Incidence and clinical characteristics of National Institutes of Health type III prostatitis in the community.
Few population-based epidemiological studies of prostatitis have been performed. We used coded physician diagnoses and subsequent chart reviews to estimate the incidence and clinical characteristics of physician diagnosed National Institutes of Health (NIH) type III prostatitis. Computer searches of the Kaiser Permanente Northwest (Portland, Oregon) database were performed on the 2-year interval May 2002 to May 2004 to identify new diagnoses of chronic prostatitis (International Classification of Diseases, 9th Revision code 601.1) and prostatitis not otherwise specified (International Classification of Diseases, 9th Revision code 601.9). Of the 1,223 men identified with these coded diagnoses, chart reviews were performed on a random subset of 413 (33.8%). Patients were categorized based on NIH prostatitis definitions of type I/II-evidence of pyuria and/or bacteriuria on urinalysis or culture, type III-presence of at least 1 of the pain or urinary symptoms in the NIH Chronic Prostatitis Symptom Index (pain in the perineum, testicles, tip of penis, pubic or bladder area, dysuria, ejaculatory pain, incomplete emptying, urinary frequency), type IV-inflammation on prostate biopsy and Other-symptoms other than those listed. Of the 413 patients 57 were previously diagnosed with prostatitis (prevalent cases), 46 had no evidence of a prostatitis diagnosis in the medical record and 7 were treated by physicians outside of the Kaiser Permanente Northwest plan. Of the remaining 303 the distribution was 58 type I/II, 189 type III, 33 type IV and 23 Other. The incidence of physician diagnosed type III prostatitis was 3.3 per 1,000 person-years. If those with isolated urinary symptoms were excluded from analysis, the incidence decreased to 2.8 per 1,000 person-years. The mean age of those with type III prostatitis was 52.9 years (range 29 to 82). The most common presenting symptoms were dysuria, urinary frequency and perineal pain. Symptom duration at presentation was less than 3 months in 44%, 3 months or greater in 31% and unspecified in 25%. The majority (78%) of new prostatitis diagnoses was made by primary care physicians. These data indicate that prostatitis is commonly diagnosed in the community setting, and that type III prostatitis accounts for the majority of these diagnoses. The duration and complexity of symptoms are less than those reported in established prostatitis research cohorts. Most prostatitis diagnoses in the community are made by nonurologists.


Direct binding of arsenic trioxide to AMPK and generation of inhibitory effects on acute myeloid leukemia precursors.
Arsenic trioxide (As2O3) exhibits potent antineoplastic effects and is used extensively in clinical oncology for the treatment of a subset of patients with acute myeloid leukemia (AML). Although As2O3 is known to regulate activation of several signaling cascades, the key events, accounting for its antileukemic properties, remain to be defined. We provide evidence that arsenic can directly bind to cysteine 299 in AMPKα and inhibit its activity. This inhibition of AMPK by arsenic is required in part for its cytotoxic effects on primitive leukemic progenitors from patients with AML, while concomitant treatment with an AMPK activator antagonizes in vivo the arsenic-induced antileukemic effects in a xenograft AML mouse model. A consequence of AMPK inhibition is activation of the mTOR pathway as a negative regulatory feedback loop. However, when AMPK expression is lost, arsenic-dependent activation of the kinase RSK downstream of MAPK activity compensates the generation of regulatory feedback signals through phosphorylation of downstream mTOR targets. Thus, therapeutic regimens with As2O3 will need to include inhibitors of both the mTOR and RSK pathways in combination to prevent engagement of negative feedback loops and maximize antineoplastic responses.


The spectrum of anorectal malformations in Africa.
Anorectal malformations (ARM) remain a significant birth defect with geographic variation in incidence, individual phenotypes and regional geographic subtypes. Although early studies indicated a low incidence in Black patients, there is a great paucity of knowledge as to the types, frequency and incidence of ARMs encountered in the African continent and their associated anomalies. Current evidence suggests a significant clinical load. This study set out to evaluate ARM in Southern and other parts of Africa to define the clinical load of ARM. We retrospectively collected data on 1,401 ARM patients from six South African Paediatric Surgical units plus representative samples from five other African countries from West, Central and Southern Africa. Data included ethnic group, age, gender as well as the anatomical pathology, classification and presence or absence of associated anomalies. ARM lesions classified by the Wingspread classification plus an analysis of fistula position was carried out in evaluable cases for purposes of comparison. South African centres reported a higher prevalence of cloacae and vestibular fistulae, whereas rectovaginal, recto prostatic and anorectal malformation without fistula were more prevalent in the Northern African group. 76% of 1,401 patients were ethnically Black African [gender ratio = 2 (vs gender ratio 1.38 overall)] and 49.8% were "low" lesions (Wingspread classification). High or intermediate lesions were mostly males (72%). Anal stenosis was most prevalent in black males and non-Black females. Fistulae were identified in 95% with 682 (52%) being low (perineal/covered anus/vestibular) fistulae. Perineal fistulae had a male predilection (n = 260; 20%), whereas vestibular fistulas (n = 416; 32%) was strikingly frequent in black females (55%). Of the remainder, 15 fistulae were rectovesical (1.2%), 544 recto-urethral or prostatic (42%), 16 recto-vaginal (1.2%). In addition, there were 43 cloacal lesions (3.3%). Isolated rare ARM anomalies included "Pouch" colon (2) and H-type fistula (2). Isolated lesions occurred in 81% but 163 associated anomalies were identified in 114 patients. These included chromosomal lesions (10), genito-urinary anomalies (50), genital (16), cardiac (31), skeletal anomalies (33), gastro-intestinal malformations (28). Other anomalies included CNS anomalies (14), anterior abdominal wall defects (2) and facial (8) abnormalities and neuroblastoma (1). The ARM is not uncommon in Black African populations and constitutes a significant clinical load to surgical practice in Africa. Ethnic differences appear to exist and vestibular fistulae predominate in black females. Cloaca (3.3%) did appear to be more prevalent. Isolated lesions are frequent but the types of associated anomalies appear similar to other series except chromosomal syndromes. This study illustrates the need for more objective data from developing countries to assess geographical differences.


Fibrinogen concentrate for bleeding--a systematic review.
Fibrinogen concentrate as part of treatment protocols increasingly draws attention. Fibrinogen substitution in cases of hypofibrinogenaemia has the potential to reduce bleeding, transfusion requirement and subsequently reduce morbidity and mortality. A systematic search for randomised controlled trials (RCTs) and non-randomised studies investigating fibrinogen concentrate in bleeding patients was conducted up to November 2013. We included 30 studies of 3480 identified (7 RCTs and 23 non-randomised). Seven RCTs included a total of 268 patients (165 adults and 103 paediatric), and all were determined to be of high risk of bias and none reported a significant effect on mortality. Two RCTs found a significant reduction in bleeding and five RCTs found a significant reduction in transfusion requirements. The 23 non-randomised studies included a total of 2825 patients, but only 11 of 23 studies included a control group. Three out of 11 found a reduction in transfusion requirements while mortality was reduced in two and bleeding in one. In the available RCTs, which all have substantial shortcomings, we found a significant reduction in bleeding and transfusions requirements. However, data on mortality were lacking. Weak evidence from RCTs supports the use of fibrinogen concentrate in bleeding patients, primarily in elective cardiac surgery, but a general use of fibrinogen across all settings is only supported by non-randomised studies with serious methodological shortcomings. It seems pre-mature to conclude whether fibrinogen concentrate has a routine role in the management of bleeding and coagulopathic patients. More RCTs are urgently warranted.


Purification and characterization of human kidney cytosolic cysteine conjugate beta-lyase activity.
The central role of cysteine conjugate beta-lyase (beta-lyase) in the bioactivation of nephrotoxic halogenated hydrocarbons and the possibility of human exposure to these chemicals has focused interest on the beta-lyase from human kidney. Human kidney tissue was collected as surgical waste material, and subcellular fractions were isolated by differential centrifugation. Human beta-lyase activity, determined with S-(2-benzothiazolyl)-L-cysteine (BTC) as the substrate, was present in the cytosolic, mitochondrial, and microsomal fractions, but was highest in the cytosolic fraction. Activity in human kidney cytosol was about 10% of that present in rat kidney cytosol. Human kidney cytosolic beta-lyase activity, with BTC as the substrate, was not stimulated by pyridoxal phosphate or by exogenous 2-keto acids. Cytosolic beta-lyase activity was purified 280-fold with a yield of 12% from human kidneys unsuitable for transplantation. The beta-lyase activity copurified with cytosolic glutamine transaminase K and exhibited a molecular mass of 85 kDa on a Sephacryl 5300 column and a subunit molecular mass of 45 kDa by gel electrophoresis. Both BTC and its homocysteine analogue S-(2-benzothiazolyl)-L-homocysteine were excellent substrates, exhibiting Km and kcat values of 0.97 mM and 2.78 mM and 9.35 min-1 and 6.90 min-1, respectively. beta-Lyase activity was inhibited by aminooxyacetic acid, indicating that the human cytosolic enzyme contains pyridoxal phosphate, and by the nephrotoxins S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)-L-homocysteine, which serve as alternative substrates.(ABSTRACT TRUNCATED AT 250 WORDS)


Validation of a consensus method for identifying delirium from hospital records.
Delirium is increasingly considered to be an important determinant of trajectories of cognitive decline. Therefore, analyses of existing cohort studies measuring cognitive outcomes could benefit from methods to ascertain a retrospective delirium diagnosis. This study aimed to develop and validate such a method for delirium detection using routine medical records in UK and Ireland. A point prevalence study of delirium provided the reference-standard ratings for delirium diagnosis. Blinded to study results, clinical vignettes were compiled from participants' medical records in a standardised manner, describing any relevant delirium symptoms recorded in the whole case record for the period leading up to case-ascertainment. An expert panel rated each vignette as unlikely, possible, or probable delirium and disagreements were resolved by consensus. From 95 case records, 424 vignettes were abstracted by 5 trained clinicians. There were 29 delirium cases according to the reference standard. Median age of subjects was 76.6 years (interquartile range 54.6 to 82.5). Against the original study DSM-IV diagnosis, the chart abstraction method gave a positive likelihood ratio (LR) of 7.8 (95% CI 5.7-12.0) and the negative LR of 0.45 (95% CI 0.40-0.47) for probable delirium (sensitivity 0.58 (95% CI 0.53-0.62); specificity 0.93 (95% CI 0.90-0.95); AUC 0.86 (95% CI 0.82-0.89)). The method diagnosed possible delirium with positive LR 3.5 (95% CI 2.9-4.3) and negative LR 0.15 (95% CI 0.11-0.21) (sensitivity 0.89 (95% CI 0.85-0.91); specificity 0.75 (95% CI 0.71-0.79); AUC 0.86 (95% CI 0.80-0.89)). This chart abstraction method can retrospectively diagnose delirium in hospitalised patients with good accuracy. This has potential for retrospectively identifying delirium in cohort studies where routine medical records are available. This example of record linkage between hospitalisations and epidemiological data may lead to further insights into the inter-relationship between acute illness, as an exposure, for a range of chronic health outcomes.


