases of African tick-bite fever was detected in six Italian tourists who had returned from South Africa. All of the patients had moderate fever and cutaneous eschars. Regional lymphangitis was observed in three of the patients and skin rash in two. By comparing the number of eschars with the number of detectable bite sites it was suggested that at least two-thirds of the biting vectors were capable of transmitting Rickettsia africae. The clinical course of disease was mild in all cases, and all but one of the patients recovered spontaneously before antibiotic treatment was initiated. The diagnosis of African tick-bite fever was confirmed serologically using both microimmunofluorescence and Western blot tests.


Trends in patient encounters: implications for family medicine clerkships.
Adequate and equivalent clinical experience is related to the number and diagnoses of patients encountered and should provide students with experiences similar to community practice. This study compares the distribution of diagnoses family medicine clerkship students encountered at a Midwest medical school during 2009-2011 with both 1997-1999 data and the 2010 National Ambulatory Medical Care Survey (NAMCS) samples of family physicians and all physicians. Electronically submitted encounter data (2009-2011) were compared to logbook data (1997-1999) and to the 2010 NAMCS data listing primary diagnoses at office visits in the United States by major disease category. Of the 15 diagnoses with ≥150 encounters, seven increased and eight decreased between the two time periods. The relative percent ratio of clerkship diagnoses distribution to the NAMCS family physician distribution revealed that diagnoses ratios were ≤100% in eight categories (clerkship experiences<national) and greater than the national distribution in seven categories. As medical care services and settings change, documenting comprehensive clinical experiences will be valuable to respond to changes in patient presentations in family physician offices, both locally and nationally. Patient encounter data evaluations should be used to ensure students' clinical experiences are adequate, equivalent, and reflective of community practice. Continuous assessment of student experiences is essential due to shifts in prevalence, practice characteristics, and changes in patient preferences.


Appropriateness of breast-conserving treatment of breast carcinoma in women with germline mutations in BRCA1 or BRCA2: a clinic-based series.
Although BRCA1 and BRCA2 were identified in 1994 and 1995, respectively, to the authors' knowledge the optimal management of women with BRCA-associated breast carcinoma remains incompletely defined. The current study evaluates the appropriateness of breast-conserving therapy (BCT) in women with BRCA mutations. Between May 1992 and October 2003, 87 female participants in genetic testing protocols were identified who 1) were found to have deleterious germline BRCA mutations and 2) reported a history of invasive breast carcinoma that was treated with wide local excision and radiation therapy. Clinical records were reviewed and follow-up was updated. The 87 subjects underwent BCT for 95 invasive breast tumors (8 women received BCT for metachronous bilateral tumors). In all 95 treated breasts, the 5-year and 10-year probabilities of metachronous ipsilateral breast carcinoma (MIBC) were 11.2% and 13.6%, respectively. Among the 87 subjects, the 5-year and 10-year probabilities of metachronous contralateral breast carcinoma (CBC) after treatment of the index tumor were 11.9% and 37.6%. No clinical factors were identified that were associated with either MIBC or CBC, including the use of tamoxifen or chemotherapy. Women with BRCA-associated breast carcinoma who undergo BCT appear to have risks of MIBC that are similar to those reported for young women without known mutations. The indications for unilateral mastectomy in this group of women should be the same as those for women with nonhereditary carcinoma. However, significant risks of CBC and possibly late MIBC may prompt the serious consideration of bilateral mastectomy as a preventive measure.


Effect of antiorthostatic bed rest on the human body.
Head-down (-4 degrees) bedrest brings about a more rapid development of changes in haemodynamics, fluid displacement and nervous tone than traditional recumbent bed rest. Changes occurring during head-down hypokinesia have much in common with the changes typical of real weightlessness. They are characterized by phasic changes in the vascular tone. Under these conditions changes in the tone and blood-filling of the brain are important for the functional state of the vestibular apparatus.


Regularization Parameter Selections via Generalized Information Criterion.
We apply the nonconcave penalized likelihood approach to obtain variable selections as well as shrinkage estimators. This approach relies heavily on the choice of regularization parameter, which controls the model complexity. In this paper, we propose employing the generalized information criterion (GIC), encompassing the commonly used Akaike information criterion (AIC) and Bayesian information criterion (BIC), for selecting the regularization parameter. Our proposal makes a connection between the classical variable selection criteria and the regularization parameter selections for the nonconcave penalized likelihood approaches. We show that the BIC-type selector enables identification of the true model consistently, and the resulting estimator possesses the oracle property in the terminology of Fan and Li (2001). In contrast, however, the AIC-type selector tends to overfit with positive probability. We further show that the AIC-type selector is asymptotically loss efficient, while the BIC-type selector is not. Our simulation results confirm these theoretical findings, and an empirical example is presented. Some technical proofs are given in the online supplementary material.


"What next now that you are sixty?" - Preliminary exploration of the self-reported aspirations of community-dwelling older persons in the Western Cape Province, South Africa within the active aging framework.
Future aspirations of older persons should interest professionals involved in health promotion services in view of World Health Organization's Active Aging Framework. With the South African government's plan to raise life expectancy to 70 years by 2030, there is likelihood that life expectancy at 60 years will increase. Future aspirations give motivations for living, with short and long-term goals to work toward. As part of a larger study exploring the profile of members of 35 Service Centers for Older Persons in the Western Cape Province, selected using stratified random sampling, this manuscript reports on the qualitative responses relating to the self-determined future aspirations of the members. Thematic analysis was utilized to explore the aspirations of 625 members, aged 60-100 years. The aspirations were classified into two, namely aspirations with and without possible future-oriented behavior. Separate six and three themes were identified respectively in the first and second categories of aspirations. Being members of centers meant to provide programs to enhance their future, an awareness of the future aspirations of older persons should inform the services provided to encourage older persons identify something to live for.


