A Nationwide Study in Denmark of the Association Between Treated Infections and the Subsequent Risk of Treated Mental Disorders in Children and Adolescents.
Infections have been associated with increased risks for mental disorders, such as schizophrenia and depression. However, the association between all infections requiring treatment and the wide range of mental disorders is unknown to date. To investigate the association between all treated infections since birth and the subsequent risk of development of any treated mental disorder during childhood and adolescence. Population-based cohort study using Danish nationwide registers. Participants were all individuals born in Denmark between January 1, 1995, and June 30, 2012 (N = 1 098 930). Dates of analysis were November 2017 to February 2018. All treated infections were identified in a time-varying manner from birth until June 30, 2013, including severe infections requiring hospitalizations and less severe infection treated with anti-infective agents in the primary care sector. This study identified all mental disorders diagnosed in a hospital setting and any redeemed prescription for psychotropic medication. Cox proportional hazards regression was performed reporting hazard rate ratios (HRRs), including 95% CIs, adjusted for age, sex, somatic comorbidity, parental education, and parental mental disorders. A total of 1 098 930 individuals (51.3% male) were followed up for 9 620 807.7 person-years until a mean (SD) age of 9.76 (4.91) years. Infections requiring hospitalizations were associated with subsequent increased risk of having a diagnosis of any mental disorder (n = 42 462) by an HRR of 1.84 (95% CI, 1.69-1.99) and with increased risk of redeeming a prescription for psychotropic medication (n = 56 847) by an HRR of 1.42 (95% CI, 1.37-1.46). Infection treated with anti-infective agents was associated with increased risk of having a diagnosis of any mental disorder (HRR, 1.40; 95% CI, 1.29-1.51) and with increased risk of redeeming a prescription for psychotropic medication (HRR, 1.22; 95% CI, 1.18-1.26). Antibiotic use was associated with particularly increased risk estimates. The risk of mental disorders after infections increased in a dose-response association and with the temporal proximity of the last infection. In particular, schizophrenia spectrum disorders, obsessive-compulsive disorder, personality and behavior disorders, mental retardation, autistic spectrum disorder, attention-deficit/hyperactivity disorder, oppositional defiant disorder and conduct disorder, and tic disorders were associated with the highest risks after infections. Although the results cannot prove causality, these findings provide evidence for the involvement of infections and the immune system in the etiology of a wide range of mental disorders in children and adolescents.


Non-invasive assessment of hepatic steatosis in patients with NAFLD using controlled attenuation parameter and 1H-MR spectroscopy.
Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a head-to-head comparison between both methods. Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34-66%, S3 ≥67%. Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiver-operating characteristics curves were 0.93 vs. 0.88 for steatosis ≥S1 and 0.94 vs. 0.88 for ≥S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2-4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa. Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.


Evaluating shape correspondence for statistical shape analysis: a benchmark study.
This paper introduces a new benchmark study to evaluate the performance of landmark-based shape correspondence used for statistical shape analysis. Different from previous shape-correspondence evaluation methods, the proposed benchmark first generates a large set of synthetic shape instances by randomly sampling a given statistical shape model that defines a ground-truth shape space. We then run a test shape-correspondence algorithm on these synthetic shape instances to identify a set of corresponded landmarks. According to the identified corresponded landmarks, we construct a new statistical shape model, which defines a new shape space. We finally compare this new shape space against the ground-truth shape space to determine the performance of the test shape-correspondence algorithm. In this paper, we introduce three new performance measures that are landmark independent to quantify the difference between the ground-truth and the newly derived shape spaces. By introducing a ground-truth shape space that is defined by a statistical shape model and three new landmark-independent performance measures, we believe the proposed benchmark allows for a more objective evaluation of shape correspondence than previous methods. In this paper, we focus on developing the proposed benchmark for 2D shape correspondence. However it can be easily extended to 3D cases.


Neuromuscular hamartomas of the head and neck.
The neuromuscular hamartoma (also referred to as the neuromuscular choristoma or benign triton tumor) is a rare developmental lesion composed of mature elements of both striated muscle and nerve. To date, less than 20 cases have been reported in the English language literature. The majority of these have involved large nerves, such as the sciatic or brachial plexus, but cutaneous lesions have also been reported. We report 2 cases that involve the head and neck and that are among the few described in this location. The majority of cases have been described in infants and young children. However, 1 of our cases (and at least 1 previously reported case) occurred in an adult. While surgical excision has been the most widely used form of therapy, a few cases have been complicated by and/or associated with a second lesion, such as a fibromatosis or lymphangioma.


Dynamic interventions to control COVID-19 pandemic: a multivariate prediction modelling study comparing 16 worldwide countries.
To date, non-pharmacological interventions (NPI) have been the mainstay for controlling the coronavirus disease-2019 (COVID-19) pandemic. While NPIs are effective in preventing health systems overload, these long-term measures are likely to have significant adverse economic consequences. Therefore, many countries are currently considering to lift the NPIs-increasing the likelihood of disease resurgence. In this regard, dynamic NPIs, with intervals of relaxed social distancing, may provide a more suitable alternative. However, the ideal frequency and duration of intermittent NPIs, and the ideal "break" when interventions can be temporarily relaxed, remain uncertain, especially in resource-poor settings. We employed a multivariate prediction model, based on up-to-date transmission and clinical parameters, to simulate outbreak trajectories in 16 countries, from diverse regions and economic categories. In each country, we then modelled the impacts on intensive care unit (ICU) admissions and deaths over an 18-month period for following scenarios: (1) no intervention, (2) consecutive cycles of mitigation measures followed by a relaxation period, and (3) consecutive cycles of suppression measures followed by a relaxation period. We defined these dynamic interventions based on reduction of the mean reproduction number during each cycle, assuming a basic reproduction number (R0) of 2.2 for no intervention, and subsequent effective reproduction numbers (R) of 0.8 and 0.5 for illustrative dynamic mitigation and suppression interventions, respectively. We found that dynamic cycles of 50-day mitigation followed by a 30-day relaxation reduced transmission, however, were unsuccessful in lowering ICU hospitalizations below manageable limits. By contrast, dynamic cycles of 50-day suppression followed by a 30-day relaxation kept the ICU demands below the national capacities. Additionally, we estimated that a significant number of new infections and deaths, especially in resource-poor countries, would be averted if these dynamic suppression measures were kept in place over an 18-month period. This multi-country analysis demonstrates that intermittent reductions of R below 1 through a potential combination of suppression interventions and relaxation can be an effective strategy for COVID-19 pandemic control. Such a "schedule" of social distancing might be particularly relevant to low-income countries, where a single, prolonged suppression intervention is unsustainable. Efficient implementation of dynamic suppression interventions, therefore, confers a pragmatic option to: (1) prevent critical care overload and deaths, (2) gain time to develop preventive and clinical measures, and (3) reduce economic hardship globally.


