The importance of group-wise registration in tract based spatial statistics study of neurodegeneration: a simulation study in Alzheimer's disease.
Tract-based spatial statistics (TBSS) is a popular method for the analysis of diffusion tensor imaging data. TBSS focuses on differences in white matter voxels with high fractional anisotropy (FA), representing the major fibre tracts, through registering all subjects to a common reference and the creation of a FA skeleton. This work considers the effect of choice of reference in the TBSS pipeline, which can be a standard template, an individual subject from the study, a study-specific template or a group-wise average. While TBSS attempts to overcome registration error by searching the neighbourhood perpendicular to the FA skeleton for the voxel with maximum FA, this projection step may not compensate for large registration errors that might occur in the presence of pathology such as atrophy in neurodegenerative diseases. This makes registration performance and choice of reference an important issue. Substantial work in the field of computational anatomy has shown the use of group-wise averages to reduce biases while avoiding the arbitrary selection of a single individual. Here, we demonstrate the impact of the choice of reference on: (a) specificity (b) sensitivity in a simulation study and (c) a real-world comparison of Alzheimer's disease patients to controls. In (a) and (b), simulated deformations and decreases in FA were applied to control subjects to simulate changes of shape and WM integrity similar to what would be seen in AD patients, in order to provide a "ground truth" for evaluating the various methods of TBSS reference. Using a group-wise average atlas as the reference outperformed other references in the TBSS pipeline in all evaluations.


A Randomized Controlled Trial of Metacognitive Therapy for Depression: Analysis of 1-Year Follow-Up.
This paper reports the 1-year follow-up results from a randomized controlled trial (RCT), which examined the efficacy of metacognitive therapy (MCT) for unipolar depression compared to a waiting condition. Thirty-nine patients with major depression were offered MCT and were divided into two conditions; immediate MCT with 10 weekly sessions or a waiting period that had a 10-week delayed MCT start. Two participants dropped out during the waiting condition. Thirty-four patients participated in the follow-up assessment. Based on the intent-to-treat sample and all patients, 67% were classified as recovered, 13% improved, and 20% were unchanged at 1-year follow-up. For the completers sample 73% recovered, 12% improved, and 15% were unchanged. Five of the 31 patients (13%) that were in remission at post-treatment experienced relapse at 1-year follow-up. Within-group effect sizes were large for reductions in symptoms of depression (d = 2.09) and anxiety (d = 1.16) at 1-year. Treatment response was associated with reductions in rumination, worry, and metacognitive beliefs as predicted by the metacognitive model, but reductions in metacognitions independently predicted reductions in depression scores from pre-treatment to 1-year follow-up. The results suggest that treatment gains are stable at 1-year follow-up. The study sets the stage for future research, which should evaluate MCT over a longer term and compare it with active treatments using suitably powered RCTs.


Resistance to thyroid hormone in a Turkish child with A317T mutation in the thyroid hormone receptor-beta gene.
Resistance to thyroid hormone (RTH) syndrome is a rare disorder usually inherited as an autosomal dominant trait. The combination of elevated serum levels of free thyroid hormones with elevated thyroid-stimulating hormone (TSH) suggest differential diagnoses of RTH, thyroxine-binding globulin abnormalities, familial dysalbuminemic hyperthyroxinemia and TSH-secreting pituitary tumors. We report a patient with RTH in a Turkish family. The diagnosis was confirmed by the identification of a known disease-causing mutation in the thyroid hormone receptor-beta (THRbeta) gene, but is the first published in the Turkish population. Genetic analysis of the mother and the patient yielded a mutation in the THRbeta gene, A317T, due to a base pair substitution of an adenine for a guanine.


Vivid memories of emotional events: the accuracy of remembered minutiae.
It has been claimed that emotional arousal causes a narrowing of attention, and, therefore, impoverished memory encoding. On this view, if details of an emotional event are reported subsequently, these details must be after-the-fact reconstructions that are open to error. Our study challenges these claims. Using a long-term (2-week), incidental learning procedure, we found that emotion promotes memory both for information central to an event and for peripheral detail. This contrasts with the results of explicit instructions to remember or to attend closely to the event, both of which seem to promote memory for the event's gist at the expense of detail. The likely mechanisms underlying these effects are discussed.


Translation, cultural adaptation and field-testing of the Thinking Healthy Program for Vietnam.
Depression and anxiety are prevalent among women in low- and lower-middle income countries who are pregnant or have recently given birth. There is promising evidence that culturally-adapted, evidence-informed, perinatal psycho-educational programs implemented in local communities are effective in reducing mental health problems. The Thinking Healthy Program (THP) has proved effective in Pakistan. The aims were to adapt the THP for rural Vietnam; establish the program's comprehensibility, acceptability and salience for universal use, and investigate whether administration to small groups of women might be of equivalent effectiveness to administration in home visits to individual women. The THP Handbook and Calendar were made available in English by the program developers and translated into Vietnamese. Cultural adaptation and field-testing were undertaken using WHO guidance. Field-testing of the four sessions of THP Module One was undertaken in weekly sessions with a small group in a rural commune and evaluated using baseline, process and endline surveys. The adapted Vietnamese version of the Thinking Healthy Program (THP-V) was found to be understandable, meaningful and relevant to pregnant women, and commune health centre and Women's Union representatives in a rural district. It was delivered effectively by trained local facilitators. Role-play, brainstorming and small-group discussions to find shared solutions to common problems were appraised as helpful learning opportunities. The THP-V is safe and comprehensible, acceptable and salient to pregnant women without mental health problems in rural Vietnam. Delivery in facilitated small groups provided valued opportunities for role-play rehearsal and shared problem solving. Local observers found the content and approach highly relevant to local needs and endorsed the approach as a mental health promotion strategy with potential for integration into local universal maternal and child health services. These preliminary data indicate that the impact of the THP-V should be tested in its complete form in a large scale trial.


The Place of PET to Assess New Therapeutic Effectiveness in Neurodegenerative Diseases.
In vivo exploration of neurodegenerative diseases by positron emission tomography (PET) imaging has matured over the last 20 years, using dedicated radiopharmaceuticals targeting cellular metabolism, neurotransmission, neuroinflammation, or abnormal protein aggregates (beta-amyloid and intracellular microtubule inclusions containing hyperphosphorylated tau). The ability of PET to characterize biological processes at the cellular and molecular levels enables early detection and identification of molecular mechanisms associated with disease progression, by providing accurate, reliable, and longitudinally reproducible quantitative biomarkers. Thus, PET imaging has become a relevant imaging method for monitoring response to therapy, approved as an outcome measure in bioclinical trials. The aim of this paper is to review and discuss the current inputs of PET in the assessment of therapeutic effectiveness in neurodegenerative diseases connected by common pathophysiological mechanisms, including Parkinson's disease, Huntington's disease, dementia, amyotrophic lateral sclerosis, multiple sclerosis, and also in psychiatric disorders. We also discuss opportunities for PET imaging to drive more personalized neuroprotective and therapeutic strategies, taking into account individual variability, within the growing framework of precision medicine.


Unlicensed and off-label drug use in a paediatric ward of a general hospital in the Netherlands.
Many drugs used in paediatric care are not licensed for that use or are prescribed outside the terms of the product license (off-label). Studies in the UK and Europe showed a large number of unlicensed and off-label drug prescription in specialised paediatric health care centres. We determined the extent and nature of use of unlicensed drugs and off-label prescriptions in children in a general hospital in the Netherlands. We conducted a longitudinal prospective cohort study in a dynamic population consisting of patients admitted to the paediatric ward and the neonatology unit of a general hospital during a 19-week period. Drug-licensing status of all prescriptions given to these patients was determined. A total of 1017 prescriptions was administered to 293 paediatric patients for 114 different drugs. The median number of prescriptions per patient was three (interquartile range 2-5). The most commonly administered drugs were acetaminophen (14%), cefotaxime (8%), amoxicillin (7%), caffeine (4%) and prednisolone (4%). Four hundred and forty-three (44%) prescriptions were off-label, and 285 (28%) were for unlicensed drugs. Ninety-two percent of patients received one or more unlicensed or off-label prescriptions, and this proportion was significantly higher in children below 6 months of age than in older children. This study shows that the extent of unlicensed and off-label drug prescription in a paediatric ward and neonatology unit of a general hospital is large and not smaller than in an academic paediatric setting. Lack of paediatric drug labelling is therefore not solely a problem with drugs used in university hospitals, but also in general hospitals. Efforts must be taken to change the current situation.


Structure-activity relationships of constrained phenylethylamine ligands for the serotonin 5-HT2 receptors.
Serotonergic ligands have proven effective drugs in the treatment of migraine, pain, obesity, and a wide range of psychiatric and neurological disorders. There is a clinical need for more highly 5-HT2 receptor subtype-selective ligands and the most attention has been given to the phenethylamine class. Conformationally constrained phenethylamine analogs have demonstrated that for optimal activity the free lone pair electrons of the 2-oxygen must be oriented syn and the 5-oxygen lone pairs anti relative to the ethylamine moiety. Also the ethyl linker has been constrained providing information about the bioactive conformation of the amine functionality. However, combined 1,2-constriction by cyclization has only been tested with one compound. Here, we present three new 1,2-cyclized phenylethylamines, 9-11, and describe their synthetic routes. Ligand docking in the 5-HT2B crystal structure showed that the 1,2-heterocyclized compounds can be accommodated in the binding site. Conformational analysis showed that 11 can only bind in a higher-energy conformation, which would explain its absent or low affinity. The amine and 2-oxygen interactions with D3.32 and S3.36, respectively, can form but shift the placement of the core scaffold. The constraints in 9-11 resulted in docking poses with the 4-bromine in closer vicinity to 5.46, which is polar only in the human 5-HT2A subtype, for which 9-11 have the lowest affinity. The new ligands, conformational analysis and docking expand the structure-activity relationships of constrained phenethylamines and contributes towards the development of 5-HT2 receptor subtype-selective ligands.


Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States.
Data on the detailed clinical progression of COVID-19 in conjunction with epidemiological and virological characteristics are limited. In this case series, we describe the first 12 US patients confirmed to have COVID-19 from 20 January to 5 February 2020, including 4 patients described previously1-3. Respiratory, stool, serum and urine specimens were submitted for SARS-CoV-2 real-time reverse-transcription polymerase chain reaction (rRT-PCR) testing, viral culture and whole genome sequencing. Median age was 53 years (range: 21-68); 8 patients were male. Common symptoms at illness onset were cough (n = 8) and fever (n = 7). Patients had mild to moderately severe illness; seven were hospitalized and demonstrated clinical or laboratory signs of worsening during the second week of illness. No patients required mechanical ventilation and all recovered. All had SARS-CoV-2 RNA detected in respiratory specimens, typically for 2-3 weeks after illness onset. Lowest real-time PCR with reverse transcription cycle threshold values in the upper respiratory tract were often detected in the first week and SARS-CoV-2 was cultured from early respiratory specimens. These data provide insight into the natural history of SARS-CoV-2. Although infectiousness is unclear, highest viral RNA levels were identified in the first week of illness. Clinicians should anticipate that some patients may worsen in the second week of illness.


Feasibility Study of Vascular Access and REBOA Placement in Quick Response Team Firefighters.
Early hemorrhage control using resuscitative endovascular balloon occlusion of the aorta (REBOA) can save lives. This study was designed to evaluate the ability to train Quick Response Team Fire Fighters (QRT-FF) to gain percutaneous femoral artery access and place a REBOA catheter in a model, using a comprehensive theoretical and practical training program. Six QRT-FF participated in the training. SOF medics from a previous training served as the control group. A formalized training curriculum included basic anatomy and endovascular materials for percutaneous access and REBOA placement. Key skills included (1) preparation of an endovascular toolkit, (2) achieving vascular access in the model, and (3) placement and positioning of REBOA. QRT-FF had significantly better scores compared with medics using endovascular materials (P = .003) and performing the procedure without unnecessary attempts (P = .032). Basic surgical anatomy scores for QRT-FF were significantly better than SOF medics (P = .048). QRT-FF subjects demonstrated a significantly higher overall technical skills point score than medics (P = .030). QRT-FF had a median total time from start of the procedure to REBOA inflation of 3:23 minutes, and medics, 5:05 minutes. All six QRT-FF subjects improved their procedure times-as did four of the five medics. Our training program using a task training model can be utilized for percutaneous femoral access and REBOA placement training of QRT-FF without prior ultrasound or endovascular experience. Training the use of advanced bleeding control options such as REBOA, as a secondary occupational task, has the potential to improve outcomes for severely bleeding casualties in the field.


Symptom experience after discontinuing use of estrogen plus progestin.
Little is known about women's experiences after stopping menopausal hormone therapy. To describe women's symptoms and management strategies after stopping the intervention in a large estrogen plus progestin trial. Cross-sectional survey of 8405 women (89.9%; N = 9351) at 40 clinical centers who were still taking study pills (conjugated equine estrogens plus medroxyprogesterone [CEE + MPA] or placebo) when the estrogen plus progestin intervention (Women's Health Initiative) was stopped. Surveys were mailed 8 to 12 months after the stop date. Logistic regression was used to model vasomotor symptoms and pain or stiffness symptoms as functions of former treatment and baseline symptoms, adjusted for appropriate covariates. Symptoms (vasomotor or pain and stiffness) and management strategies. Respondents' mean (SD) age at trial stop date was 69.1 (6.7) years. They averaged 5.7 years of taking study pills. Moderate or severe vasomotor symptoms after discontinuing study pill use were reported by 21.2% of former CEE + MPA and 4.8% of placebo group respondents overall and by 55.5% and 21.3%, respectively, with these symptoms at baseline (randomization). Compared with respondents in the former placebo group, moderate or severe vasomotor symptoms (adjusted odds ratio [AOR] 5.82; 95% confidence interval [CI], 4.92-6.89) and pain or stiffness symptoms (AOR, 2.16; 95% CI, 1.95-2.40) were more likely in respondents in the former CEE + MPA group. Both vasomotor symptoms (AOR, 5.36; 95% CI, 4.51-6.38) and pain or stiffness symptoms (AOR, 3.21; 95% CI, 2.90-3.56) also were more likely in women with these symptoms at baseline. Women reported a wide range of strategies to manage symptoms. More than half of the women with vasomotor symptoms at randomization to active CEE + MPA also reported these symptoms after discontinuing use of the study pills. However, these participants did not include women who were unwilling to be randomized or who had stopped taking the study pills earlier. These findings should be considered when advising women to treat menopausal symptoms with hormone therapy for as short duration as possible. Investigation of alternative strategies to manage menopausal symptoms is warranted.


Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free kidney transplant immunosuppression.
We performed a pilot study in which 22 kidney recipients (14 LD: 8 DCD) were given alemtuzumab induction (30 mg day 0 and 1), steroids (500 mg mp day 0 and 1, none thereafter), mycophenolate mofetil (MMF) maintenance (500 mg b.i.d) and sirolimus (concentration controlled 8-12 ng/mL). With a mean follow-up of 15.9 months, patient survival is (21/22) 96% and graft survival (19/22) 87%. Acute rejections occurred in (8) 36.3% (two humoral). Of 19 surviving grafts, 18 (95%) remain steroid and 15 (79%) CNI-free. At 1 year, mean creatinine was 1.43 mg/dL. Overall infection rates were low, but 2 patients developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, respectively, resulting in mortality in one and a graft loss in the other. No cancer or PTLD was observed. Leukopenia was common and MMF dose was reduced or eliminated in 6/22 (27%) patients. The reported higher than expected rate of acute rejection, leukopenia and possible pulmonary toxicity suggests excessive morbidity. Modifications such as an initial period of CNI use should be considered.


The psychological effects of meditation: a meta-analysis.
In this meta-analysis, we give a comprehensive overview of the effects of meditation on psychological variables that can be extracted from empirical studies, concentrating on the effects of meditation on nonclinical groups of adult meditators. Mostly because of methodological problems, almost ¾ of an initially identified 595 studies had to be excluded. Most studies appear to have been conducted without sufficient theoretical background. To put the results into perspective, we briefly summarize the major theoretical approaches from both East and West. The 163 studies that allowed the calculation of effect sizes exhibited medium average effects (r = .28 for all studies and r = .27 for the n = 125 studies from reviewed journals), which cannot be explained by mere relaxation or cognitive restructuring effects. In general, results were strongest (medium to large) for changes in emotionality and relationship issues, less strong (about medium) for measures of attention, and weakest (small to medium) for more cognitive measures. However, specific findings varied across different approaches to meditation (transcendental meditation, mindfulness meditation, and other meditation techniques). Surprisingly, meditation experience only partially covaried with long-term impact on the variables examined. In general, the dependent variables used cover only some of the content areas about which predictions can be made from already existing theories about meditation; still, such predictions lack precision at present. We conclude that to arrive at a comprehensive understanding of why and how meditation works, emphasis should be placed on the development of more precise theories and measurement devices.


Tools and techniques for computational reproducibility.
When reporting research findings, scientists document the steps they followed so that others can verify and build upon the research. When those steps have been described in sufficient detail that others can retrace the steps and obtain similar results, the research is said to be reproducible. Computers play a vital role in many research disciplines and present both opportunities and challenges for reproducibility. Computers can be programmed to execute analysis tasks, and those programs can be repeated and shared with others. The deterministic nature of most computer programs means that the same analysis tasks, applied to the same data, will often produce the same outputs. However, in practice, computational findings often cannot be reproduced because of complexities in how software is packaged, installed, and executed-and because of limitations associated with how scientists document analysis steps. Many tools and techniques are available to help overcome these challenges; here we describe seven such strategies. With a broad scientific audience in mind, we describe the strengths and limitations of each approach, as well as the circumstances under which each might be applied. No single strategy is sufficient for every scenario; thus we emphasize that it is often useful to combine approaches.


Inequality of household water security follows a Development Kuznets Curve.
Water security requires not only sufficient availability of and access to safe and acceptable quality for domestic uses, but also fair distribution within and across populations. However, a key research gap remains in understanding water security inequality and its dynamics, which in turn creates an impediment to tracking progress towards sustainable development. Therefore, we analyse the inequality of water security using data from 7603 households across 28 sites in 22 low- and middle-income countries, measured using the Household Water Insecurity Experiences Scale. Here we show an inverted-U shaped relationship between site water security and inequality of household water security. This Kuznets-like curve suggests a process that as water security grows, the inequality of water security first increases then decreases. This research extends the Kuznets curve applications and introduces the Development Kuznets Curve concept. Its practical implications support building water security and achieving more fair, inclusive, and sustainable development.


Central Precocious Puberty in a Child With Metachromatic Leukodystrophy.
Metachromatic leucodystrophy (MLD) is a rare inherited lysosomal disorder caused by reduced activity of the enzyme arylsulfatase A with accumulation of sulfatides in the nervous system. We report a female child affected by MLD who developed central precocious puberty (CPP). This association has not been described so far. The proposita, after normal growth and psychomotor development, at age of 30 months presented with a rapidly progressive gait disturbance with frequent falls and with loss of acquired language skills. Magnetic resonance imaging showed leukoencephalopathy. Biochemical blood essays showed a 91% reduction in the arylsulfatase A activity and genetic analysis revealed compound heterozygous mutations of the Arylsulfatase A gene, enabling diagnosis of MLD. Subsequently, the patient had further rapid deterioration of motor and cognitive functions and developed drug-resistant epilepsy. At 4 years and 7 months of age bilateral thelarche occurred. Magnetic resonance imaging showed a small pituitary gland, extensive signal changes of the brain white matter, increased choline, decreased N-acetyl-aspartate and presence of lactate on 1HMR spectroscopy. Pelvic ultrasound demonstrated a slightly augmented uterine longitudinal diameter (42 mm). The gonadotropin-releasing hormone stimulation test revealed a pubertal LH peak of 12.9 UI/l. A diagnosis of CPP was made and treatment with gonadotropin-releasing hormone agonists was initiated, with good response. In conclusion, a CPP may occur in MLD as in other metabolic diseases with white matter involvement. We hypothesize that brain accumulation of sulfatides could have interfered with the complex network regulating with the hypothalamic-pituitary axis and thus triggering CPP in our patient.