Health behaviours, socioeconomic status, and mortality: further analyses of the British Whitehall II and the French GAZEL prospective cohorts.
Differences in morbidity and mortality between socioeconomic groups constitute one of the most consistent findings of epidemiologic research. However, research on social inequalities in health has yet to provide a comprehensive understanding of the mechanisms underlying this association. In recent analysis, we showed health behaviours, assessed longitudinally over the follow-up, to explain a major proportion of the association of socioeconomic status (SES) with mortality in the British Whitehall II study. However, whether health behaviours are equally important mediators of the SES-mortality association in different cultural settings remains unknown. In the present paper, we examine this issue in Whitehall II and another prospective European cohort, the French GAZEL study. We included 9,771 participants from the Whitehall II study and 17,760 from the GAZEL study. Over the follow-up (mean 19.5 y in Whitehall II and 16.5 y in GAZEL), health behaviours (smoking, alcohol consumption, diet, and physical activity), were assessed longitudinally. Occupation (in the main analysis), education, and income (supplementary analysis) were the markers of SES. The socioeconomic gradient in smoking was greater (p<0.001) in Whitehall II (odds ratio [OR] = 3.68, 95% confidence interval [CI] 3.11-4.36) than in GAZEL (OR = 1.33, 95% CI 1.18-1.49); this was also true for unhealthy diet (OR = 7.42, 95% CI 5.19-10.60 in Whitehall II and OR = 1.31, 95% CI 1.15-1.49 in GAZEL, p<0.001). Socioeconomic differences in mortality were similar in the two cohorts, a hazard ratio of 1.62 (95% CI 1.28-2.05) in Whitehall II and 1.94 in GAZEL (95% CI 1.58-2.39) for lowest versus highest occupational position. Health behaviours attenuated the association of SES with mortality by 75% (95% CI 44%-149%) in Whitehall II but only by 19% (95% CI 13%-29%) in GAZEL. Analysis using education and income yielded similar results. Health behaviours were strong predictors of mortality in both cohorts but their association with SES was remarkably different. Thus, health behaviours are likely to be major contributors of socioeconomic differences in health only in contexts with a marked social characterisation of health behaviours. Please see later in the article for the Editors' Summary.


Frontal and parietal components of a cerebral network mediating voluntary attention to novel events.
Despite the important role that attending to novel events plays in human behavior, there is limited information about the neuroanatomical underpinnings of this vital activity. This study investigated the relative contributions of the frontal and posterior parietal lobes to the differential processing of novel and target stimuli under an experimental condition in which subjects actively directed attention to novel events. Event-related potentials were recorded from well-matched frontal patients, parietal patients, and non-brain-injured subjects who controlled their viewing duration (by button press) of line drawings that included a frequent, repetitive background stimulus, an infrequent target stimulus, and infrequent, novel visual stimuli. Subjects also responded to target stimuli by pressing a foot pedal. Damage to the frontal cortex resulted in a much greater disruption of response to novel stimuli than to designated targets. Frontal patients exhibited a widely distributed, profound reduction of the novelty P3 response and a marked diminution of the viewing duration of novel events. In contrast, damage to posterior parietal lobes was associated with a substantial reduction of both target P3 and novelty P3 amplitude; however, there was less disruption of the processing of novel than of target stimuli. We conclude that two nodes of the neuroanatomical network for responding to and processing novelty are the prefrontal and posterior parietal regions, which participate in the voluntary allocation of attention to novel events. Injury to this network is indexed by reduced novelty P3 amplitude, which is tightly associated with diminished attention to novel stimuli. The prefrontal cortex may serve as the central node in determining the allocation of attentional resources to novel events, whereas the posterior parietal lobe may provide the neural substrate for the dynamic process of updating one's internal model of the environment to take into account a novel event.


Adverse consequences of low-dose methotrexate medication errors: data from French poison control and pharmacovigilance centers.
The objectives of this study are to carefully describe the context of methotrexate medication errors, to details medical consequences and management approaches, and to determine the rate of fatal outcome. Data on methotrexate medication errors were obtained from the French network of poison control and pharmacovigilance centres, which collected and documented reported drug-induced adverse effects. Cases were included if the intake was more than 2-fold the intended weekly dose or a weekly cumulative dose ≥ 30 mg and a follow-up of at least 4 days after the last dose. Data were analysed for demographics, treatment indication, prescribed dose, drug interactions, clinical complications and medical outcomes. Seventy four patients were included. The causes of methotrexate errors resulted from an erroneous prescription renewal (23.3%), incomprehensiveness of the weekly schedule by patients or at-home caregivers (56.2%) and administration of a wrong dose by a health care professional (20.5%). Of the 70 patients who took methotrexate daily, the mean daily dose received over the whole duration of the error was 9.6 ± 4.1 mg (range 2.5-22.5) with a mean duration of the error of 11.7 ± 12.2 days (range 2 to 90). Thirteen (18%) patients remained asymptomatic and 61 (82%) developed complications of which 46 (62.2%) were severe. Nine (14.8%) patients died within 11 to 45 days after the first dosing error. Compared to patients with no or mild symptoms, those with severe symptoms were more likely to be older (75.6 ± 10.8 vs. 69.5 ± 12.9 years) and to be exposed to a higher cumulative dose (94.8 ± 46.2 vs. 68.0 ± 45.7 mg). This study confirms that dosing errors with methotrexate can be lethal and persisted despite several warnings from drug agencies. Further measures are awaited from the European Medicine Agency.


ESC Education Committee.
The European Society of Cardiology plans to become the postgraduate Academy of Cardiology and sub-specialties. This explains the role of education and, as a consequence, the importance of the education committee in the activities of the ESC.


Human long-term deregulated circadian rhythm alters regenerative properties of skin and hair precursor cells.
In mammals, desynchronized circadian rhythm leads to various biological symptoms. In skin and hair, human epidermal stem cell function in vitro is regulated by circadian oscillations, and thus contributes to tissue aging when deregulated. In mice, circadian arrhythmia of hair follicle stem cells contributes to age-related hair follicle cycling defects. Despite the well-described impact of circadian oscillations through a feedback loop involving the clock pathway on hair and skin stem cell function in vitro, little is known about the change in characteristics or regenerative properties of hHF (human hair follicle keratinocytes), hEpi (human interfollicular epidermal keratinocytes), and hHFDP (hair follicle dermal papilla stem cells) after long-term alteration of circadian rhythm in vivo. The present study was designed to asses hHF, hEpi, and hHFDP precursors and stem cell properties in response to clock pathway alteration due to long-term deregulated circadian rhythm in vivo. A clinical study protocol was designed to include two groups of women: diurnal workers (control) and shift workers (deregulated). After informed consent, two 3-mm fresh punch biopsies were taken from the occipital region of each donor (10 donors/group). Cell culture characterization, measurement of colony area, culture medium analysis, and RT-qPCR analysis were carried out. Long-term circadian rhythm deregulation affected clock pathway protein expression and correlated with alterations in hHF, hEpi, and hHFDP properties. This study provides, for the first time in humans, evidence that in vivo deregulation of the clock pathway affects regenerative properties of human skin and hair precursor cells.


Requirement of subunit co-assembly and ankyrin-G for M-channel localization at the axon initial segment.
The potassium channel subunits KCNQ2 and KCNQ3 are believed to underlie the M current of hippocampal neurons. The M-type potassium current plays a key role in the regulation of neuronal excitability; however, the subcellular location of the ion channels underlying this regulation has been controversial. We report here that KCNQ2 and KCNQ3 subunits are localized to the axon initial segment of pyramidal neurons of adult rat hippocampus and in cultured hippocampal neurons. We demonstrate that the localization of the KCNQ2/3 channel complex to the axon initial segment is favored by co-expression of the two channel subunits. Deletion of the ankyrin-G-binding motif in both the KCNQ2 and KCNQ3 C-terminals leads to the disappearance of the complex from the axon initial segment, albeit the channel complex remains functional and still reaches the plasma membrane. We further show that although heteromeric assembly of the channel complex favours localization to the axon initial segment, deletion of the ankyrin-G-binding motif in KCNQ2 alone does not alter the subcellular localization of KCNQ2/3 heteromers. By contrast, deletion of the ankyrin-G-binding motif in KCNQ3 significantly reduces AIS enrichment of the complex, implicating KCNQ3 as a major determinant of M channel localization to the AIS.