Effect of self-care interventions on sleep quality in post-coronary artery bypass grafting patients: A single-center, randomized-controlled study.
This study aims to evaluate the effect of self-care interventions based on sleep hygiene practices, nutrition, and physical activity on sleep quality in post-coronary artery bypass grafting patients. This randomized-controlled study included a total of 146 patients (109 males, 37 females; mean age 55.31 years; range, 41 to 65 years) who underwent isolated coronary artery bypass grafting at Seyyed Al- Shohada Hospital of Urmia Medical Sciences University, between September 2017 and May 2018. The patients were divided into two groups as the self-care intervention group (n=73) and as the control group (n=73). The self-care intervention group received six educational courses on sleep hygiene, nutrition, and physical activity. Then they received individualized consulting weekly for three months. The control group was instructed to continue their normal life and routine care and received no education. The Demographic Information Form and the Pittsburgh Sleep Quality Index were used for data collection. The mean Pittsburgh Sleep Quality Index scores in the self-care intervention group decreased to 7.1±2.3 after the intervention, while it increased to 9.5±2.1 in the control group. There was no significant difference between the two groups in terms of the mean global Pittsburgh Sleep Quality Index scores before the study (p=0.91); however, the scores were statistically significantly higher after the self-care intervention (p=0.001). Patients undergoing coronary artery bypass grafting may benefit from self-care interventions based on sleep hygiene, nutrition, and physical activity to improve the quality of sleep.


Developmental options and functional plasticity of innate lymphoid cells.
Innate lymphoid cells (ILCs) are lineage- and antigen receptor-negative lymphocytes including natural killer (NK) cells and at least three distinguishable cell subsets (ILC1, ILC2, ILC3) that rapidly produce cytokines (IFN-γ, IL-5, IL-13, IL-17A, IL-22) upon activation. As such, ILCs can act as first-line defenders in the context of infection, inflammation and cancer. Because of the strong conservation between the expression of key transcription factors that can drive signature cytokine outputs in ILCs and differentiated helper T cells, it has been proposed that ILCs represent innate counterparts of the latter. Several distinct ILC precursors (ILCP) with pan-ILC (giving rise to all ILCs) or subset-restricted potentials have been described in both mouse and man. How and where these different ILCP give rise to more mature tissue-resident ILCs remains unclear. Recently, environmental signals have been shown to epigenetically influence canonical ILC differentiation pathways, generating substantial functional plasticity. These new results suggest that while ILC differentiation may be 'fixed' in principle, it remains 'flexible' in practice. A more comprehensive knowledge in the molecular mechanisms that regulate ILC development and effector functions may allow for therapeutic manipulation of ILCs for diverse disease conditions.


High heritability of speech and language impairments in 6-year-old twins demonstrated using parent and teacher report.
Previous twin studies have demonstrated high heritability of specific language impairment (SLI) when the diagnosis is based on psychometric testing. The current study measured the effectiveness of parent and teacher ratings of communication skills in identifying heritable language impairment. The Children's Communication Checklist was completed by parents and teachers of 6-year-old twins recruited from a general population sample. One hundred and thirty twin pairs (65 MZ) were selected because at least one twin had low language skills at 4 years of age; a further 66 pairs (37 MZ) were a low risk group with no indication of language difficulties at 4 years. Internal consistency, inter-rater reliability, and validity in identifying language impairment were assessed for all CCC scales. CCC scales, especially those assessing structural language skills, were highly effective in identifying cases of language impairment, but agreement between parent and teacher ratings was modest. Genetic analysis revealed negligible environmental influence and substantial genetic influence on most scales. A rater-specific effects model was fit to the data to assess how far parents and teachers assess a common genetic factor on the CCC. Ratings of parents and teachers were influenced to some extent by the same child characteristics, but rater-specific effects were also evident, especially on scales measuring pragmatic aspects of communication. This study shows that there are strong genetic influences on both structural and pragmatic language impairments in children, and these can be detected using a simple checklist completed by parents or teachers.


In utero exposure to cigarette smoking, environmental tobacco smoke and reproductive hormones in US girls approaching puberty.
Evidence is unclear whether prenatal smoking affects age at menarche and pubertal development, and its impact upon hormones has not been well studied. We aim to identify potential pathways through which prenatal smoking and environmental tobacco smoke (ETS) affect reproductive hormones in girls approaching puberty. We examined the association between prenatal smoking, current ETS and luteinizing hormone (LH) and inhibin B (InB) in 6- to 11-year-old girls in the 3rd National Health and Nutrition Examination Survey, 1988-1994. Parents/guardians completed interviewer-assisted questionnaires on health and demographics at the time of physical examination. Residual blood samples were analyzed for reproductive hormones in 2008. Of 660 girls, 19 and 39% were exposed to prenatal smoke and current ETS, respectively. Accounting for multiple pathways in structural equation models, prenatally exposed girls had significantly lower LH (β = -0.205 log-mIU/ml, p < 0.0001) and InB (β = -0.162, log-pg/ml, p < 0.0001). Prenatal smoking also influenced LH positively and InB negatively indirectly through BMI-for-age. ETS was positively associated with LH, but not with InB. Exposure to maternal smoking may disrupt reproductive development manifesting in altered hormone levels near puberty.


Neurofibromatous changes in dermatofibrosarcoma protuberans: a potential pitfall in the diagnosis of a serious cutaneous soft tissue neoplasm.
Dermatofibrosarcoma protuberans (DFSP) is a low-grade malignant neoplasm that has the potential for aggressive local growth and destruction if not treated appropriately. Although the storiform arrangement of spindle cells in DFSP is relatively characteristic, histologic patterns simulating other benign as well as malignant neoplasms such as dermatofibroma, neurofibroma, malignant fibrous histiocytoma, and atypical fibroxanthoma have been described. We collected and analyzed six cases of probable DFSP in which a specific diagnosis could not be rendered due to the predominant neurofibromatous changes in the histologic sections. In an attempt to reach a definitive diagnosis, the clinical history and physical characteristics of the lesions were taken into account, and all cases were further evaluated using immunostaining for CD34 and S-100 protein. The average age of the patient was 56 years (range 21-80), and the male to female ratio was 1 : 1. The location of lesions included the scalp, neck, back, and abdomen. All cases displayed two distinct histological patterns: (i) a proliferation of spindle cells with wavy nuclei in a loose mucinous stroma suggesting neural differentiation and (ii) a proliferation of spindle cells which interweaved and filled the reticular dermis extending into the subcutis. The wide variety of clinical impressions and descriptions indicated that the diagnoses were not always straightforward, and clinical information did not always assist in the clinicopathologic correlation. All lesions stained positively for CD34; however, three of six cases also stained positively for S-100. The three cases which were CD34 positive and S-100 negative were likely DFSP, and this was the final diagnosis given. The three cases that were CD34 and S-100 positive did not allow for a straightforward diagnosis. DFSP may demonstrate areas with features more characteristic of a benign neural lesion, such as a neurofibroma, which can lead to underdiagnosis and subsequent failure to treat. Clinicians and pathologists should recognize this potential diagnostic pitfall and understand that equivocal clinical information, combined with non-specific immunohistochemical staining patterns, can further complicate the dilemma. In these situations, where DFSP is the likely diagnosis but definitive evidence cannot be obtained, full excision of the lesion should be recommended to avoid mistreatment of a potentially malignant lesion.


