Power-scalable system of phase-locked single-mode diode lasers.
The direct use of diode lasers for high-power applications in material processing is limited to applications with relatively low beam quality and power density requirements. To achieve high beam quality one must use single-mode diode lasers, however with the drawback of relatively low optical output powers from these components. To realize a high-power system while conserving the high beam quality of the individual emitters requires coherent coupling of the emitters. Such a power-scalable system consisting of 19 slave lasers that are injection locked by one master laser has been built and investigated, with low-power diode lasers used for system demonstration. The optical power of the 19 injection-locked lasers is coupled into polarization-maintaining single-mode fibers and geometrically superimposed by a lens array and a focusing lens. The phase of each emitter is controlled by a simple electronic phase-control loop. The coherence of each slave laser is stabilized by computer control of the laser current and guarantees a stable degree of coherence of the whole system of 0.7. An enhancement factor of 13.2 in peak power density compared with that which was achievable with the incoherent superposition of the diode lasers was observed.


Effects of long term storage on secondary metabolite profiles of cannabis resin.
The structural identification and the monitoring of the relative concentrations of a wide range of major (3) and minor secondary (16) metabolites used as marker substances for profiling of cannabis resin using GC-FID at the Swedish National Forensic Centre (NFC) has facilitated the mapping of their chemical and physical behaviors over a period of 48months whilst stored under different conditions (exposure to light, exposure to air, temperature). In all cases the behavior of this group of sesquiterpenes, sesquiterpenoids, cannabinoids and waxes could be directly related to their chemical lability/functionality. In particular, the identification of homologue triads for both Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) together with a group of seemingly chemically inert substances (for example, cannabicyclol(CBL) and the waxes (n-alkanes)) has created new tools for the establishment of common origins between samples of cannabis resins aged under different conditions. Since sampling of the resin blocks in NFC's method for profiling of cannabis resin is made below the surface, the effects of light incursion were found to be negligible. The effects of exposure to air (and indirectly temperature) were found to be more significant, not unexpectedly as many of the observed transformations were based on oxidation or rearrangement processes.


Predialysis nephrology care among older veterans using Department of Veterans Affairs or Medicare-covered services.
To examine the effect of exclusive and dual use of Department of Veterans Affairs (VA) and Medicare healthcare systems on outpatient predialysis nephrology care. Retrospective cohort study. Receipt, timeliness, and intensity of predialysis nephrology care were evaluated among 8033 veterans who initiated dialysis in 2000 and 2001 and were eligible for both VA and Medicare coverage in the 12 months preceding dialysis initiation. Propensity scores were incorporated into analyses to minimize potential selection bias from nonrandom veteran allocation to healthcare systems. Among the cohort, 17.4% were users of VA services only (VA-only users), 38.5% were users of Medicare-covered services only (Medicare-only users), and 44.1% were users of both VA and Medicare-covered services (dual users). Sixty-six percent of VA-only and dual users and 58.1% of Medicare-only users received predialysis nephrology care. Compared with Medicare-only users, dual users were more likely (risk ratio [RR], 1.12; 95% confidence interval [CI], 1.07-1.17) and VA-only users were as likely (RR, 0.98; 95% CI, 0.88-1.08) to have received predialysis nephrology care. Compared with Medicare-only use, VA-only use (RR, 0.63; 95% CI, 0.50-0.81) and dual use (RR, 0.78; 95% CI, 0.70-0.88) were associated with a lower likelihood of late nephrology care (<3 months before dialysis initiation). More than one-third of older veterans initiating dialysis do not receive nephrology care beforehand. Dual use of VA and Medicare-covered services was associated with greater receipt and favorable timeliness of predialysis nephrology care, while use of only Medicare-covered services was associated with late predialysis nephrology care. Further studies to identify reasons for system-level variations in access to predialysis nephrology care may assist in identifying opportunities for improvement.


Subacute neurotoxicity induced in mice by potent organophosphorus neuropathy target esterase inhibitors.
The mouse is considered to be insensitive and the hen sensitive to clinical expression of organophosphorus-induced delayed neuropathy (OPIDN) which is associated with inhibition of neuropathy target esterase (NTE). This species difference is reevaluated with two optimized inhibitors of hen brain NTE by examining them for potential neurotoxic effects in mice. 2-Octyl-4H-1,3,2-benzodioxaphosphorin 2-oxide (OBDPO) and ethyl octylphosphonofluoridate (EOPF) inhibit mouse brain NTE in vitro by 50% at 0.12 and 0.02 nM and induce neurotoxic signs in mice at 10 and 5 mg/kg, respectively. The action of these compounds in both l- and 6-month-old mice, sometimes after early transient cholinergic signs, involves ataxia, paralysis, and death in 1 to 3 days and is accordingly referred to as subacute neurotoxicity. The neurotoxic signs are associated with brain edema and severe vacuolation in the grey matter of the brain and spinal cord, particularly the neuropile. Subacute neurotoxic signs are always associated with at least 80% inhibition of brain NTE activity 16-24 hr after treatment. Acetylcholinesterase and butyrylcholinesterase are much less sensitive than NTE to inhibition by OBDPO and EOPF both in vitro and in vivo. Selected carbamates, thiocarbamates, phosphinates, and sulfanyl fluorides are prophylactic agents and dipentyl 2,2-dichlorovinyl phosphate is a promoter for OBDPO-induced subacute neurotoxicity. Although this type of neurotoxicity in mice is similar to OPIDN in the correlation with NTE inhibition and the prophylactic action of reversible NTE inhibitors, it differs from OPIDN in the delay time prior to onset, the sensitivity of both young and old animals, and the high incidence of fatality. A full neuropathological study is desirable to further characterize this subacute neurotoxicity.


Dissociation, somatization, and affect dysregulation: the complexity of adaptation of trauma.
A century of clinical research has noted a range of trauma-related psychological problems that are not captured in the DSM-IV framework of posttraumatic stress disorder (PTSD). This study investigated the relationships between exposure to extreme stress, the emergence of PTSD, and symptoms traditionally associated with "hysteria," which can be understood as problems with stimulus discrimination, self-regulation, and cognitive integration of experience. The DSM-IV field trial for PTSD studied 395 traumatized treatment-seeking subjects and 125 non-treatment-seeking subjects who had also been exposed to traumatic experiences. Data on age at onset, the nature of the trauma, PTSD, dissociation, somatization, and affect dysregulation were collected. PTSD, dissociation, somatization, and affect dysregulation were highly interrelated. The subjects meeting the criteria for lifetime (but not current) PTSD scored significantly lower on these disorders than those with current PTSD, but significantly higher than those who never had PTSD. Subjects who developed PTSD after interpersonal trauma as adults had significantly fewer symptoms than those with childhood trauma, but significantly more than victims of disasters. PTSD, dissociation, somatization, and affect dysregulation represent a spectrum of adaptations to trauma. They often occur together, but traumatized individuals may suffer from various combinations of symptoms over time. In treating these patients, it is critical to attend to the relative contributions of loss of stimulus discrimination, self-regulation, and cognitive integration of experience to overall impairment and provide systematic treatment that addresses both unbidden intrusive recollections and these other symptoms associated with having been overwhelmed by exposure to traumatic experiences.


Incidence and Etiologies of Acquired Third Nerve Palsy Using a Population-Based Method.
Among cranial nerve palsies, a third nerve palsy is important because a subset is caused by life-threatening aneurysms. However, there is significant disagreement regarding its incidence and the reported etiologies. To determine the incidence and etiologies of acquired third nerve palsy using a population-based method. All newly diagnosed cases of acquired third nerve palsy from January 1, 1978, through December 31, 2014, in Olmsted County, Minnesota, were identified using the Rochester Epidemiology Project, a record-linkage system of medical records for all patient-physician encounters among Olmsted County residents. All medical records were reviewed to confirm a diagnosis of acquired third nerve palsy and determine the etiologies, presenting signs, and symptoms. Incidence rates were adjusted to the age and sex distribution of the 2010 US white population. Incidence and etiologies of acquired third nerve palsies. The secondary outcome was incidence of pupil involvement in acquired third nerve palsies. We identified 145 newly diagnosed cases of acquired third nerve palsy in Olmsted County, Minnesota, over the 37-year period. The age- and sex-adjusted annual incidence of acquired third nerve palsy was 4.0 per 100 000 (95% CI, 3.3-4.7 per 100 000). The annual incidence in patients older than 60 was greater than patients younger than 60 (12.5 vs 1.7 per 100 000; difference, 10.8 per 100 000; 95% CI, 4.7-16.9; P < .001). The most common causes of acquired third nerve palsy were presumed microvascular (42%), trauma (12%), compression from neoplasm (11%), postneurosurgery (10%), and compression from aneurysm (6%). Ten patients (17%) with microvascular third nerve palsies had pupil involvement, while pupil involvement was seen in 16 patients (64%) with compressive third nerve palsies. This population-based cohort demonstrates a higher incidence of presumed microvascular third nerve palsies and a lower incidence of aneurysmal compression than previously reported in non-population-based studies. While compressive lesions had a higher likelihood of pupil involvement, pupil involvement did not exclude microvascular third nerve palsy and lack of pupil involvement did not rule out compressive third nerve palsy.


A Hidden Epidemic of "Intermediate Risk" Oropharynx Cancer.
Oropharyngeal squamous cell carcinoma (OPSCC) incidence is rapidly increasing in the United States and around the world, driven in large part by infection with the human papillomavirus (HPV). HPV associated OPSCC (HPV+OPSCC) has been shown to have improved response to treatment relative to tobacco-associated OPSCC. However, improvement in patient survival has not been uniform. Subsets of OPSCC patients in the US and around the world continue to have poor oncologic outcomes. Although the drivers of this phenomenon remain unclear, there is increasing evidence that tobacco exposure plays an important role in modulating HPV+OPSCC clinical outcomes. We conducted a review of the literature. We discuss the potential biological and epidemiological interplay between tobacco and HPV exposure in the context of OPSCC. Multiple retrospective and prospective cohorts show that HPV+OPSCC patients with a history of tobacco exposure have response to treatment and clinical outcomes distinct from HPV+OPSCC non-smokers which poses clinical and scientific challenges to be addressed over the next decade. The interaction between tobacco exposure and HPV infection in the context of OPSCC has significant implications for both standard of care treatment regimens and development of novel therapeutic approaches, in particular those which incorporate immunomodulatory agents. 5.