Work, life, and the gender effect: Perspectives of ACVIM Diplomates in 2017. Part 1-Specialty demographics and measures of professional achievement.
Barriers to achieving work-life balance, as well as gender-based differences, exist in the male-dominated surgical specialty in veterinary medicine. Similar information does not exist for the more feminized American College of Veterinary Internal Medicine (ACVIM). To provide data on the professional and personal lives of Diplomates of the ACVIM so as to help define the state of the specialty, including gender-related differences, and identify areas requiring intervention to improve work-life balance. A total of 896 surveys (781 completed) of Diplomates of the ACVIM, including cardiology, large animal internal medicine, neurology, oncology, and small animal internal medicine. An 82-item online survey was distributed in February 2017 to ACVIM Diplomates via their respective ACVIM listserv. Participation was voluntary. Thirty percent of the total ACVIM registered membership responded and 26% completed surveys; 25% were men and 75% were women. Specialists in academia worked significantly more hours, with larger numbers of diplomates per specialty section, and made less money compared with those in private practice. Women were less likely to report full-time employment, practice ownership, or higher academic rank, and reported 20% lower income overall (after adjustment for relevant factors) as compared with men. Men and women differed in their subjective assessment of the effect of gender in the workplace. Eighty-three percent of respondents were somewhat satisfied or better with their career. Specialization in the ACVIM is a satisfying and potentially profitable career. However, despite a highly feminized workforce, significant gender-related imbalances are evident.


Transient intrahepatic portal hypertension. A case report.
We report the case of a patient with transient hypertension in relation to acute veno-occlusive disease of the liver. Ascites and esophageal varices, both transient, occurred in this patient and a transient elevation of the gradient between wedged and free hepatic venous pressures was observed.


Questionnaires for knee instability assessment in people with anterior cruciate ligament injury: a systematic review of original questionnaires and their translated versions.
Purpose: To verify the quality of questionnaires/scales regarding knee instability caused by anterior cruciate ligament (ACL) insufficiency and their translated versions.Materials and methods: Searches were conducted on Web of Science, Pubmed, Medline, Cinahl, and SportDiscuss. The COnsensus-based Standards for the selection of Health Measurement INstruments (COSMIN) scale was used to assess the article's quality; and the measurement properties of each questionnaire/scale were also analysed.Results: Searches identified 7703 studies and 29 were included in this review. Nine were articles reporting the original development of a questionnaire/scale and 20 were translations. The original questionnaires/scales were written in English or French and were translated into Brazilian Portuguese, Portuguese, Dutch, Turkish, German, Korean, Italian, Arabic, Polish, French, and Chinese. The questionnaires/scales with best overall quality were the Cincinatti Knee Rating System, the International Knee Documentation Committee - Subjective Knee Form and the PPLP. The International Knee Documentation Committee had positive results for internal consistency (Cronbach's alpha 0.89-0.92); for reliability and agreement (intraclass correlation coefficient (ICC) ranging from 0.88 to 0.99); and for construct validity (Pearson's r ranged from 0.1 to 0.85).Conclusions: The International Knee Documentation Committee had the largest number of translated versions and it was considered the best instrument assessed. Furthermore, The International Knee Documentation Committee was considered to be easy to apply, short and accessible, thus it is the choice of several clinicians and researchers.Implications for rehabilitationKnee instability is one of the most important factors to be evaluated during rehabilitation of people with anterior cruciate ligament injury in both surgical and non-surgical approach.The use of questionnaires may provide a better overall functionality assessment of people with knee instability from ACL injury.To choose the most appropriate questionnaire, clinicians should consider their needs and should consider validated questionnaires linked with adequate psychometric properties which guarantee the original characteristics of a questionnaire and also guarantee reliable results.


Characterization of human renal stones with MDCT: advantage of dual energy and limitations due to respiratory motion.
Our aim was to determine, using CT attenuation values, the chemical composition of 241 human renal stones placed in a jelly phantom and to analyze the influence of respiratory motion on the classification. The stones were placed in a jelly simulating the X-ray attenuation of the kidneys. A dynamic platform was used to apply to the phantom free-breathing motion (sinusoidal motion in z-axis) and motion due to lack of maintenance of a breath-hold (5 mm x s(-1) in z-axis). Determination of the chemical composition was performed with mean CT attenuation values obtained at 80 and 120 kV and with dual-energy CT attenuation values. Two hundred forty-one human urinary stones were classified into six groups: uric acid, cystine, struvite, weddellite (calcium oxalate dihydrate), whewellite (calcium oxalate monohydrate), and brushite. With no motion, the use of dual energy enabled differentiation of all of the types of stones with statistically significant differences. Uric acid (-20 +/- 22 H), cystine (106 +/- 19 H), struvite (271 +/- 16 H), weddellite (323 +/- 5 H), brushite (415 +/- 30 H), and whewellite (510 +/- 17 H) were identified as distinct groups. Motion-induced mean CT attenuation values were significantly different from those obtained with no motion. With motion, dual-energy CT attenuation values did not allow differentiation of all stone types. Dual-energy CT attenuation values can be used to predict the chemical composition of stones in vitro. However, when slight motion is applied to renal stones during image acquisition, the values become significantly different from those obtained with no motion. Consequently, confusion arises in differentiating stone types. A perfect breath-hold has to be performed for in vivo use of attenuation value to discern stone type.


Treatment of Legg-Calvé-Perthes disease.
It seems that early, energetic treatment with containment of the femoral head and preservation of the range of motion are the methods of choice for the patient in the early stages of the problem. Most patients with early involvement can be treated with the conservative method. This can be concluded within approximately 12 to 14 months, when the sclerotic and dense bone has disappeared and an adequate range of motion has been maintained. Reconstructive procedures are rarely indicated. They must be entered with great caution because of the risk of shortening the symptom-free interval, which presently is about 20 or 30 years, before reconstructive treatment is necessary.


HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer.
HSP70/HSP90-organizing protein (HOP) is an adaptor protein that mediates heat shock protein 70 (HSP70) and HSP90 folding. HOP can be secreted by cancer cells and promote malignant cell growth in an autocrine manner. Here, we studied its role in gastric cancer (GC). HOP mRNA and protein levels were detected by quantitative real-time PCR and western blotting, respectively, and enzyme-linked immunosorbent assay was used to determine the serum levels. Immunohistochemistry was performed to analyze HOP expression in 117 GC tissues and 32 adjacent normal tissues. The Cell Counting Kit-8 cell viability assay, flow cytometry, and western blotting were used to analyze the effects of HOP on cell proliferation and apoptosis, and the potential underlying mechanisms. HOP mRNA and protein levels were significantly higher in GC tissues than in normal tissues in our medical center (P< 0.001) and in The Cancer Genome Atlas database (P< 0.001). GC patients had higher serum levels of HOP than age-matched healthy controls (P< 0.001); however, once tumors were removed, serum levels significantly decreased (P< 0.01). In human GC tissues, increased HOP expression was associated with tumor progression and poor survival. Notably, autocrine HOP promoted cell proliferation through the phospholipase Cγ1-extracellular signal-regulated kinase 1/2-dependent pathway, and inhibited cell apoptosis by regulating the activities of caspase 9, caspase 3, and B-cell lymphoma 2. Blocking extracellular HOP with neutralizing antibody reduced proliferation and enhanced fluorouracil-induced apoptosis of GC cells. Our findings demonstrate that HOP is an important molecular marker and prognostic factor for GC, and functionally contributes to tumor cell growth and survival. These results provide a rationale for considering HOP as a potential therapeutic target and chemosensitizer in GC.


Tele-evidence: A videoconferencing tool as a viable alternative to physical appearance of doctors for the judicial summons.
The role of physicians often extends beyond provision of direct patient care and includes appearance in courts as professional or expert witnesses to give their testimony in various legal cases. This often consumes precious time and resources of the doctors and the hospitals. This study was taken up to evaluate the present system of the physical appearance of the doctors to various courts and compare it with the videoconferencing mode of giving testimony (tele-evidence). Available records of summons and vehicles used were analyzed to calculate the cost involved and man-hours consumed in honoring the court summons. Telemedicine facility, available in our institute, was used for conducting tele-evidence with selected courts of the two states as a pilot, which was later expanded. A survey was also done to assess the experience of the physicians with physical appearance and videoconferencing using structured questionnaire after approval from the Institute's Ethics Committee. Likert scale of 0-10 points was used to measure satisfaction. There was 43% drop in the monthly mileage of vehicles, 49% reduction in the fuel cost per month, and 28% savings in terms of time consumed for court duties. Satisfaction score for parameters of time consumed, physical strain, mental strain, communication with Honorable Judges, and overall experience was 87% through tele-evidence as compared to 31% with physical appearance. Tele-evidence is an acceptable and implementable mode of testifying and has led to tremendous resource savings in our tertiary care setting. The model needs to be replicated for deliverance of justice and is in consonance with Government's push toward Digital India.


Reduced common carotid artery longitudinal wall motion and intramural shear strain in individuals with elevated cardiovascular disease risk using speckle tracking.
Longitudinal motion of the intima-media and adventitia layers of the common carotid artery (CCA) wall were assessed with ultrasound speckle tracking in seven individuals with spinal cord injury (SCI), who are considered at increased risk of cardiovascular disease, and in seven able-bodied participants. CCA longitudinal wall displacement and intramural shear strain were compared to traditional markers of arterial health, including CCA stiffness and intima-media thickness (IMT). For each cardiac cycle, longitudinal CCA wall motion was characterized by bidirectional movement patterns containing motion retrograde to blood flow during systole, followed by antegrade motion during diastole. Relative displacement of the intima-media versus the adventitia was used to calculate longitudinal intramural shear strain and provided insight to local arterial wall properties. The retrograde intramural shear strain was smaller in individuals with SCI by 60·2% (P<0·05) compared to able-bodied participants, showing smaller peak displacements in both the intima-media (P<0·05) and adventitia (P<0·05). In the antegrade direction, there were no group differences in either longitudinal displacements or shear strain. The group differences observed in the retrograde wall motion phase were greater than those observed for CCA stiffness or IMT and were found to be independent of both indices, indicating indices of the retrograde phase intramural shear strain may be a novel and sensitive marker of vascular health. Our findings demonstrate that assessment of longitudinal arterial wall shear strain may provide valuable insight into vascular structure and function and may hold potential for the early detection of cardiovascular disease.


Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.
To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed solely to rosuvastatin treatment. A limitation of the study is the absence of a control group. These findings suggest that rosuvastatin monotherapy could ameliorate biopsy proven NASH and resolve MetS within 12 mo. These effects and the reduction of fasting plasma glucose and SUA levels may reduce the risk of vascular and liver morbidity and mortality in NASH patients. These findings need confirmation in larger studies.


Disorders of the lower cranial nerves.
Lesions of the lower cranial nerves (LCN) are due to numerous causes, which need to be differentiated to optimize management and outcome. This review aims at summarizing and discussing diseases affecting LCN. Review of publications dealing with disorders of the LCN in humans. Affection of multiple LCN is much more frequent than the affection of a single LCN. LCN may be affected solely or together with more proximal cranial nerves, with central nervous system disease, or with nonneurological disorders. LCN lesions have to be suspected if there are typical symptoms or signs attributable to a LCN. Causes of LCN lesions can be classified as genetic, vascular, traumatic, iatrogenic, infectious, immunologic, metabolic, nutritional, degenerative, or neoplastic. Treatment of LCN lesions depends on the underlying cause. An effective treatment is available in the majority of the cases, but a prerequisite for complete recovery is the prompt and correct diagnosis. LCN lesions need to be considered in case of disturbed speech, swallowing, coughing, deglutition, sensory functions, taste, or autonomic functions, neuralgic pain, dysphagia, head, pharyngeal, or neck pain, cardiac or gastrointestinal compromise, or weakness of the trapezius, sternocleidomastoid, or the tongue muscles. To correctly assess manifestations of LCN lesions, precise knowledge of the anatomy and physiology of the area is required.


Mutation of the miaA gene of Agrobacterium tumefaciens results in reduced vir gene expression.
vir regulon expression in Agrobacterium tumefaciens involves both chromosome- and Ti-plasmid-encoded gene products. We have isolated and characterized a new chromosomal gene that when mutated results in a 2- to 10-fold reduction in the induced expression of vir genes by acetosyringone. This reduced expression occurs in AB minimal medium (pH 5.5) containing either sucrose or glucose and containing phosphate at high or low concentrations. The locus was cloned and used to complement A. tumefaciens strains harboring Tn5 insertions in the gene. Sequence analysis of this locus revealed an open reading frame with strong homology to the miaA locus of Escherichia coli and the mod5 locus of Saccharomyces cerevisiae. These genes encode tRNA: isopentenyltransferase enzymes responsible for the specific modification of the A-37 residue in UNN codon tRNA species. The function of the homologous gene in A. tumefaciens was proven by genetic complementation of E. coli miaA mutant strains. tRNA undermodification in A. tumefaciens miaA mutant strains may reduce vir gene expression by causing a reduced translation efficiency. A slight reduction in the virulence of these mutant Agrobacterium strains on red potato plants, but not on tobacco, tomato, kalanchoe, or sunflower plants, was observed.