Identification and characterization of transmissible Pseudomonas aeruginosa strains in cystic fibrosis patients in England and Wales.
Most past studies of cross-infection with Pseudomonas aeruginosa among cystic fibrosis (CF) patients in the UK suggest that it is a rare occurrence. However, two recent reports of highly transmissible strains in patients in regional centres in England (Liverpool and Manchester) have raised questions as to the extent of the problem and prompted a nationwide survey to establish the distribution of P. aeruginosa strain genotypes among these patients. Isolates of P. aeruginosa were requested from over 120 hospitals in England and Wales and a sample size of approximately 20% of the CF patient population in each centre was recommended. In total, 1225 isolates were received from 31 centres (range 1 to 330). Single patient isolates were typed by SpeI macrorestriction and PFGE. A panel of strains of the common genotypes including representatives of reported transmissible strains was assembled and further characterized by fluorescent amplified fragment length polymorphism (FAFLP) genotyping. At least 72% of all patients harboured strains with unique genotypes. Small clusters of related strains were evident in some centres, presumably indicating limited transmission of local strains. The most prevalent strain was indistinguishable from that previously described as the 'Liverpool' genotype, and accounted for approximately 11% of patient isolates from 15 centres in England and Wales. The second most common genotype (termed Midlands 1) was recovered from 86 patients in nine centres and the third genotype, which matched closely the PFGE profile of Clone C, a genotype originally described in Germany, was found in eight centres and was isolated from 15 patients. A fourth genotype, identical to the published Manchester strain, was found in three centres. FAFLP analysis revealed some microheterogeneity among strains of the Liverpool genotype but all isolates of this genotype were positive by PCR for a strain-specific marker. These data suggest that cross-infection with P. aeruginosa has occurred both within and widely between CF centres in England and Wales. The two most common genotypes accounted for more than one-fifth of patients' isolates examined and transmissible genotypes were found in all but three centres studied. These results emphasize the need for continued surveillance of P. aeruginosa genotypes in CF patients to provide informed infection control policy in treatment centres.


Modulation of transcription factor and metabolic pathway genes in response to water-deficit stress in rice.
Water-deficit stress is detrimental for rice growth, development, and yield. Transcriptome analysis of 1-week-old rice (Oryza sativa L. var. IR64) seedling under water-deficit stress condition using Affymetrix 57 K GeneChip® has revealed 1,563 and 1,746 genes to be up- and downregulated, respectively. In an effort to amalgamate data across laboratories, we identified 5,611 differentially expressing genes under varying extrinsic water-deficit stress conditions in six vegetative and one reproductive stage of development in rice. Transcription factors (TFs) involved in ABA-dependent and ABA-independent pathways have been found to be upregulated during water-deficit stress. Members of zinc-finger TFs namely, C₂H₂, C₂C₂, C₃H, LIM, PHD, WRKY, ZF-HD, and ZIM, along with TF families like GeBP, jumonji, MBF1 and ULT express differentially under water-deficit conditions. NAC (NAM, ATAF and CUC) TF family emerges to be a potential key regulator of multiple abiotic stresses. Among the 12 TF genes that are co-upregulated under water-deficit, salt and cold stress conditions, five belong to the NAC TF family. We identified water-deficit stress-responsive genes encoding key enzymes involved in biosynthesis of osmoprotectants like polyols and sugars; amino acid and quaternary ammonium compounds; cell wall loosening and structural components; cholesterol and very long chain fatty acid; cytokinin and secondary metabolites. Comparison of genes responsive to water-deficit stress conditions with genes preferentially expressed during panicle and seed development revealed a significant overlap of transcriptome alteration and pathways.


Maintenance of statin use over 3 years following acute coronary syndromes: a national data linkage study (ANZACS-QI-2).
To describe patterns of statin use and predictors of poor maintenance over a 3-year period following an acute coronary syndrome (ACS). National hospitalisation, mortality and pharmaceutical dispensing data were linked for all subjects aged 35-84 years discharged from a public hospital with an ACS in New Zealand in 2007. A Medication Possession Ratio (MPR; percentage of follow-up days patients were dispensed statins) was calculated for each patient. Adequate maintenance was defined by a MPR ≥80%. In 2007, 11 348 patients aged 35-84 years were discharged from hospital with ACS. Within 90 days of discharge, 83% had received a statin. Over the follow-up period, 66% were adequately maintained on a statin (MPR ≥80%): 69% in the first year, 67% in the second year and 66% in the third year. Patients taking statins prior to admission and those who underwent a coronary procedure were 20-50% more likely to have a MPR ≥80% over 3 years than others. In contrast, people aged 35-45 years and those of Maori or Pacific ethnicity were 13-25% less likely to have a MPR ≥80% than those aged 55-64 years and Europeans. One-third of patients were not adequately maintained on statins over the 3-year period following ACS, but 82% of those on a statin prior to admission had an MPR ≥80% over 3 years of follow-up. These findings define achievable treatment levels and identify groups who may benefit from efforts to improve statin use.


Mitral Valve Imaging with CT: Relationship with Transcatheter Mitral Valve Interventions.
The role of noninvasive imaging to help guide transcatheter aortic valvular interventions is well established and has grown with the advances in the procedure. With the rapid development of new transcatheter mitral valve interventions there is both an opportunity and a challenge for noninvasive imaging to grow understanding of mitral valve anatomy and disease, help with patient selection, and improve downstream clinical outcomes. This review will discuss the role of both echocardiography and multidetector CT in the diagnosis of mitral regurgitation, as well as grading of its severity and defining its etiology. Additionally, new concepts including measurements pertaining to mitral annular sizing, segmentation of mitral annular calcium, prediction of neo-left ventricular out flow tract obstruction, hybrid or fusion multidetector CT/echocardiographic imaging, and CT-based fluoroscopic guidance will be discussed.


Increased Na+/Li+ countertransport activity may help to identify type 1 diabetic adolescents and young adults at risk for developing persistent microalbuminuria.
To evaluate whether erythrocyte sodium-lithium countertransport (Na+/Li+ CT) activity may identify adolescents and young adults with childhood-onset of type 1 diabetes to be at greater risk to develop persistent microalbuminuria and incipient diabetic nephropathy. In January 1989, Na+/Li+ CT was measured in 170 normoalbuminuric diabetic adolescents and young adults (age 12-23 years; onset of diabetes before age 18 years; duration of diabetes longer than 7 years). Participants were clinically examined at baseline and biennially thereafter. Na+/Li+ CT activity was measured every 2 years during the 8-year follow-up period. Na+/Li+ CT activity was measured also in parents of diabetic offspring. Over 8 years, 18 (10 male, 8 female) out of 170 patients (10.5%) developed persistent microalbuminuria; no patient developed overt nephropathy. The risk of developing microalbuminuria was higher in children with increased Na+/Li+ CT (using 300 mumol.1 erythrocytes-1.h-1 as the arbitrary cutoff point) (group 1) compared with those with normal Na+/Li+ CT at the beginning of the study (group 2) (18.98 vs. 3.29%, P < 0.01; sensitivity 96.7%; specificity 57.9%). Sex did not influence predictive value, sensitivity, or specificity. Na+/Li+ CT was not significantly correlated with HbA1c or duration of type 1 diabetes. The percentage of offspring with both parents having Na+/Li+ CT activity above the median values was significantly higher in patients in group 1 than in group 2. The odds ratio for the occurrence of microalbuminuria after adjustment for confounding variables (albumin excretion rate [AER], sex, HbA1c, mean blood pressure, cholesterol, triglycerides) in type 1 diabetic adolescents with elevated baseline erythrocyte Na+/Li+ CT was 4.5 (95% CI of 2.1-11.4). These results confirm those of previous studies and suggest that Na+/Li+ CT may be one of the predictors and risk factors for incipient diabetic nephropathy in adolescents and young adults with onset of diabetes during childhood. Persistently increased Na+/Li+ CT activity may help to identify normotensive, normoalbuminuric patients with type 1 diabetes who are predisposed to develop microalbuminuria and incipient diabetic nephropathy.


Resting state functional connectivity and task-related effective connectivity changes after upper extremity rehabilitation: a pilot study.
In this study we investigated the effect of 2 weeks of robot-aided virtual reality therapy for the paretic upper limb in stroke patients on changes in brain activation. Brain activation was acquired during the resting state and during visually-guided hand movement. fMRI analysis focused on characterizing functional connectivity with ipsilesional primary motor cortex (iM1) at rest and during execution of paretic hand movement. Two subjects who sustained a stroke more than 6 months ago participated. Before and after the training period, motor function was evaluated (Wolf Motor Function Test [WMFT], Jebsen Test of Hand Function [JTHF]). After the training period, clinical outcomes (WMFT and JTHF) improved in both subjects. The resting state functional connectivity (rsFC) maps and task-related functional connectivity with iM1 showed different magnitudes of activation, however, the general directionality of the pattern (increases versus decreases) was similar. Specifically, both the rsFC and the task-related functional connectivity between iM1 and contralesional primary motor cortex (cM1) decreased after the therapy for the first subject and increased for the second subject. Our preliminary data suggest that resting state functional connectivity may be a useful measure of brain reorganization, particularly for subjects with limited volitional control of the paretic limb.