The Hound of the Baskervilles effect: natural experiment on the influence of psychological stress on timing of death.
To determine whether cardiac mortality is abnormally high on days considered unlucky: Chinese and Japanese people consider the number 4 unlucky, white Americans do not. Examination of cardiac and non-cardiac mortality on and around the fourth of each month in Chinese and Japanese subjects and white controls. United States. All Chinese and Japanese (n=209 908) and white (n=47 328 762) Americans whose computerised death certificates were recorded between the beginning of January 1973 and the end of December 1998. Ratio of observed to expected numbers of deaths on the fourth day of the month (expected number was estimated from mortality on other days of the month). Cardiac mortality in Chinese and Japanese people peaked on the fourth of the month. The peak was particularly large for deaths from chronic heart disease (ratio of observed to expected deaths = 1.13, 95% confidence interval 1.06 to 1.21) and still larger for deaths from chronic heart disease in California (1.27, 1.15 to 1.39). Within this group, inpatients showed a particularly large peak on the fourth day(1.45, 1.19 to 1.81). The peak was not followed by a compensatory drop in number of deaths. White controls, matched on age, sex, marital status, hospital status, location, and cause of death, showed no similar peak in cardiac mortality. Our findings of excess cardiac mortality on "unlucky" days are consistent with the hypothesis that cardiac mortality increases on psychologically stressful occasions. The results are inconsistent with nine other possible explanations for the findings-for example, the fourth day peak does not seem to occur because of changes in the patient's diet, alcohol intake, exercise, or drug regimens.


High-resolution sonography versus EMG in the diagnosis of carpal tunnel syndrome.
Carpal tunnel syndrome (CTS) is a common entrapment neuropathy. Electrodiagnostic testing (EMG) is used to confirm the diagnosis. It is not known what the diagnostic accuracy of high-resolution sonography is in comparison to EMG. The aim of this study was to compare the diagnostic accuracy of both tests in CTS patients. A prospective cohort of 207 patients with possible CTS underwent high-resolution sonography and EMG. The diagnosis of CTS was based on clinical signs and symptoms. The cross-sectional area of the median nerve at the carpal tunnel inlet and at the distal one-third level of the forearm was assessed by an investigator, blinded to the clinical and EMG data. Normal sonographic values were obtained from 137 controls. All patients and 40 controls underwent a standardised nerve conduction study. The kappa coefficient was used to evaluate the relationship between sonography, EMG and clinical diagnosis. The cross-sectional area at the distal one-third of the forearm was not significantly different between the controls and patients (p = 0.59), whereas the cross-sectional area at the carpal tunnel inlet was significantly increased in the patient group (p<0.0001). The kappa coefficient for EMG using the median-ulnar distal sensory latency difference versus clinical evaluation was 0.64 and, for sonography, this coefficient was 0.69; these were not statistically different (p = 0.37). Combining the two tests resulted in a kappa coefficient of 0.72, which was not significantly different from sonography alone (p = 0.73). In patients with a clinical diagnosis of CTS, the accuracy of sonography is similar to that for EMG. Sonography is probably preferable because it is painless, easily accessible and preferred by the patients.


How mindfulness changed my sleep: focus groups with chronic insomnia patients.
Chronic insomnia is a major public health problem affecting approximately 10% of adults. Use of meditation and yoga to develop mindful awareness ('mindfulness training') may be an effective approach to treat chronic insomnia, with sleep outcomes comparable to nightly use of prescription sedatives, but more durable and with minimal or no side effects. The purpose of this study was to understand mindfulness training as experienced by patients with chronic insomnia, and suggest procedures that may be useful in optimizing sleep benefits. Adults (N = 18) who completed an 8-week mindfulness-based stress reduction (MBSR) program as part of a randomized, controlled clinical trial to evaluate MBSR as a treatment for chronic insomnia were invited to participate in post-trial focus groups. Two groups were held. Participants (n = 9) described how their sleep routine, thoughts and emotions were affected by MBSR and about utility (or not) of various mindfulness techniques. Groups were audio-recorded, transcribed and analyzed using content analysis. Four themes were identified: the impact of mindfulness on sleep and motivation to adopt a healthy sleep lifestyle; benefits of mindfulness on aspects of life beyond sleep; challenges and successes in adopting mindfulness-based practices; and the importance of group sharing and support. Participants said they were not sleeping more, but sleeping better, waking more refreshed, feeling less distressed about insomnia, and better able to cope when it occurred. Some participants experienced the course as a call to action, and for them, practicing meditation and following sleep hygiene guidelines became priorities. Motivation to sustain behavioral changes was reinforced by feeling physically better and more emotionally stable, and seeing others in the MBSR class improve. The body scan was identified as an effective tool to enable falling asleep faster. Participants described needing to continue practicing mindfulness to maintain benefits. First-person accounts are consistent with published trial results of positive impacts of MBSR on sleep measured by sleep diary, actigraphy, and self-report sleep scales. Findings indicate that mindfulness training in a group format, combined with sleep hygiene education, is important for effective application of MBSR as a treatment for chronic insomnia.


Identification and continuity of the distributions of burst-length and interspike intervals in the stochastic Morris-Lecar neuron.
Using the Morris-Lecar model neuron with a type II parameter set and K(+)-channel noise, we investigate the interspike interval distribution as increasing levels of applied current drive the model through a subcritical Hopf bifurcation. Our goal is to provide a quantitative description of the distributions associated with spiking as a function of applied current. The model generates bursty spiking behavior with sequences of random numbers of spikes (bursts) separated by interburst intervals of random length. This kind of spiking behavior is found in many places in the nervous system, most notably, perhaps, in stuttering inhibitory interneurons in cortex. Here we show several practical and inviting aspects of this model, combining analysis of the stochastic dynamics of the model with estimation based on simulations. We show that the parameter of the exponential tail of the interspike interval distribution is in fact continuous over the entire range of plausible applied current, regardless of the bifurcations in the phase portrait of the model. Further, we show that the spike sequence length, apparently studied for the first time here, has a geometric distribution whose associated parameter is continuous as a function of applied current over the entire input range. Hence, this model is applicable over a much wider range of applied current than has been thought.