Laser scanning and confocal microscopy of daunorubicin, doxorubicin, and rhodamine 123 in multidrug-resistant cells.
The multidrug-resistant gene (MDR1) encodes an energy-dependent drug efflux pump (P-glycoprotein) for many anti-cancer drugs. We have studied the intracellular distribution of rhodamine 123 (R123), daunorubicin (DN), and doxorubicin (DOX) in cells expressing a human MDR1 gene. The distribution of these fluorescent drugs was measured by laser scanning microscopy and confocal microscopy. We devised a new method for analysis of fluorescence line scan data to determine the intracellular distribution of fluorescent probes. This method and confocal microscopy showed that R123, DN, and DOX are localized to both plasma membrane and intracellular compartments in multidrug-resistant cells. When the cells are treated with verapamil, an inhibitor of the multidrug transporter, the amount of DOX, DN, and R123 associated with the cell rises. After inhibition, the relative distribution of DOX and DN between the cell surface and intracellular structures does not change dramatically. However, R123 tends to relocalize to intracellular sites from predominantly plasma membrane sites, indicating that this dye behaves differently than the anti-cancer drugs. These results show the subcellular distributions of R123, DN, and DOX in plasma membrane, cytoplasm, and intracellular membrane systems, but do not allow definitive distinctions among existing models of how P-glycoprotein affects the distribution of drugs.


Macrophage Mediated Immunomodulation During Cryptococcus Pulmonary Infection.
Macrophages are key cellular components of innate immunity, acting as the first line of defense against pathogens to modulate homeostatic and inflammatory responses. They help clear pathogens and shape the T-cell response through the production of cytokines and chemokines. The facultative intracellular fungal pathogen Cryptococcus neoformans has developed a unique ability to interact with and manipulate host macrophages. These interactions dictate how Cryptococcus infection can remain latent or how dissemination within the host is achieved. In addition, differences in the activities of macrophages have been correlated with differential susceptibilities of hosts to Cryptococcus infection, highlighting the importance of macrophages in determining disease outcomes. There is now abundant information on the interaction between Cryptococcus and macrophages. In this review we discuss recent advances regarding macrophage origin, polarization, activation, and effector functions during Cryptococcus infection. The importance of these strategies in pathogenesis and the potential of immunotherapy for cryptococcosis treatment is also discussed.


Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes in an older adult mimicking cerebral infarction: a Chinese case report.
Few cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) with an onset older than 60 years have been reported. Herein, we report a 63-year-old Chinese female initially suspected of ischemic infarction but was ultimately diagnosed with MELAS. Therefore, even in the elderly, a diagnosis of MELAS should be considered when encountering patients with recurrent stroke-like episodes, cognitive dysfunction, and psychotic symptoms. In order to achieve the correct diagnosis and launch the appropriate management in time, a detailed medical history together with appropriate diagnostic laboratory investigations should therefore be collected.


Rab22a regulates the establishment of epithelial polarity.
Membrane trafficking establishes and maintains epithelial polarity. Rab22a has a polarized distribution in activated T-cells, but its role in epithelial polarity has not been investigated. We showed previously that Rab14 acts upstream of Arf6 to establish the apical membrane initiation site (AMIS), but its interaction with Rab22a is unknown. Here we show that Rab14 and Rab22a colocalize in endosomes of both unpolarized and polarized MDCK cells and Rab22a localizes to the cell:cell interface of polarizing cell pairs. Knockdown of Rab22a results in a multi-lumen phenotype in three-dimensional culture. Further, overexpression of Rab22a in Rab14 knockdown cells rescues the multi-lumen phenotype observed with Rab14 knockdown, suggesting that Rab22a is downstream of Rab14. Because of the relationship between Rab14 and Arf6, we investigated the effect of Rab22a knockdown on Arf6. We find that Rab22a knockdown results in decreased active Arf6 and that Rab22a co-immunoprecipitates with the Arf6 GEF EFA6. In addition, EFA6 is retained in intracellular puncta in Rab22a KD cells. These results suggest that Rab22a acts downstream of Rab14 to traffic EFA6 to the AMIS to regulate Arf6 in the establishment of polarity.


[Motility-recording capsule simplifies gastrointestinal examination. Safe diagnostics in motility disorders].
The wireless motility-recording capsule, "SmartPill", is an ingested one-time use electronic capsule that measures gastrointestinal luminal pressure, pH and temperature along the whole gastrointestinal tract. The pH profile and the pressure patterns define the time at which the capsule moves from the stomach to the duodenum and from the ileum to the caecum, whereas changes in temperature define the times of ingestion and expulsion. The recordings from the wireless motility capsule are sent from a radio transmitter in the capsule to a receiver carried around the waist. Wireless motility recordings have several advantages over imaging and manometry that have been used previously. Primarily the simplicity by which motility recordings are done, as well as the tolerability for the patient and limited need of assistance are valuable aspects. The wireless motility capsule provides standardized measures of transit with relevant normal values for the clinical work-up of patients with motility disturbances.


Establishing Control Frequency of Embryonic and Fetal Loss in a Mutant Mouse Colony.
In the analysis of prenatal lethal recessive mutations, one must account for embryonic losses that are not related to the mutant phenotype. This protocol details the way to determine what the background level of unrelated embryonic loss is by a simple backcrossing strategy in the particular mouse strain that carries the lethal recessive mutation.


Nilotinib in patients with metastatic melanoma harboring KIT gene aberration.
Patients with metastatic melanoma have a poor prognosis and few treatment options are available. We evaluated the anti-tumor activity and safety of nilotinib, a KIT inhibitor, in patients with metastatic melanoma harboring KIT alterations, either mutations or amplifications. This study was open-label, single center, prospective phase II clinical trial. Between October 2009 and April 2011, 11 patients with metastatic melanoma harboring KIT gene mutations or KIT gene amplifications were enrolled in the first stage of phase II study and nilotinib was administered orally at a dose of 400 mg twice a day until disease progression or intolerable toxicities. The primary endpoint was response rate and secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Of 11 patients, 9 patients were evaluable for treatment response. Of 9 patients, three patients had KIT mutations in exon 11, Leu576Pro, Val559Ala and Lys558Arg; and 6 patients had KIT amplifications > 50 copies compared to control DNA. Two patients achieved partial response (22.2%) and 5 patients achieved stable disease (55.6%). In two patients who responded to nilotinib, both had KIT mutations and showed durable response for 8.4 months and 10.0+ months. Of note, one patient with KIT amplification had stable disease with response for 6 months. A decrease in tumor size from baseline was observed in four patients (44.4%). Nilotinib 800 mg/d was very well tolerated with grade 1 nausea and grade 1 dry-eye being the most common adverse events. We have decided to publish the preliminary results because anti-tumor activity of nilotinib was promising in KIT mutated patients. Although our results are preliminary, nilotinib had very favorable toxicity profile with durable response in metastatic melanoma patients with KIT mutations. The anti-tumor activity of nilotinib in melanoma patients with KIT amplification is yet to be determined in future studies. Currently, phase II nilotinib trial is ongoing in Korea as multi-center study.