The temporal and spatial origins of cortical interneurons predict their physiological subtype.
Interneurons of the cerebral cortex represent a heterogeneous population of cells with important roles in network function. At present, little is known about how these neurons are specified in the developing telencephalon. To explore whether this diversity is established in the early progenitor populations, we conducted in utero fate-mapping of the mouse medial and caudal ganglionic eminences (MGE and CGE, respectively), from which most cortical interneurons arise. Mature interneuron subtypes were assessed by electrophysiological and immunological analysis, as well as by morphological reconstruction. At E13.5, the MGE gives rise to fast-spiking (FS) interneurons, whereas the CGE generates predominantly regular-spiking interneurons (RSNP). Later at E15.5, the CGE produces RSNP classes distinct from those generated from the E13.5 CGE. Thus, we provide evidence that the spatial and temporal origin of interneuron precursors in the developing telencephalic eminences predicts the intrinsic physiological properties of mature interneurons.


A step towards the automation of intracytoplasmic sperm injection: real time confirmation of mouse and human oocyte penetration and viability by electrical resistance measurement.
To evaluate if oocyte penetration and viability can be confirmed by an electrical resistance increase. Automated (robotic) intracytoplasmic sperm injection (ICSI) requires confirmation of oolemma penetration before sperm injection. Visual assessment using image processing algorithms have been developed but remain unreliable. We hypothesized that an increase in electrical resistance upon oolemma piercing during ICSI can serve as an objective tool to confirm oocyte penetration and viability. Experimental study. Research laboratory in an academic center. Oocytes from female mice and women undergoing oocyte retrieval procedure. Oolemma piercing attempts with the ICSI pipette were performed by advancing the pipette towards mature (metaphase II) oocytes collected from 6 to 12-week-old mice and immature (germinal vesicle stage and metaphase I) oocytes donated by women who underwent oocyte retrieval. Electrical resistance was measured using a conventional electrophysiological setup that includes an electrical resistance meter and two electrical wires located in the lumina of the holding and ICSI pipettes. The measure of interest was the change in electrical resistance (ΔR) before and after advancing the ICSI pipette in an attempt to penetrate an oocyte. The experiments of resistance measurements were done in 3 steps: Step 1 (proof of concept), penetrated vs. non-penetrated mouse oocytes. Step 2, mouse oocytes with visually intact oolemma vs. fragmented mouse oocytes. Step 3, human oocytes with visually intact oolemma vs. fragmented human oocytes. For each group, median and range (in parenthesis) of ΔR were determined in MΩ. Mann-Whitney test was performed to compare the two groups in each step. In Step 1, the penetrated mouse oocytes showed a statistically significant resistance increase compared to the non-penetrated ones (n = 20, median ΔR = 7.79 [2.57 - 106.00] vs. n = 15, median ΔR = 0.10 [-0.06 - 0.69], respectively. In Step 2, the mouse oocytes with visually intact oolemma showed a statistically significant resistance increase compared to the fragmented ones (n = 45, median ΔR = 6.5 [0.1 - 191.7] vs. n = 13, median ΔR = 0.1 [-0.3 - 2.2], respectively. In Step 3, the human oocytes with visually intact oolemma showed a statistically significant resistance increase compared to the fragmented ones (n = 96, median ΔR = 1.92 [-0.05 - 6.70] vs. n = 17, median ΔR = 0.11 [0.00 - 0.30], respectively. An electrical resistance increase can serve as a reliable tool to confirm oocyte penetration and viability, independent of optical visualization. Following further validation and safety assessment, this technology can potentially be integrated into manual and robotic ICSI systems.


Racial disparities among patients with lung cancer who were recommended operative therapy.
Health care system and provider biases and differences in patient characteristics are thought to be prevailing factors underlying racial disparities. The influence of these factors on the receipt of care would likely be mitigated among patients who are recommended optimal therapy. We hypothesized that there would be no significant evidence of racial disparities among patients with early-stage lung cancer who are recommended surgical therapy. Retrospective cohort study of patients in the Surveillance, Epidemiology, and End Results-Medicare database who were diagnosed with stage I or II lung cancer between January 1, 1992, and December 31, 2002 (follow-up through December 31, 2005). Receipt of lung resection and overall survival. Among 17,739 patients who were recommended surgical therapy (mean [SD] age, 75 [5] years; 89% white, 6% black), black patients less frequently underwent resection compared with white patients (69% vs 83%, respectively; P < .001). After adjustment, black race was associated with lower odds of receiving surgical therapy (odds ratio = 0.43; 99% confidence interval, 0.36-0.52). Unadjusted 5-year survival rates were lower for black patients compared with white patients (36% vs 42%, respectively; P < .001). After adjustment, there was no significant association between race and death (hazard ratio = 1.03; 99% confidence interval, 0.92-1.14) despite a 14% difference in receipt of optimal therapy. Even among patients who were recommended surgical therapy, black patients underwent lung resection less often than white patients. Unexpectedly, racial differences in the receipt of optimal therapy did not appear to affect outcomes. These findings suggest that distrust, beliefs and perceptions about lung cancer and its treatment, and limited access to care (despite insurance) might have a more dominant role in perpetuating racial disparities than previously recognized.


Dual-stage growth factor release within 3D protein-engineered hydrogel niches promotes adipogenesis.
Engineered biomimetic microenvironments from hydrogels are an emerging strategy to achieve lineage-specific differentiation in vitro. In addition to recapitulating critical matrix cues found in the native three-dimensional (3D) niche, the hydrogel can also be designed to deliver soluble factors that are present within the native inductive microenvironment. We demonstrate a versatile materials approach for the dual-stage delivery of multiple soluble factors within a 3D hydrogel to induce adipogenesis. We use a Mixing-Induced Two-Component Hydrogel (MITCH) embedded with alginate microgels to deliver two pro-adipogenic soluble factors, fibroblast growth factor 1 (FGF-1) and bone morphogenetic protein 4 (BMP-4) with two distinct delivery profiles. We show that dual-stage delivery of FGF-1 and BMP-4 to human adipose-derived stromal cells (hADSCs) significantly increases lipid accumulation compared with the simultaneous delivery of both growth factors together. Furthermore, dual-stage growth factor delivery within a 3D hydrogel resulted in substantially more lipid accumulation compared to identical delivery profiles in 2D cultures. Gene expression analysis shows upregulation of key adipogenic markers indicative of brown-like adipocytes. These data suggest that dual-stage release of FGF-1 and BMP-4 within 3D microenvironments can promote the in vitro development of mature adipocytes.


Artificial light at night increases growth and reproductive output in Anolis lizards.
Since the invention of electric lighting, artificial light at night (ALAN) has become a defining, and evolutionary novel, feature of human-altered environments especially in cities. ALAN imposes negative impacts on many organisms, including disrupting endocrine function, metabolism, and reproduction. However, we do not know how generalized these impacts are across taxa that exploit urban environments. We exposed brown anole lizards, an abundant and invasive urban exploiter, to relevant levels of ALAN in the laboratory and assessed effects on growth and reproduction at the start of the breeding season. Male and female anoles exposed to ALAN increased growth and did not suffer increased levels of corticosterone. ALAN exposure induced earlier egg-laying, likely by mimicking a longer photoperiod, and increased reproductive output without reducing offspring quality. These increases in growth and reproduction should increase fitness. Anoles, and potentially other taxa, may be resistant to some negative effects of ALAN and able to take advantage of the novel niche space ALAN creates. ALAN and both its negative and positive impacts may play a crucial role in determining which species invade and exploit urban environments.


Impact of bicarbonate, ammonium chloride, and acetazolamide on hepatic and renal SLC26A4 expression.
SLC26A4 encodes pendrin, a transporter exchanging anions such as chloride, bicarbonate, and iodide. Loss of function mutations of SLC26A4 cause Pendred syndrome characterized by hearing loss and enlarged vestibular aqueducts as well as variable hypothyroidism and goiter. In the kidney, pendrin is expressed in the distal nephron and accomplishes HCO(3)(-) secretion and Cl(-) reabsorption. Renal pendrin expression is regulated by acid-base balance. The liver contributes to acid-base regulation by producing or consuming glutamine, which is utilized by the kidney for generation and excretion of NH(4)(+), paralleled by HCO(3)(-) formation. Little is known about the regulation of pendrin in liver. The present study thus examined the expression of Slc26a4 in liver and kidney of mice drinking tap water without or with NaHCO(3) (150 mM), NH(4)Cl (280 mM) or acetazolamide (3.6 mM) for seven days. As compared to Gapdh transcript levels, Slc26a4 transcript levels were moderately lower in liver than in renal tissue. Slc26a4 transcript levels were not significantly affected by NaHCO(3) in liver, but significantly increased by NaHCO(3) in kidney. Pendrin protein expression was significantly enhanced in kidney and reduced in liver by NaHCO(3). Slc26a4 transcript levels were significantly increased by NH(4)Cl and acetazolamide in liver, and significantly decreased by NH(4)Cl and by acetazolamide in kidney. NH(4)Cl and acetazolamide reduced pendrin protein expression significantly in kidney, but did not significantly modify pendrin protein expression in liver. The observations point to expression of pendrin in the liver and to opposite effects of acidosis on pendrin transcription in liver and kidney.


Effectiveness of Market-Level Biosecurity at Reducing Exposure of Poultry and Humans to Avian Influenza: A Systematic Review and Meta-Analysis.
In this study, we aimed to identify the effect of market-level risk factors on avian influenza (AI) infection in poultry and humans and generate evidence that will inform AI prevention and control programs at live bird markets (LBMs). We performed a systematic literature review in both English and Chinese search engines. We estimated the pooled odds ratios of biosecurity indicators relating to AI infections at market level using a quality effects (QE) meta-analysis model. Biosecurity measures effective at reducing AI market contamination and poultry infection at LBMs include smaller market size, selling single poultry species and separating different species, performing cleaning and disinfection and market closures, ban on overnight storage, and sourcing poultry from local areas. Our meta-analysis indicates that higher risk of exposure to AI infection occurs in workers at retail LBMs, female workers, and those who contact ducks, conduct cleaning, slaughtering, defeathering, or evisceration. The most effective strategies to reduce AI market contamination identified in this study should target larger LBMs that are located at noncentral city areas and sell and slaughter multispecies of live poultry. Live bird market workers directly involved in cleaning and poultry processing tasks should participate in occupational health and safety programs.