Prediction Model for Extended Hospital Stay Among Medicare Beneficiaries After Percutaneous Coronary Intervention.
The authors conducted a retrospective analysis to develop a predictive model consisting of factors associated with extended hospital stay among Medicare beneficiaries undergoing percutaneous coronary intervention (PCI). Retrospective cohort study. Multi-institutional. Data were obtained from the National (Nationwide) Inpatient Sample registry from 2013 to 2014 over a 2-year period. None. The primary outcome was extended hospital stay, which was defined as an inpatient stay greater than 75th percentile for the cohort (≥5 d), among Medicare beneficiaries (fee-for-service and managed care) undergoing PCI. A multivariable logistic regression analysis was built on a training set to develop the predictive model. The authors evaluated model performance with area under the receiver operating characteristic curve (AUC) and performed k-folds cross-validation to calculate the average AUC. The final analysis included 91,880 patients. Inpatient hospital length of stay ranged from 0 to 247 days, with 3 and 5 days as the median and 3rd quartile hospital stay, respectively. The final multivariable analysis suggested that sociodemographic variables, hospital-related factors, and comorbidities were associated with a greater odds of extended hospital stay (all p < 0.05). The use of PCI with drug-eluting stent was associated with a 31% decrease in extended hospital stay (odds ratio 0.69, 95% confidence interval 0.66-0.72; p < 0.001). Model discrimination was deemed excellent with an AUC (95% confidence interval) of 0.814 (0.811-0.817) and 0.809 (0.799-0.819) for the training and testing sets, respectively. The authors' predictive model identified risk factors that have a higher probability of extended hospital stay. This model can be used to improve periprocedural optimization and improved discharge planning, which may help to decrease costs associated with PCIs. Management of Medicare beneficiaries after PCI calls for a multidisciplinary approach among healthcare teams and hospital administrators.


Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients With Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial.
In clinical practice, patients with primary metastatic renal cell carcinoma (mRCC) have been offered cytoreductive nephrectomy (CN) followed by targeted therapy, but the optimal sequence of surgery and systemic therapy is unknown. To examine whether a period of sunitinib therapy before CN improves outcome compared with immediate CN followed by sunitinib. This randomized clinical trial began as a phase 3 trial on July 14, 2010, and continued until March 24, 2016, with a median follow-up of 3.3 years and a clinical cutoff date for this report of May 5, 2017. Patients with mRCC of clear cell subtype, resectable primary tumor, and 3 or fewer surgical risk factors were studied. Immediate CN followed by sunitinib therapy vs treatment with 3 cycles of sunitinib followed by CN in the absence of progression followed by sunitinib therapy. Progression-free survival was the primary end point, which needed a sample size of 458 patients. Because of poor accrual, the independent data monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate (PFR) instead. Overall survival (OS), adverse events, and postoperative progression were secondary end points. The study closed after 5.7 years with 99 patients (80 men and 19 women; mean [SD] age, 60 [8.5] years). The 28-week PFR was 42% in the immediate CN arm (n = 50) and 43% in the deferred CN arm (n = 49) (P = .61). The intention-to-treat OS hazard ratio of deferred vs immediate CN was 0.57 (95% CI, 0.34-0.95; P = .03), with a median OS of 32.4 months (95% CI, 14.5-65.3 months) in the deferred CN arm and 15.0 months (95% CI, 9.3-29.5 months) in the immediate CN arm. In the deferred CN arm, 48 of 49 patients (98%; 95% CI, 89%-100%) received sunitinib vs 40 of 50 (80%; 95% CI, 67%-89%) in the immediate arm. Systemic progression before planned CN in the deferred CN arm resulted in a per-protocol recommendation against nephrectomy in 14 patients (29%; 95% CI, 18%-43%). Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS results were higher. Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN. This evidence complements recent data from randomized clinical trials to inform treatment decisions in patients with primary clear cell mRCC requiring sunitinib. ClinicalTrials.gov identifier: NCT01099423.


A randomized multicenter study of gamolenic acid (Efamast) with and without antioxidant vitamins and minerals in the management of mastalgia.
In a double-blind, placebo-controlled, parallel group, multicenter study, 555 women with moderate to severe mastalgia were randomized to one of the four treatment groups to receive (a) gamolenic acid (GLA) and antioxidants, (b) placebo fatty acids and antioxidants, (c) GLA and placebo antioxidants, or (d) placebo fatty acids and placebo antioxidants, for four menstrual cycles. This was followed by a further eight menstrual cycles of open treatment in which all patients received GLA, but continued to be randomized to active or placebo antioxidants as in the preceding parallel phase. Diary pain cards and linear analog charts were used for assessment of response. A reduction in breast pain was seen in all four treatment groups during the blinded treatment phase. There was a substantial improvement in the placebo fatty acids groups (response rate of 40%), and there were no significant differences among the four treatment groups. During the open treatment phase, a further reduction in breast pain was seen in all groups, with no statistically significant differences between groups. This study showed that GLA (Efamast) efficacy did not differ from that of placebo fatty acids, regardless of whether or not antioxidant vitamins were present.


Influence of androgen on translatable renin mRNA in the mouse submandibular gland.
In mature outbred Swiss male mice, submandibular gland renin enzyme activity is 4- and 10-fold higher than in glands of prepubescent males and mature females, respectively. Levels of translatable renin mRNA have been studied in mouse submandibular gland during postnatal development and following administration of testosterone. The [35S]methionine-labeled cell-free translation products directed by male glandular mRNA contain a 47 +/- 2kd renin precursor that is not detected in products coded by prepubescent male or female gland mRNA. This cell-free synthesized precursor is detected immunochemically only in the translation products of gland mRNA from males of 33 days or older and from females receiving testosterone administration, a pattern consistent with the measurements of renin enzyme activity. This increase in biologically active renin mRNA is a selective one, since unfractionated male and female mRNAs have similar overall nucleotide sequence complexity corresponding to 1% of mouse single copy DNA. The cDNA transcribed from male gland mRNA reacts 5- and 10-fold faster with the template mRNA than with female or prepubescent male gland mRNA, respectively, which indicates that the male gland contains abundant nucleotide sequences that exist at low concentration in the female or prepubescent male. Selective hybrid arrested translation confirms that the levels of renin mRNA are lower in the glands of prepubescent males than in those of the mature males. These data indicate that the regulation of renin enzymatic activity by androgens is mediated by an increase in the levels of translatable renin mRNA both during postnatal development and after testosterone administration.


Follicular mechanisms associated with 4-vinylcyclohexene diepoxide-induced ovotoxicity in rats.
The mechanism of 4-vinylcyclohexene diepoxide (VCD)-induced oocyte destruction in small preantral follicles of rats and mice has not been elucidated. This study examined the effects of daily dosing of female rats with VCD on protein synthesis and follicle viability. An investigation of granulosa cells as a target for VCD was also made. Small preantral follicles (25 to 100 microns) isolated from untreated immature rats (day 28) as well as from rats injected daily for 10 d with VCD (0.57 mmol/kg, IP) or vehicle control (sesame oil) were incubated for 3, 6, or 10 h in vitro with or without VCD. Viability (trypan blue dye exclusion) or protein synthesis (3H-leucine incorporation) in follicles was measured. Large preantral follicles (100 to 250 microns), isolated oocytes or granulosa cells from small preantral follicles, hepatocytes, and adrenal cells served as controls. Viability was not compromised in small follicles isolated from untreated or VCD-injected rats. However, following in vitro incubation of small preantral follicles with VCD, there was a significant decrease in viability by 6 h. This loss in viability was observed in granulosa cells and was even greater in follicles from dosed as compared with undosed animals. The various cell types were incubated in vitro with or without VCD for 3 h and the rate of protein synthesis was measured by 3H-leucine incorporation during the last hour of incubation. Incubation of small preantral follicles from untreated animals with VCD for 3 h produced significant inhibition in the rate of protein synthesis. This effect was reversed and significantly stimulated after 6 and 10 h of incubation with VCD. Follicles from animals that had been dosed daily with VCD for 10 d demonstrated similar inhibition of protein synthesis following 3 h in vitro incubation with VCD; however, unlike those from undosed rats, follicles from dosed rats did not recover from this inhibition after 6 or 10 h of in vitro incubation with VCD. In vitro incubation with VCD stimulated the rate of protein synthesis in large preantral follicles; however, no effect on the rate of protein synthesis was observed in isolated oocytes and granulosa cells, hepatocytes, or adrenal cells. These observations suggest that VCD affects follicular viability via an effect on granulosa cells and that daily dosing of rats with VCD makes small preantral follicles more susceptible to ovotoxicity by VCD.