Utilization of fecal occult blood test in the acute hospital setting and its impact on clinical management and outcomes.
Despite lack of evidence supporting the use of fecal occult blood test (FOBT) in the acute hospital setting, FOBT is commonly used in the inpatient setting for reasons other than colorectal cancer (CRC) screening. To evaluate practice trends in utilizing FOBT on inpatients and its impact on affecting clinical management and outcomes. A cross-sectional study of consecutive adult patients undergoing FOBT from January 1, 2011 to December 31, 2011 during an acute medical admission at a large urban safety net hospital was performed. Indications for FOBT, and the impact of FOBT results on endoscopic procedures performed and clinical outcomes were assessed. The number of inpatient endoscopic procedures before and after discontinuing inpatient FOBT was also assessed. A total of 207 inpatient FOBTs were performed in 2011. The most common reason cited for FOBT was anemia (36%, n = 74) followed by gastrointestinal (GI) bleeding (27%, n = 55). Interestingly, 23% (n = 47) of the patients undergoing inpatient FOBT had overt GI bleeding. As expected, patients with positive FOBT were significantly more likely to undergo endoscopic examinations (P < 0.01). After discontinuing the availability of inpatient FOBT, patients were less likely to undergo endoscopic examinations [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.75-0.85]. Inappropriate utilization of FOBT in the inpatient setting is common, even when the indication does not support its use. Setting limitations on inpatient FOBT may reduce the inappropriate utilization of inpatient FOBT. Quality improvement initiatives are needed to educate clinicians on the appropriate use of FOBT, which is primarily for average risk CRC screening.


Long COVID - An Early Perspective.
A new syndrome called "Long COVID" has emerged amongst the survivors of acute COVID-19 infection. Its protracted and debilitating nature will almost certainly result in many short and long-term disability claims. Insurers need to understand the nature of Long COVID, including its definition, its prevalence, its natural history, and underlying risk factors. This article will summarize current knowledge of Long COVID and provide a perspective on its evolution and its impact.


Highly efficient nanofocusing in a single step-like microslit.
Highly efficient plasmonic nanofocusing is numerically predicted in a single step-like microslit, which is placed on a high-index dielectric layer. Because of the high throughput of the impinging light on the wide microslit, highly efficient nanofocusing is achieved in the proposed structure based on the multimode interferences in the microslits, the constructive interference between the transmitted light and the scattered surface plasmon polaritons, and the Fabry-Perot resonator effect in the high-index dielectric layer. Compared with previous nanofocusing structures containing plenty of substructures arranged laterally, the proposed structure has a much smaller lateral dimension because of the vertical arrangement of the microslits. This is of importance for realizing densely integrated plasmonic circuits.


Pain control with intrathecally and peridurally administered opioids and other drugs.
Sharp pain is conducted rapidly by myelinated delta A fibers and diffused pain slowly by nonmyelinated C fibers to pseudobipolar neurons in the posterior ganglion and from there to neurons located in the posterolateral horn of the spinal cord. From here on nociferous impulses are transmitted by excitatory peptides (e.g. substance P) or amino acids (e.g. glutamate, aspartate) through interconnecting neurons of the pain pathways, primarily on the contralateral side, to the brain stem and from there to the sensory cortex, where they are appreciated and acted upon. There are specific inhibitory receptors located on axon terminals, near to the release sites of the excitatory amino acids and peptides. Stimulation of these receptors by their appropriate ligands such as endogenous (e.g. enkephalis, endorphins) or exogenous opioids, clonidine, serotonin, somatostatin inhibits the release of excitatory neurotransmitters and relieves pain. There are at least 3 different opioid receptors, called mu-, kappa- and delta-receptors in the spinal cord. These can be differentiated from one another by their specific affinity toward different endogenous or exogenous opioids and the pure narcotic antagonist, naloxone. It appears that the nociferous impulses transmitted by parallel pathways equipped with different inhibitory receptors have to be integrated to produce pain sensation and partial inhibition of transmission in different pathways or complete inhibition in one of the pathways may relieve pain. In recent years the concept of "selective spinal analgesia" has been applied clinically for the relief of postoperative, obstetrical and chronic pain. At first it was expected that the intrathecal or peridural administration of morphine will produce analgesia without the side effects of systemically administered morphine. It soon became evident, however, that intrathecally and peridurally administered morphine after several hours of delay reaches the fourth ventricle and by stimulating mu-receptors may cause respiratory depression and other undesired effects (e.g. nausea, vomiting, pruritus). Several different approaches are being investigated for the production of selective spinal analgesia without side effects. They include: a. the use of more lipophilic, long-lasting opioids (e.g. lofentanil) which would be almost completely absorbed by the spinal cord and therefore would not reach the medullary centers; b. the development of opioids with specific affinity to kappa- and for delta- and little or no affinity to mu-receptors, primarily responsible for side effects; and c. combining lower doses of opioid agonists with alpha 2-adrenergic agonists (e.g. clonidine) or with somatostatin. It is conceivable that in the not-too-distant future, it will be possible to achieve through these measures, selective spinal analgesia without side effects.


Genetics and epigenetics of the X chromosome.
A consequence of Mendelian inheritance of X-linked traits is that women are more than equal to men in the face of X-linked diseases, protected as they are by the presence of two X chromosomes in their genome. This potentially beneficial inequality is diminished by the molecular mechanism known as X-chromosome inactivation (XCI), which triggers the transcriptional silencing of one of the X chromosomes in each female cell. The determination of which X to inactivate, a process that occurs during early embryogenesis, is random and clonally inherited. As a result, females are mosaic for the expression of X-linked genes. XCI is a highly regulated process involving large noncoding RNAs, chromatin remodeling, and nuclear reorganization of the X chromosome. It is a paradigm for epigenetic regulation and is frequently used as a biomarker for monitoring long-range gene reprogramming during cell differentiation and dedifferentiation. Our review analyses how XCI affects the expression of X-linked mutations, describes some of the most recent discoveries on the molecular mechanisms triggering XCI, and explores the therapeutic potentialities of the XCI process per se.


Sixteen years of social and ecological dynamics reveal challenges and opportunities for adaptive management in sustaining the commons.
Efforts to confront the challenges of environmental change and uncertainty include attempts to adaptively manage social-ecological systems. However, critical questions remain about whether adaptive management can lead to sustainable outcomes for both ecosystems and society. Here, we make a contribution to these efforts by presenting a 16-y analysis of ecological outcomes and perceived livelihood impacts from adaptive coral reef management in Papua New Guinea. The adaptive management system we studied was a customary rotational fisheries closure system (akin to fallow agriculture), which helped to increase the biomass of reef fish and make fish less wary (more catchable) relative to openly fished areas. However, over time the amount of fish in openly fished reefs slowly declined. We found that, overall, resource users tended to have positive perceptions about this system, but there were negative perceptions when fishing was being prohibited. We also highlight some of the key traits of this adaptive management system, including 1) strong social cohesion, whereby leaders played a critical role in knowledge exchange; 2) high levels of compliance, which was facilitated via a "carrot-and-stick" approach that publicly rewarded good behavior and punished deviant behavior; and 3) high levels of participation by community actors.


Clinical applications of the histoculture drug response assay.
There is a need for a clinically useful drug-response assay for cancer patients to individualize their chemotherapy. Collagen sponge-gel-supported histoculture has been shown to maintain tissue architecture and function in vitro and has been utilized to develop the histoculture drug-response assay (HDRA) for individualizing chemotherapy. In order to evaluate the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point for clinical use, chemosensitivity to mitomycin C, doxorubicin, 5-fluorouracil, and cisplatin of 107 advanced gastric and 109 advanced colorectal cancers was determined in vitro in a correlative clinical trial. Two hundred eight (96.3%) of 216 of the patient specimens were evaluable in the HDRA. Thirty-eight patients with remaining measurable lesions after surgery were evaluable for comparison of the effects of chemotherapy in the HDRA with clinical outcome. Their overall response in the HDRA to all four drugs correlated to published historical data. Twenty-nine patients were treated with drugs shown to be ineffective in the HDRA, and all 29 cases showed clinical chemoresistance. In nine patients treated with drugs shown to be effective in the HDRA, six showed clinical chemoresponse and three showed arrest of disease progression. The correlation rate of the assay to clinical drug-sensitivity response was thus calculated to be 92.1% (35/38), with 100% (29/29) true-negative and 66.7% (6/9) true-positive rates, 100% (6/6) sensitivity, and 90.6% (29/32) specificity. Thirty-two patients with stage III and IV gastric cancer without remaining measurable tumor lesions after surgery were treated with mitomycin C and a fluoropyrimidine adjuvantly. The survival rate of 10 patients whose tumors were sensitive to either mitomycin C and/or 5-fluorouracil in the assay was significantly (P < 0.005) better than that of 22 patients whose tumors were shown to be insensitive to both drugs. Twenty-nine patients with stage III and IV colorectal cancer without remaining measurable tumor lesions after surgery were treated with fluoropyrimidines adjuvantly. The recurrence-free survival rate of 7 patients whose tumors were sensitive to 5-fluorouracil in the assay was significantly (P < 0.05) better than that of 22 patients whose tumors were insensitive. Thus the HDRA with the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide end point should be of clinical value to choose optimal chemotherapy for response as well as for survival.


Comparison between US Preventive Services Task Force recommendations and Medicare coverage.
The US Preventive Services Task Force (USPSTF) is authorized by the US government to review and disseminate the scientific evidence for clinical preventive services. The purpose of this study was to evaluate the alignment of Medicare preventive services coverage with the recommendations of the USPSTF before implementation of health reform. We recorded all Medicare coverage for preventive services as listed in the Medicare preventive services guide of 2007 (including the 2009 update) for all recommended (A-or B-rated) USPSTF and not recommended (D-rated) guidelines for preventive screening and counseling in adults aged 65 years and older. We analyzed 2 components of preventive care: preventive coordination (risk assessment, patient motivation, and arranging of preventive service) and the preventive service itself. The main outcome measure was the percentage of agreement between USPSTF recommendations and Medicare coverage. The USPSTF recommended 15 preventive interventions for adults aged 65 years and older. Although Medicare partially reimbursed 93% of recommended services, full reimbursement for the preventive coordination, as well as the service, was available for only 7% of these services. This partial coverage is available mostly as part of the Welcome to Medicare Visit. Further, the USPSTF recommended against 16 preventive services; Medicare reimbursed clinicians for 44% of these services. Medicare coverage for preventive services needs to be reassessed, with special focus on preventive coordination. Continuing previous practices will likely promote both inadequate and excessive delivery of preventive services. The new health care reform law has the potential to improve the provision of preventive services to Medicare beneficiaries.