Radiotherapy for bladder cancer.
The radiotherapy panel met to develop international consensus about the optimal use of radiotherapy, alone or in combination with surgery and chemotherapy, in the radical treatment of patients with bladder cancer. A consensus meeting of experts in the treatment of bladder cancer was convened by the Société Internationale d'Urologie (SIU). The radiotherapy committee, which had international representation from 6 countries, performed a critical review of the English-language literature and developed evidence-based guidelines for the use of radiotherapy in the treatment of patients with bladder cancer. The strength of the evidence supporting each recommendation was ranked according to a 4-point scale. Consensus statements were developed that address (1) the effectiveness of radiotherapy in the treatment of bladder cancer, (2) the most appropriate patients for curative treatment with radiotherapy, (3) the optimal method of delivery of radiotherapy, (4) the best radiation prescription for treating bladder cancer, and (5) optimal management of the patient's condition after radiotherapy has been provided. Radiotherapy is effective treatment for selected patients with bladder cancer; it produces long-term disease control with preservation of normal bladder function. Modern radiotherapy treatment techniques offer the potential to improve cure rates and reduce adverse effects. All patients in whom the condition is newly diagnosed should be assessed in a multidisciplinary setting, where the relative merits of surgery, radiotherapy, and chemotherapy can be considered on an individual basis with the aim of optimizing overall outcomes.


Polyamide 66 microspheres metallised with in situ synthesised gold nanoparticles for a catalytic application.
A simple concept is proposed to metallise polyamide 66 (PA66) spherulite structures with in situ synthesised gold nanoparticles (Au NPs) using a wet chemical method. This cost-effective approach, applied to produce a PA66/Au NP hybrid material, offers the advantages of controlling the nanoparticle size, the size distribution and the organic-inorganic interactions. These are the key factors that have to be controlled to construct consistent Au nanostructures which are essential for producing the catalytic activities of interest. The hybrid materials obtained are characterised by means of scanning electron microscopy, transmission electron microscopy, attenuated total reflection-Fourier transform infrared spectrometry and X-ray diffraction spectrometry. The results show that PA66 microspheres obtained via the crystallisation process are coated with Au NPs of 13 nm in size. It was found that controlling the metal coordination is the key parameter to template the Au NPs on the spherulite surfaces. The preparation processes and the key factors leading to the formation of PA66 spherulites coated with Au NPs are discussed. Moreover, the efficiency of the coated spherulites as a potential catalyst is proved by demonstrating the reduction of methylene blue via UV-visible spectrometry.


Effect of Febuxostat on the Endothelial Dysfunction in Hemodialysis Patients: A Randomized, Placebo-Controlled, Double-Blinded Study.
Endothelial dysfunction is an important risk factor for cardiovascular diseases to occur in end-stage renal disease patients. Febuxostat, being a novel xanthine oxidase inhibitor, is apparently having a beneficial role in improving the endothelial dysfunction; however, data among hemodialysis patients are still limited. A prospective, placebo-controlled, block-randomized, double-blinded study was carried out to evaluate the effect of oral febuxostat on the endothelial dysfunction in hemodialysis patients. Fifty-seven eligible hemodialysis patients were randomly assigned to either the drug group (40 mg thrice weekly) or the placebo group. Serum Asymmetric dimethylarginine (ADMA), Serum uric acid (UA), and serum high sensitivity C-reactive protein (hsCRP) were measured at baseline and at the end of a 2-month study. Serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and the occurrence of pancytopenia were tested as safety parameters at baseline and at the end of study. Serum UA significantly decreased from 7.5 ± 0.8 to 5.1 ± 1.2 mg/dL in the febuxostat group, while it did not change significantly in the placebo group. Treatment with febuxostat resulted in a significant decrease in the serum ADMA level from 1.027 ± 0.116 to 0.944 ± 0.104 µmol/L and the serum hsCRP level from 12.5 ± 1.65 to 12.1 ± 1.70 mg/L. Testing of serum ALT, serum AST, and pancytopenia revealed no significant difference in both groups. Febuxostat appears to improve hyperuricemia and endothelial dysfunction and ameliorate inflammation in hemodialysis patients with no safety concerns.


Clinicopathological Significance and Antitumor Effect of MPHOSPH1 in Testicular Germ Cell Tumor.
MPHOSPH1, which is one of the kinesin superfamily proteins, has been reported to play an essential role in the carcinogenesis and progression of several kinds of cancers. MPHOSPH1 has also been suggested to be involved in STAT3 phosphorylation in hepatocellular carcinoma. However, the biological behavior of MPHOSPH1 in testicular germ cell tumors (TGCTs) is unclear at present. The purposes of this study were to investigate the correlation between the expression of MPHOSPH1 and clinicopathological factors and to examine the efficacy of MPHOSPH1 target therapy in TGCTs. We investigated 75 formalin-fixed paraffin-embedded TGCT samples, containing a total of 86 germ cell tumor components, by immunohistochemistry and 12 frozen samples by Western blotting. Moreover, we carried out in vitro studies to clarify the antitumor effect of MPHOSPH1 knockdown in embryonal carcinoma cell lines, NEC8 and NEC14, using small interference RNA (siRNA). A significantly high expression of MPHOSPH1 was recognized in embryonal carcinoma and yolk sac tumor components compared to the seminoma component (p<0.001, respectively). Clinically, non-seminoma cases are known to have worse prognosis than pure-seminoma cases. Interestingly, high MPHOSPH1 expression was associated with distant metastasis (p=0.001), and thus with advanced-stage disease in this study. High expression of MPHOSPH1 interacted with high expression of phosphorylated STAT3 (p=0.01). The in vitro experiments demonstrated that MPHOSPH1 interruption by siRNA resulted in a significant reduction of cell migration, invasion, proliferation and colony formation in both embryonal carcinoma cell lines (p<0.001, respectively). In conclusion, MPHOSPH1 may be a potential treatment option for TGCTs, and its expression may be a novel biomarker of poor prognosis.


Intravenous home inotropic use is safe in pediatric patients awaiting transplantation.
Intravenous inotropic therapy can be used to support children awaiting heart transplantation. Although use of this therapy is discouraged in adults because of poor outcomes, its use in children, particularly outpatient, has had limited evaluation. We aimed to evaluate the safety and efficacy of this practice. A retrospective analysis of an intent to treat protocol was completed on United Network for Organ Sharing status 1A patients discharged on inotropic therapy from 1999 until 2012. Intravenous inotropic therapy was initiated for cardiac symptoms not amenable to oral therapy. Patients who were not status 1A or required >1 inotrope were excluded. Efficacy was analyzed by time to first event: transplantation; readmission until transplantation; improvement leading to inotrope withdrawal; or death. Safety included analysis of infection rates, line malfunctions, temporary hospitalization, neurological events, and arrhythmias. One hundred six patients met inclusion criteria. The mean age was 10.1±6.4 years, 47% of patients had congenital heart disease, and 80% of these patients had single ventricle physiology. In patients without congenital heart disease, 53% had dilated cardiomyopathy, 91% of patients received milrinone, 85% of patients underwent transplantation, 8% of patients successfully weaned from support as outpatients, whereas 6% died. Fifty percent of patients were readmitted before transplantation or weaning from support, of which 64% required only 1 readmission. The majority of readmissions were for heart failure. Outpatient intravenous inotropic therapy can be safely used as a bridge to transplantation in pediatric patients. A minority of patients can discontinue inotropic therapy because of clinical improvement.


Structure/cleavage-based insights into helical perturbations at bulge sites within T. thermophilus Argonaute silencing complexes.
We have undertaken a systematic structural study of Thermus thermophilus Argonaute (TtAgo) ternary complexes containing single-base bulges positioned either within the seed segment of the guide or target strands and at the cleavage site. Our studies establish that single-base bulges 7T8, 5A6 and 4A5 on the guide strand are stacked-into the duplex, with conformational changes localized to the bulge site, thereby having minimal impact on the cleavage site. By contrast, single-base bulges 6'U7' and 6'A7' on the target strand are looped-out of the duplex, with the resulting conformational transitions shifting the cleavable phosphate by one step. We observe a stable alignment for the looped-out 6'N7' bulge base, which stacks on the unpaired first base of the guide strand, with the looped-out alignment facilitated by weakened Watson-Crick and reversed non-canonical flanking pairs. These structural studies are complemented by cleavage assays that independently monitor the impact of bulges on TtAgo-mediated cleavage reaction.