Phenotypic heterogeneity of melanoma. Relation to the differentiation program of melanoma cells.
Phenotypic heterogeneity is a characteristic feature of tumor lesions in patients with melanoma. Variability can be observed in cell morphology, pigmentation, and antigen expression. To test whether phenotypic heterogeneity could be the result of events regulated during cell differentiation, we evaluated the expression of a panel of differentiation traits on melanoma cells. Metastatic melanoma lesions from two patients, designated FD and AP, were examined histologically and found to contain mixed populations of cells. Established melanoma cell lines derived from each of these lesions were subcloned at early passage in culture (passages 7 and 8) to create a panel of clones derived from each tumor. There was heterogeneity in the expression of differentiation-related traits in clones, corresponding to distinct phenotypes observed within the original tumors. Clones from patient FD corresponded to early to intermediate stages of melanocyte differentiation, and clones from patient AP ranged from intermediate to late stages. The influence of cholera toxin and PMA on differentiation of parental cultures and subclone was studied. Results of induction studies demonstrated a number of features of differentiation of melanoma cells: regulation of differentiation traits is coordinated as a program of traits expressed sequentially at specific stages; early traits, such as the epidermal growth factor receptor and the melanoma chondroitin sulfate proteoglycan antigen, are downregulated as melanoma cells differentiate, whereas late markers, including melanin, tyrosinase activity, and antigens expressed in mature melanosomes, are upregulated; Ia (class II major histocompatibility) antigens are characteristically expressed on melanomas corresponding to early or intermediate stages of differentiation and are regulated as part of the differentiation program; minimal changes in stage of differentiation were observed during induction of parental cultures with either cholera toxin or PMA, whereas definite shifts in differentiation could be induced in selected cloned subpopulations. We conclude that melanoma cells are not frozen at a specific stage of differentiation, but rather are capable of differentiating when exposed to appropriate signals. Diversity in the differentiation state of melanoma cells can account for much of the phenotypic heterogeneity observed in melanoma lesions.


Dynamic behavior of postfilamentation Raman pulses.
We report on the postfilamentation behavior of a Stokes pulse created from intense and collimated ultrashort pulses propagating in air. A systematic analysis of the pulse propagation revealed that the redshifted Raman pulse produced during filamentation had a larger divergence than the postfilamentation intense pump pulse. Also, the analysis of the far-field Stokes transverse ring revealed that the intensity in this ionization-free light channel is still sufficiently high to induce stimulated Raman scattering after ionization had ended. This behavior further extends the potential of filamentation to remotely induce third-order nonlinearities.


Common Misconceptions Regarding Pediatric Auditory Processing Disorder.
Pediatric hearing evaluation based on pure tone audiometry does not always reflect how a child hears in everyday life. This practice is inappropriate when evaluating the difficulties children experiencing auditory processing disorder (APD) in school or on the playground. Despite the marked increase in research on pediatric APD, there remains limited access to proper evaluation worldwide. This perspective article presents five common misconceptions of APD that contribute to inappropriate or limited management in children experiencing these deficits. The misconceptions discussed are (1) the disorder cannot be diagnosed due to the lack of a gold standard diagnostic test; (2) making generalizations based on profiles of children suspected of APD and not diagnosed with the disorder; (3) it is best to discard an APD diagnosis when another disorder is present; (4) arguing that the known link between auditory perception and higher cognition function precludes the validity of APD as a clinical entity; and (5) APD is not a clinical entity. These five misconceptions are described and rebutted using published data as well as critical thinking on current available knowledge on APD.


Where does attention go when it moves? Spatial properties and locus of the attentional repulsion effect.
Reliable effects of spatial attention on perceptual measures have been well documented, yet little is known about how attention affects perception of space per se. The present study examined the effects of involuntary shifts of spatial attention on perceived location using a paradigm developed by S. Suzuki and P. Cavanagh (1997) that produces an attentional repulsion effect (ARE). The ARE refers to the illusory displacement of two vernier lines away from briefly presented cues. In Experiment 1, we show that the magnitude of the ARE depends on cue-target distance, indicating that the effects of attention on perceived location are not uniform across the visual field. Experiments 2 and 3 tested whether repulsion occurs away from cue center of mass or from cue contour. Perceived repulsion always occurred away from the cues' center of mass, regardless of the arrangement of the cue contours relative to the vernier lines. Moreover, the magnitude of the ARE varied with shifts in the position of the cues' center of mass. These experiments suggest that the onset of the cue produces a shift of attention to its center of mass rather than to the salient luminance contours that define it, and that this mechanism underlies the ARE.


Implementing liquid biopsies into clinical decision making for cancer immunotherapy.
During the last decade, novel immunotherapeutic strategies, in particular antibodies directed against immune checkpoint inhibitors, have revolutionized the treatment of different malignancies leading to an improved survival of patients. Identification of immune-related biomarkers for diagnosis, prognosis, monitoring of immune responses and selection of patients for specific cancer immunotherapies is urgently required and therefore areas of intensive research. Easily accessible samples in particular liquid biopsies (body fluids), such as blood, saliva or urine, are preferred for serial tumor biopsies.Although monitoring of immune and tumor responses prior, during and post immunotherapy has led to significant advances of patients' outcome, valid and stable prognostic biomarkers are still missing. This might be due to the limited capacity of the technologies employed, reproducibility of results as well as assay stability and validation of results. Therefore solid approaches to assess immune regulation and modulation as well as to follow up the nature of the tumor in liquid biopsies are urgently required to discover valuable and relevant biomarkers including sample preparation, timing of the collection and the type of liquid samples. This article summarizes our knowledge of the well-known liquid material in a new context as liquid biopsy and focuses on collection and assay requirements for the analysis and the technical developments that allow the implementation of different high-throughput assays to detect alterations at the genetic and immunologic level, which could be used for monitoring treatment efficiency, acquired therapy resistance mechanisms and the prognostic value of the liquid biopsies.