Rapid changes in rotaviral genotypes in Ecuador.
Previous studies suggest that the emerging G9P[8] genotype was the most prevalent rotavirus genotype in Ecuador during 2005. This present study provides a temporal analysis of the distribution of rotavirus genotypes in two locations within Ecuador by adding additional years (2006 - early 2008) to the originally reported 2005 data. Data were collected in a rural (northern coastal Ecuador) and urban (Quito) area. In the rural area, a community sample of cases (those presenting diarrhea) and controls (those not presenting diarrhea) were collected between August 2003 and March 2008 resulting in a total of 3,300 stool samples (876 cases and 2,424 controls). Of these samples, 260 were positive for rotavirus by an immunochromatographic test (196 cases and 64 controls). In Quito, 59 fecal samples were collected from children presenting diarrhea and diagnosed with rotavirus. An RT-PCR analysis of samples collected between 2005 and 2007 suggested that G9 was replaced by G1 and G2 in the rural and urban settings. During this period G9 decreased from 79% to 9% while G2 increased from 0% to 43% in the rural communities, and G9 decreased from 79% to 37% while G2 increased from 3% to 57% in the urban area of Quito. This rapid replacement of G9 by G1 and G2 reinforces the necessity of surveillance to inform vaccination programs.


The role of economies of scale in the cost of dialysis across the world: a macroeconomic perspective.
The treatment of chronic kidney disease through dialysis is a considerable expense in most health systems. The two chief methods of providing dialysis, haemodialysis (HD) and peritoneal dialysis (PD) have significant differences in cost composition and factors of production. The aim of this article is to identify and quantify the macroeconomic variables that influence the relative cost of such modalities across different countries. From previously published literature, we extracted the estimates of HD/PD cost ratios in a total of 46 countries. We conducted a multivariate regression analysis using the estimated HD/PD cost ratio in each country, with several country level indicators as explanatory variables. We found a strong statistical effect of the following variables on the HD/PD cost ratio: country's level of development, economies of scale and percentage of private health-care expenditure. The statistical effects on HD/PD ratio by local manufacturing and relaxed import regulation of PD equipment were calculated and were found to be very significant. it is possible for a country to still reap the benefits of economies of scale in provision of PD, even in the absence of a large enough market to make local production of PD equipment feasible in that country.


Patterns and risk factors associated with aromatase inhibitor-related arthralgia among breast cancer survivors.
Arthralgia is common in postmenopausal breast cancer survivors (BCS) who are receiving aromatase inhibitors (AIs). The objective of this study was to evaluate the perceived onset, characteristics, and risk factors for AI-related arthralgia (AIA). In a cross-sectional survey of postmenopausal BCS who were receiving adjuvant AI therapy at a university-based oncology clinic, patient-reported attribution of AIs as a cause of joint pain was used as the primary outcome. Multivariate logistic regression analyses were performed to evaluate risk factors. Among 300 survey respondents, 139 (47%) attributed AI as a cause of their current arthralgia. Of those patients, 74% recognized the onset of AIA within 3 months of starting medication, and 67% rated joint pain as moderate or severe in the previous 7 days. In multivariate logistic regression analyses, the time since last menstrual period (LMP) was the only significant predictor of AIA. Controlling for covariates, the women who had their LMP within 5 years had the highest probability of reporting AIA (73%), whereas those who had their LMP > or =10 years previously had the lowest probability of reporting AIA (35%; adjusted odds radio, 3.39; 95% confidence interval, 1.21-9.44; P = .02). Wrists/hands, ankles/feet, elbows, and knees appeared to be associated more strongly with AI-related symptoms than non-AI-related joint symptoms (all P < .01). AIA was common, began within the first 3 months of therapy in most patients, and appeared to be related inversely to the length of time since cessation of menstrual function. These findings suggest that estrogen withdrawal may play a role in the mechanism of this disorder.


Consistency and change in functional status among older adults over time.
Consistency and change between 1984 and the last reinterview (either two, four, or six years later) on 22 individual functional status markers and the five summary scales that they form are examined among the 5,986 members of the Longitudinal Study on Aging who were reinterviewed at least once. At baseline, at least three-fifths of the respondents are without limitations on any individual marker. At the last reinterview, at least 43.4% of the respondents are without such limitations. Among those who had limitations at baseline, at least one-fifth get better. For those without limitations at baseline, one-seventeenth to two-fifths get worse. Difficulties in walking and doing heavy housework were the most common, most likely to develop, and least likely to resolve of any of the ADL or IADL items, and lower body limitations were more common, more likely to develop, and less likely to resolve than upper body limitations. Linear panel analysis of the five summary scales indicates that the top predictors of increased functional limitation are baseline levels of functional limitation, older age, decedent status, and poorer perceived health (in that order). Other less consistent and less robust predictors include the length of the exposure window, being female, having a history of arthritis, lower educational attainment, having fewer nonkin social supports, higher prior physician visit levels, and not living alone.


Influence of early posttransplantation prednisone and calcineurin inhibitor dosages on the incidence of new-onset diabetes.
Risk for new-onset diabetes (NOD) after renal transplantation is higher with tacrolimus (Tac) than with cyclosporine (CsA), but the extent to which the diabetogenic effect of Tac is dosage dependent or steroid dependent remains uncertain. Patients who received a transplant between 1995 and 2002 were drawn from the United Network for Organ Sharing registry and prescription records and NOD diagnoses from Medicare claims, both provided by the United States Renal Data System. Patients were divided into six groups of steroid and Tac doses at 30 d after transplantation and referenced against CsA. Relative hazards of NOD with Cox proportional hazards regression were estimated incorporating propensity scores for Tac and nonimmunosuppressive factors related to NOD. A total of 8839 patients with valid immunosuppression records and without pretransplantation evidence of diabetes were included in the study. Unadjusted, cumulative, NOD incidence 1 yr after transplantation was 14.6% with CsA and 22.2% with Tac and at 3 yr after transplantation was 23.4% with CsA and 32.9% with Tac (P < 0.0001). Neither higher CsA nor higher steroid dosages were associated with NOD in CsA-treated patients. However, NOD hazard was significantly higher with Tac than with CsA in all six steroid/Tac dosing groups, including the cohort with the lowest dosages of Tac (dosage thresholds at 30 d after transplantation <0.12 mg/kg per d [mean 0.07 mg/kg per d] and steroids (<0.75 mg/kg per d; hazard ratio 1.28; 95% confidence interval 1.10 to 1.48; P = 0.0012). Whereas the incidence of NOD is greatest with high Tac dosages, the increased risk versus CsA is sustained with lower Tac dosages. Higher steroid dosages increase the early diabetogenic effect of Tac but not of CsA.


MUC1 and MUC2 mucins in flat and polypoid colorectal adenomas.
To examine the expression of MUC1 and MUC2 apomucins and distribution of MUC phenotypes (MUC2+/ MUC-, MUC2+/MUC1+, MUC2-/ MUC1+, MUC2-/MUC1-) in colorectal tubular adenomas in order to compare the distribution of phenotypes in flat and polypoid adenomas. Endoscopically resected specimens of 35 flat and 15 polypoid tubular adenomas measuring less than 10 mm were examined and compared for the expression of MUC1 (MUSE11) and MUC2 (CCP58) and combined MUC phenotype distribution using conventional immunohistochemistry. There was no significant difference between flat and polypoid adenomas in their expression of MUC1 and MUC2 and the MUC phenotype distribution when stratified by grade of histological atypia. Adenomas with low grade atypia showed more extensive MUC2 expression than MUC1 (MUC2+/MUC1-phenotype). Expression of MUC1 was more extensive in adenomas with high grade atypia and the majority displayed either MUC2+/ MUC1+ or MUC2-/MUC1+ phenotypes. MUC2/MUC1 phenotypes were similar in flat and polypoid adenomas when stratified by grade of atypia. High grade atypia was characterised by reduced MUC2 and increased MUC1 expression in both types of adenoma. The phenotype MUC2-/MUC1+ occurs in tubular adenomas and cannot be a specific marker for de novo colorectal cancer.


Safety and efficacy of daclatasvir in the management of patients with chronic hepatitis C.
Daclatasvir (Daklinza™), a new oral direct-acting antiviral, is an inhibitor of hepatitis C virus NS5A protein and has recently been approved in the United States, Europe and Japan in chronic hepatitis C. It shows potent pangenotypic activity and moderately high genetic barrier to resistance improving the sustained virological response (SVR) rates. In COMMAND phase 2 trials, daclatasvir demonstrated high SVR rates in HCV genotype 1-4 chronically infected patients treated with peginterferon-a (pegIFNα) plus ribavirin (RBV). Furthermore, it produced even higher response rates in all-oral combination with sofosbuvir, an interferon-free regimen, with or without ribavirin, in patients with advanced liver disease, HCV/HIV coinfection, liver transplantation in ALLY studies and other real-world studies. This narrative review provides information on the pharmacological properties, role, efficacy and safety of daclatasvir-containing regimens in chronic hepatitis C patients. Daclatasvir administered once-daily in combination with sofosbuvir is an effective 12-week treatment in adult patients with chronic hepatitis C and is generally safe and well tolerated.


High-dimensional variable selection in meta-analysis for censored data.
This article considers the problem of selecting predictors of time to an event from a high-dimensional set of candidate predictors using data from multiple studies. As an alternative to the current multistage testing approaches, we propose to model the study-to-study heterogeneity explicitly using a hierarchical model to borrow strength. Our method incorporates censored data through an accelerated failure time model. Using a carefully formulated prior specification, we develop a fast approach to predictor selection and shrinkage estimation for high-dimensional predictors. For model fitting, we develop a Monte Carlo expectation maximization (MC-EM) algorithm to accommodate censored data. The proposed approach, which is related to the relevance vector machine (RVM), relies on maximum a posteriori estimation to rapidly obtain a sparse estimate. As for the typical RVM, there is an intrinsic thresholding property in which unimportant predictors tend to have their coefficients shrunk to zero. We compare our method with some commonly used procedures through simulation studies. We also illustrate the method using the gene expression barcode data from three breast cancer studies.