Postvasectomy semen analysis: why patients don't follow-up.
Semen analysis following elective vasectomy is necessary to confirm that the procedure was successful. However, many patients fail to follow postoperative instructions to obtain semen analysis. One hundred forty-one patients who had undergone vasectomy at the Family Practice Center of the Medical College of Ohio were surveyed to assess reasons for a poor rate of follow-up after vasectomy. Only 26 percent of respondents had returned two or more semen samples following surgery. Forty-five percent had not returned any samples. The inconvenience and embarrassment of having to bring semen specimens to the laboratory were identified as factors that can affect patient adherence to instructions. Respondents who had not returned any semen specimens were more likely to answer that their spouse would not be very upset if the vasectomy failed and pregnancy resulted. Our survey results identify issues for improving patient care following vasectomy. These include patient education and postoperative protocols.


Cohort profile of the Sloane Project: methodology for a prospective UK cohort study of >15 000 women with screen-detected non-invasive breast neoplasia.
The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study. Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term. To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods. Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.


Probing striatal function in obsessive-compulsive disorder: a PET study of implicit sequence learning.
Positron emission tomography was employed to contrast the brain activation pattern in patients with obsessive-compulsive disorder (OCD) to that of matched control subjects while they performed an implicit learning task. Although patients and control subjects evidenced comparable learning, imaging data from control subjects indicated bilateral inferior striatal activation, whereas OCD patients did not activate right or left inferior striatum and instead showed bilateral medial temporal activation. The findings further implicate corticostriatal dysfunction in obsessive-compulsive disorder. Furthermore, when OCD patients are confronted with stimuli that call for recruitment of corticostriatal systems, they instead appear to access brain regions normally associated with explicit (conscious) information processing.


Superficial fungal infections: clinical and epidemiological study in adolescents from marginal districts of Lima and Callao, Peru.
Since limited data on superficial fungal infections in teenagers exist in our setting, this study provides the first description of the clinical and epidemiological characteristics of these infections among teenagers in Lima and Callao, Peru. The study involved 1,387 adolescents in five public schools from June to November 2006. Participants were examined for superficial fungal lesions. Samples of skin scrapings for microbiological investigations were obtained from suspicious lesions. A total of 257 subjects were identified with suspected superficial fungal infections. Microbiological assessment was positive for 166 of 257 (64.59%). The average prevalence was 12.61% with variation between different districts. Males were more affected (64%) than females (36%) (p = 0.001). Pet ownership, use of public baths, and wearing sneakers were identified as important risk factors. The majority (61.5%) of the subjects presented with itching although 38.5% were asymptomatic. Tinea pedis was observed in 62.6%, onychomycosis in 24% and pityriasis versicolor in 10.8%. Dermatophytes were isolated in 105 cases with T. rubrum being identified in 86 cases (59.7%), T. mentagrophytes in 14 (9.7%) and yeast in 39 (23.4%). Malassezia spp. was found by direct examination in 18 cases (12.5%), C. kruseii in 8 cases (5.6%), and C. albicans in 2 cases (1.4%). Mixed infections were found in 22 cases. Superficial fungal infection manifesting as tinea pedis, onychomycosysis and tinea versicolor is prevalent in our setting. As many infections remain asymptomatic, regular examination of this population is advocated. The associated risk factors for these infections also need to be addressed.


The Public Sphere in Emerging Infectious Disease Communication: Recipient or Active and Vocal Partner?
Recent years have seen advances in theories and models of risk and crisis communication, with a focus on emerging epidemic infection. Nevertheless, information flow remains unilateral in many countries and does not take into account the public's polyvocality and the fact that its opinions and knowledge often "compete" with those of health authorities. This article addresses the challenges organizations face in communicating with the public sphere. Our theoretical approach is conceptualized through a framework that focuses on the public sphere and that builds upon existing guidelines and studies in the context of health and pandemics. We examine how health organizations cope with the public's transformation from recipients to an active and vocal entity, ie, how and to what extent health organizations address the public's anxiety and concerns arising in the social media during outbreaks. Although international organizations have aspired to relate to the public as a partner, this article identifies notable gaps. Organizations must involve the public throughout the crisis and conduct dialogues free of prejudices, paternalism, and preconceptions. Thereby, they can impart precise and updated information reflecting uncertainty and considering cultural differences to build trust and facilitate cooperation with the public sphere.


Pediatric lymphoma: a 10-year experience at a tertiary care hospital in Pakistan.
Lymphoma is the third most common childhood malignancy. Less information is available on this disease and its outcome from our country. We present here a single institute experience. A retrospective study was carried out at Aga Khan University Hospital, Karachi on children (<15 y) diagnosed with lymphoma from 1998 to 2007. Sixty-eight patients were identified. Fifty-one children were diagnosed as non-Hodgkin lymphoma (NHL). Mean age of presentation was 8.4 years with male-to-female ratio of 5.8 : 1. Most common histopathologic subtype of NHL was Burkitt lymphoma (55%). Abdominal mass was the main presenting feature of Burkitt and diffuse large B cell lymphoma. T-lymphoblastic lymphoma presented mainly as mediastinal mass. Ten children died, 4 secondary to tumor lysis syndrome, 5 because of disease progression, and 1 with chemotherapy-induced toxicity. One-third of the patients left without treatment. Seventeen children were diagnosed as Hodgkin lymphoma with mixed cellularity as the commonest subtype (65%). Overall survival of children with NHL and Hodgkin lymphoma was 62% and 94%, respectively. A greater proportion of NHL, advanced stage, and profound male preponderance were observed. Improvement in survival can only be achieved with increasing awareness, identifying and tackling causes of abandonment, early referral, and better supportive care.


Immunotherapy with low-dose interleukin-2 and a polysaccharopeptide derived from Coriolus versicolor.
The purpose of the present study was to evaluate the therapeutic efficacy of locally administered low-dose interleukin-2 (IL-2) and a polysaccharopeptide (PSP) derived from Cariolous versicolor in a herpes virus Type 2-transformed murine tumor (H238) model and to determine possible mechanisms of action. BALB/c mice were inoculated subcutaneously (s.c.) with H238 tumor cells and randomized into groups: a) no tumor and no treatment control, b) tumor and no treatment control, c) tumor + IL-2 at 0 to 4 days, d) tumor + PSP at 0 to 10 days, e) tumor + IL-2 at 0 to 4 days + PSP at 0 to 10 days, and f) tumor + IL-2 at 15 to 19 days + PSP at 15 to 25 days. The IL-2 was administered s.c. at 2 x 10(4) i.u./mouse/injection; PSP was given s.c. at 2 mg/mouse/injection. No obvious toxicity was noted during the treatments. IL-2 and, to a lesser extent, PSP significantly slowed (p < 0.05) tumor progression when given alone immediately after tumor cell injection. The combination of the two modalities did not significantly enhance the antitumor effect of IL-2 alone. However, mice receiving both agents had IL-2 in the plasma, their tumors expressed low levels of transforming growth factor-beta, and their splenocyte response to mitogenic stimulation was significantly higher than in untreated controls. Changes in blood leukocyte populations and splenic oxidative burst capacity were associated with tumor presence, but not with the type of treatment. In vitro assays showed that both IL-2 and PSP can suppress the uptake of 3H-thymidine by tumor cells and that the effect is more pronounced whent the agents are used in combination. These results indicate that IL-2 and PSP can slow progression of H238 tumors and that the mechanisms of action may be related to their direct cytotoxic effects, as well to their immunomodulatory properties.


Intron conservation in the DNA polymerase gene encoded by Chlorella viruses.
Previously we reported that 19 of 42 viruses that infect Chlorella strain NC64A (NC64A viruses) contain a short, nuclear-located, spliceosomal-processed intron in a pyrimidine dimer-specific glycosylase/apyrimidine lyase (pdg) gene. Surprisingly, the nucleotide sequence of the intron region is more conserved than the exon regions of the gene (L. Sun et al., 2000, J. Mol. Evol. 50, 82-92). For comparative purposes, we determined the nucleotide sequence of a similar intron type and its flanking coding regions in the DNA polymerase (dnapol) gene from the same 42 NC64A viruses and also 5 viruses that infect Chlorella strain Pbi. Thirty-eight of the 42 NC64A viruses contained a 101-nucleotide intron and the remaining 4 had an 86-nucleotide intron located in the same position in dnapol. The 4 viruses with the smaller intron in dnapol also have a smaller intron in their pdg gene. There was no intron in the dnapol gene of the 5 Pbi viruses. Phylogenetic analyses indicate that the dnapol genes containing the 86-nucleotide intron represent the ancestral condition among the NC64A viruses. The intron in the dnapol gene is phase 0 (keeps codons intact), which differs from the phase 1 intron in the pdg gene. The intron in the dnapol gene, unlike the pdg intron, was conserved (83 to 100% identical) to about the same extent as the coding regions of the gene (78 to 100% identical).


In vivo biocompatibility and in vitro characterization of poly-lactide-co-glycolide structures containing levetiracetam, for the treatment of epilepsy.
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, and is highly resistant to medication with up to 40% of patients continuing to experience seizures whilst taking oral antiepileptic drugs. Recent research suggests that this may be due to abnormalities in the blood-brain barrier, which prevent the passage of therapeutic substances into the brain. We sought to develop a drug delivery material that could be implanted within the brain at the origin of the seizures to release antiepileptic drugs locally and avoid the blood brain barrier. We produced poly-lactide-co-glycolide drop-cast films and wet-spun fibers loaded with the novel antiepileptic drug Levetiracetam, and investigated their morphology, in vitro drug release characteristics, and brain biocompatibility in adult rats. The best performing structures released Levetiracetam constantly for at least 5 months in vitro, and were found to be highly brain biocompatible following month-long implantations in the motor cortex of adult rats. These results demonstrate the potential of polymer-based drug delivery devices in the treatment of epilepsy and warrant their investigation in animal models of focal epilepsy.