In Vitro Antifungal Resistance of Candida auris Isolates from Bloodstream Infections, South Africa.
Candida auris is a multidrug-resistant fungal pathogen that is endemic in South African hospitals. We tested bloodstream C. auris isolates that were submitted to a reference laboratory for national laboratory-based surveillance for candidemia in 2016 and 2017. We confirmed the species identification by phenotypic/molecular methods. We tested susceptibility to amphotericin B, anidulafungin, caspofungin, micafungin, itraconazole, posaconazole, voriconazole, fluconazole, and flucytosine using broth microdilution and Etest methods. We interpreted MICs using tentative breakpoints. We sequenced the genomes of a subset of isolates and compared them to the C. auris B8441 reference strain. Of 400 C. auris isolates, 361 (90%) were resistant to at least one antifungal agent, 339 (94%) to fluconazole alone (MICs of ≥32 µg/ml), 19 (6%) to fluconazole and amphotericin B (MICs of ≥2 µg/ml), and 1 (0.3%) to amphotericin B alone. Two (0.5%) isolates from a single patient were pan-resistant (resistant to fluconazole, amphotericin B, and echinocandins). Of 92 isolates selected for whole-genome sequencing, 77 clustered in clade III, including the pan-resistant isolates, 13 in clade I, and 2 in clade IV. Eighty-four of the isolates (91%) were resistant to at least one antifungal agent; both resistant and susceptible isolates had mutations. The common substitutions identified across the different clades were VF125AL, Y132F, K177R, N335S, and E343D in ERG11; N647T in MRR1; A651P, A657V, and S195G in TAC1b; S639P in FKS1HP1; and S58T in ERG3. Most South African C. auris isolates were resistant to azoles, although resistance to polyenes and echinocandins was less common. We observed mutations in resistance genes even in phenotypically susceptible isolates.


Propionate analogues of zearalenone bind to Hsp90.
By replacement of an acetate with propionate through organic synthesis a range of zearalenone analogues were prepared. As key steps in the synthesis of the analogues we used the Noyori hydrogenation of methyl acetoacetate followed by Frater alkylation of the enantiomeric 3-hydroxybutyrates. This converted the second acetate to a propionate. Through the derived alkyne, chain extension led to 3-methylundec-10-en-2-ol derivatives. These were condensed with 2,4-dimethoxy-6-vinylbenzoic acid. Ring-closing metathesis of the obtained esters led to macrolactones, which were deproteced to give the zearalenone analogues. Several of the analogues showed cytotoxicity against the L929 mouse fibroblast cell line comparable to zearalenone (9 microM) itself. In the thermal-shift assay, two analogues 35 and ent-35 displayed stronger binding than the natural product geldanamycin to the chaperone Hsp90.


Long-term effects of lysine concentration on growth performance, intestinal microbiome, and metabolic profiles in a pig model.
Lysine is a common limiting amino acid in human and animal diets and plays an important role in cell proliferation and metabolism. Our previous study suggested that short-term lysine restriction improved feed intake. Herein, we further investigated the long-term effects of lysine restriction on intestinal microbial communities and metabolic profiles in pigs by 16S rDNA sequencing and metabolomic analysis. The results showed that 30% lysine limitation increased the feed intake in piglets but not in growing and finishing pigs. Microbiota sequencing was conducted, and we identified 12 differentiated microbes at the genus level in response to dietary lysine restriction. Metagenomic predictions by PICRUSt suggested that the altered microbiota was mainly involved in the host metabolism, especially in amino acid metabolism. Intestinal metabolomic study identified 20 differentiated metabolites in finishing pigs, which were mapped into 5 metabolic pathways including glutamine and glutamate metabolism, taurine metabolism, alanine, aspartate and glutamate metabolism, vitamin B6 metabolism, and pentose and glucoronate metabolism. Determination of serum amino acids and intestinal amino acid transporters further validated the results obtained from PICRUSt and metabolomic analyses, which showed that long-term lysine restriction influenced amino acid metabolism. Phosphorylation of mTOR in the intestine was not altered in lysine-restricted pigs, whereas lysine limitation markedly inhibited the AMPK signaling. In conclusion, long-term lysine restriction from piglets to finishing pigs affected the amino acid metabolism, which might be associated with gut microbiota and AMPK signaling.


'I just thought it was normal aches and pains': a qualitative study of decision-making processes in patients with early rheumatoid arthritis.
Effective treatment can only be given during the early stages of RA if patients are seen early. However, many patients delay for prolonged periods before seeking medical advice. This study explores factors influencing the decision to seek medical advice in RA patients. In-depth, semi-structured interviews were carried out with 24 patients. Purposive sampling ensured a cross-section in terms of time to presentation, gender, age and ethnic background. Interview transcripts were analysed and themes identified using established methods. Four main themes influenced the decision to seek medical advice: (i) symptom experience: the severity of symptoms and their impact on functional ability; (ii) symptom evaluation: the patient's explanation for their symptoms and recognition of their significance; (iii) knowledge of RA and available therapies; and (iv) experience of and attitudes towards health care providers. A significant and rapid impact of the disease on functional ability characterized those presenting early. Many developed an explanation for their symptoms that related to preceding activities. Recognition that this explanation was inadequate to explain symptom progression frequently prompted a consultation. Only one patient sought advice because she thought that she might have RA. Symptom evaluation is a key factor influencing how quickly medical advice is sought in other diseases. In contrast to the situation with many cancers where there is widespread association of symptoms and signs with the eventual diagnosis, this was not the case in RA. Our findings should inform strategies to reduce delays in help-seeking in people with early RA.


The DoTS classification is a useful way to classify adverse drug reactions: a preliminary study in hospitalized patients.
The aim was to determine the prevalence of adverse drug reactions (ADRs) in hospitalized patients in a university hospital. ADRs were identified by two evaluators, who reviewed the clinical histories of all patients admitted between 24 April and 24 May 2006. Patients with suspected ADRs were contacted. Three different investigators evaluated causality, the degree of preventability, and the mechanism producing the ADR. Causality was assessed using the scale proposed by the World Health Organization (WHO), and preventability was assessed using the modified Schumock and Thornton criteria. There were 32 ADRs in 104 hospitalized patients. Effects on the autonomic nervous system were the most common (13%) and the drugs most frequently implicated were systemic antimicrobial drugs (19%). Fifty-four per cent of the ADRs were classified as possible. Using the Dose, Time and Susceptibility (DoTS) classification, 77% of the ADRs were classified as being of collateral dose-responsiveness (i.e. they occurred within the range of therapeutic doses), and 65% were classified as intermediate reactions. The susceptibility factors associated most frequently with ADRs were comorbidities (i.e. the presence of diseases that were considered as risk factors to developing an ADR; 36%), age (26%) and exogenous factors (i.e. the presence of drug interactions that were involved in the occurrence of ADRs; 17%). Fifty per cent of the ADRs could have been prevented. ADRs are very frequent in hospitalized patients and a significant proportion of them is preventable. The DoTS classification allowed complete evaluation of the types of ADR encountered. We are currently carrying out a much larger prospective study.


Hong Kong Urological Association-Hong Kong Society of Uro-Oncology consensus statements on the management of advanced prostate cancer-2019 Updates.
To update the Hong Kong Urological Association-Hong Kong Society of Uro-Oncology consensus statements on the management of advanced prostate cancer, the same panelists as in the previous consensus panel held a series of meetings to discuss updated clinical evidence and experiences. The previous consensus statements were retained, deleted, or revised, and new statements were added. At the final meeting, all statements were reviewed and amended as appropriate, followed by panel voting. There were significant changes and additions to the previous consensus statements, primarily driven by the advances in androgen receptor signaling inhibitors, treatment sequencing in metastatic castration-resistant prostate cancer, and increasing recognition of oligometastatic prostate cancer since the introduction of prostate-specific membrane antigen positron emission tomography. In this update, a total of 59 consensus statements were accepted and established. The consensus panel updated consensus statements on the management of advanced prostate cancer, aiming to allow physicians in the region to keep abreast of the recent evidence on optimal clinical practices.


Identification of muscarinic receptor subtypes in RINm5F cells by means of polymerase chain reaction, subcloning, and DNA sequencing.
Carbachol can stimulate insulin release in RINm5F cells by a mechanism that does not involve the elevation of cytosolic free Ca2+ concentrations or the activation of conventional protein kinase Cs (Mol Pharmacol 47:863-870, 1995). Thus, a novel signal transduction pathway links the muscarinic activation of the cells to increased insulin secretion. The question arises as to whether the pathway results from a novel receptor, different from the five established muscarinic receptors, or whether a "normal" receptor in the RINm5F cell activates a novel pathway. To distinguish between these two possibilities, the muscarinic receptors in the RINm5F cell were identified. Using polymerase chain reaction, combined with subcloning and DNA sequencing techniques, the cDNAs that encode the established M3 and M4 receptors were identified. The cDNAs for the Ml, M2, and M5 receptors were not found. Pharmacological studies showed a rank order of potency for muscarinic receptor subtype antagonists to inhibit carbachol-induced insulin release (half-maximal inhibitory concentration [pIC50] values given in parentheses): atropine (nonselective, 9.0) > 4-diphenyl-acetoxy-N-methyl piperidine methiodide (M3/M1, 8.6) > para-fluoro-hexahydrosiladiphenidol (M3, 8.1) > hexahydrosiladiphenidol (M3, 8.0) > tropicamide (M4, 6.4) > pirenzepine (M1, 6.1) > methoctramine (M2, 5.9). This antagonist profile suggests that it is the M3 receptor that mediates carbachol-induced insulin release. In this case, the novel signaling involved in the unusual carbachol response would not be due to a novel receptor but to the well-characterized M3 receptor. It appears, therefore, that the novel portion of the signaling pathway lies downstream of the M3 receptor and may consist of products of phosphatidylinositol hydrolysis, other than inositol triphosphate and diacylglycerol, resulting from the activation of phospholipase C. While a contributory role of the M4 receptor cannot be ruled out, there is no evidence in its favor other than its presence in the cell.