Using ecosystem services to inform decisions on U.S. air quality standards.
The ecosystem services (ES) framework provides a link between changes in a natural system's structure and function and public welfare. This systematic integration of ecology and economics allows for more consistency and transparency in environmental decision making by enabling valuation of nature's goods and services in a manner that is understood by the public. This policy analysis (1) assesses the utility of the ES conceptual framework in the context of setting a secondary National Ambient Air Quality Standard (NAAQS), (2) describes how economic valuation was used to summarize changes in ES affected by NOx and SOx in the review, and (3) uses the secondary NOxSOx NAAQS review as a case study to highlight the advantages and challenges of quantifying air pollutant effects on ES in a decision making context. Using an ES framework can benefit the decision making process by accounting for environmental, ecological, and social elements in a holistic manner. As formal quantitative linkages are developed between ecosystem structure and function and ES, this framework will increasingly allow for a clearer, more transparent link between changes in air quality and public welfare.


Auditory discrimination: the relationship between psychophysical and electrophysiological measures.
This study aimed to (1) investigate the relationship between the acoustic change complex (ACC) and perceptual measures of frequency and intensity discrimination, and gap detection; and (2) examine the effects of acoustic change on the amplitudes and latencies of the ACC. Psychophysical thresholds for frequency and intensity discrimination and gap detection, as well as ACCs elicited by stimuli containing increments in frequency, or intensity or gaps, were recorded from the same group of subjects. The magnitude of the acoustic change was systematically varied for the ACC recording. Twenty-six adults with normal hearing, ranging in age between 19 and 39 years. Electrophysiological and psychophysical measures for frequency and intensity discrimination were significantly correlated. Electrophysiological thresholds were comparable to psychophysical thresholds for intensity discrimination but were higher than psychophysical thresholds for gap detection and frequency discrimination. Increasing the magnitude of acoustic change increased the ACC amplitude but did not show consistent effects across acoustic dimensions for ACC latency. The ACC can be used as an objective index of auditory discrimination in frequency and intensity. The ACC amplitude is a better indicator for auditory processing than the ACC latency.


Clarifying the Relation Between Extraversion and Positive Affect.
This article clarifies two sources of ambiguity surrounding the relation between extraversion and positive affect. First, positive affect is defined differently across major models of the structure of affect. Second, no previous research has examined potentially diverging associations of lower-order aspects of extraversion (i.e., assertiveness and enthusiasm) with positive affect. Australian (Study 1: N = 437, 78% female, Mage = 20.41) and American (Study 2: N = 262, 39% female, Mage = 33.86) participants completed multiple measures of extraversion and positive affect. Correlations were employed to examine relations among these measures. In both studies, extraversion was most clearly associated with positive affect as conceptualized within a major factor model of affect-specifically, as positive activation (Watson & Tellegen, 1985)-rather than the valence-based conceptualization of positive affect provided by a circumplex model of affect (Russell, 1980). This was also the case for the assertiveness and enthusiasm aspects of extraversion. Our findings clarify the nature of the positive affective component of extraversion, which is best described in terms of both positive valence and high activation.


Differing activities of oxysterol-binding protein (OSBP) targeting anti-viral compounds.
Oxysterol-binding Protein (OSBP) is a human lipid-transport protein required for the cellular replication of many types of viruses, including several human pathogens. The structurally-diverse small molecule compounds OSW-1, itraconazole (ITZ), T-00127-HEV2 (THEV) and TTP-8307 (TTP) inhibit viral replication through interaction with the OSBP protein. The OSW-1 compound reduces intracellular OSBP, and the reduction of OSBP protein levels persists multiple days after the OSW-1-compound treatment is stopped. The OSW-1-induced reduction of OSBP levels inhibited Enterovirus replication prophylactically in cells. In this report, the OSBP-interacting compounds ITZ, THEV, and TTP are shown not to reduce OSBP levels in cells, unlike the OSW-1-compound, and the OSW-1 compound is determined to be the only compound capable of providing prophylactic antiviral activity in cells. Furthermore, OSW-1 and THEV inhibit the binding of 25-hydroxycholesterol (25-OHC) to OSBP indicating that these compounds bind at the conserved sterol ligand binding site. The ITZ and TTP compounds do not inhibit 25-hydroxycholesterol binding to OSBP, and therefore ITZ and TTP interact with OSBP through other, unidentified binding sites. Co-administration of the THEV compound partially blocks the cellular activity of OSW-1, including the reduction of cellular OSBP protein levels; co-administration of the ITZ and TTP compounds have minimal effect on OSW-1 cellular activity further supporting different modes of interaction with these compounds to OSBP. OSW-1, ITZ, THEV, and TTP treatment alter OSBP cellular localization and levels, but in four distinct ways. Co-administration of OSW-1 and ITZ induced OSBP cellular localization patterns with features similar to the effects of ITZ and OSW-1 treatment alone. Based on these results, OSBP is capable of interacting with multiple structural classes of antiviral small molecule compounds at different binding sites, and the different compounds have distinct effects on OSBP cellular activity.


The metabotropic glutamate receptor subtype 5 antagonist fenobam is analgesic and has improved in vivo selectivity compared with the prototypical antagonist 2-methyl-6-(phenylethynyl)-pyridine.
Metabotropic glutamate receptor subtype 5 (mGlu5) has been demonstrated to play a role in the modulation of numerous nociceptive modalities. When administered via peripheral, intrathecal, or systemic routes, mGlu5 antagonists have analgesic properties in a variety of preclinical pain models. Despite a wealth of data supporting the use of mGlu5 antagonists to treat pain, studies have been limited to preclinical animal models due to a lack of mGlu5 antagonists that are approved for use in humans. It has been demonstrated previously that fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea], an anxiolytic shown to be safe and effective in human trials, is a selective and potent noncompetitive antagonist of mGlu5 (J Pharmacol Exp Ther 315:711-721, 2005). Here, we report a series of studies aimed at testing whether fenobam, similar to the prototypical mGlu5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP), has analgesic properties in mice. We show that fenobam reduces formalin-induced pain behaviors and relieves established inflammation-induced thermal hypersensitivity in mice. Similar results were seen with MPEP. Administration of fenobam resulted in an increase in locomotor activity in the open-field task but did not impair performance on the accelerating Rotarod. Analysis of brain and plasma fenobam levels indicated that fenobam is rapidly concentrated in brain after intraperitoneal administration in mice but is essentially cleared from circulation within 1 h after injection. Fenobam had no analgesic effect in mGlu5 knockout mice, whereas the prototypical antagonist MPEP retained significant analgesic efficacy in mGlu5 knockouts. These results demonstrate that fenobam is analgesic in mice and has an improved in vivo selectivity for mGlu5 over MPEP.


Evidence for genetic basis of multiple sclerosis. The Canadian Collaborative Study Group.
BACKGROUND Increased familial risks in multiple sclerosis (MS) range from 300-fold for monozygotic twins to 20-40-fold for biological first-degree relatives, suggesting a genetic influence. Yet if one identical twin has MS the other usually will not. One way of sorting out the contributions of genes and environment is to study half-sibs. METHODS In a Canadian population-based sample of 16 000 MS cases seen at 14 regional MS clinics one half-sib (or more) was reported by 939 index cases. By interview we elicited information on family structure and an illness in half-sibs and any full brothers or sisters. FINDINGS The age-adjusted MS rate in the 1839 half-sibs of these index cases was 1.32 percent compared with 3.46 percent for the 1395 full sibs of the same cases (p<0.001; likelihood ratio test). There were no significant differences in risk for maternal versus paternal half-sibs (1.42 percent vs 1.19 percent) or for those raised together versus those raised apart from the index case (1.17 percent vs 1.47 percent). INTERPRETATION Besides demonstrating the power and the feasibility of using half-sib studies to throw light on the aetiology of complex disorders, our findings show that a shared environment does not account for familial risk in MS and that maternal effects (such as intrauterine and perinatal factors, breastfeeding, and genomic imprinting) have no demonstrable effect on familial risk. Halving the number of potentially contributory genes (by comparing full-sib and half-sib rates) lowers the risk of MS by a factor of 2.62, an observation consistent with a polygenic hypothesis.


The ectodermal placodes: a dysfunctional family.
The ectodermal placodes are focal thickenings of the cranial embryonic ectoderm that contribute extensively to the cranial sensory systems of the vertebrates. The ectodermal placodes have long been thought of as representing a coherent group, which share a developmental and evolutionary history. However, it is now becoming clear that there are substantial differences between the placodes with respect to their early development, their induction and their evolution. Indeed, it is now hard to consider the ectodermal placodes as a single entity. Rather, they fall into a number of distinct classes and it is within each of these that the members share a common development and evolution.


Tocolytic indomethacin: effects on neonatal haemodynamics and cerebral autoregulation in the preterm newborn.
Indomethacin has vasoactive properties in cerebral and systemic vascular beds, and it improves cerebral autoregulatory ability. We speculated that tocolytic indomethacin will improve cerebral autoregulatory ability in the very preterm infant in early postnatal life. Eighteen stable preterm infants gestational age (GA) 25.3-29.6 weeks, birth weight (BW) 660-1430 grams), whose mothers had received 50-150 mg of tocolytic indomethacin within 24 h before birth, and 18 individually matched controls (GA 25.0-29.7 weeks, BW 700-1390 grams) were studied four times for 15 min in the first 24 h of life. Autoregulation was assessed by determining correlations between mean arterial blood pressure (MABP (mm Hg)) and near-infrared spectroscopy-monitored cerebral oxygenation (rScO2). MABPs were significantly higher in the indomethacin infants than in the control infants (p=0.03). A decreased ability to autoregulate was found in four of the indomethacin infants, and in six of the control infants, which is not significantly different. Prenatally administered indomethacin, given as a tocolytic in doses of 50-150 mg per day, improved transitional circulation in very preterm infants by significantly raising the MABP. It did not have an effect on the ability to autoregulate the cerebral circulation. In this study, no differences in short-term outcomes, like haemorrhagic or ischaemic cerebral lesions, were observed.