Chagas' disease: a clinical, parasitological, immunological, and pathological study in rabbits.
Thirty-four rabbits were experimentally infected with trypomastigotes of either the Ernestina or the Albuquerque strains of Trypanosoma cruzi. These animals showed patent parasitemias, as demonstrated by xenodiagnosis, in the acute phases of the infections. Typical chagoma signs developed in two rabbits 1 week after parasite inoculation in the skin, although the acute phase of Chagas' disease in the rabbit model was usually asymptomatic. In the 6th month of infection the parasitemias became negative and the infections remained subpatent, as indicated by the persistence of positive serologic tests and of delayed-type skin reactions elicited in Chagas' rabbits against a microsomal T. cruzi antigen. This latent infection continued asymptomatically, in the absence of electrocardiographic (ECG) alterations. However, ECG changes consistent with enlargement and overload of cardiac chambers, alterations of ventricular repolarization, S-T changes and bundle-branch blocks were frequently recorded later in the chronic phase of Chagas' disease. The pathological manifestations of these ECG alterations were confirmed at the autopsy of each experimental rabbit. Congestive heart failure and pulmonary thromboemboli related to chronic myocarditis of Chagas' disease were frequent causes of death. Megacolon was seen in two rabbits inoculated with the Ernestina strain of the parasite. The relatively limited duration of detectable parasitemia even when xenodiagnosis is used, the lack of correlation between parasitemia and severity of pathological manifestations, and the fact that all infected animals showed histopathological evidence of myocarditis, destructive inflammatory lesions characterized by mononuclear infiltrates in skeletal muscles, as well as cutaneous delayed hypersensitivity to T. cruzi antigens, are notable observations in this animal model of the human disease.


Āyurveda's Contributions to Vegetarian Nutrition in Medicine.
Āyurveda is one of the oldest codified traditional systems of medicine on a global scale. Grounded in Indian culture it has developed a sophisticated approach to healthy nutrition and nutritional therapy for the management of diseases within the framework of its whole systems paradigm. Medical interventions have been considered to be ineffective without the support of a balanced diet. Vegetarian nutrition plays a key role in customized preventive and therapeutic Āyurvedic strategies based on an individualized approach to healthcare, while broadly labeling Āyurveda as 'vegetarian medicine' would be an exaggeration. Revolt against animal slaughter, compassion through spiritual practices, and the Āyurvedic understanding of the nutritional properties of the plant kingdom led to the dominance of vegetarianism in India. Āyurveda elaborates on 8 crucial aspects to be considered with respect to a balanced diet. This paper illuminates the complex historic embedding of the Āyurvedic nutritional approach and gives a detailed text-based explanation on why and how vegetarian nutrition can be applied in both prevention and cure of diseases from the perspective of traditional Indian medicine.


Vasoactive mediators and renal haemodynamics in exertional heat stroke complicated by acute renal failure.
Although vasoactive substances may be important in the pathogenesis of some types of acute renal failure (ARF), their potential role in exertional heat stroke (ExHS) with ARF has not been explored. To evaluate whether changes in concentration of individual vasoactive mediators correlated with alterations in renal function and haemodynamics in patients with ExHS and ARF. Prospective case-control study. Systemic and renal haemodynamics, circulating vasoactive hormones and urinary vasodilator metabolites were determined in 12 military recruits who developed ExHS with ARF but without other organ failure during a three-year period. The control group consisted of 12 recruits who performed similar exercise under the same conditions without developing ExHS. There were significant elevations in circulating pressor hormones (catecholamines, renin, aldosterone and endothelin-1 (ET-1)) and significant decreases in the vasodilatory hormone prostaglandin E(2) (PGE(2)) in the acute phase of ExHS with ARF when compared to ExC. There was also a significant rise in nitric oxide metabolites (NOx) in the acute phase of ExHS. All of these abnormalities in circulating hormones returned to normal range during the recovery phase of ExHS. The ERPF correlated positively with GFR and urinary PGE(2) and negatively with plasma catecholamines, renin, ET-1 and NOx. The changes in the plasma levels of these hormones, together with enhanced NO production, may both contribute to the pathophysiology of ARF in ExHS.


Vascular Surgery in Japan: 2013 Annual Report by the Japanese Society for Vascular Surgery.
Objectives: This is an annual report indicating the number and early clinical results of annual vascular treatment performed by vascular surgeon in Japan in 2013, as analyzed by database management committee (DBC) members of the JSVS. Materials and Methods: To survey the current status of vascular treatments performed by vascular surgeons in Japan, the DBC members of the JSVS analyzed the vascular treatment data provided by the National Clinical Database (NCD), including the number of treatments and early results such as operative and in-hospital mortality. Results: In total 100,470 vascular treatments were registered by 1,045 institutions in 2013. This database is composed of 7 fields including treatment of aneurysms, chronic arterial occlusive disease, acute arterial occlusive disease, vascular injury, complication of previous vascular reconstruction, venous diseases, and other vascular treatments. The number of vascular treatments in each field was 19,439, 13,276, 4,688, 1,563, 1,777, 37,643, and 23,971, respectively. In the field of aneurysm treatment, 16,694 cases of abdominal aortic aneurysm (AAA) including common iliac aneurysm were registered, and 52.9% were treated by endovascular aneurysm repair (EVAR). Among AAA cases, 1,598 (9.6%) cases were registered as ruptured AAA. The operative mortality of ruptured and un-ruptured AAA was 17.9%, and 1.0%, respectively. 25.5% of ruptured AAA were treated by EVAR, and the EVAR ratio was gradually increasing, but the operative mortality of open repair and EVAR for ruptured AAA was 16.1%, and 15.8%, respectively. Regarding chronic arterial occlusive disease, open repair was performed in 7,437 cases, including 1,121 distal bypasses to the crural or pedal artery, whereas endovascular treatment (EVT) were performed in 5,839 cases. The EVT ratio was gradually increased at 44.0%. Venous treatment including 35,986 cases with varicose vein treatments and 506 cases with lower limb deep vein thrombosis were registered. Regarding other vascular operations, 22,572 cases of vascular access operations and 1,185 amputation surgeries were included. Conclusions: The number of vascular treatments increased since 2011, and the proportion of endovascular procedures increased in almost all field of vascular diseases, especially EVAR for AAA, EVT for chronic arterial occlusive disease, and endovenous laser ablation (EVLA) for varicose veins. (This is a translation of Jpn J Vasc Surg 2019; 28: 273-292.).


Ultrafast structural dynamics of the Fe-pnictide parent compound BaFe(2)As(2).
Using femtosecond time-resolved x-ray diffraction we investigate the structural dynamics of the coherently excited A(1g) phonon mode in the Fe-pnictide parent compound BaFe(2)As(2). The fluence dependent intensity oscillations of two specific Bragg reflections with distinctly different sensitivity to the pnictogen height in the compound allow us to quantify the coherent modifications of the Fe-As tetrahedra, indicating a transient increase of the Fe magnetic moments. By a comparison with time-resolved photoemission data, we derive the electron-phonon deformation potential for this particular mode. The value of Δμ/Δz=-(1.0-1.5) eV/Å is comparable with theoretical predictions and demonstrates the importance of this degree of freedom for the electron-phonon coupling in the Fe pnictides.


MicroRNAs: Crucial Regulators of Stress.
Signaling pathways including gene silencing, cellular differentiation, homeostasis, development and apoptosis are regulated and controlled by a wide range of miRNAs. Due to their potential binding sites in human-protein coding genes, many studies have also linked their altered expressions in various cancer types making them tumor suppressors agents. Moreover, each miRNA is predicted to have many mRNA targets indicating their extensive regulatory role in cell survival and developmental processes. Nowadays, diagnosis of early cancer stage development is now dependent on variable miRNA expression levels as potential oncogenic biomarkers in validating and targeting microRNAs for cancer therapy. As the majority of miRNA, transcripts are derived from RNA polymerase II-directed transcription, stress response could result on a general reduction in the abundance of these transcripts. Over expression of various microRNAs have lead to B cell malignancy, potentiated KrasG12Dinduced lung tumorigenesis, chronic lymphocytic leukemia, lymphoproliferative disease and autoimmunity. Altered miRNA expressions could have a significant impact on the abundance of proteins, making them attractive candidates as biomarkers for cancer detection and important regulators of apoptosis.


Assessment of brain-machine interfaces from the perspective of people with paralysis.
One of the main goals of brain-machine interface (BMI) research is to restore function to people with paralysis. Currently, multiple BMI design features are being investigated, based on various input modalities (externally applied and surgically implantable sensors) and output modalities (e.g. control of computer systems, prosthetic arms, and functional electrical stimulation systems). While these technologies may eventually provide some level of benefit, they each carry associated burdens for end-users. We sought to assess the attitudes of people with paralysis toward using various technologies to achieve particular benefits, given the burdens currently associated with the use of each system. We designed and distributed a technology survey to determine the level of benefit necessary for people with tetraplegia due to spinal cord injury to consider using different technologies, given the burdens currently associated with them. The survey queried user preferences for 8 BMI technologies including electroencephalography, electrocorticography, and intracortical microelectrode arrays, as well as a commercially available eye tracking system for comparison. Participants used a 5-point scale to rate their likelihood to adopt these technologies for 13 potential control capabilities. Survey respondents were most likely to adopt BMI technology to restore some of their natural upper extremity function, including restoration of hand grasp and/or some degree of natural arm movement. High speed typing and control of a fast robot arm were also of interest to this population. Surgically implanted wireless technologies were twice as 'likely' to be adopted as their wired equivalents. Assessing end-user preferences is an essential prerequisite to the design and implementation of any assistive technology. The results of this survey suggest that people with tetraplegia would adopt an unobtrusive, autonomous BMI system for both restoration of upper extremity function and control of external devices such as communication interfaces.


The Effect of Pre-Post Differences in Walking, Health, and Weight on Retirees' Long-Term Quality of Life.
This research examined the effect of pre-post differences in walking duration, health, and weight on retirees' long-term quality of life (QoL). It used data from a 2018 randomized mail survey of 483 suburban New Jersey retirees. Ordinary least squares and three-stage least squares models were used. The analysis showed that changes in walking duration during the first 2 years of retirement are directly associated with health change, health change has an effect on long-term QoL, and weight variation of 10 lb or more has an effect on health change and long-term QoL. Although QoL peaks for the sample of retirees at around age 75, people whose average walking duration increased, health improved, and weight did not increase substantially after retirement continued to experience high QoL for a longer time. The results show that people can achieve high long-term QoL by choosing an active lifestyle when transitioning to retirement.