Characterization of the HCMV-Specific CD4 T Cell Responses that Are Associated with Protective Immunity.
Most humans become infected with human cytomegalovirus (HCMV). Typically, the immune system controls the infection, but the virus persists and can reactivate in states of immunodeficiency. While substantial information is available on the contribution of CD8 T cells and antibodies to anti-HCMV immunity, studies of the TH1, TH2, and TH17 subsets have been limited by the low frequency of HCMV-specific CD4 T cells in peripheral blood mononuclear cell (PBMC). Using the enzyme-linked Immunospotr assay (ELISPOT) that excels in low frequency measurements, we have established these in a sizable cohort of healthy HCMV controllers. Cytokine recall responses were seen in all seropositive donors. Specifically, interferon (IFN)- and/or interleukin (IL)-17 were seen in isolation or with IL-4 in all test subjects. IL-4 recall did not occur in isolation. While the ratios of TH1, TH2, and TH17 cells exhibited substantial variations between different individuals these ratios and the frequencies were relatively stable when tested in samples drawn up to five years apart. IFN- and IL-2 co-expressing polyfunctional cells were seen in most subjects. Around half of the HCMV-specific CD4 cells were in a reversible state of exhaustion. The data provided here established the TH1, TH2, and TH17 characteristic of the CD4 cells that convey immune protection for successful immune surveillance against which reactivity can be compared when the immune surveillance of HCMV fails.


Racial differences in central blood pressure and vascular function in young men.
Young African-American men have altered macrovascular and microvascular function. In this cross-sectional study, we tested the hypothesis that vascular dysfunction in young African-American men would contribute to greater central blood pressure (BP) compared with young white men. Fifty-five young (23 yr), healthy men (25 African-American and 30 white) underwent measures of vascular structure and function, including carotid artery intima-media thickness (IMT) and carotid artery beta-stiffness via ultrasonography, aortic pulse wave velocity, aortic augmentation index (AIx), and wave reflection travel time (Tr) via radial artery tonometery and a generalized transfer function, and microvascular vasodilatory capacity of forearm resistance arteries with strain-gauge plethysmography. African-American men had similar brachial systolic BP (SBP) but greater aortic SBP (P<0.05) and carotid SBP (P<0.05). African-American men also had greater carotid IMT, greater carotid beta-stiffness, greater aortic stiffness and AIx, reduced aortic Tr and reduced peak hyperemic, and total hyperemic forearm blood flow compared with white men (P<0.05). In conclusion, young African-American men have greater central BP, despite comparable brachial BP, compared with young white men. Diffuse macrovascular and microvascular dysfunction manifesting as carotid hypertrophy, increased stiffness of central elastic arteries, heightened resistance artery constriction/blunted resistance artery dilation, and greater arterial wave reflection are present at a young age in apparently healthy African-American men, and conventional brachial BP measurement does not reflect this vascular burden.


Hyperdense sylvian fissure MCA "dot" sign: A CT marker of acute ischemia.
The hyperdense appearance of the main middle cerebral artery (HMCA) is now a familiar early warning of large cerebral infarction, brain edema, and poor prognosis. This article describes the hyperdensity associated with embolic occlusion of branches of the middle cerebral artery in the sylvian fissure (MCA "dot" sign). We define it and determine its incidence, diagnostic value, and reliability. CT scans performed on patients with acute ischemic stroke within 3 hours of symptom onset were analyzed for signs of thromboembolic stroke and evidence of early CT ischemia. Two neuroradiologists and 2 stroke neurologists initially blinded to all clinical information and then with knowledge of the affected hemisphere evaluated scans for the presence of the MCA dot sign, the HMCA sign, and early MCA territory ischemic changes. Of 100 consecutive patients who presented within 3 hours of symptom onset, 91 were considered at symptom onset to have anterior circulation stroke syndromes. Early CT ischemia was seen in 74% of these baseline CT scans. The HMCA sign was seen in 5% of CT scans, whereas the MCA dot sign was seen in 16%. All patients then received intravenous tissue plasminogen activator. All 5 patients with an HMCA sign, including 2 with an associated MCA dot sign, were either dead or dependent at 3 months. The 14 patients with an MCA dot sign alone were independent at 3 months in 64% of cases, compared with 50% without the sign (Fisher's exact test P:=0.79). Balanced kappa statistics for both the HMCA and the MCA dot sign were in the moderate to good range when the stroke symptom side was given. The MCA dot sign is an early marker of thromboembolic occlusion of the distal MCA branches seen in the sylvian fissure and is associated with better outcome than the HMCA sign.


Synthesis and redox reactions of bis(verdazyl)palladium complexes.
The synthesis and ligand-centered redox chemistry of palladium complexes bearing two potentially bidentate verdazyl ligands is explored. Reaction of 1,5-diisopropyl-3-pyridin-2-yl-6-oxoverdazyl radical 1 with Pd(NCMe)4·2BF4 gives a complex containing two coordinated verdazyl radicals. The structure of this complex consists of one verdazyl bound to Pd in a bidentate mode and the second verdazyl bound in a monodentate fashion through the pyridine substituent; the fourth coordination site is occupied by a solvent molecule (acetonitrile (3) or dimethyl sulfoxide (4)). Two-electron reduction of this complex with decamethylferrocene affords a bis(verdazyl) palladium complex (5) in which both verdazyls have been reduced to their anionic state and are both bound to Pd in bidentate manner. Complex 5 can be independently synthesized by a redox reaction between 1 and Pd2(dba)3. Reduced complex 5 can be re-oxidized to 3 or 4 with AgBF4; in contrast, oxidation with PhICl2 leads to ligand dissociation, ultimately giving radical 1 and a mono(verdazyl)dichloropalladium complex 2. One-electron oxidation using PhICl2 produces a formally "mixed valent" (in ligand) bis(verdazyl)chloropalladium complex (6) with one bidentate verdazyl anion ligand and one monodentate (pyridine-bound) verdazyl radical. Attempted protonation of the verdazyl ligands in complex 5 leads to complete ligand dissociation and protonation of both the tetrazine and pyridine moieties; deprotonation regenerates 5. Subsequent air oxidation of the tetrazane/pyridinium cation (formed as a tetrachloropalladate salt) leads to re-coordination of the verdazyl ligands to give 6 initially, but ultimately produces a combination of free radical 1 and 2.