Whole genome resequencing of the human parasite Schistosoma mansoni reveals population history and effects of selection.
Schistosoma mansoni is a parasitic fluke that infects millions of people in the developing world. This study presents the first application of population genomics to S. mansoni based on high-coverage resequencing data from 10 global isolates and an isolate of the closely-related Schistosoma rodhaini, which infects rodents. Using population genetic tests, we document genes under directional and balancing selection in S. mansoni that may facilitate adaptation to the human host. Coalescence modeling reveals the speciation of S. mansoni and S. rodhaini as 107.5-147.6KYA, a period which overlaps with the earliest archaeological evidence for fishing in Africa. Our results indicate that S. mansoni originated in East Africa and experienced a decline in effective population size 20-90KYA, before dispersing across the continent during the Holocene. In addition, we find strong evidence that S. mansoni migrated to the New World with the 16-19th Century Atlantic Slave Trade.


Molecularly imprinted polymer microspheres for solid-phase extraction of protocatechuic acid in Rhizoma homalomenae.
Molecularly imprinted polymers (MIPs) had been prepared by precipitation polymerization method using acrylamide as the functional monomer, ethylene glycol dimethacrylate as the cross-linker, acetonitrile as the porogen solvent and protocatechuic acid (PA), one of phenolic acids, as the template molecule. The MIPs were characterized by scanning electron microscopy and Fourier transform infrared, and their performance relative to non-imprinted polymers was assessed by equilibrium binding experiments. Six structurally similar phenolic acids, including p-hydroxybenzoic acid, gallic acid, salicylic acid, syringic acid, vanillic acid, ferulic acid were selected to assess the selectivity and recognition capability of the MIPs. The MIPs were applied to extract PA from the traditional Chinese medicines as a solid-phase extraction sorbent. The resultant cartridge showed that the MIPs have a good extraction performance and were able to selectively extract almost 82% of PA from the extract of Rhizoma homalomenae. Thus, the proposed molecularly imprinted-solid phase extraction-high performance liquid chromatography method can be successfully used to extract and analyse PA in traditional Chinese medicines.


Optimal local dimming for LC image formation with controllable backlighting.
Light emitting diode (LED)-backlit liquid crystal displays (LCDs) hold the promise of improving image quality while reducing the energy consumption with signal-dependent local dimming. However, most existing local dimming algorithms are mostly motivated by simple implementation, and they often lack concern for visual quality. To fully realize the potential of LED-backlit LCDs and reduce the artifacts that often occur in current systems, we propose a novel local dimming technique that can achieve the theoretical highest fidelity of intensity reproduction in either l(1) or l(2) metrics. Both the exact and fast approximate versions of the optimal local dimming algorithm are proposed. Simulation results demonstrate superior performances of the proposed algorithm in terms of visual quality and power consumption.


Linking the wintering and breeding grounds of warblers along the Pacific Flyway.
Long-distance migration is a behavior that is exhibited by many animal groups. The evolution of novel migration routes can play an important role in range expansions, ecological interactions, and speciation. New migration routes may evolve in response to selection in favor of reducing distance between breeding and wintering areas, or avoiding navigational barriers. Many migratory changes are likely to evolve gradually and are therefore difficult to study. Here, we attempt to connect breeding and wintering populations of myrtle warblers (Setophaga coronata coronata) to better understand the possible evolution of distinct migration routes within this species. Myrtle warblers, unlike most other warblers with breeding ranges primarily in eastern North America, have two disjunct overwintering concentrations-one in the southeastern USA and one along the Pacific Coast-and presumably distinct routes to-and-from these locations. We studied both myrtle and Audubon's warblers (S. c. auduboni) captured during their spring migration along the Pacific Coast, south of the narrow region where these two taxa hybridize. Using stable hydrogen isotopes and biometric data, we show that those myrtle warblers wintering along the southern Pacific Coast of North America are likely to breed at high latitudes in Alaska and the Yukon rather than in Alberta or further east. Our interpretation is that the evolution of this wintering range and migration route along the Pacific Coast may have facilitated the breeding expansion of myrtle warblers into northwestern North America. Moreover, these data suggest that there may be a migratory divide within genetically similar populations of myrtle warblers.


Hepatitis B virus replication induces methylation of both host and viral DNA.
Control of viral replication is a major therapeutic goal to reduce morbidity and mortality from chronic hepatitis B virus (HBV) infection. Recently, methylation has been identified as a novel host defense mechanism, and methylation of viral DNA leads to downregulation of HBV gene expression. To better understand the mechanisms of HBV methylation, cell lines were exposed to HBV using a model system that mimics natural infection and the expression of host DNA methyltransferase genes (DNMTs) was measured. DNMT1, DNMT2, and DNMT3 were all significantly upregulated in response to HBV. DNMT3 was further studied because of its known role in the de novo methylation of DNA. Cotransfection experiments with full-length HBV and DNMT3 led to the downregulation of viral protein and pregenomic RNA production. To investigate whether the upregulation of DNMTs could also have an effect on the methylation of host DNA, cell lines were exposed to HBV in two independent model systems, one that mimics natural infection and a second model with temporary transfection. Host DNA methylation was measured by DNA microarray analysis. Increased methylation of host CpG islands was detected in both experimental systems. Two CpG islands, corresponding to genes SUFU and TIRAP, were selected, and the downregulation of these genes in hepatocellular carcinomas was confirmed. In conclusion, hepatocytes respond to HBV infection by upregulating DNMTs. The DNMTs methylate viral DNA, leading to decreased viral gene expression and decreased viral replication. However, virus-induced overexpression of DNMTs also leads to methylation of host CpG islands.


Insights into the Genetic Basis of the Renal Cell Carcinomas from The Cancer Genome Atlas.
The renal cell carcinomas (RCC), clear cell, papillary, and chromophobe, have recently undergone an unmatched genomic characterization by The Cancer Genome Atlas. This analysis has revealed new insights into each of these malignancies and underscores the unique biology of clear cell, papillary, and chromophobe RCC. Themes that have emerged include distinct mechanisms of metabolic dysregulation and common mutations in chromatin modifier genes. Importantly, the papillary RCC classification encompasses a heterogeneous group of diseases, each with highly distinct genetic and molecular features. In conclusion, this review summarizes RCCs that represent a diverse set of malignancies, each with novel biologic programs that define new paradigms for cancer biology. Mol Cancer Res; 14(7); 589-98. ©2016 AACR.


Graded nanowell arrays: a fine plasmonic "library" with an adjustable spectral range.
We present an effective approach for fabricating graded plasmonic arrays based on ordered micro-/nanostructures with a geometric gradient. Ag nanowell arrays with graded geometric parameters were fabricated and systematically investigated. The order of the graded plasmonic arrays is generated by colloidal lithography, while the geometric gradient is the result of inclined reactive ion etching. The surface plasmon resonance (SPR) peaks were measured at different positions, which move gradually along the Ag nanowell arrays with a geometric gradient. Such micro-/nanostructure arrays with graded and integrated SPR peaks can work as a fine plasmonic "library" (FPL), and the spectral range can be controlled using a "coarse adjustment knob" (lattice constant) and a "fine adjustment knob" (pore diameter). Additionally, the spectral resolution of the FPL is high, which benefits from the high value of the full height/full width at half-maximum and the small step size of the wavelength shift (0.5 nm). Meanwhile, the FPL could be effectively applied as a well-defined model to verify the plasmonic enhancement in surface enhanced Raman scattering. As the FPL is an integrated optical material with graded individual SPR peaks, it can not only be a theoretical model for fundamental research, but also has great potential in high-throughput screening of optical materials, multiplex sensors, etc.


A probabilistic approach for collective similarity-based drug-drug interaction prediction.
As concurrent use of multiple medications becomes ubiquitous among patients, it is crucial to characterize both adverse and synergistic interactions between drugs. Statistical methods for prediction of putative drug-drug interactions (DDIs) can guide in vitro testing and cut down significant cost and effort. With the abundance of experimental data characterizing drugs and their associated targets, such methods must effectively fuse multiple sources of information and perform inference over the network of drugs. We propose a probabilistic approach for jointly inferring unknown DDIs from a network of multiple drug-based similarities and known interactions. We use the highly scalable and easily extensible probabilistic programming framework Probabilistic Soft Logic We compare against two methods including a state-of-the-art DDI prediction system across three experiments and show best performing improvements of more than 50% in AUPR over both baselines. We find five novel interactions validated by external sources among the top-ranked predictions of our model. Final versions of all datasets and implementations will be made publicly available. email@example.com.


Percutaneous Placement of Pancreatico-biliary Drainage Catheter for the Treatment of Complicated Pancreatic Anastomotic Leakage: an Alternative Treatment Option.
A 58-year-old female patient who had anastomotic leakage after a Whipple operation was treated with a percutaneously placed pancreatico-biliary drainage catheter. Complete secondary healing of the anastomotic defect and leakage was seen on control cholangiography examination on the 35th postoperative day, and the pancreatico-biliary drainage catheter was removed. She was discharged on the 39th postoperative day uneventfully. Percutaneous pancreatico-biliary drainage should be kept in mind as an alternative treatment option of complicated pancreatic anastomotic leakage after a Whipple operation.


Pedal dermatophyte infection in psoriasis.
Dermatophyte infections have been considered rare in psoriasis. However, there are data indicating that tinea unguium is as common or even more common in psoriasis compared with healthy controls. Tinea unguium is generally a secondary event to tinea pedis infection. To study the prevalence of tinea pedis and tinea unguium in psoriasis compared with a control group. Consecutive psoriasis outpatients aged 18-64 years attending a department of dermatology were examined. Samples for direct microscopy and culture were taken from the interdigital spaces, soles and toenails. Consecutive patients without signs of psoriasis or atopic dermatitis seeking examination of moles constituted the control group. In total, 239 patients with psoriasis and 245 control patients were studied. The prevalence of tinea pedis was 8.8%[95% confidence interval (CI) +/- 3.6%] in the psoriasis group and 7.8% (95% CI +/- 3.4%) in the control group. The corresponding figures for prevalence of tinea unguium were 4.6% (95% CI +/- 2.7%) and 2.4% (95% CI +/- 1.9%), respectively. The differences found in the psoriasis vs. the control groups were not statistically significant. This study does not support the hypothesis that the prevalence of tinea pedis and tinea unguium in patients with psoriasis differs from that in a normal population.