Potential side effects of currently available pharmacotherapies in male lower urinary tract symptoms suggestive of benign prostatic hyperplasia.
The drug classes of α1-adrenoceptor antagonists, 5α-reductase inhibitors, and phosphodiesterase type 5 inhibitors are guideline-recommended treatments of lower urinary tract symptoms suggestive of benign prostatic hyperplasia; muscarinic receptor antagonists and β3-adrenoceptor agonists are also recommended if storage symptoms are insufficiently addressed with one of the other three drug classes. We provide a narrative review (no formalized literature searches performed) of the tolerability of these drug classes with emphasis on the more recently introduced medications, on combination treatment, and on more lately emerging risks. The tolerability profiles are distinct between drug classes but, with few exceptions, similar within a drug class. Within a drug, formulations with longer duration of action tend to have better tolerability. Efficacy gains using combination treatment at least partly come at a cost of lesser tolerability. Greater susceptibility to experience adverse events based on age, comorbidities, and comedications appears conceptually important but remains under-investigated in this therapeutic area.


[Geographic distribution of planorbidae in Santa Catarina, Brazil].
A revision of the malacological surveys carried out in Santa Catarina, Brazil, by the National Health Foundation in 52 counties of 8 microregions between 1981 and 1994 was made. Fifty of them were positive for Biomphalaria tenagophila, the only schistosome vector identified in the 94,535 specimens collected. Of 1,358 districts, 617 (45.4%) were positive to the vector, varying from 4.3% to 89.4% per municipality. The percentages of water bodies with planorbids varied from 0.2% to 26.3% and, of the total 28,120 examined 2,013 (7.1%) were positive. Snails infected with cercariae of Schistosoma mansoni were found in the counties of Araquari, Massaranduba, Joinville, Jaraguá do Sul and São Francisco do Sul, the last two constituting the southernmost focus of schistosomiasis mansoni in Brazil. Other planorbid species identified were B. peregrina, B. oligoza, B. schrammi, B. straminea and B. occidentalis.


Comparative quantitative analysis of ultraviolet B-induced skin blood flow change using laser Doppler perfusion imaging technique.
Laser Doppler perfusion imaging (LDI), recently developed, can generate a color-coded image of tissue perfusion, making it possible to assess the spatial distribution of skin perfusion without touching the surface. Using this apparatus, we investigated ultraviolet B (UVB)-induced perfusion profile of the skin and compared the results with those obtained from laser Doppler flowmetry (LDF). Fifteen adult male Korean volunteers were irradiated with several doses of UVB ranging from 25 mJ/cm2 to 186 mJ/cm2. Twenty-four hours later, the erythema reaction was evaluated with LDF and LDI systems. There was a significant correlation between the logarithmic dose of UVB and erythema values. The curves consisted of two parts, an initial, flat phase and then a linear, steep one. Also, there was a good correlation between LDF and LDI. The LDI is as sensitive as conventional LDF, but has the many advantages of measuring blood flow over large areas without contact with the skin surface. This instrument will be useful in the measurement of skin blood flow in many areas of dermatological application.


Ozone-induced respiratory symptoms: exposure-response models and association with lung function.
Ozone-induced respiratory symptoms are known to be functions of concentration, minute ventilation, and duration of exposure. The purposes of this study were to identify an exposure-response model for symptoms, to determine whether response was related to age, and to assess the relationships between symptom and lung function responses to ozone. Four hundred and eighty-five healthy male volunteers (ages 18-35 yrs) were exposed to one of six ozone concentrations at one of three activity levels for 2 h. Symptoms and forced expiratory volume in one second (FEV1) were assessed at the end of 1 and 2 h. The exposure and response data were fitted by a nonlinear exposure-response model previously found to describe FEV1 response. The proportion of individuals experiencing moderate or severe cough, shortness of breath, and pain on deep inspiration were accurately described as functions of concentration, minute ventilation, and time. Response was inversely related to age for shortness of breath (p=0.0001), pain on deep inspiration (p=0.0002), and cough (p=0.0013). Controlling for exposure differences, symptom responses were significantly but weakly (correlation coefficient 0.30-0.41) related to the FEV1 response. In conclusion, the exposure-response model did accurately predict symptoms, response was inversely related to age.


Autocrine/paracrine erythropoietin regulates migration and invasion potential and the stemness of human breast cancer cells.
Recent studies suggest that erythropoietin (EPO) has pleiotropic effects in several cell types in addition to hematopoietic cells; however, the role of EPO-mediated cell signaling in nonhematopoietic cells, including in cancer cells, remains controversial. Here, we report our findings of autocrine/paracrine production of EPO by breast cancer cells and its functional significance. We detected a significant level of autocrine/paracrine EPO in the conditioned medium from the culture of SKBR3 breast cancer cells, particularly when the cells were cultured in hypoxia. Through knockdown of EPO and EPO receptor expression and experimental elevation of EPO receptor expression in SKBR3 breast cancer cells, we demonstrated novel roles of autocrine/paracrine EPO-mediated cell signaling in regulating migration and invasion potential and stemness-like properties of breast cancer cells.