Dormancy-defense syndromes and tradeoffs between physical and chemical defenses in seeds of pioneer species.
Seeds of tropical pioneer trees have chemical and physical characteristics that determine their capacity to persist in the soil seed bank. These traits allow seeds to survive in the soil despite diverse predators and pathogens, and to germinate and recruit even decades after dispersal. Defenses in seedlings and adult plants often are described in terms of tradeoffs between chemical and physical defense, but the interplay of defensive strategies has been evaluated only rarely for seeds. Here we evaluated whether classes of seed defenses were negatively correlated across species (consistent with tradeoffs in defense strategies), or whether groups of traits formed associations across species (consistent with seed defense syndromes). Using 16 of the most common pioneer tree species in a neotropical lowland forest in Panama we investigated relationships among four physical traits (seed fracture resistance, seed coat thickness, seed permeability, and seed mass) and two chemical traits (number of phenolic compounds and phenolic peak area), and their association with seed persistence. In addition, seed toxicity was assessed with bioassays in which we evaluated the activity of seed extracts against representative fungal pathogens and a model invertebrate. We did not find univariate tradeoffs between chemical and physical defenses. Instead, we found that seed permeability - a trait that distinguishes physical dormancy from other dormancy types - was positively associated with chemical defense traits and negatively associated with physical defense traits. Using a linear discriminant analysis and a hierarchical cluster analysis we found evidence to distinguish three distinct seed defense syndromes that correspond directly with seed dormancy classes (i.e., quiescent, physical, and physiological). Our data suggest that short and long-term persistence of seeds can be achieved via two strategies: having permeable seeds that are well defended chemically, corresponding to the physiologically dormant defense syndrome; or having impermeable seeds that are well defended physically, corresponding to the physically dormant defense syndrome. In turn, transient seeds appear to have a lower degree of chemical and physical defenses, corresponding to the quiescent defense syndrome. Overall, we find that seed defense and seed dormancy are linked, suggesting that environmental pressures on seed persistence and for delayed germination can select for trait combinations defining distinct dormancy-defense syndromes.


Social determinants of mammography screening among women aged 50 to 59, Peru 2015.
Breast cancer (BC) screening could reduce its mortality; however, its access is influenced by societal forces. Our objective is to identify the social determinants associated with mammography screening (MS) in women aged 50 to 59 in Peru. In this cross-sectional analysis of the Peruvian Demographic Health Survey, 2015, MS within the past two years was evaluated through self-report. Prevalence for MS was 21.9% [95% CI: 18.9 to 25.1]. The average age was 54 years (s.d.: 2.5). The higher the socioeconomic status, the higher the prevalence of screening (3.2% vs 41.4% in extreme quintiles, p < .001). In the adjusted models, higher socioeconomic status (PR: 5.81, 95% CI: 2.28 to 14.79), higher education level (PR: 2.03, 95% CI: 1.30 a 3,15) and having health insurance from the Ministry of Health (PR: 2.21, 95% CI: 1.28 to 3.82) and EsSalud (PR: 4.37, 95% CI: 2.67 to 7.15), were positively associated with MS. Social inequalities in screening access exist and might translate into inequalities in cancer morbidity and mortality. The Peruvian government urgently needs to improve screening rates in these vulnerable populations.


Differential earth mover's distance with its applications to visual tracking.
The Earth Mover's Distance (EMD) is a similarity measure that captures perceptual difference between two distributions. Its computational complexity, however, prevents a direct use in many applications. This paper proposes a novel Differential EMD (DEMD) algorithm based on the sensitivity analysis of the simplex method and offers a speedup at orders of magnitude compared with its brute-force counterparts. The DEMD algorithm is discussed and empirically verified in the visual tracking context. The deformations of the distributions for objects at different time instances are accommodated well by the EMD, and the differential algorithm makes the use of EMD in real-time tracking possible. To further reduce the computation, signatures, i.e., variable-size descriptions of distributions, are employed as an object representation. The new algorithm models and estimates local background scenes as well as foreground objects to handle scale changes in a principled way. Extensive quantitative evaluation of the proposed algorithm has been carried out using benchmark sequences and the improvement over the standard Mean Shift tracker is demonstrated.


Targeted oligonucleotide-mediated microsatellite identification (TOMMI) from large-insert library clones.
In the last few years, microsatellites have become the most popular molecular marker system and have intensively been applied in genome mapping, biodiversity and phylogeny studies of livestock. Compared to single nucleotide polymorphism (SNP) as another popular marker system, microsatellites reveal obvious advantages. They are multi-allelic, possibly more polymorphic and cheaper to genotype. Calculations showed that a multi-allelic marker system always has more power to detect Linkage Disequilibrium (LD) than does a di-allelic marker system. Traditional isolation methods using partial genomic libraries are time-consuming and cost-intensive. In order to directly generate microsatellites from large-insert libraries a sequencing approach with repeat-containing oligonucleotides is introduced. Seventeen porcine microsatellite markers were isolated from eleven PAC clones by targeted oligonucleotide-mediated microsatellite identification (TOMMI), an improved efficient and rapid flanking sequence-based approach for the isolation of STS-markers. With the application of TOMMI, an average of 1.55 (CA/GT) microsatellites per PAC clone was identified. The number of alleles, allele size distribution, polymorphism information content (PIC), average heterozygosity (HT), and effective allele number (NE) for the STS-markers were calculated using a sampling of 336 unrelated animals representing fifteen pig breeds (nine European and six Chinese breeds). Sixteen of the microsatellite markers proved to be polymorphic (2 to 22 alleles) in this heterogeneous sampling. Most of the publicly available (porcine) microsatellite amplicons range from approximately 80 bp to 200 bp. Here, we attempted to utilize as much sequence information as possible to develop STS-markers with larger amplicons. Indeed, fourteen of the seventeen STS-marker amplicons have minimal allele sizes of at least 200 bp. Thus, most of the generated STS-markers can easily be integrated into multilocus assays covering a broader separation spectrum. Linkage mapping results of the markers indicate their potential immediate use in QTL studies to further dissect trait associated chromosomal regions. The sequencing strategy described in this study provides a targeted, inexpensive and fast method to develop microsatellites from large-insert libraries. It is well suited to generate polymorphic markers for selected chromosomal regions, contigs of overlapping clones and yields sufficient high quality sequence data to develop amplicons greater than 250 bases.


Whole-Body Vibration Partially Reverses Aging-Induced Increases in Visceral Adiposity and Hepatic Lipid Storage in Mice.
At old age, humans generally have declining muscle mass and increased fat deposition, which can increase the risk of developing cardiometabolic diseases. While regular physical activity postpones these age-related derangements, this is not always possible in the elderly because of disabilities or risk of injury. Whole-body vibration (WBV) training may be considered as an alternative to physical activity particularly in the frail population. To explore this possibility, we characterized whole-body and organ-specific metabolic processes in 6-month and 25-month old mice, over a period of 14 weeks of WBV versus sham training. WBV training tended to increase blood glucose turnover rates and stimulated hepatic glycogen utilization during fasting irrespective of age. WBV was effective in reducing white fat mass and hepatic triglyceride content only in old but not in young mice and these reductions were related to upregulation of hepatic mitochondrial uncoupling of metabolism (assessed by high-resolution respirometry) and increased expression of uncoupling protein 2. Because these changes occurred independent of changes in food intake and whole-body metabolic rate (assessed by indirect calorimetry), the liver-specific effects of WBV may be a primary mechanism to improve metabolic health during aging, rather than that it is a consequence of alterations in energy balance.


Purely in silico BCS classification: science based quality standards for the world's drugs.
BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list included significantly less class 1 and more class 3 drugs in comparison to the countries' lists, probably due to differences in commonly used drugs in developing vs industrial countries. BDDCS classified more drugs as class 1 compared to in silico BCS, likely due to the more lax benchmark for metabolism (70%), in comparison to the strict permeability benchmark (metoprolol). For 185 out of the 363 drugs, in silico solubility values were calculated, and successfully matched the literature solubility data. In conclusion, relatively simple in silico methods can be used to estimate both permeability and solubility. While CLogP produced the best correlation to experimental values, even KLogP, the most simplified in silico method that is based on molecular formula with no knowledge of molecular structure, produced comparable BCS classification to the sophisticated methods. This KLogP, when combined with a mean melting point and estimated dose, can be used to provisionally classify potential drugs from just molecular formula, even before synthesis. 49-59% of the world's top-selling drugs are highly soluble (class 1 and class 3), and are therefore candidates for waivers of in vivo bioequivalence studies. For these drugs, the replacement of expensive human studies with affordable in vitro dissolution tests would ensure their bioequivalence, and encourage the development and availability of generic drug products in both industrial and developing countries.


The effect of even, positive and negative pacing on metabolic, kinematic and temporal variables during breaststroke swimming.
The aim of this investigation was to determine the effect of even, negative and positive pacing on metabolic, kinematic and temporal variables during breaststroke swimming. Nine male swimmers [mean (SD): age 21 (3) years, height 178 (5) cm, body mass 77.2 (6.7) kg, 200 m-time 158.6 (13.6) s] completed a 200-m breaststroke time trial and then 72 h later three paced (even, positive, negative) 175-m breaststroke swims in random order, 48 h apart. The swimmers paced accurately in all trials. The evenly paced trial produced lower post-exercise peak blood lactate and rating of perceived exertion values compared to the positively paced trial ( P<0.05). Peak oxygen uptake was not significantly different between trials ( P>0.05). Heart rate immediately following exercise was lower in the negatively paced trial ( P<0.05) than the other paced trials. Stroke rates were lower during the first half of the evenly and negatively paced trials compared to the positively paced trial ( P<0.01), but no differences were observed between the second half of the trials. Across all trials the stroke count increased as the trials progressed ( P<0.01). Turning times were observed to be shorter during the first half of the positively paced trial compared to the other paced trials ( P<0.01). Even paced swimming appears to be less physically stressful than positively paced swimming during high intensity exercise, as indicated by a lower post-exercise blood lactate concentration, perceived exertion and variability within turning times.