Knockout Serum Replacement Promotes Cell Survival by Preventing BIM from Inducing Mitochondrial Cytochrome C Release.
Knockout serum replacement (KOSR) is a nutrient supplement commonly used to replace serum for culturing stem cells. We show here that KOSR has pro-survival activity in chronic myelogenous leukemia (CML) cells transformed by the BCR-ABL oncogene. Inhibitors of BCR-ABL tyrosine kinase kill CML cells by stimulating pro-apoptotic BIM and inhibiting anti-apoptotic BCL2, BCLxL and MCL1. We found that KOSR protects CML cells from killing by BCR-ABL inhibitors--imatinib, dasatinib and nilotinib. The protective effect of KOSR is reversible and not due to the selective outgrowth of drug-resistant clones. In KOSR-protected CML cells, imatinib still inhibited the BCR-ABL tyrosine kinase, reduced the phosphorylation of STAT, ERK and AKT, down-regulated BCL2, BCLxL, MCL1 and up-regulated BIM. However, these pro-apoptotic alterations failed to cause cytochrome c release from the mitochondria. With mitochondria isolated from KOSR-cultured CML cells, we showed that addition of recombinant BIM protein also failed to cause cytochrome c release. Besides the kinase inhibitors, KOSR could protect cells from menadione, an inducer of oxidative stress, but it did not protect cells from DNA damaging agents. Switching from serum to KOSR caused a transient increase in reactive oxygen species and AKT phosphorylation in CML cells that were protected by KOSR but not in those that were not protected by this nutrient supplement. Treatment of KOSR-cultured cells with the PH-domain inhibitor MK2206 blocked AKT phosphorylation, abrogated the formation of BIM-resistant mitochondria and stimulated cell death. These results show that KOSR has cell-context dependent pro-survival activity that is linked to AKT activation and the inhibition of BIM-induced cytochrome c release from the mitochondria.


Exploring the influence of context in a community-based facilitation intervention focusing on neonatal health and survival in Vietnam: a qualitative study.
In the Neonatal health - Knowledge into Practice (NeoKIP) trial in Vietnam, local stakeholder groups, supported by trained laywomen acting as facilitators, promoted knowledge translation (KT) resulting in decreased neonatal mortality. In general, as well as in the community-based NeoKIP trial, there is a need to further understand how context influences KT interventions in low- and middle-income countries (LMICs). Thus, the objective of this study was to explore the influence of context on the facilitation process in the NeoKIP intervention. A secondary content analysis was performed on 16 Focus Group Discussions with facilitators and participants of the stakeholder groups, applying an inductive approach to the content on context through naïve understanding and structured analysis. The three main-categories of context found to influence the facilitation process in the NeoKIP intervention were: (1) Support and collaboration of local authorities and other communal stakeholders; (2) Incentives to, and motivation of, participants; and (3) Low health care coverage and utilization. In particular, the role of local authorities in a KT intervention was recognized as important. Also, while project participants expected financial incentives, non-financial benefits such as individual learning were considered to balance the lack of reimbursement in the NeoKIP intervention. Further, project participants recognized the need to acknowledge the needs of disadvantaged groups. This study provides insight for further understanding of the influence of contextual aspects to improve effects of a KT intervention in Vietnam. We suggest that future KT interventions should apply strategies to improve local authorities' engagement, to identify and communicate non-financial incentives, and to make disadvantaged groups a priority. Further studies to evaluate the contextual aspects in KT interventions in LMICs are also needed.


Label-free, three-dimensional multiphoton microscopy of the connective tissue in the anterior vaginal wall.
Multiphoton microscopy (MPM) is a nonlinear, high-resolution laser scanning technique and a powerful approach for analyzing the spatial architecture within tissues. To demonstrate the potential of this technique for studying the extracellular matrix of the pelvic organs, we aimed to establish protocols for the detection of collagen and elastin in the vagina and to compare the MPM density of these fibers to fibers detected using standard histological methods. Samples of the anterior vaginal wall were obtained from nine patients undergoing a hysterectomy or cystocele repair. Samples were shock frozen, fixed with formaldehyde or Thiel's solution, or left untreated. Samples were imaged with MPM to quantify the amount of collagen and elastin via second harmonic generation and autofluorescence, respectively. In six patients, sample sections were also histologically stained and imaged with brightfield microscopy. The density of the fibers was quantified using the StereoInvestigator and Cavalieri software. With MPM, collagen and elastin could be visualized to a depth of 100 μm, and no overlap of signals was detected. The different tissue processing protocols used did not result in significantly different fiber counts after MPM. MPM-based fiber quantifications are comparable to those based on conventional histological stains. However, MPM provided superior resolution, particularly of collagen fibers. MPM is a robust, rapid, and label-free method that can be used to quantify the collagen and elastin content in thick specimens of the vagina. It is an excellent tool for future three-dimensional studies of the extracellular matrix in patients with pelvic organ prolapse.


Magnetic resonance microscopy defines ethanol-induced brain abnormalities in prenatal mice: effects of acute insult on gestational day 7.
This magnetic resonance microscopy (MRM)-based report is the second in a series designed to illustrate the spectrum of craniofacial and central nervous system (CNS) dysmorphia resulting from single- and multiple-day maternal ethanol treatment. The study described in this report examined the consequences of ethanol exposure on gestational day (GD) 7 in mice, a time in development when gastrulation and neural plate development begins; corresponding to the mid- to late third week postfertilization in humans. Acute GD 7 ethanol exposure in mice has previously been shown to result in CNS defects consistent with holoprosencephaly (HPE) and craniofacial anomalies typical of those in Fetal Alcohol Syndrome (FAS). MRM has facilitated further definition of the range of GD 7 ethanol-induced defects. C57Bl/6J female mice were intraperitoneally (i.p.) administered vehicle or 2 injections of 2.9 g/kg ethanol on day 7 of pregnancy. Stage-matched control and ethanol-exposed GD 17 fetuses selected for imaging were immersion fixed in a Bouins/Prohance solution. MRM was conducted at either 7.0 Tesla (T) or 9.4 T. Resulting 29 microm isotropic spatial resolution scans were segmented and reconstructed to provide 3D images. Linear and volumetric brain measures, as well as morphological features, were compared for control and ethanol-exposed fetuses. Following MRM, selected specimens were processed for routine histology and light microscopic examination. Gestational day 7 ethanol exposure resulted in a spectrum of median facial and forebrain deficiencies, as expected. This range of abnormalities falls within the HPE spectrum; a spectrum for which facial dysmorphology is consistent with and typically is predictive of that of the forebrain. In addition, other defects including median facial cleft, cleft palate, micrognathia, pituitary agenesis, and third ventricular dilatation were identified. MRM analyses also revealed cerebral cortical dysplasia/heterotopias resulting from this acute, early insult and facilitated a subsequent focused histological investigation of these defects. Individual MRM scans and 3D reconstructions of fetal mouse brains have facilitated demonstration of a broad range of GD 7 ethanol-induced morphological abnormality. These results, including the discovery of cerebral cortical heterotopias, elucidate the teratogenic potential of ethanol insult during the third week of human prenatal development.


Theoretical Elastic Deformations of a 4-m Diameter Optical Mirror Using Dynamic Relaxation.
This paper describes the results of an elastic analysis of a 4-m diam mirror. The mirror is solid quartz with a large central hole, flat back, and spherically dished front surface (f/2.75 system). We solved the three-dimensional elastic equations by a technique known as dynamic relaxation programmed for a digital computer. In this way, the resulting deformation of the optical surface is found for any proposed support system at any desired orientation of the mirror.


The metabolic syndrome and development of cognitive impairment among older women.
Several studies support a role for cardiovascular risk factors in cognitive aging. The metabolic syndrome, a constellation of cardiovascular risk factors, is common in elderly people. A growing but conflicting body of literature suggests that the metabolic syndrome may be associated with cognitive impairment. To investigate the association between the metabolic syndrome and its components and incident cognitive impairment in older women. We prospectively determined if the metabolic syndrome and its components were associated with a 4-year risk of developing cognitive impairment (dementia, mild cognitive impairment, or low global cognitive test score). The study was conducted at 180 clinical centers in 25 countries. A total of 4895 older women (mean age, 66.2 years) with osteoporosis who were part of an ancillary study to determine clinically relevant cognitive impairment were included in this study. These women were free of baseline cognitive impairment and had metabolic syndrome component measures. Clinically significant cognitive impairment was defined to include women with clinically adjudicated dementia or MCI and women who had a Short Blessed test score greater than 6 (consistent with impairment), but whose cases were not clinically adjudicated. Logistic regression analysis was used to examine the association between presence of the metabolic syndrome and development of clinically significant cognitive impairment. A total of 497 women (10.2%) had the metabolic syndrome and, of these, 36 (7.2%) developed cognitive impairment compared with 181 (of 4398 or 4.1%) without the syndrome (age-adjusted odds ratio, 1.66; 95% confidence interval, 1.14-2.41). The mean (SD) number of metabolic syndrome components for all women was 1.0 (1.1); 518 women (10.6%) were obese, 895 (18.3%) had hypertriglyceridemia, 1200 (24.5%) had low high-density lipoprotein cholesterol levels, 1944 (39.7%) had high blood pressure, and 381 (7.8%) had high fasting blood glucose levels. There was a 23.0% age-adjusted increase in the risk of developing cognitive impairment (odds ratio, 1.23; 95% confidence interval, 1.09-1.39) per unit increase in the number of components. Further multivariable adjustment somewhat reduced the effect. We found an association between the metabolic syndrome and the number of components and risk of developing cognitive impairment in older women. Additional studies are needed to determine if screening and close management of these at-risk elderly women would diminish the incidence of cognitive impairment.