Alteration of cholecystokinin-mediated phosphatidylinositol hydrolysis in pancreatic acini from insulin-deficient rats. Evidence for defective G protein activation.
Insulin deficiency leads to a decreased ability of cholecystokinin octapeptide (CCK-8) to raise cytosolic free-calcium levels in the pancreatic acinar cell. To elucidate the mechanisms underlying this defect, we studied the effects of CCK-8 on phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis in pancreatic acini prepared from nondiabetic and streptozocin-induced diabetic rats. Analysis by high-pressure liquid chromatography indicated that, in diabetic rat acini, the CCK-8-mediated increase in [3H]inositol 1,4,5-trisphosphate ([3H]IP3) levels was delayed, and the increase in [3H]inositol 1,3,4,5-tetrakisphosphate ([3H]IP4) levels was markedly attenuated compared with nondiabetic rat acini. The expected increase in the mass levels of IP3, measured in a competitive binding assay, was reduced in the diabetic group after incubation with CCK-8, carbachol, and bombesin. Phospholipase C activity was decreased by 30% in diabetic rat acini, whereas the specific activity of PIP2 and the amount of myo-[3H]inositol in the free and trichloroacetic acid-precipitable pools were similar in both groups. The nonhydrolyzable analogue of GTP guanosine-5'-O-(3'-thiotriphosphate) rapidly enhanced IP3 levels in permeabilized acini, and the percent increase above basal was greater in the diabetic group. When added for 5 s or 2 h, insulin did not alter basal or CCK-8-stimulated [3H]IP3 and [3H]IP4 levels in either nondiabetic or diabetic rat acini. However, after a 4-h incubation, insulin increased basal [3H]IP3 and [3H]IP4 levels in diabetic rat acini and potentiated the actions of CCK-8 on both inositol phosphates. Insulinlike growth factor I did not alter [3H]IP3 and [3H]IP4 levels either acutely or after a 4-h incubation. These findings point to a defect in the signal-transduction pathway that is activated by CCK-8 and other calcium-mobilizing agonists in the diabetic rat pancreas and suggest that insulin, acting via its own receptor, exerts long-term regulatory effects on PIP2 hydrolysis in the pancreatic acinar cell.


Toward reassessing data-deficient species.
One in 6 species (13,465 species) on the International Union for Conservation of Nature (IUCN) Red List is classified as data deficient due to lack of information on their taxonomy, population status, or impact of threats. Despite the chance that many are at high risk of extinction, data-deficient species are typically excluded from global and local conservation priorities, as well as funding schemes. The number of data-deficient species will greatly increase as the IUCN Red List becomes more inclusive of poorly known and speciose groups. A strategic approach is urgently needed to enhance the conservation value of data-deficient assessments. To develop this, we reviewed 2879 data-deficient assessments in 6 animal groups and identified 8 main justifications for assigning data-deficient status (type series, few records, old records, uncertain provenance, uncertain population status or distribution, uncertain threats, taxonomic uncertainty, and new species). Assigning a consistent set of justification tags (i.e., consistent assignment to assessment justifications) to species classified as data deficient is a simple way to achieve more strategic assessments. Such tags would clarify the causes of data deficiency; facilitate the prediction of extinction risk; facilitate comparisons of data deficiency among taxonomic groups; and help prioritize species for reassessment. With renewed efforts, it could be straightforward to prevent thousands of data-deficient species slipping unnoticed toward extinction.


Wavelength dependence of birefringence in single-mode fiber.
Real single-mode fibers generally exhibit elliptical birefringence caused by deviations of the core shape from circularity, by transverse internal stress, and by residual twist. These three contributions can be individually determined by analyzing on a Poincaré sphere the wavelength dependence of the output state of polarization of a short section of fiber with fixed input polarization. Various types of polarization eigenstates of a twisted birefringent fiber are discussed, and the resulting group delay difference is derived.


Evolution of the concept of oxygen transport in the critically ill, with a focus on children after cardiopulmonary bypass.
The concept of oxygen transport, defined as the relation between oxygen consumption (VO2) and delivery (DO2), is of fundamental importance in critically ill patients. The past 200 years have witnessed a stepwise progressive improvement in the understanding of pathophysiological disturbances in the balance of DO2 and VO2 in critically ill patients including those after cardiopulmonary bypass surgery. Intermittent spectacular technological achievements have accelerated the rate of progress. Therapeutic advances have been particularly impressive during the recent decades. Examination of the relation between DO2 and VO2 provides a useful framework around which the care of the critically ill may be developed. Until now, only a few groups have used this framework to examine children after cardiopulmonary bypass. The key topics that will be covered in this review article are the evolution of the concept from its early development to its present, increasingly sophisticated, role in the management of critically ill patients, with a focus on children after cardiopulmonary bypass surgery.


Effects of polysaccharide from mycelia of Ganoderma lucidum on intestinal barrier functions of rats.
The intestinal mucosal barriers play essential roles not only in the digestion and absorption of nutrients, but also the innate defense against most intestinal pathogens. In the present study, polysaccharide from the mycelia of Ganoderma lucidum was given via oral administration to rats (100mg/kg body weight, 21days) to investigate its effects on intestinal barrier functions, including the mechanical barrier, immunological barrier and biological barrier function. It was found that the polysaccharide administration could significantly up-regulate the expression of occludin, nuclear factor-κB p65 (NF-κB p65) and secretory immunoglobulin A (SIgA) in ileum, markedly improve the levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), and IL-4, and decrease the level of diamine oxidase (DAO) in serum. Meanwhile, rats from the polysaccharide group showed significant higher microbiota richness in cecum as reflected by the Chao 1 index compared with the control group. Moreover, the polysaccharide decreased the Firmicutes-to-Bacteroidetes ratio. Our results indicated that the polysaccharide from the mycelia of G. lucidum might be used as functional agent to regulate the intestinal barrier functions.


JNJ-56136379, an HBV Capsid Assembly Modulator, Is Well-Tolerated and Has Antiviral Activity in a Phase 1 Study of Patients With Chronic Infection.
JNJ-56136379 (JNJ-6379), a capsid assembly modulator that blocks hepatitis B virus (HBV) replication, was well tolerated and demonstrated dose-proportional pharmacokinetics in healthy participants in part 1 of its first clinical trial. In part 2, we have evaluated the safety, pharmacokinetics, and antiviral activity of multiple doses of JNJ-6379 in patients with chronic HBV infection. We performed a double-blind study of 57 treatment-naïve patients with HB e antigen-positive or -negative (74%) chronic HBV infection without cirrhosis. Patients were randomly assigned to groups given JNJ-6379 at 25 mg (100 mg loading dose), 75 mg, 150 mg, or 250 mg or placebo daily for 4 weeks with an 8-week follow-up period. Twenty-three (56%) of 41 patients given JNJ-6379 had at least 1 adverse event (AE) during treatment, compared with 10 (63%) of 16 patients given placebo. No serious AEs were reported during the treatment period. Three patients (7%) given JNJ-6379 vs none given placebo had grade 3 AEs; of these, 1 patient (150 mg) also had an isolated grade 4 increase in the level of alanine aminotransferase that led to treatment discontinuation. JNJ-6379 exposure increased with dose, with time-linear pharmacokinetics. HBV-DNA and HBV-RNA decreased from baseline in patients receiving all doses of JNJ-6379, independently of viral genotype and HB e antigen status. On day 29, 13 (32%) of 41 patients had levels of HBV DNA below the lower limit of quantification. No clinically significant changes in levels of HB surface antigen were observed. In a phase 1 study of treatment-naïve patients with chronic HBV infection, all doses tested of JNJ-6379 were well tolerated, showed dose-dependent pharmacokinetics, and had potent antiviral activity in patients with CHB. The findings support a phase 2a study to evaluate JNJ-6379 ± nucleos(t)ide analogs in patients with chronic HBV infection, which is under way. ClinicalTrials.gov identifier: NCT02662712.