Estimating network parameters from combined dynamics of firing rate and irregularity of single neurons.
High firing irregularity is a hallmark of cortical neurons in vivo, and modeling studies suggest a balance of excitation and inhibition is necessary to explain this high irregularity. Such a balance must be generated, at least partly, from local interconnected networks of excitatory and inhibitory neurons, but the details of the local network structure are largely unknown. The dynamics of the neural activity depends on the local network structure; this in turn suggests the possibility of estimating network structure from the dynamics of the firing statistics. Here we report a new method to estimate properties of the local cortical network from the instantaneous firing rate and irregularity (CV(2)) under the assumption that recorded neurons are a part of a randomly connected sparse network. The firing irregularity, measured in monkey motor cortex, exhibits two features; many neurons show relatively stable firing irregularity in time and across different task conditions; the time-averaged CV(2) is widely distributed from quasi-regular to irregular (CV(2) = 0.3-1.0). For each recorded neuron, we estimate the three parameters of a local network [balance of local excitation-inhibition, number of recurrent connections per neuron, and excitatory postsynaptic potential (EPSP) size] that best describe the dynamics of the measured firing rates and irregularities. Our analysis shows that optimal parameter sets form a two-dimensional manifold in the three-dimensional parameter space that is confined for most of the neurons to the inhibition-dominated region. High irregularity neurons tend to be more strongly connected to the local network, either in terms of larger EPSP and inhibitory PSP size or larger number of recurrent connections, compared with the low irregularity neurons, for a given excitatory/inhibitory balance. Incorporating either synaptic short-term depression or conductance-based synapses leads many low CV(2) neurons to move to the excitation-dominated region as well as to an increase of EPSP size.


The glycine-rich motif of Pyrococcus abyssi DNA polymerase D is critical for protein stability.
A glycine-rich motif described as being involved in human polymerase delta proliferating cell nuclear antigen (PCNA) binding has also been identified in all euryarchaeal DNA polymerase D (Pol D) family members. We redefined the motif as the (G)-PYF box. In the present study, Pol D (G)-PYF box motif mutants from Pyrococcus abyssi were generated to investigate its role in functional interactions with the cognate PCNA. We demonstrated that this motif is not essential for interactions between PabPol D (P. abyssi Pol D) and PCNA, using surface plasmon resonance and primer extension studies. Interestingly, the (G)-PYF box is located in a hydrophobic region close to the active site. The (G)-PYF box mutants exhibited altered DNA binding properties. In addition, the thermal stability of all mutants was reduced compared to that of wild type, and this effect could be attributed to increased exposure of the hydrophobic region. These studies suggest that the (G)-PYF box motif mediates intersubunit interactions and that it may be crucial for the thermostability of PabPol D.


Nitric oxide modulates the expression of cell cycle regulatory genes during lateral root formation in tomato.
Nitric oxide (NO) is a bioactive molecule involved in diverse physiological functions in plants. It has previously been reported that the NO donor sodium nitroprusside (SNP) applied to germinated tomato seeds was able to induce lateral root (LR) formation in the same way that auxin treatment does. In this paper, it is shown that NO modulates the expression of cell cycle regulatory genes in tomato pericycle cells and leads, in turn, to induced LR formation. The addition of the NO scavenger CPTIO at different time points during auxin-mediated LR development indicates that NO is required for LR primordia formation and not for LR emergence. The SNP-mediated LR promotion could be prevented by the cell cycle inhibitor olomoucine, suggesting that NO is involved in cell cycle regulation. A system was developed in which the formation of LRs was synchronized. It was based on the control of NO availability in roots by treatment with the NO scavenger CPTIO. The expression of the cell cycle regulatory genes encoding CYCA2;1, CYCA3;1, CYCD3;1, CDKA1, and the Kip-Related Protein KRP2 was studied using RT-PCR analysis in roots with synchronized and non-synchronized LR formation. NO mediates the induction of the CYCD3;1 gene and the repression of the CDK inhibitor KRP2 gene at the beginning of LR primordia formation. In addition, auxin-dependent cell cycle gene regulation was dependent on NO.


Intravital imaging of amyloid plaques in a transgenic mouse model using optical-resolution photoacoustic microscopy.
We report optical-resolution photoacoustic microscopy (OR-PAM) for in vivo imaging of amyloid plaques in an Alzheimer's disease mouse model. Validation using conventional fluorescence microscopy and multiphoton microscopy shows that OR-PAM has sufficient sensitivity and spatial resolution to identify amyloid plaques in living brains. In addition, with dual-wavelength OR-PAM, the three-dimensional morphology of amyloid plaques and the surrounding microvasculature are imaged simultaneously through a cranial window without angiographic contrast agents. OR-PAM, capable of providing both exogenous molecular contrast and endogenous hemoglobin contrast, has the potential to serve as a new technology for in vivo microscopic observations of cerebral plaque deposits.


Maximal-intensity intermittent exercise: effect of recovery duration.
Seven male subjects performed 15 x 40m sprints, on three occasions, with rest periods of either 120 s (R120), 60 s (R60) or 30 s (R30) between each sprint. Sprint times were recorded with four photo cells placed at 0, 15, 30 and 40 m. The performance data indicated that whereas running speed over the last 10 m of each sprint decreased in all three protocols (after 11 sprints in R120, 7 sprints in R60 and 3 sprints in R30), performance during the initial acceleration period from 0-15 m was only affected with the shortest rest periods increasing from (mean +/- SEM) 2.58 +/- .03 (sprint 1) to 2.78 +/- .04 s (spring 15) (p < .05). Post-exercise blood lactate concentration was not significantly different in R120 (12.1 +/- 1.3 mmol.l-1) and R60 (13.9 +/- 1.2 mmol.l-1), but a higher concentration was found in R30 (17.2 +/- .7 mmol.l-1) (p < .05). After 6 sprints there was no significant difference in blood lactate concentration with the different recovery durations, however, there were significant differences in sprint times at this point, suggesting that blood lactate is a poor predictor of performance during this type of exercise. Although the work bouts could be classified primarily as anaerobic exercise, oxygen uptake measured during rest periods increased to 52, 57 and 66% of maximum oxygen uptake in R120, R60 and R30, respectively. Evidence of adenine nucleotide degradation was provided by plasma hypoxanthine and uric acid concentrations elevated post-exercise in all three protocols. Post-exercise uric acid concentration was not significantly affected by recovery duration.(ABSTRACT TRUNCATED AT 250 WORDS)


Indications for brain computed tomography and hospital admission in pediatric patients with minor head injury: how much can we rely upon clinical findings?
The aim of this study was to describe the characteristics of patients with a minor head injury (MHI) who were admitted to a pediatric emergency unit and to identify the clinical signs and symptoms that most reliably predict the need for cranial computed tomography (CCT) and hospital admission following MHI. All patients were retrospectively evaluated according to age, gender, details of injury, presenting symptoms, physical examination findings, radiological investigations ordered and results, length of stay, outcome of the injury and hospitalization rates. The factors affecting indications for computed tomography and hospitalization were retrospectively analyzed in 916 patients--585 males and 331 females, aged between 1 month and 15 years (mean: 5.01 +/- 3.58 years), with MHI. A multivariate analysis revealed significant correlations between CCT abnormalities and Glasgow Coma Scale scores of 13 or 14, headache, posttraumatic amnesia, blurred vision, cephalohematomas, periorbital ecchymoses, otorrhea and abnormal neurological findings. CCT abnormalities were identified in 67 (19.8%) of the 338 CCT scans. Twenty of the 67 patients (29.9%) with CCT scan abnormality had no clinical signs. Of all cases, 125 (13.6%) were hospitalized, 617 (67.4%) were treated as outpatients, and 174 (19.0%) left the emergency department based on a personal decision. Some clinical risk factors can be used as predictors of abnormalities in CCT scans following MHI, but the absence of such clinical findings does not exclude the possibility of intracranial injuries.


Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination.
The increasing effectiveness of new disease-modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhancement of remyelination have emerged, few lend themselves readily to conventional drug development. Here, we used transcription profiling to identify mitogen-activated protein kinase (Mapk) signalling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signalling by elevation of intracellular levels of cyclic adenosine monophosphate (cAMP) using administration of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolysing enzyme phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin-induced demyelination and a consequent acceleration of remyelination. These data reveal a novel approach to therapeutic enhancement of remyelination amenable to pharmacological intervention and hence with significant potential for translation.


Evaluation of lead levels in children living near a Los Angeles county battery recycling facility.
This cross-sectional study examined the association between environmental lead measurements surrounding a Los Angeles County battery recycling facility and the blood lead levels of the children living nearby. Environmental lead measurements and blood lead levels of young children living in a community adjacent to a stationary lead source were compared to those living in a community without a stationary lead source. Predictors of blood lead level were identified. The blood lead levels of the children living near the secondary lead smelter were within the normal range (< 5 micrograms/dl). The absence of ground cover was associated with slightly increased blood lead levels; however, this increase was not of biological significance. Lead levels in surface soil near the stationary lead source were elevated compared to the control community; however, the soil affected community, which may be due in part to controls recently installed at the stationary lead source.