[Detection of central auditory compensation in unilateral deafness with functional magnetic resonance tomography].
Functional magnetic resonance imaging (fMRI) is a noninvasive method to detect focal brain activity at high spatial resolution. Acoustic stimulation induces an increase of regional cerebral blood flow in the primary auditory cortex. This entails an increased concentration of diamagnetic oxyhemoglobin in the capillaries and the venous system. The resulting decrease of the local magnetic susceptibility was detected as a signal increase in T2*-weighted images. The central auditory pathways predominantly cross to the contralateral hemisphere in normally hearing subjects. The aim of the present study was to investigate the primary auditory cortex after acoustic stimulation in unilateral deaf patients using fMRI. Magnetic resonance images were acquired on a 1.5 T Siemens Vision scanner. For fMRI, a single shot gradient recalled, echo planar imaging (EPI) sequence with decreasing excitation order was used, allowing the aquisition of 9 slices within 1.8 s. The 9 slices covered a slab of 3.6 cm in cranio-caudal extension in the region of the temporal lobes. For statistical processing of the raw image data the SPM96 software package was used. A p-value of p < 0.01 was applied to differentiate between activated and non-activated. The resulting functional activation maps were superimposed onto the EPI scan. The number of activated pixels was used to quantitate the cortical response upon acoustic stimulation. Stimulation consisted of a 1000-Hz sine tone (100 dB SPL at the distal end of the head phone, pulsed at 6 Hz) to which the patients were asked to listen passively. A piezoelectric loudspeaker was mounted on the subject table and connected to a plastic tube system leading to a combination of bilateral ear- and headphones. Auditory paradigms require disentangling experimental excitation from the scanner noise that approximates 90 dB. Headphones suppress noise by approximately 30 dB. To decrease the acoustic background-to-stimulation ratio and to keep background noise constant during stimulation and resting, we employed short scanning (1.8 s) and long resting periods (10.2 s; TR = 12 s). This acquisition mode allows sufficient recovery during off-periods and sufficient excitation during on-periods. 14 unilateral deaf patients were examined. The mean duration of deafness was 22.5 years. Acoustic stimulation of the deaf ear revealed only weak cortical activation which could be explained by sound transmission via bone conduction to the other ear. A significant increase of BOLD (blood oxygen level dependent)-activation in the primary auditory cortex could be demonstrated in all patients after stimulation of the hearing ear. However, remarkable individual differences were noticed concerning the absolute number of activated pixels. The lateralization ratio was calculated by the number of activated pixels on the hearing side divided by the number of activated pixels on the deaf side. A mean lateralization ratio of 0.9 (Stdv +/- 0.6) was found. The mean lateralization ratio for patients with a right deaf ear (n = 8) and those with a left deaf ear (n = 5) was 1.1 (Stdv +/- 0.7) and 0.6 (Stdv +/- 0.3) respectively. However, the difference was not significant (Wilcoxon test: p = 0.08). Central-auditory compensation by bilateral cortical activation was demonstrated in unilateral deaf patients. Moreover, a tendency towards a dominance of the left primary auditory cortex was found, although the difference between both hemispheres was not significant. The lateralization ratio in unilateral deaf patients is similar to findings after binaural stimulation in normally hearing subjects.


Utilizing Information Technology to Improve Influenza Vaccination in Pediatric Patients With Inflammatory Bowel Disease.
Pediatric patients with inflammatory bowel disease are undervaccinated against influenza. Gastroenterology nurses are ideally situated to assist in improving vaccination in this population. The objective of this quality improvement project was to evaluate the implementation of information technology prompts within the electronic medical record to improve influenza vaccination during specialty clinic visits. The proportion of patients with yearly influenza vaccination was evaluated at baseline, Year 1, and Year 2 following implementation. At baseline, only 10% of a random sample had documented influenza vaccination. Vaccination documentation improved to 39% (96/246) by Year 1 and to 61% (175/287) by Year 2 (p < .001). Vaccine counseling improved from 27% to 77% by Year 2 for unvaccinated patients (p < .001). Among patients seen by gastroenterology nurses, the proportion of patients with either documented vaccination or counseling was 94% by Year 2 compared with 70% if seen only by a physician (p < .001). Documentation of influenza vaccination improved with the use of customized prompts. Patients seen by a gastroenterology nurse had higher vaccination documentation and vaccine counseling than those who were seen by a physician alone.


Central papillary atrophy of the tongue among bidi smokers in India: a 10-year study of 182 lesions.
The occurrence of central papillary atrophy of the tongue among tobacco users, its clinical characteristics and the long term behavior in relation to changes in tobacco use was studied in 182 individuals in Ernakulam district, Kerala, India. Almost all (98%) lesions occurred among bidi smokers. Clinically, about 31% occurred in combination with bidi smoking associated lesions such as palatal erythema (14%), leukoplakia (8%) or both (3%). Histologic evaluation in 12 biopsies using single PAS stained sections showed candidal hyphae in 67%. A 10-yr follow-up (mean: 6.7 yr) of the 182 lesions showed that the regression was highest (87%) among those who stopped their smoking habit and persistence among those who did not reduce or stop their smoking habits. The findings from this study confirm a strong link between bidi smoking and central papillary atrophy of the tongue in rural Indian populations.


Estimating computational limits on theoretical descriptions of biological cells.
There has been much success recently in theoretically simulating parts of complex biological systems on the molecular level, with the goal of first-principles modeling of whole cells. However, there is the question of whether such simulations can be performed because of the enormous complexity of cells. We establish approximate equations to estimate computation times required to simulate highly simplified models of cells by either molecular dynamics calculations or by solving molecular kinetic equations. Our equations place limits on the complexity of cells that can be theoretically understood with these two methods and provide a first step in developing what can be considered biological uncertainty relations for molecular models of cells. While a molecular kinetics description of the genetically simplest bacterial cell may indeed soon be possible, neither theoretical description for a multicellular system, such as the human brain, will be possible for many decades and may never be possible even with quantum computing.


Molecular recognition of bisphosphonate-based drugs by di-zinc receptors in aqueous solution and on gold nanoparticles.
Metal-based anion receptors have several important applications in sensing, separation and transport of negatively charged species. Amongst these receptors, di-zinc(ii) complexes are of particular interest for the recognition of oxoanions, in particular phosphate derivatives. Herein we report the synthesis of a di-zinc(ii) receptor and show that it has high affinity and selectivity for bisphosphonates such as alendronate and etidronate - which are used to treat a number of skeletal disorders as well as showing interesting anticancer properties. The binding mode of the di-zinc(ii) receptor with alendronate and etidronate has been unambiguously established by single crystal X-ray crystallography. In addition, by modifying the backbone of the receptor, we show that the drug-loaded receptor can be attached onto gold nanoparticles as potential drug-delivery vehicles.


In vivo light-microscopic documentation for primary calcification processes in the hermatypic coral Stylophora pistillata.
Skeletogenesis in the hermatypic coral Stylophora pistillata was studied by using the lateral skeleton preparative (LSP) assay, viz., a coral nubbin attached to a glass coverslip glued to the bottom of a Petri dish. Observations on tissue and skeletal growth were made by polarized microscopy and by using vital staining. The horizontal distal tissue edges developed thin transparent extensions of ectodermal and calicoblastic layers only. Four stages (I-IV) of skeletogenesis were observed at these edges, underneath the newly developed tissue. In stage I, a thin clear layer of coral tissue advanced 3-40 microm beyond the existing LSP peripheral zone, revealing no sign of spiculae deposition. At stage II, primary fusiform crystals (1 microm each) were deposited, forming a primary discontinuous skeletal front 5-30 microm away from the previously deposited skeleton. During stage III, needle-like crystals appeared, covering the primary fusiform crystals. Stage IV involved further lengthening of the needle-like crystals, a process that resulted in occlusion of the spaces between adjacent crystals. Calcification stages I-III developed within hours, whereas stage IV was completed in several days to weeks. Two basic skeletal structures, "scattered" and "laminar" skeletons, were formed, integrating the growth patterns of the needle-like crystals. High variation was recorded in the expression of the four calcification stages, either between different locations along a single LSP or between different preparations observed at the same diurnal time. All four skeletogenesis stages took place during both day and night periods, indicating that an intrinsic process controls S. pistillata calcification.