Association of physical activity and physical performance with tibial cartilage volume and bone area in young adults.
Physical activity has been recommended to patients with knee osteoarthritis for improving their symptoms. However, it is still controversial if physical activity has effects on joint structures including cartilage volume. The aim of this study was to describe the associations between physical activity and performance measured 5 years prior and tibial cartilage volume and bone area in young adults. Subjects broadly representative of the Australian population (n = 328, aged 31-41 years, female 47.3 %) were selected from the Childhood Determinants of Adult Health study. They underwent T1-weighted fat-suppressed magnetic resonance imaging (MRI) scans of their knees. Tibial bone area and cartilage volume were measured from MRI. Physical activity (measured using long international physical activity questionnaire (IPAQ)) and performance measures (long jump, leg muscle strength, physical work capacity (PWC170)) were measured 5 years prior. In multivariable analyses, total physical activity (min/week) (β: 0.30 mm(3), 95 % CI: 0.13,0.47), vigorous (β: 0.54 mm(3), 95 % CI: 0.13,0.94), moderate (β: 0.34 mm(3), 95 % CI: 0.01,0.67), walking (β: 0.40 mm(3), 95 % CI: 0.07,0.72) and IPAQ category (β: 182.9 mm(3), 95 % CI: 51.8,314.0) were positively associated with total tibial cartilage volume but not tibial bone area. PWC170, long jump and leg muscle strength were positively and significantly associated with both total tibial cartilage volume and total tibial bone area; and the associations with tibial cartilage volume decreased in magnitude but remained significant for PWC170 and long jump after further adjustment for tibial bone area. While tibial bone area is affected only by physical performance, total tibial cartilage volume can be influenced by both physical activity and performance in younger adults. The clinical significance suggests a beneficial effect for cartilage but the bone area association was restricted to performance suggesting other factors rather than physical activity may be important.


Trace and toxic element patterns in nonsmoker patients with noninsulin-dependent diabetes mellitus, impaired glucose tolerance, and fasting glucose.
Noninsulin dependent diabetes mellitus is supposed to be associated with fluctuations in the plasma levels of several trace elements. There is accumulating evidence that the metabolism of several trace elements is altered in patients with noninsulin dependent diabetes mellitus and that these nutrients might have specific roles in the pathogenesis and progression of this disorder. The aim of the present study is to compare the levels of essential trace and toxic elements including lead (Pb), arsenic (As), cadmium (Cd), chromium (Cr), aluminium (Al), nickel (Ni), cobalt (Co), iron (Fe), copper (Cu), selenium (Se), zinc (Zn), vanadium (V), manganese (Mn), barium (Ba), silver (Ag), and mercury (Hg) in patients with noninsulin dependent diabetes mellitus (n = 31), impaired glucose tolerance (n = 20), impaired fasting glucose (n = 14), and healthy controls (n = 22). Plasma concentrations of the elements were measured by using inductively coupled plasma mass spectrometry. The results indicated that values of lead, nickel, aluminium, copper, and chromium were significantly higher, but not above toxic levels, in the plasma of nonsmoker patients with noninsulin dependent diabetes mellitus (P < 0.05). The values for these elements were found to be significantly higher (P < 0.05) in patients with impaired fasting glucose than in controls. Moreover, a statistically significant correlation was found between plasma levels of glycated hemoglobin and of some trace elements like lead, nickel, aluminium, copper, chromium, cadmium, and mercury. Thus, it was concluded that chronic complications of glucose metabolism disorders might be associated with alterations in the levels of some trace elements. Nevertheless, some more timely and extensive studies are required to clarify the exact mechanisms of each of these changes.


Cyclophilins and nucleoporins are required for infection mediated by capsids from circulating HIV-2 primary isolates.
HIV-2 groups have emerged from sooty mangabey SIV and entered the human population in Africa on several separate occasions. Compared to world pandemic HIV-1 that arose from the chimpanzee SIVcpz virus, the SIVsm-derived HIV-2, largely confined to West Africa, is less replicative, less transmissible and less pathogenic. Here, we evaluated the interactions between host cellular factors, which control HIV-1 infection and target the capsid, and HIV-2 capsids obtained from primary isolates from patients with different disease progression status. We showed that, like HIV-1, all HIV-2 CA we tested exhibited a dependence on cyclophilin A. However, we observed no correlation between HIV-2 viremia and susceptibility to hu-TRIM5alpha or dependence to CypA. Finally, we found that all CA from HIV-2 primary isolates exploit Nup358 and Nup153 for nucleus transposition. Altogether, these findings indicate that the ability to use the two latter nucleoporins is essential to infection of human cells for both HIV-1 and HIV-2. This dependence provides another molecular target that could be used for antiviral strategies against both HIV-1 and 2, based on both nucleoporins.


Tumor and viral recognition by natural killer cells receptors.
Natural killer (NK) cells destroy hazardous cells such as tumors and virus-infected cells immediately without the need for prior antigen stimulation. The activation of NK cells largely depends on the recently identified natural cytotoxic receptors (NCRs), which include three members: NKp46, NKp44 and NKp30. The NCRs are unique in their expression pattern that is almost conclusively confined to NK cells, and in their broad specificity towards a wide range of targets. However, very little is known about the ligands identity of the NCRs and so far the only ligands known are two virally derived molecules: the hemagglutinin protein of influenza viruses that directly binds and activates two of the NCRs; NKp46 and NKp44, and the human cytomegalovirus tegument protein, pp65, which binds the NKp30 receptor and inhibits its activation thus promoting survival of the virus. In this review we describe the function of the NCRs in various pathological conditions with a special emphasis on tumor targeting.


Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson's disease.
The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease (PD). PD is characterized by the degeneration of dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequent neuroinflammatory response is increasingly recognized as a prominent neuropathological feature of PD. There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10 mg/kg, i.p.), initiated 24 hr after MPTP injection (20 mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra. Furthermore, chronic PEA reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated MPTP systemic toxicity, while PEA-induced neuroprotection seemed be partially PPARα-dependent. The effects of PEA on molecules typically involved in apoptotic pathways were also analyzed. Our results indicate that PEA protects against MPTP-induced neurotoxicity and the ensuing functional deficits even when administered once the insult has been initiated.


Comparison of clinical outcome with radiological findings after trapeziectomy with ligament reconstruction and tendon interposition.
The aim of our study was to investigate if pre- and postoperative radiographic thumb carpometacarpal position is correlated with clinical and subjective outcomes. Radiographs of 105 patients undergoing trapeziectomy with ligament reconstruction and tendon interposition were analysed before, as well as 1 year after, surgery for dorsal subluxation and proximal migration of the thumb metacarpal bone. Furthermore, key pinch strength was measured and patients completed the Michigan Hand Outcomes Questionnaire. Baseline dorsal subluxation and scaphometacarpal distances significantly decreased from 8.2 mm and 11.0 mm to 5.2 mm and 5.1 mm at 1 year, respectively. There was no correlation between the amount of subluxation or proximal migration and the Michigan Hand Outcomes Questionnaire score or key pinch strength. These results suggest that postoperative position of the metacarpal base of the thumb does not affect clinical or subjective outcomes after trapeziectomy with ligament reconstruction and tendon reposition of the thumb carpometacarpal joint. Level 3.


Pleural drainage and its role in management of the isolated penetrating chest injuries during the war time in Sarajevo, 1992.-1995.
Penetrating chest injuries are the most frequent causes of serious demage and death in wounded indivisuals. In reports from the last wars where wounds caused by high velocity projectiles predominated, thoracotomies were perfomed in about 15% of the wounded individuals, mostly encompassing injuries of the heart and great vessels, accomanied by massive bleeding that could not be resolved by chest tube insertion. This retrospective analysis was performed on the medical records of 477 patients tretaed for isolated penetrating chest injuries in Department of Thoracic Surgery Clinical Center of the University in Sarajevo between april 1992 - june 1995. We analised the ways of their menagement with special view on pleural drainage, indication for this method and results of treatment. 398 (83,4%) wounded individuals have been treated with pleural tube inserting as definitive mesaure and for the urgent thoracotomy there were 79 (16,6%) patients left. Average hospital treatment in wounded drained patients was 7,68 days. With shrapnels there were 357 (74,84%) wounded individuals, and with bullet 120 (25,16%) wounded individuals. The complications of plaural tube inserting were - empyema in 34 (7,13%) patients and there were no other complications. Chest tube inserting as definitive mesaure was used in 398 (83,44%) patients. Chest tube inserting as preoperative measure (urgent thoracotomy) was used in 79 (16,56%) patients. There were 460 (96,44%) healed patients. Death occurred in 17 (3,56%) patients.


Histochemical demonstration of five enzymes' activities in Macrogyrodactylus clarii (Monogenea: Gyrodactylidae) from the catfish Clarias gariepinus.
Histochemical techniques were applied to whole mounts, to study the distribution of the enzymes alkaline phosphatase, acid phosphatase, adenosine triphosphatase, 5'-nucleotidase and glucose-6-phosphatase in the organs and tissues of a viviparous monogenean, Macrogyrodactylus clarii Gussev, 1961, from the gills of the North African catfish Clarias gariepinus (Burchell) in Egypt. The following organs and tissues were studied: head region, anterior adhesive glands, mouth region, pharynx, intestine, testis, vesicula seminalis, male accessory gland, male accessory reservoir, copulatory organ, receptaculum seminis, egg-cell forming region, embryonic cells, excretory system, nerve cells, haptor, muscle fibres and subtegumental cell bodies (cytons). The enzymes showed marked differences in their activities among the studied organs and tissues. Alkaline phosphatase and acid phosphatase activities were detected in many organs and tissues, while the activities of adenosine triphosphatase, 5'-nucleotidase and glucose-6-phosphatase were restricted to a few organs. Although no positive reaction for any enzyme was observed in the anterior adhesive gland cells, a positive reaction for acid phosphatase was detected in the anterior adhesive areas. All enzymes showed marked activity in the digestive and excretory systems. The distribution of the enzymes in the tissues and organs of M clarii is compared with those of other monogeneans, including other gyrodactylids parasitizing the same host fish. Some possible functions of the enzymes are discussed.