ChatGPT to enhance learning in dental education at a historically black medical college.
In dental education of today, the didactic curriculum primarily relies on lecture-based courses, where instructors impart knowledge through presentations and discussions. The recent rise of powerful large language model-based tools, exemplified by ChatGPT (Chat Generative Pre-Trained Transformer), poses a great challenge to traditional dental education while simultaneously offering a unique resource and approach that potentially complements today's teaching and learning, where existing widely available learning resources have often fallen short. In this paper, we used dental course materials, syllabi, and textbooks adopted currently in the School of Dentistry at Meharry Medical College to assess the potential utility and effectiveness of ChatGPT in dental education. We collected the responses of the chatbot to questions as well as students' interactions with it for assessment. Our results showed that ChatGPT can assist in dental essay writing and generate relevant content for dental students, in addition to other benefits. The limitations of ChatGPT were also discussed in the paper.


Efficiency of ODI and APDI of Kim's cephalometric analysis in a Latin American population with skeletal open bite.
The objective of this research was to demonstrate the efficiency of the overbite depth indicator (ODI) and the anteroposterior dysplasia indicator (APDI) from Kim's cephalometric analysis, regarding the determination of the vertical and sagittal patterns of Latin American individuals. Two hundred lateral cephalometric radiographs were selected and divided into four study groups, with 50 radiographs each, for carrying out a cross-sectional study. The control group included radiographs of balanced individuals, and the other three groups had lateral cephalometric radiographs of subjects with Class I, II and III malocclusions and with skeletal open bite. After the pilot test was performed to calibrate the investigator, the ODI and APDI were measured. Descriptive statistics were performed and the one-way ANOVA with post-hoc Tukey HSD, or Kruskal-Wallis and Mann-Whitney U-test were used. Also a multiple linear regression was employed. Statistically significant differences were found for the ODI of all groups (p< 0.001), except between Class I group (65.87 ± 4.26) and Class II open bite group (67.19 ± 3.58), both with similar values to each other. For APDI, statistically significant differences were also found for all groups (p< 0.001). However, no statistically significant differences were found between the balanced group (83.18 ± 1.71) and Class I group with skeletal open bite (81.78 ± 2.69). ODI and APDI are reliable indicators to evaluate the sagittal and vertical patterns of an individual, demonstrating their efficiency when a Latin American population was evaluated.


Intensive Glucose Control in Patients with Type 2 Diabetes - 15-Year Follow-up.
We previously reported that a median of 5.6 years of intensive as compared with standard glucose lowering in 1791 military veterans with type 2 diabetes resulted in a risk of major cardiovascular events that was significantly lower (by 17%) after a total of 10 years of combined intervention and observational follow-up. We now report the full 15-year follow-up. We observationally followed enrolled participants (complete cohort) after the conclusion of the original clinical trial by using central databases to identify cardiovascular events, hospitalizations, and deaths. Participants were asked whether they would be willing to provide additional data by means of surveys and chart reviews (survey cohort). The prespecified primary outcome was a composite of major cardiovascular events, including nonfatal myocardial infarction, nonfatal stroke, new or worsening congestive heart failure, amputation for ischemic gangrene, and death from cardiovascular causes. Death from any cause was a prespecified secondary outcome. There were 1655 participants in the complete cohort and 1391 in the survey cohort. During the trial (which originally enrolled 1791 participants), the separation of the glycated hemoglobin curves between the intensive-therapy group (892 participants) and the standard-therapy group (899 participants) averaged 1.5 percentage points, and this difference declined to 0.2 to 0.3 percentage points by 3 years after the trial ended. Over a period of 15 years of follow-up (active treatment plus post-trial observation), the risks of major cardiovascular events or death were not lower in the intensive-therapy group than in the standard-therapy group (hazard ratio for primary outcome, 0.91; 95% confidence interval [CI], 0.78 to 1.06; P = 0.23; hazard ratio for death, 1.02; 95% CI, 0.88 to 1.18). The risk of major cardiovascular disease outcomes was reduced, however, during an extended interval of separation of the glycated hemoglobin curves (hazard ratio, 0.83; 95% CI, 0.70 to 0.99), but this benefit did not continue after equalization of the glycated hemoglobin levels (hazard ratio, 1.26; 95% CI, 0.90 to 1.75). Participants with type 2 diabetes who had been randomly assigned to intensive glucose control for 5.6 years had a lower risk of cardiovascular events than those who received standard therapy only during the prolonged period in which the glycated hemoglobin curves were separated. There was no evidence of a legacy effect or a mortality benefit with intensive glucose control. (Funded by the VA Cooperative Studies Program; VADT ClinicalTrials.gov number, NCT00032487.).


Resurfacing of pitted facial acne scars with a long-pulsed Er:YAG laser.
Conventional short-pulsed Er:YAG lasers show less effective hemostasis and weak photothermal damage on papillary dermis. Recently, newer long-pulsed Er:YAG laser systems has been developed. To evaluate the clinical and histologic effects of long-pulsed Er:YAG laser resurfacing for pitted facial acne scars. Thirty-five patients with pitted facial acne scars were treated with a long-pulsed Er:YAG laser. All patients had Fitzpatrick skin phototypes III-V. A pulsed Er:YAG laser with a 5 mm handpiece at a setting of 7.0-7.5 J/cm2 with a 10-msec pulse duration was used. The laser was fired at 5 Hz, with four to five passes. In 28 patients, the results of laser treatment were evaluated for the degree of clinical improvement, duration of erythema, pigmentary change, and any adverse events at 2 weeks, 1 month, and 3 months. In seven patients, skin biopsy specimens were obtained at the following intervals: immediately, 1 week, 2 weeks, 4 weeks, and 8 weeks postoperatively for histologic examination. The results of long-pulsed Er:YAG laser resurfacing for pitted facial acne scars were excellent in 10 patients (36%), good in 16 patients (57%), and fair in 2 patients (7%). Erythema occurred in all patients after laser treatment and lasted longer than 3 months in 15 patients (54%). Postinflammatory hyperpigmentation occurred in 8 patients (29%). But the pigmentation faded or disappeared within 3 months. One patient (4%) experienced mild hypopigmentation. Pruritic symptoms that required medical intervention occurred in 16 patients (57%). Mild to moderate postoperative acne flare-up occurred in 8 patients (29%). No other adverse effects such as scarring, bacterial infection, or contact dermatitis were observed. In conclusion, resurfacing with a long-pulsed Er:YAG laser is a safe and very effective treatment modality for pitted facial acne scars.


The 1',4'-iminopyrimidine tautomer of thiamin diphosphate is poised for catalysis in asymmetric active centers on enzymes.
Thiamin diphosphate, a key coenzyme in sugar metabolism, is comprised of the thiazolium and 4'-aminopyrimidine aromatic rings, but only recently has participation of the 4'-aminopyrimidine moiety in catalysis gained wider acceptance. We report the use of electronic spectroscopy to identify the various tautomeric forms of the 4'-aminopyrimidine ring on four thiamin diphosphate enzymes, all of which decarboxylate pyruvate: the E1 component of human pyruvate dehydrogenase complex, the E1 subunit of Escherichia coli pyruvate dehydrogenase complex, yeast pyruvate decarboxylase, and pyruvate oxidase from Lactobacillus plantarum. It is shown that, according to circular dichroism spectroscopy, both the 1',4'-iminopyrimidine and the 4'-aminopyrimidine tautomers coexist on the E1 component of human pyruvate dehydrogenase complex and pyruvate oxidase. Because both tautomers are seen simultaneously, these two enzymes provide excellent evidence for nonidentical active centers (asymmetry) in solution in these multimeric enzymes. Asymmetry of active centers can also be induced upon addition of acetylphosphinate, an excellent electrostatic pyruvate mimic, which participates in an enzyme-catalyzed addition to form a stable adduct, resembling the common predecarboxylation thiamin-bound intermediate, which exists in its 1',4'-iminopyrimidine form. The identification of the 1',4'-iminopyrimidine tautomer on four enzymes is almost certainly applicable to all thiamin diphosphate enzymes: this tautomer is the intramolecular trigger to generate the reactive ylide/carbene at the thiazolium C2 position in the first fundamental step of thiamin catalysis.


Staphylococcus saprophyticus as a urinary pathogen: a six year prospective survey.
Over six years (1978-83, inclusive) weekly laboratory records of organisms causing urinary tract infection in women aged 15-25 not attending hospital were kept prospectively and analysed. The incidence of infection with Staphylococcus saprophyticus defined by age and sex was confirmed. This organism caused an increasing proportion of infections in young women over the six years studied, and these infections showed noticeable seasonality. All but four isolates of S saprophyticus were sensitive to all the commonly used antimicrobial agents that were tested. This might be because the organism is not often present in the body as a commensal and therefore not subject to the selection pressures exerted by such agents. As infection with S saprophyticus has different clinical connotations from infection with other coagulase negative staphylococci it should be differentiated from them in routine laboratory practice.