Portraits of communication in neuronal networks.
The brain is organized as a network of highly specialized networks of spiking neurons. To exploit such a modular architecture for computation, the brain has to be able to regulate the flow of spiking activity between these specialized networks. In this Opinion article, we review various prominent mechanisms that may underlie communication between neuronal networks. We show that communication between neuronal networks can be understood as trajectories in a two-dimensional state space, spanned by the properties of the input. Thus, we propose a common framework to understand neuronal communication mediated by seemingly different mechanisms. We also suggest that the nesting of slow (for example, alpha-band and theta-band) oscillations and fast (gamma-band) oscillations can serve as an important control mechanism that allows or prevents spiking signals to be routed between specific networks. We argue that slow oscillations can modulate the time required to establish network resonance or entrainment and, thereby, regulate communication between neuronal networks.


What Is the Relationship between the Neighbourhood Built Environment and Time Spent in Outdoor Play? A Systematic Review.
Outdoor play has been associated with children's and adolescents' healthy development and physical activity. Attributes of the neighbourhood built environment can influence play behaviours. This systematic review examined the relationship between attributes of the neighbourhood built environment and the time children and adolescents (0-18 years) spend in self-directed outdoor play. We identified and evaluated 18 relevant papers using the Mixed Methods Appraisal Tool and developed a narrative synthesis of study results. We found moderate evidence that lower traffic volumes (ages 6-11), yard access (ages 3-10), and increased neighbourhood greenness (ages 2-15) were positively associated with time spent in outdoor play, as well as limited evidence that specific traffic-calming street features such as fewer intersections, low traffic speeds, neighbourhood disorder, and low residential density were positively associated with time spent in outdoor play. To our knowledge, this is the first systematic review on this topic. The limited number of "good quality" studies identified highlights the need for additional research on the topic.


[Clinical studies on SM-4300, a new intravenous human gamma-globulin].
With the recent development of new potential antibiotics, it has become easier to treat patients with common bacterial infections. However, we find it difficult to handle severe infections due to opportunistic pathogens, developed in the so-called immunocompromised patients. SM-4300 is a newly developed intravenous human gamma-globulin, which is said to be intact without conventional enzyme-treatment and sulfonization. SM-4300 is also free from large molecules of aggregated gamma-globulin. SM-4300 was administered in combination with antibiotics to 2 patients of severe respiratory infections, having refractory underlying diseases. Case No. 1 was a 65-year-old female with bronchopneumonia, who had been suffering from pulmonary fibrosis, chronic bronchitis, chronic congestive heart failure and tricuspid insufficiency for several years. During her hospitalization because of these diseases, she developed cough with slight sputum and exertional dyspnea accompanied by high body temperature of 38 degrees C on January 1983. Chest X-ray revealed infiltration in the right lung field which was compatible with bronchopneumonia. SM-4300 of 5 g was added intravenously on 5th day after 4 day-cefotiam treatment with no improvement. High body temperature subsided and laboratory data became normal around 3 days after single SM-4300 injection. Case No. 2 was a 68-year-old male patient of chronic bronchitis with chronic pulmonary emphysema and bronchial asthma. Around the end of May 1983, he complained of dyspnea on exertion and had mucopurulent sputum, more than 100 ml daily, from which Pseudomonas aeruginosa was cultured in large number. He was afebrile.(ABSTRACT TRUNCATED AT 250 WORDS)


Web-Based Dietary and Physical Activity Intervention Programs for Patients With Hypertension: Scoping Review.
Hypertension is the root cause of many chronic diseases. Lifestyle changes (ie, dietary alterations and physical activity) are seen to be an important step in the prevention and treatment of hypertension. Educating people through web-based interventional programs could offer an effective solution and help these patients with hypertension in the existing health care scenario. In this study, the researchers conducted a scoping literature review of the web-based dietary changes and physical activity-related intervention programs designed for the patients with hypertension and identified the methodologies, effectiveness, protocols, and theories, which could affect and improve existing clinical activities. This review followed the scoping review methodology to identify and process the peer-reviewed studies published between 2010 and 2020. The literature searches were conducted on the following electronic databases: PubMed, Web of Science, MEDLINE (Medical Literature Analysis and Retrieval System Online), ScienceDirect, Scopus, and Google Scholar. By using relevant search terms, studies were included if they offered information related to the web-based intervention tools, specifically dietary and physical activity intervention for patients with hypertension. Studies written or translated in English language and published within the date range (January 2010 to March 2020) were included. Overall, 1441 articles were initially identified. The reviewers included 35 articles after removing duplicates and screening titles. Only 21 articles were assessed for full review, and 15 were kept for analysis. The researchers selected 15 web-based intervention articles published on the topic of hypertension from 7 countries. A few of these 15 web-based tools (4, 27%) included more than 3 functions and provided a lot of important information (such as appointments, health records, or viewable care). Several tools were standalone tools (11, 73%), while most of the tools supported communication intervention-related lifestyle or behavioral changes (13, 87%) and medication adherence (6, 40%). It was found that physicians (9, 60%), allied health professionals (5, 33%), and nurses (5, 33%) were the health care providers who generally used these tools for communicating with their patients. More than half of the above tools (10, 67%) were assessed by different researchers in randomized controlled trials, while 5 tools (33%) were investigated in nonrandomized studies. We identified many web-based intervention programs for patients with hypertension from the literature databases. The findings indicate that numerous benefits can be derived after using a web-based dietary and physical activity intervention program for hypertension focusing on lifestyle changes. However, developers need to consider the preferences of the patients with regard to the information or the design features while developing or modifying web-based educational websites. These tools could be used for designing a patient-tailored website intervention program that is based on diet and physical activities for patients with hypertension.


The genetic and transcriptional organization of the vir region of the A6 Ti plasmid of Agrobacterium tumefaciens.
The genetic transformation of plant cells by Agrobacterium tumefaciens is mediated by the genes of the Ti plasmid vir region. To determine the genetic and transcriptional organization of the vir region of pTiA6, vir plasmid clones were saturated with insertion mutations of a Tn3-lacZ transposon. This element is both an insertion mutagen and a reporter for the expression of the sequences into which it has inserted. One hundred and twenty-four vir::Tn3-lac insertions were analyzed for their mutagenic effect on Agrobacterium virulence, and for their expression of beta-galactosidase activity, the lacZ gene product, in vegetative bacteria and in bacteria cocultivated with plant cells. These data in conjunction with genetic complementation results show that the pTiA6 vir region contains six distinct vir complementation groups: virA, virB, virC, virD, virE and virG. Mutations in these loci eliminate (virA, virB, virD and virG) or significantly restrict (virC and virE) the ability of Agrobacterium to transform plant cells. Each of the vir loci corresponds to a single vir transcription unit: virA is constitutively expressed and non-inducible; virB, virC, virD and virE are expressed only upon activation by plant cells; and virG is both constitutively expressed and plant-inducible. The two largest vir operons, virB and virD, are probably polycistronic. The pTiA6 vir region also contains plant-inducible loci (pin) which are non-essential for virulence.