A focus on the use of subcutaneous C1-inhibitor for treatment of hereditary angioedema.
HAE is a very debilitating disease that causes significant distress for patients not only during an acute attack but also constant fear for a subsequent attack. It is important to address long-term prophylactic (LTP) therapy to prevent attacks, decrease morbidity and increase the quality of life. When discussing LTP, the drug burden, convenience and efficacy must be taken into account. We review the literature and the different phases of clinical trials leading up to approval by the US FDA of subcutaneous highly concentrated C1-Inhibitor (SC-C1-INH), called Haegarda. The dose approved is of 60 IU/kg twice weekly showing significant improvement in the reduction of attacks and need for on-demand therapy for attacks with minimal side effects. SC-C1-INH has added significantly to the armamentarium of physicians that treat HAE. The ability to achieve a steady state of C1-INH above 40% function is key to the success of the drug. The drug burden is an SC injection twice a week that exceeds the newly approved lanadelumab. The benefit may be that the protein that is deficient in HAE is replaced and with this the complement, fibrinolytic, coagulation pathways, and contact system are also regulated; however, evidence that this is of benefit is still lacking.


A cost-benefit analysis of a proposed overseas refugee latent tuberculosis infection screening and treatment program.
This study explored the effect of screening and treatment of refugees for latent tuberculosis infection (LTBI) before entrance to the United States as a strategy for reducing active tuberculosis (TB). The purpose of this study was to estimate the costs and benefits of LTBI screening and treatment in United States bound refugees prior to arrival. Costs were included for foreign and domestic LTBI screening and treatment and the domestic treatment of active TB. A decision tree with multiple Markov nodes was developed to determine the total costs and number of active TB cases that occurred in refugee populations that tested 55, 35, and 20 % tuberculin skin test positive under two models: no overseas LTBI screening and overseas LTBI screening and treatment. For this analysis, refugees that tested 55, 35, and 20 % tuberculin skin test positive were divided into high, moderate, and low LTBI prevalence categories to denote their prevalence of LTBI relative to other refugee populations. For a hypothetical 1-year cohort of 100,000 refugees arriving in the United States from regions with high, moderate, and low LTBI prevalence, implementation of overseas screening would be expected to prevent 440, 220, and 57 active TB cases in the United States during the first 20 years after arrival. The cost savings associated with treatment of these averted cases would offset the cost of LTBI screening and treatment for refugees from countries with high (net cost-saving: $4.9 million) and moderate (net cost-saving: $1.6 million) LTBI prevalence. For low LTBI prevalence populations, LTBI screening and treatment exceed expected future TB treatment cost savings (net cost of $780,000). Implementing LTBI screening and treatment for United States bound refugees from countries with high or moderate LTBI prevalence would potentially save millions of dollars and contribute to United States TB elimination goals. These estimates are conservative since secondary transmission from tuberculosis cases in the United States was not considered in the model.


Albuminuria and tolvaptan in autosomal-dominant polycystic kidney disease: results of the TEMPO 3:4 Trial.
The TEMPO 3:4 Trial results suggested that tolvaptan had no effect compared with placebo on albuminuria in autosomal-dominant polycystic kidney disease (ADPKD) patients. However, the use of categorical 'albuminuria events' may have resulted in a loss of sensitivity to detect changes. The aim of this study is to investigate the effects of tolvaptan on albuminuria as a continuous variable. Post hoc analysis of a 3-year prospective, blinded randomized controlled trial, including 1375 ADPKD patients. Albuminuria was measured in a spot morning urine sample prior to tolvaptan dosing and expressed as albumin-to-creatinine ratio (ACR). Baseline median (interquartile range) ACR was 3.2 (1.7-7.1) mg/mmol. Of note, 47.9% of ADPKD patients had normal, 48.7% moderately increased and 3.4% severely increased ACR. Subjects with higher baseline ACR had higher blood pressure and total kidney volume (TKV) and lower estimated glomerular filtration rate (eGFR). During follow-up, higher baseline ACR was associated with more rapid eGFR loss (P < 0.0001 for trend), but not with rate of growth in TKV. During the 3-year trial, ACR rose in placebo- and decreased in tolvaptan-treated patients (+0.23 versus -0.40 mg/mmol). The difference ACR increased over time, reaching a maximum of 24% at Month 36 (P < 0.001). At that time only a minor difference in blood pressure was observed (mean arterial pressure -1.9 mmHg for tolvaptan). The decrease in ACR was similar in all subgroups investigated, and remained after withdrawal of study drug. The beneficial effect of tolvaptan on TKV growth and eGFR loss was stronger in patients with higher baseline ACR. In ADPKD, higher baseline albuminuria was associated with more eGFR loss. Tolvaptan decreased albuminuria compared with placebo, independent of blood pressure. Treatment efficacy of tolvaptan on changes in TKV and eGFR was more readily detected in patients with higher albuminuria.


Effect of changes in local skin temperature on postural vasoconstriction in man.
1. The effects of locally induced alterations in skin temperature on the postural changes in skin blood flow of the foot were assessed in 38 healthy subjects in a constant-temperature environment (22 +/- 0.5 degrees C, mean +/- SD). 2. Moderate local cooling and warming of the foot (26-36 degrees C) was induced by blowing cold or hot air. Higher ranges of temperature (38-44 degrees C) were achieved by a thermostatically controlled disc heater. 3. Skin blood flow was measured before and during each change in local skin temperature using a laser Doppler flowmeter with the foot maintained at heart level, and placed passively 50 cm below the heart. Blood flow was measured in two skin areas: (i) the dorsum on the foot, where arteriovenous anastomoses are absent, and (ii) the pulp of the big toe, where these anastomoses are relatively numerous. 4. It was found that within the physiological temperature range of 26-36 degrees C the normal postural fall in foot skin blood flow was preserved, whereas it was markedly attenuated or totally abolished at higher temperatures (38-44 degrees C). The pattern of response was quite similar in areas having or lacking arteriovenous anastomoses. 5. It is suggested that the failure of postural vasoconstriction observed at the higher skin temperatures might contribute to some of the problems of cardiovascular adaptations seen in a hot environment.


Dynamically enhanced low-coherence interferometry.
In the investigations of inhomogeneous media, availability of methods to study the interior of the material without affecting it is valuable. Optical coherence tomography provides such a functionality by providing depth resolved images of semi-transparent objects non-invasively. This is especially useful in medicine and is used not only in research but also in clinical practice. Optical coherence tomography characterizes each cross section by its reflectance. The basic physics principle underlying optical coherence tomography is low-coherence interferometry, which is combined with lateral scanning to produce cross sections. It is clearly desirable to obtain more detailed information regarding each cross section, if available. We have developed a system which measures the fluctuation spectra at all depths in low-coherence interferometry. By providing more information for each cross section, this can in principle be effective in tissue characterization and pathological diagnosis. The system uses the time dependence of the low-coherence interferometry data to obtain the fluctuation spectrum at each depth. Additionally, noise reduction is applied to obtain the spectra without unwanted noise, such as shot-noise, which can swamp the signal. The measurement system is applied to samples with no external stimuli, and depth resolved thermal fluctuation spectra of the samples are obtained. These spectra are compared with their corresponding theoretical expectations and are found to agree. The measurement system requires dualizing the detectors in the low-coherence interferometer but otherwise requires little additional equipment. The measurements were performed in ten to a hundred seconds.


Growth factor stimulation improves the structure and properties of scaffold-free engineered auricular cartilage constructs.
The reconstruction of the external ear to correct congenital deformities or repair following trauma remains a significant challenge in reconstructive surgery. Previously, we have developed a novel approach to create scaffold-free, tissue engineering elastic cartilage constructs directly from a small population of donor cells. Although the developed constructs appeared to adopt the structural appearance of native auricular cartilage, the constructs displayed limited expression and poor localization of elastin. In the present study, the effect of growth factor supplementation (insulin, IGF-1, or TGF-β1) was investigated to stimulate elastogenesis as well as to improve overall tissue formation. Using rabbit auricular chondrocytes, bioreactor-cultivated constructs supplemented with either insulin or IGF-1 displayed increased deposition of cartilaginous ECM, improved mechanical properties, and thicknesses comparable to native auricular cartilage after 4 weeks of growth. Similarly, growth factor supplementation resulted in increased expression and improved localization of elastin, primarily restricted within the cartilaginous region of the tissue construct. Additional studies were conducted to determine whether scaffold-free engineered auricular cartilage constructs could be developed in the 3D shape of the external ear. Isolated auricular chondrocytes were grown in rapid-prototyped tissue culture molds with additional insulin or IGF-1 supplementation during bioreactor cultivation. Using this approach, the developed tissue constructs were flexible and had a 3D shape in very good agreement to the culture mold (average error <400 µm). While scaffold-free, engineered auricular cartilage constructs can be created with both the appropriate tissue structure and 3D shape of the external ear, future studies will be aimed assessing potential changes in construct shape and properties after subcutaneous implantation.


Cannabis and schizophrenia spectrum disorders: a review of clinical studies.
Cannabis is the most widely used illegitimate substance in the world, and the number of users has increased by 10% over the last decade worldwide. Therefore, it is important to review the evidence on psychoactive properties of cannabis and its possible association with schizophrenia spectrum disorders (SSD). We searched MEDLINE with the key words cannabis and schizophrenia. The search was limited to articles published in English over the last 10 years (1999-2009). Bibliographies of cited literature were also searched. Data sources included reviews published in core clinical journals, cohort studies, interventional studies, case-control studies, cross-sectional analyses and epidemiological data. Results are discussed under 2 topics. Firstly, evidence related to biochemical functioning of cannabinoids and their relationship to endocannabinoid system is discussed briefly. Secondly, the evidence from clinical studies on cannabis, psychosis proneness and SSD are discussed in detail. The discussion is structured to fit in the evidence from results section to 3 plausible hypotheses on cannabis use and SSD. The evidence for and against each hypothesis is discussed. Despite new evidence, the exact relationship between cannabis and SSD is unclear. There is no firm evidence that cannabis causes SSD. The evidence for the argument that schizophrenic patients are attracted to cannabis is also not strong. The most plausible explanation is that cannabis use and psychosis proneness may have synergistic effects in a vulnerable minority.