Adjuvant Whole-Brain Radiation Therapy Compared With Observation After Local Treatment of Melanoma Brain Metastases: A Multicenter, Randomized Phase III Trial.
The brain is a common site of metastasis for patients with high-risk melanoma. Although surgery or stereotactic radiosurgery are highly effective local treatments for a small number of metastases, there is a high risk of developing additional brain metastases. The role of adjuvant whole-brain radiotherapy (WBRT) in reducing new metastases is controversial, with a lack of high-level evidence specifically for melanoma. In this randomized phase III trial, patients who had local treatment of one to three melanoma brain metastases were randomly assigned to WBRT or observation. The primary end point was distant intracranial failure within 12 months, and secondary end points included time to intracranial failure, survival, and time to deterioration in performance status. Between April 2009 and September 2017, 215 patients were randomly assigned from 24 centers. Median follow-up was 48.1 months (range, 39.6 to 68 months). Forty-two percent of patients in the WBRT group and 50.5% of those in the observation developed distant intracranial failure within 12 months (odds ratio, 0.71; 95% CI, 0.41 to 1.23; P = .22) and the rates over the entire follow-up period were 52.0% and 57.9%, respectively (odds ratio, 0.79; 95% CI, 0.45 to 1.36; P = .39). Local failure rate was lower after WBRT (20.0% v 33.6%; P = .03). At 12 months, 41.5% of patients in the WBRT group and 51.4% of patients in the observation group had died (P = .28), with no difference in the rate of neurologic death. Median time to deterioration in performance status was 3.8 months after WBRT and 4.4 months with observation (P = .32). WBRT was associated with more grade 1 to 2 acute toxicity. After local treatment of one to three melanoma brain metastases, adjuvant WBRT does not provide clinical benefit in terms of distant intracranial control, survival, or preservation of performance status.


High resolution mapping of genetic factors affecting abdominal bristle number in Drosophila melanogaster.
Factors responsible for selection response for abdominal bristle number and correlated responses in sternopleural bristle number were mapped to the X and third chromosome of Drosophila melanogaster. Lines divergent for high and low abdominal bristle number were created by 25 generations of artificial selection from a large base population, with an intensity of 25 individuals of each sex selected from 100 individuals of each sex scored per generation. Isogenic chromosome substitution lines in which the high (H) X or third chromosome were placed in an isogenic low (L) background were derived from the selection lines and from the 93 recombinant isogenic (RI) HL X and 67 RI chromosome 3 lines constructed from them. Highly polymorphic neutral roo transposable elements were hybridized in situ to the polytene chromosomes of the RI lines to create a set of cytogenetic markers. These techniques yielded a dense map with an average spacing of 4 cM between informative markers. Factors affecting bristle number, and relative viability of the chromosome 3 RI lines, were mapped using a multiple regression interval mapping approach, conditioning on all markers > or = 10 cM from the tested interval. Two factors with large effects on abdominal bristle number were mapped on the X chromosome and five factors on the third chromosome. One factor with a large effect on sternopleural bristle number was mapped to the X and two were mapped to the third chromosome; all factors with sternopleural effects corresponded to those with effects on abdominal bristle number. Two of the chromosome 3 factors with large effects on abdominal bristle number were also associated with reduced viability. Significant sex-specific effects and epistatic interactions between mapped factors of the same order of magnitude as the additive effects were observed. All factors mapped to the approximate positions of likely candidate loci (ASC, bb, emc, h, mab, Dl and E(spl), previously characterized by mutations with large effects on bristle number.


Electrical Stimulation of the Suprahyoid Muscles in Brain-injured Patients with Dysphagia: A Pilot Study.
To investigate the therapeutic effects of repetitive electrical stimulation of the suprahyoid muscles in brain-injured patients with dysphagia. Twenty-eight brain-injured patients who showed reduced laryngeal elevation and supraglottic penetration or subglottic aspiration during a videofluoroscopic swallowing study (VFSS) were selected. The patients received either conventional dysphagia management (CDM) or CDM with repetitive electrical stimulation of the suprahyoid muscles (ESSM) for 4 weeks. The videofluoroscopic dysphagia scale (VDS) using the VFSS and American Speech-Language-Hearing Association National Outcome Measurement System (ASHA NOMS) swallowing scale (ASHA level) was used to determine swallowing function before and after treatment. VDS scores decreased from 29.8 to 17.9 in the ESSM group, and from 29.2 to 16.6 in the CDM group. However, there was no significant difference between the groups (p=0.796). Six patients (85.7%) in the ESSM group and 14 patients (66.7%) in the CDM group showed improvement according to the ASHA level with no significant difference between the ESSM and CDM groups (p=0.633). Although repetitive neuromuscular electrical stimulation of the suprahyoid muscles did not further improve the swallowing function of dysphagia patients with reduced laryngeal elevation, more patients in the ESSM group showed improvement in the ASHA level than those in the CDM group. Further studies with concurrent controls and a larger sample group are required to fully establish the effects of repetitive neuromuscular electrical stimulation of the suprahyoid muscles in dysphagia patients.


Synchronization in human musical rhythms and mutually interacting complex systems.
Though the music produced by an ensemble is influenced by multiple factors, including musical genre, musician skill, and individual interpretation, rhythmic synchronization is at the foundation of musical interaction. Here, we study the statistical nature of the mutual interaction between two humans synchronizing rhythms. We find that the interbeat intervals of both laypeople and professional musicians exhibit scale-free (power law) cross-correlations. Surprisingly, the next beat to be played by one person is dependent on the entire history of the other person's interbeat intervals on timescales up to several minutes. To understand this finding, we propose a general stochastic model for mutually interacting complex systems, which suggests a physiologically motivated explanation for the occurrence of scale-free cross-correlations. We show that the observed long-term memory phenomenon in rhythmic synchronization can be imitated by fractal coupling of separately recorded or synthesized audio tracks and thus applied in electronic music. Though this study provides an understanding of fundamental characteristics of timing and synchronization at the interbrain level, the mutually interacting complex systems model may also be applied to study the dynamics of other complex systems where scale-free cross-correlations have been observed, including econophysics, physiological time series, and collective behavior of animal flocks.


Clinical controversies in anticoagulation monitoring and antithrombin supplementation for ECMO.
During extracorporeal membrane oxygenation (ECMO), a delicate balance is required to titrate systemic anticoagulation to prevent thrombotic complications within the circuit and prevent bleeding in the patient. Despite focused efforts to achieve this balance, the frequency of both thrombotic and bleeding events remains high. Anticoagulation is complicated to manage in this population due to the complexities of the hemostatic system that are compounded by age-related developmental hemostatic changes, variable effects of the etiology of critical illness on hemostasis, and blood-circuit interaction. Lack of high-quality data to guide anticoagulation management in ECMO patients results in marked practice variability among centers. One aspect of anticoagulation therapy that is particularly challenging is the use of antithrombin (AT) supplementation for heparin resistance. This is especially controversial in the neonatal and pediatric population due to the baseline higher risk of bleeding in this cohort. The indication for AT supplementation is further compounded by the potential inaccuracy of the diagnosis of heparin resistance based on the standard laboratory parameters used to assess heparin effect. With concerns regarding the adverse impact of bleeding and thrombosis, clinicians and institutions are faced with making difficult, real-time decisions aimed at optimizing anticoagulation in this setting. In this clinically focused review, the authors discuss the complexities of anticoagulation monitoring and therapeutic intervention for patients on ECMO and examine the challenges surrounding AT supplementation given both the historical and current perspectives summarized in the literature on these topics.


Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.
The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.


Enzymatically degradable hybrid organic-inorganic bridged silsesquioxane nanoparticles for in vitro imaging.
We describe biodegradable bridged silsesquioxane (BS) composite nanomaterials with an unusually high organic content (ca. 50%) based on oxamide components mimicking amino acid biocleavable groups. Unlike most bulk BS materials, the design of sub-200 nm nearly monodisperse nanoparticles (NPs) was achieved. These enzymatically degradable BS NPs were further tested as promising imaging nanoprobes.


Phosphorylation by p44 MAP Kinase/ERK1 stimulates CBP histone acetyl transferase activity in vitro.
The transcriptional coactivator CBP displays an intrinsic histone acetyl transferase (HAT) activity which seems to participate in transcriptional activation through the destabilization of nucleosome structure. CBP is involved in the activity of several transcription factors that are nuclear endpoints of intracellular signal transduction pathways. In some instances, the transcription factors are phosphorylated upon cell activation, which induces their interaction with CBP. CBP itself is a phosphoprotein and can be phosphorylated by cycle-dependent kinases or by MAP kinases. Here we show that CBP phosphorylation by p44 MAP kinase/ERK1 results in the stimulation of its HAT enzymatic activity. The p44 MAP kinase/ERK1 phosphorylation sites are located in the C-terminal part of the protein, outside of the HAT domain. These sites are required for enzymatic stimulation, suggesting that phosphorylation by p44 MAP kinase/ERK1 induces a conformational change of the CBP molecule. Our data suggest that, in some instances, CBP itself might be a target for signal transduction pathways.


Therapeutic doses of radiation alter proliferation and attachment of osteoblasts to implant surfaces.
Osseointegration of implants in irradiated bone is inadequate. The effect of radiation on cell-implant material interaction has not been adequately studied. The goal of this study was to investigate the effects of ionizing radiationon the proliferation, differentiation, and attachment of osteoblasts to commercially pure titanium (cpTi). Human fetal osteoblasts (hFOB) were irradiated either before or after plating in tissue culture (TC) dishes with or without cpTi disks. Radiation was single dose of 10 cGy, 25 cGy, 50 cGy, 1 Gy, 2 Gy, 4 Gy or 8 Gy. Cell proliferation was determined by counting trypsinized cells on 7 days after irradiation. Attachment of irradiated hFOB was measured indirectly by counting cells 2 and 6 h after plating. Differentiation was evaluated by alkaline phosphatase activity. Compared with nonirradiated sham controls, higher doses of radiation significantly reduced cell attachment and proliferation. Both proliferation and attachment were significantly lower on cpTi compared with TC. Attachment decreased based on the length of postirradiation period. Although differentiation was significantly enhanced by a dose of 8 Gy, proliferation was lowest. These initial studies show that effects of therapeutic doses of radiation on osteoblasts varied depending on the surface, time-elapsed, and amount of radiation.