[Progress in management of severe tuberculosis or tuberculosis with severe complication].
The management and therapy of miliary tuberculosis: Nobuharu OHSHIMA (Asthma and Allergy Center, National Hospital Organization Tokyo National Hospital). Treatment and management of severe pulmonary tuberculosis: Yuta HAYASHI, Kenji OGAWA (Department of Respiratory Medicine, National Hospital Organization Higashi Nagoya National Hospital). Death of a young (non-elderly) patient may become a large psychological burden not only for patient's family but also for medical staff. We analyzed non-elderly cases with severe pulmonary tuberculosis by comparing 13 patients who died of tuberculosis in the hospital (death group) and 31 patients who survived and were discharged from hospital (survivor group). The mean age was older and there were more patients who were out of employment in the death group compared to the survivor group. Among the factors related to the general condition evaluated on the admission, disturbance of consciousness, respiratory insufficiency, impairment in the ADL, poor dietary intake, and decubitus ulcer were more observed in the death group. Chest X-ray finding was not a predictive factor of poor prognosis. Among the laboratory findings, the numbers of peripheral blood lymphocytes, red blood cells, and thrombocytes significantly decreased in the death group. Serum level of total cholesterol, cholinesterase, and albumin were also significantly lower in the death group, indicating that malnutrition was related to the death of severe tuberculosis. Further studies are needed to establish the optimal nutritional management and evaluate the effectiveness of adjunctive use of steroid for severe tuberculosis patients. Invasive fungal infection complicated with pulmonary tuberculosis: Akira WATANABE, Katsuhiko KAMEI (Division of Clinical Research, Medical Mycology Research Center, Chiba University). Among the invasive mycoses, chronic pulmonary aspergillosis (CPA) is the most frequent disease as a sequel to pulmonary tuberculosis. However, identifying CPA early in patient with persistent pulmonary shadows from pulmonary tuberculosis is difficult. Serum microbiological tests such as Aspergillus precipitans (principally for Aspergillus IgG antibodies) are useful but sensitivity and specificity of this test are not high. Even treated, CPA has a case mortality rate of 50% over a span of 5 years. Morbidity is marked by both systemic and respiratory symptom and hemoptysis. Loss of lung function and life-threatening hemoptysis are common. As invasive pulmonary aspergillosis, early diagnosis and treatment of CPA might improve the outcome. Regarding the treatment, concomitant use of some anti-tubercular agents and antifungals is contradicted. Treatment and management for pulmonary tuberculosis complicated with COPD and interstitial pneumonia: Shinji TAMAKI, Takashi KUGE, Midori TAMURA, Sayuri TANAKA, Eiko YOSHINO, Mouka TAMURA (National Hospital Organization Nara Medical Center), Hiroshi KIMURA (Second Department of Internal Medicine and Respiratory Medicine, Nara Medical University) Recently, patients of pulmonary tuberculosis have many complications especially in the elderly population. It is recognized that patients with COPD and interstitial pneumonia (IP) have an increased risk for developing active tuberculosis. The aim of this report is to describe the clinical findings of pulmonary tuberculosis complicated with COPD and IP. We reviewed 327 patients who were diagnosed as pulmonary tuberculosis. Twenty-six cases were complicated with COPD. All patients were male, and had smoking history. Cavitary lesions were observed only in 5 cases. Acute exacerbation of COPD occurred in one fatal case. Ten cases were complicated with IP. Cavitary lesions were observed in 3 cases. Acute exacerbation of IP were observed in 7 cases, and 4 patients died during the anti-tuberculosis treatment. Careful evaluation and treatment are necessary for tuberculosis patients complicated with COPD and IP.


The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis.
Ankylosing spondylitis (AS) is a common and highly heritable inflammatory arthropathy. Although the gene HLA-B27 is almost essential for the inheritance of the condition, it alone is not sufficient to explain the pattern of familial recurrence of the disease. We have previously demonstrated suggestive linkage of AS to chromosome 2q13, a region containing the interleukin 1 (IL-1) family gene cluster, which includes several strong candidates for involvement in the disease. In the current study, we describe strong association and transmission of IL-1 family gene cluster single-nucleotide polymorphisms and haplotypes with AS.


Characteristics and measurements of an aperture-limited in-line hologram image.
The intensity distribution in the neighborhood of the real image reconstructed from an in-line Fraunhofer hologram was investigated. Assuming a finite amount of information recorded on the hologram in terms of a limiting aperture, the image is shown to possess intensity variations that are dependent on the argument of a first-order Bessel function recorded on the hologram. The theoretical results are presented on isophote diagrams and are verified experimentally. Three measurements of the image width are presented, and the inherent errors are found. The focal tolerance of the aperture-limited image relative to the recording parameters is discussed.


Molecular dissection of valproic acid effects in acute myeloid leukemia identifies predictive networks.
Histone deacetylase inhibitors (HDACIs) like valproic acid (VPA) display activity in leukemia models and induce tumor-selective cytotoxicity against acute myeloid leukemia (AML) blasts. As there are limited data on HDACIs effects, we aimed to dissect VPA effects in vitro using myeloid cell lines with the idea to integrate findings with in vivo data from AML patients treated with VPA additionally to intensive chemotherapy (n = 12). By gene expression profiling we identified an in vitro VPA response signature enriched for genes/pathways known to be implicated in cell cycle arrest, apoptosis, and DNA repair. Following VPA treatment in vivo, gene expression changes in AML patients showed concordant results with the in vitro VPA response despite concomitant intensive chemotherapy. Comparative miRNA profiling revealed VPA-associated miRNA expression changes likely contributing to a VPA-induced reversion of deregulated gene expression. In addition, we were able to define markers predicting VPA response in vivo such as CXCR4 and LBH. These could be validated in an independent cohort of VPA and intensive chemotherapy treated AML patients (n = 114) in which they were inversely correlated with relapse-free survival. In summary, our data provide new insights into the molecular mechanisms of VPA in myeloid blasts, which might be useful in further advancing HDAC inhibition based treatment approaches in AML.


Technical nuances of commonly used vascularised flaps for skull base reconstruction.
Reconstruction with a vascularised flap provides the most reliable outcome, with post-operative cerebrospinal fluid leak rates of less than 5 per cent. This article aims to review and summarise the critical technical aspects of the vascularised flaps most commonly used for skull base reconstruction. Vascularised flaps are classified as intranasal or extranasal. The intranasal group includes the Hadad-Bassagaisteguy nasoseptal flap, the Caicedo reverse nasoseptal flap, the nasoseptal rescue flap, the posteriorly or anteriorly based lateral wall flaps, and the middle turbinate flap. Extranasal flaps include the transfrontal pericranial and transpterygoid temporoparietal flaps. The Hadad-Bassagaisteguy nasoseptal flap is overwhelmingly favoured for reconstructing extensive defects of anterior, middle and posterior cranial base. Its pertinent technical features are described. However, it is essential to master the skills required for the various extranasal or regional vascularised flaps because each can offer a reconstructive alternative for specific patients, especially when open approaches are needed and/or intranasal vascularised flaps are not feasible.


Relative Prevalence and Antimicrobial Susceptibility of Clinical Isolates of Elizabethkingia Species Based on 16S rRNA Gene Sequencing.
Some of the previously reported clinical isolates of Elizabethkingia meningoseptica may be later named species of Elizabethkingia We determined the accuracy of species identification (with two matrix-assisted laser desorption ionization-time of flight mass spectrometry [MALDI-TOF MS] systems and the Vitek 2 GN card), relative prevalence of three Elizabethkingia spp. in clinical specimens, and antimicrobial susceptibility of the species identified by 16S rRNA gene sequencing. Specimens for culture were collected from patients in a university hospital in Seoul, South Korea, between 2009 and 2015. All 3 Elizabethkingia spp. were detected in patients; among the 86 isolates identified by 16S rRNA gene sequencing, 17 (19.8%) were E. meningoseptica, 18 (20.9%) were Elizabethkingia miricola, and 51 (59.3%) were Elizabethkingia anophelis Only the MALDI-TOF Vitek MS system with an amended database correctly identified all of the isolates. The majority (76.7%) of the isolates were from the lower respiratory tract, and 8 (9.3%) were from blood. Over 90% of E. meningoseptica and E. anophelis isolates were susceptible to piperacillin-tazobactam and rifampin. In contrast, all E. miricola isolates were susceptible to fluoroquinolones except ciprofloxacin. Further studies are urgently needed to determine the optimal antimicrobial agents for the treatment of infections due to each individual Elizabethkingia species.


Square wave jerks and anxiety as distinctive biomarkers for anorexia nervosa.
The factors contributing to the cause and maintenance of anorexia nervosa (AN) are poorly understood, though increasing interest surrounds the neurobiological underpinnings of the condition. The examination of saccadic eye movements has proven useful in our understanding of the neurobiology of some other psychiatric illnesses, as they utilize identifiable brain circuits. Square wave jerks (SWJs), which describe an involuntary saccade away and back to fixation, have been observed to occur at abnormally high rates in neurodegenerative disorders and some psychiatric illnesses, but have not been examined in AN. Therefore, the aim of this study was to investigate whether individuals with AN and healthy control (HC) individuals differ in SWJ rate during attempted fixation. Square wave jerk frequency was compared across 23 female participants with AN and 22 HC participants matched for age, sex, and premorbid intelligence. Anorexia nervosa participants were found to make SWJs at a significantly higher rate than HC participants. The rate of SWJs in AN was also found to negatively correlate with anxiety. Square wave jerk rate and anxiety were found to correctly classify groups, with an accuracy of 87% for AN participants and 95.5% for HCs. Given our current understanding of saccadic eye movements, the findings suggest a potential role of γ-aminobutyric acid (GABA) in the superior colliculus, frontal eye fields, or posterior parietal cortex in the psychopathology of AN.


Flt3 is dispensable to the Hoxa9/Meis1 leukemogenic cooperation.
HOX genes, MEIS1, and FLT3 are frequently up-regulated in human myeloid leukemias. Meis1 cooperates with Hox genes to induce leukemias in mice, hypothetically the consequence of Meis1-induced Flt3 overexpression. To test this, we compared the properties of Flt3(-/-) and Flt3(+/+) progenitors transduced with Hoxa9 or Hoxa9/Meis1. In a myeloid clonogenic assay, Meis1 greatly enhanced the proliferation of Hoxa9-expressing cells, massively up-regulating Flt3 protein. However, the transforming potential of Hoxa9/Meis1 was unaltered in Flt3(-/-) cells. All mice that received Hoxa9/Meis1-transduced progenitors succumbed to rapid acute myeloid leukemias regardless of Flt3 genotype. Flt3 expression levels in leukemic blasts did not correlate with parameters reflecting their proliferative rate or their impaired differentiation. Furthermore, analysis of c-Myb expression levels in Hoxa9/Meis1-transformed cells showed that the up-regulation of this critical downstream effector was independent of Flt3. Altogether, our findings demonstrate that Flt3 is dispensable to the oncogenic cooperation of Meis1 with Hoxa9.


Strategies for success: orienting to the role of a clinical nurse specialist in critical care.
Successful integration of a new clinical nurse specialist within an organization optimizes the safe, cost-effective implementation of evidence-based practice and research. This article provides strategies and information to support the clinical nurse specialist during his or her role transition, highlights opportunities and challenges to the role, and provides examples of orientation and performance tools that can assist in a successful orientation process.