Temporal decline in sirolimus elimination immediately after pancreatic islet transplantation.
Pancreatic islet transplantation is a curable treatment for type 1 diabetes and has been put into practice in various countries. In this study, we analyzed the pharmacokinetic characteristics of sirolimus and tacrolimus in six Japanese patients with pancreatic islet transplants immediately after surgery, and monitored efficacy and toxicity. The patients were treated with immunosuppressive therapy based on the Edmonton protocol, that is, sirolimus and low-dose tacrolimus. Pharmacokinetic analyses were performed using the nonlinear mixed-effects modeling program NONMEM. Large inter- and intra-individual variability was observed in the pharmacokinetics of sirolimus and tacrolimus. A model with increased apparent clearance in the postoperative period explained well the intra-individual variability in the pharmacokinetics of both drugs. The most frequent drug-induced toxicity was a decrease in the white blood cell count, and two of six patients required the administration of granulocyte colony-stimulating factor. Clinical laboratory tests immediately before the transplantation and cytochrome P450 3A5 genotype were not related to the high blood concentrations of sirolimus after the loading dose. From these results, the apparent clearance of sirolimus and tacrolimus might temporally decline immediately after pancreatic islet transplantation. A high trough concentration of sirolimus might increase the risk of hematological toxicy, and adjustment of the dosage for immunosuppressive treatment will be necessary in Japanese patients.


An integrative approach to cultural competence in the psychiatric curriculum.
As it is increasingly recognized that cultural competence is an essential quality for any practicing psychiatrist, postgraduate psychiatry training programs need to incorporate cultural competence training into their curricula. This article documents the unique approach to resident cultural competence training being developed in the Department of Psychiatry at the University of Toronto, which has the largest residency training program in North America and is situated in an ethnically diverse city and country. The authors conducted a systematic review of cultural competence by searching databases including PubMed, PsycINFO, PsycArticles, CINAHL, Social Science Abstracts, and Sociological Abstracts; by searching government and professional association publications; and through on-site visits to local cross-cultural training programs. Based on the results of the review, a resident survey, and a staff retreat, the authors developed a deliberate "integrative" approach with a mindful, balanced emphasis on both generic and specific cultural competencies. Learning objectives were derived from integrating the seven core competencies of a physician as defined by the Canadian Medical Education Directions for Specialists (CanMEDS) roles framework with the tripartite model of attitudes, knowledge, and skills. The learning objectives and teaching program were further integrated across different psychiatric subspecialties and across the successive years of residency. Another unique strategy used to foster curricular and institutional change was the program's emphasis on evaluation, making use of insights from modern educational theories such as formative feedback and blueprinting. Course evaluations of the core curriculum from the first group of residents were positive. The authors propose that these changes to the curriculum may lead to enhanced cultural competence and clinical effectiveness in health care.


Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB Study.
The temporal development of autoantibodies was studied in 1,353 offspring of parents with type 1 diabetes. Islet cell antibodies (ICAs) and autoantibodies to insulin (IAAs), glutamic acid decarboxylase, and IA-2 were measured at birth, 9 months, 2 years, and 5 years of age. At birth, no offspring had islet autoimmunity other than maternally acquired antibodies, which were shown to influence antibody prevalence up to age 6 months. Antibodies detected thereafter were likely to represent a true de novo production, since prevalences were the same for offspring from mothers and fathers with diabetes, antibodies detected at 9 months were almost always confirmed in the 2-year sample and were associated with an increased likelihood of having or developing other antibodies. By 2 years of age, autoantibodies appeared in 11% of offspring, 3.5% having more than one autoantibody. IAAs were detected most frequently, and few had autoantibodies in the absence of IAAs. In 23 offspring with multiple islet autoantibodies, IAAs preceded other antibodies in 10 cases and were first detected concurrently with other antibodies in 12 and after detection of other antibodies in 1. Development of additional antibodies and changes in levels, including decline of IAAs at older age, was frequent. Nine children, all with IAAs and ICAs, developed diabetes. Overall cumulative risk for disease by 5 years of age was 1.8% (95% CI 0.2-3.4) and was 50% (95% CI 19-81) for offspring with more than one autoantibody in their 2-year sample. Autoimmunity associated with childhood diabetes is an early event and a dynamic process. Presence of IAAs is a consistent feature of this autoimmunity, and IAA detection can identify children at risk.


THE EFFECT OF THE INTERNET ADDICTION ON THE INFORMATION-SEEKING BEHAVIOR OF THE POSTGRADUATE STUDENTS.
Internet addiction is a typical use of the internet that causes the psychological, social, educational, or occupational problems for the people. Students need the internet more than other people due to their educational or research needs. The rate and type of the internet use may affect their information-seeking behavior too. This study aims to investigate the effect of the internet addiction on the information-seeking behavior of the postgraduate students. This applied study that uses the correlation method. The research population composed of 1149 postgraduate students of Isfahan University of Medical Sciences, of which 284 were selected using the stratified random sampling as the sample. Yang's internet addiction questionnaire and the researcher-developed questionnaire of the information-seeking behavior were used as the data collection instruments. Instrument validity was confirmed by the specialists of librarianship and medical sciences and its reliability was confirmed using the Cronbach's alpha coefficient (0.86). Research data were analyzed using the descriptive statistics (mean and standard deviation) and inferential statistics (independent-t tests, Pearson correlation coefficient, and variance analysis). Based on the findings, there was no sign of internet addiction among the 86.6% of the students. However, 13% of the students were exposed to the internet addiction and only 0.4% of internet addiction was observed among the students. There was no significant difference between the information-seeking behavior of the male and female respondents. There was no sign of the internet addiction in any dimension of the information-seeking behavior of the students. This study showed that there is no relationship between the information-seeking behavior of the students and the age and the rate of the internet use. Promoting the network infrastructures and increasing the internet speed as well as facilitating the use of electronic resources should be prioritized by the officials.


Histone variant H2A.Z deposition and acetylation directs the canonical Notch signaling response.
A fundamental as yet incompletely understood feature of Notch signal transduction is a transcriptional shift from repression to activation that depends on chromatin regulation mediated by transcription factor RBP-J and associated cofactors. Incorporation of histone variants alter the functional properties of chromatin and are implicated in the regulation of gene expression. Here, we show that depletion of histone variant H2A.Z leads to upregulation of canonical Notch target genes and that the H2A.Z-chaperone TRRAP/p400/Tip60 complex physically associates with RBP-J at Notch-dependent enhancers. When targeted to RBP-J-bound enhancers, the acetyltransferase Tip60 acetylates H2A.Z and upregulates Notch target gene expression. Importantly, the Drosophila homologs of Tip60, p400 and H2A.Z modulate Notch signaling response and growth in vivo. Together, our data reveal that loading and acetylation of H2A.Z are required to assure tight control of canonical Notch activation.


IFITM proteins inhibit placental syncytiotrophoblast formation and promote fetal demise.
Elevated levels of type I interferon (IFN) during pregnancy are associated with intrauterine growth retardation, preterm birth, and fetal demise through mechanisms that are not well understood. A critical step of placental development is the fusion of trophoblast cells into a multinucleated syncytiotrophoblast (ST) layer. Fusion is mediated by syncytins, proteins deriving from ancestral endogenous retroviral envelopes. Using cultures of human trophoblasts or mouse cells, we show that IFN-induced transmembrane proteins (IFITMs), a family of restriction factors blocking the entry step of many viruses, impair ST formation and inhibit syncytin-mediated fusion. Moreover, the IFN inducer polyinosinic:polycytidylic acid promotes fetal resorption and placental abnormalities in wild-type but not in Ifitm-deleted mice. Thus, excessive levels of IFITMs may mediate the pregnancy complications observed during congenital infections and other IFN-induced pathologies.


New insights into implication of the SLIT/ROBO pathway in the prehierarchical follicle development of hen ovary.
The SLIT/Roundabout (ROBO) pathway is involved in follicle development of mammalian ovary, and 2 secreted hormones activin A and inhibin A have potential roles in modulation of the SLIT/ROBO system, but the related actions remain poorly understood in bird. The aims of the present study were to examine the spatial and temporal expression of the SLIT ligand genes (SLIT1, SLIT2, and SLIT3) and their receptor ROBO1, ROBO2, ROBO3, and ROBO4 genes in various-sized prehierarchical follicles during hen ovary development and the effects of activin A and inhibin A on the expression of these genes in the cultured hen follicles. Our result demonstrated that the transcripts of the 3 SLIT genes were highly expressed in the developing follicles and expression patterns of the SLIT transcripts were different from those of ROBO genes detected by real-time quantitative reverse transcriptase PCR. Both SLIT and ROBO transcripts were predominantly expressed in oocytes and granulosa cells from the prehierarchichal follicles examined by in situ hybridization. The localization for SLIT and ROBO proteins was revealed by immunohistochemistry similar to the spatial distribution of their transcript. In cultured follicles (4 to 8 mm in diameter), the expression levels of SLIT and ROBO members are hormonally regulated by activin A (10 ng/mL) and/or inhibin A (20 ng/mL) after treatment for 24 h. However, the expression of only SLIT2, SLIT3, and ROBO3 mRNA presented a directly opposite response to activin A and inhibin A hormones. These results indicate that SLIT/ROBO pathway is implicated in the prehierarchical follicular development of the hen ovary by an intrafollicular autocrine and/or paracrine action, and is influenced by activin A and inhibin A hormones.


Image-enhanced endoscopy technology in the gastrointestinal tract: what is available?
Gastrointestinal malignancy accounts for approximately a fifth of all cancer deaths in the United Kingdom. By the time patients are symptomatic, lesions are often advanced, with limited treatment options available. The development of effective endoscopic therapies means that neoplastic lesions can now be treated with improved patient outcomes. This has led to a paradigm shift, whereby the aim of digestive endoscopy is to identify premalignant conditions or early neoplastic change, in order to make an impact on their natural history. This has necessitated an improvement in imaging techniques in order to identify subtle mucosal changes that may harbour precancerous cells. At present there is an array of available imaging modalities, each with implications on cost, training and lesion detection. Here we describe the scientific rationale behind the major commercially available techniques as well as offering a glimpse at possible future directions.


[Central venous catheters-related infections in patients with parenteral nutrition].
Infections related to central venous catheters (CVC) are complications with a high prevalence and possible serious consequences. Administration of total parenteral nutrition (TPN) is a risk factor, although the information available for these patients and conventional inpatient units is scarce. To determine the rate of catheter-related bacteremia (CRB) in patients with TPN and to identify possible relationships with administration route or place of insertion, to determinate the current situation and identify possible preventive measures. Prospective-observational study of 13 months. All adult patients who received TPN were included. Infection rate used was the CRB per 1,000 days of CVC. 176 CVC were registered in 159 patients. In 47% of CVC, vein access was jugular vein, despite being a location of greatest risk of infection. In critically ill patients, which followed a zero bacteremia project, there was no cases of infection. In other patients, bacteremia rate was 13.10 per 1,000 days of CVC. The average time elapsed between catheter insertion and infection was 11 days (range: 4-22) and the most frequent species were S. epidermidis (38%) and S. hominis (19%). In our environment there is a high rate of BRC in non-critical patients, with a high proportion of CVC in locations with higher risk of infection, despite not having found in the sample a higher rate of infection depending on the access route. Place of insertion, operating room face ward, is related to a lower rate of BRC. Measures to standardize clinical practice may reduce its incidence. The zero bacteremia project is confirmed as a highly effective method.


A multicenter blinded analysis indicates no association between chronic fatigue syndrome/myalgic encephalomyelitis and either xenotropic murine leukemia virus-related virus or polytropic murine leukemia virus.
The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. IMPORTANCE Chronic fatigue syndrome/myalgic encephalomyelitis has an estimated prevalence of 42/10,000 in the United States, with annual direct medical costs of $7 billion. Here, the original investigators who found XMRV and pMLV (polytropic murine leukemia virus) in blood of subjects with this disorder report that this association is not confirmed in a blinded analysis of samples from rigorously characterized subjects. The increasing frequency with which molecular methods are used for pathogen discovery poses new challenges to public health and support of science. It is imperative that strategies be developed to rapidly and coherently address discoveries so that they can be carried forward for translation to clinical medicine or abandoned to focus resource investment more productively. Our study provides a paradigm for pathogen dediscovery that may be helpful to others working in this field.


[The General Principles of Suicide Prevention Policy from the perspective of clinical psychiatry].
In view of the fact that the suicide rate in Japan has remained high since 1998, the Basic Act on Suicide Prevention was implemented in 2006 with the objective of comprehensively promoting suicide prevention measures on a national scale. Based on this Basic Act, in 2007, the Japanese government formulated the General Principles of Suicide Prevention Policy as a guideline for recommended suicide prevention measures. These General Principles were revised in 2012 in accordance with the initial plan of holding a review after five years. The Basic Act places an emphasis on the various social factors that underlie suicides and takes the perspective that suicide prevention measures are also social measures. The slogan of the revised General Principles is "Toward Realization of a Society in which Nobody is Driven to Commit Suicide". The General Principles list various measures that are able to be used universally. These contents would be sufficient if the objective of the General Principles were "realization of a society that is easy to live in"; however, the absence of information on the effectiveness and order of priority for each measure may limit the specific effectiveness of the measures in relation to the actual prevention of suicide. In addition, considering that nearly 90% of suicide victims are in a state at the time of committing suicide in which a psychiatric disorder would be diagnosed, it would appear from a psychiatric standpoint that measures related to mental health, including expansion of psychiatric services, should be the top priority in suicide prevention measures. However, this is not the case in the General Principles, in either its original or revised form. Revisions to the General Principles related to clinical psychiatry provide more detailed descriptions of measures for individuals who unsuccessfully attempt suicide and identify newly targeted mental disorders other than depression; however, the overall proportion of contents relating to psychiatric care remains small. In particular, it must be noted that almost no measures are provided for individuals with chronic psychiatric disorders. We believe that the role of academic societies involved in suicide prevention, including our own, is to organize the contents of the General Principles based on evidence, to advance research in areas lacking in evidence, and to promote support for implementation of activities in areas with clear evidence.


Prospective open-label clinical trial of trihexyphenidyl in children with secondary dystonia due to cerebral palsy.
Although trihexyphenidyl is used clinically to treat both primary and secondary dystonia in children, limited evidence exists to support its effectiveness, particularly in dystonia secondary to disorders such as cerebral palsy. A prospective, open-label, multicenter pilot trial of high-dose trihexyphenidyl was conducted in 23 children aged 4 to 15 years with cerebral palsy judged to have secondary dystonia impairing function in the dominant upper extremity. All children were given trihexyphenidyl at increasing doses over a 9-week period up to a maximum of 0.75 mg/kg/d. Trihexyphenidyl was subsequently tapered off over the next 5 weeks. Objective motor assessments were performed at baseline, 9 weeks, and 15 weeks. The primary outcome measure was the Melbourne Assessment of Unilateral Upper Limb Function, tested in the dominant arm. Tolerability and safety were monitored closely throughout the trial. Of the 31 children who agreed to participate in the study, 5 failed to meet entry criteria and 3 withdrew due to nonserious adverse events (chorea, drug rash, and hyperactivity). Three children required a dosage reduction because of nonserious adverse events but continued to participate. The 23 children who completed the study showed a significant improvement in arm function at 15 weeks (P = .045) but not at 9 weeks (P = .985). Post hoc analysis showed that a subgroup (n = 10) with hyperkinetic dystonia (excess involuntary movements) worsened at 9 weeks (P = .04) but subsequently returned to baseline following taper of the medicine. The authors conclude that scientific evidence for the clinical use of trihexyphenidyl in cerebral palsy remains equivocal. Trihexyphenidyl may be a safe and effective for treatment for arm dystonia in some children with cerebral palsy if given sufficient time to respond to the medication. Post hoc analyses based on the type of movement disorder suggested that children with hyperkinetic forms of dystonia may worsen. A larger, randomized prospective trial stratified by the presence or absence of hyperkinetic movements is needed to confirm these results.


Possum-A Framework for Three-Dimensional Reconstruction of Brain Images from Serial Sections.
Techniques based on imaging serial sections of brain tissue provide insight into brain structure and function. However, to compare or combine them with results from three dimensional imaging methods, reconstruction into a volumetric form is required. Currently, there are no tools for performing such a task in a streamlined way. Here we propose the Possum volumetric reconstruction framework which provides a selection of 2D to 3D image reconstruction routines allowing one to build workflows tailored to one's specific requirements. The main components include routines for reconstruction with or without using external reference and solutions for typical issues encountered during the reconstruction process, such as propagation of the registration errors due to distorted sections. We validate the implementation using synthetic datasets and actual experimental imaging data derived from publicly available resources. We also evaluate efficiency of a subset of the algorithms implemented. The Possum framework is distributed under MIT license and it provides researchers with a possibility of building reconstruction workflows from existing components, without the need for low-level implementation. As a consequence, it also facilitates sharing and data exchange between researchers and laboratories.


Upconversion detection near 2 μm at the single photon level.
We have demonstrated upconversion detection at the single photon level in the 2 μm spectral window using a pump wavelength near 1550 nm, a periodically poled lithium niobate (PPLN) waveguide, and a volume Bragg grating (VBG) to reduce noise. We achieve a system photon detection efficiency of 10%, with a noise count rate of 24,500 counts per second, competitive with other 2 μm single photon detection technologies. This detector has potential applications in environmental gas monitoring, life science, and classical and quantum communication.


Fast, multiphase volume adaptation to hyperosmotic shock by Escherichia coli.
All living cells employ an array of different mechanisms to help them survive changes in extra cellular osmotic pressure. The difference in the concentration of chemicals in a bacterium's cytoplasm and the external environment generates an osmotic pressure that inflates the cell. It is thought that the bacterium Escherichia coli use a number of interconnected systems to adapt to changes in external pressure, allowing them to maintain turgor and live in surroundings that range more than two-hundred-fold in external osmolality. Here, we use fluorescence imaging to make the first measurements of cell volume changes over time during hyperosmotic shock and subsequent adaptation on a single cell level in vivo with a time resolution on the order of seconds. We directly observe two previously unseen phases of the cytoplasmic water efflux upon hyperosmotic shock. Furthermore, we monitor cell volume changes during the post-shock recovery and observe a two-phase response that depends on the shock magnitude. The initial phase of recovery is fast, on the order of 15-20 min and shows little cell-to-cell variation. For large sucrose shocks, a secondary phase that lasts several hours adds to the recovery. We find that cells are able to recover fully from shocks as high as 1 Osmol/kg using existing systems, but that for larger shocks, protein synthesis is required for full recovery.


Selective synthesis of iridium(iii)-derived molecular Borromean rings, [2]catenane and ring-in-ring macrocycles via coordination-driven self-assembly.
This paper reports the formation of unprecedented iridium(iii)-derived topological macrocycles. Discrete molecular Borromean rings 1 and 3 in pure form are synthesized via coordination-driven self-assembly of an acceptor [(Cp*Ir)2(OO∩OO)](OTf)2 (Cp* = pentamethylcyclopentadienyl, OO∩OO = 6,11-dioxido-5,12-naphthacenedione) (A) with dipyridyl donors 1,4-bis(4-pyridinylethynyl)benzene (L1) and 2,5-bis(4-pyridinylethynyl)thiophene (L2) respectively in methanol. Self-assembly using the same acceptor under similar conditions with two other donors 9,10-bis(4-pyridinylethynyl)anthracene (L3) and 1,4-di(4-pyridinylethynyl)buta-1,3-diyne (L4) resulted in [2]catenane 5 and non-catenane ring-in-ring topological macrocycle 7 respectively. Rectangular macrocycles 2, 4, 6, and 8 were respectively obtained when the self-assembly of acceptor A with one of the donors L1-L4 was carried out under dilute conditions in nitromethane or methanol. All these new macrocycles were characterized by 1H and 13C NMR, 2D NMR, ESI-MS and elemental analyses. Single crystal X-ray structures of Borromean rings 1 and 3, and ring-in-ring macrocycle 7 revealed that the length and functionality of donors enabling CHπ and ππ interactions govern the topology.