The accuracy of two different extra-medullary tibial cutting guides for posterior tibial slope in total knee arthroplasty.
This study aims to evaluate the effectiveness of two different external tibial cutting guides with and without a spike anchoring to the intercondylar eminentia to achieve a desired posterior tibial slope. Between January 2008 and December 2011, 120 posterior cruciate ligament protecting total knee arthroplasty (TKA) surgeries of 83 patients in which two different external tibial cutting guides used were included. Fifty-nine knees were included into the spiked and 61 knees were included into the spikeless cutting guide group. Posterior tibial slope angles were measured using the postoperative X-rays. There was no significant difference between two groups in terms of age, sex, and body mass indexes (p<0.05). While the mean postoperative slope angle was 2.66°±2.001°(range 0°-7°) in spiked group, it was 2.46°±2.277° (range 0°-7°) in spikeless group. Both systems had identical accuracy, indicating a low rate. The comparison of variances of two groups showed that both cutting guides had similar precision (p=0.234). There was no effect of body mass index on the results in both groups. Although different extra-medullary tibial cutting guides with and without a spike can reproducibly impart a desired posterior tibial slope in TKA, we concluded that a spiked guide was considered user-friendly.


[A manual of good professional practices for the Clinical Investigation Centres].
Clinical Investigation Centres (CICs) are academic organisations for performing clinical studies. They are a part of a national network which is co-ordinated by French national institute for health and medical research (Inserm), and the head office of healthcare provision (DGOS). There are working groups and specialised networks within the overall CIC network. The Harmonisation of CIC Procedures (HPCIC) group wrote a manual of good professional practices for clinical research. This manual is described here. This manual was written by consensus. It was approved by the coordinators of all CICs, external experts, and validated by representatives of both Inserm and the General directorate of healthcare provision (DGOS). The CIC Good Professional Practices manual is a guide divided into two sections. The first section covers the general management of a CIC (common to all CICs). The second section covers the core activities of CICs, running clinical studies (clinical study coordination, clinical investigation, data management, statistical analysis, valorisation). This manual is available for all CICs and any other clinical research organisations. It will serve as a basis for CIC self-quality evaluation, audits between CICs, and external audits. This manual shows how much the CICs want to standardise practices and procedures nationwide to offer their partners the best quality in performing clinical studies.


Selective induction of IL-1β after a brief isoflurane anesthetic in children undergoing MRI examination.
To determine if isoflurane anesthesia without surgery causes systemic inflammation in children. Inflammation is targeted as responsible for the development of many neurologic pathologies. The effect will be evaluated by measuring serum cytokine levels before and after isoflurane anesthesia. The possible neurotoxic effect of anesthetic agents is a concern in pediatric anesthesia. Questions remain as to the true effects of anesthesia alone on systemic inflammation. The current study assesses systemic inflammatory response to general anesthesia in children not exposed to surgical stress. Twenty-five patients, aged 6 months to 11 years undergoing MRI scanning were recruited. Patients with ASA Physical Status Classification >II, known neurologic disease, prematurity, recent infection, or current treatment with anti-inflammatory medications were excluded. Each patient received a sevoflurane induction, peripheral intravenous catheterization, and laryngeal mask airway placement. Isoflurane was titrated to ensure adequate depth of anesthesia. Two peripheral blood samples were obtained: one immediately after placement of the PIV and one upon arrival to the post-anesthesia care unit. Serum cytokine levels were compared between pre- and post-isoflurane time points using paired t tests. For all patients, interleukin-1β increased after isoflurane when compared to pre-isoflurane samples (pre = 25.97 ± 9.01, post = 38.53 ± 16.56, p = 0.0002). Serum levels of IL-6 (pre = 2.28 ± 2.27, post = 2.04 ± 2.15, p = 0.146) and tumor necrosis factor-α (pre = 94.26 ± 18.07, post = 85.84 ± 12.12, p = 0.057) were not significantly changed. Interleukin-10 and vascular endothelial growth factor were undetectable in pre- and post-isoflurane samples at a minimum detection threshold of 6.6 and 10 pg/ml, respectively. A brief (approximately 60 min) exposure to isoflurane general anesthesia, without induced surgical stress, significantly increased serum IL-1β, a selective activation marker of systemic inflammation (IL-1β pathway).


Addition of sodium bicarbonate to either 1 or 2 feedings of colostrum replacer: effect on uptake and rate of absorption of immunoglobulin G in neonatal calves.
Forty Holstein dairy calves were blocked by birth date and sex, and randomly assigned to 1 of 4 treatments within each block to elucidate the effect of feeding regimen and sodium bicarbonate (NaHCO₃) supplementation on absorption of IgG from colostrum replacer (CR). Calves received CR containing 191.4 g of IgG fed either in 1 feeding at 0 h (within 45 min of birth), with or without 30 g of NaHCO₃, or in 2 feedings (127.6 g of IgG at 0 h, with or without 20 g of NaHCO₃, and 63.8 g of IgG at 6 h, with or without 10 g of NaHCO₃). The treatments were (1) 1 feeding of CR+0 g of NaHCO₃; (2) 1 feeding of CR+30 g of NaHCO₃; (3) 2 feedings of CR+0 g of NaHCO₃; and (4) 2 feedings of CR+30 g total of NaHCO₃. Only calves born with no dystocia were used on this study. Blood samples were taken at 0, 6, 12, 18, and 24h postpartum and were analyzed for IgG using a radial immunoassay. Results indicated that, individually, feeding regimen and NaHCO₃ treatments had no effect. However, the interaction was significant for 24-h IgG and area under the curve, and showed a trend for apparent efficiency of absorption. Absorption rate data indicated that, for calves fed within 45 min of birth, most IgG absorption occurred in the first 6 h after birth. From 6 to 12 h postpartum, IgG absorption started to decrease; however, IgG absorption remained higher for calves fed in a single feeding than in 2 feedings. These data indicated that NaHCO₃ may increase IgG absorption when calves are fed colostrum in a single feeding but is not beneficial when colostrum is fed in 2 feedings.


Resolution enhancement in medical ultrasound imaging.
Image resolution enhancement is a problem of considerable interest in all medical imaging modalities. Unlike general purpose imaging or video processing, for a very long time, medical image resolution enhancement has been based on optimization of the imaging devices. Although some recent works purport to deal with image postprocessing, much remains to be done regarding medical image enhancement via postprocessing, especially in ultrasound imaging. We face a resolution improvement issue in the case of medical ultrasound imaging. We propose to investigate this problem using multidimensional autoregressive (AR) models. Noting that the estimation of the envelope of an ultrasound radio frequency (RF) signal is very similar to the estimation of classical Fourier-based power spectrum estimation, we theoretically show that a domain change and a multidimensional AR model can be used to achieve super-resolution in ultrasound imaging provided the order is estimated correctly. Here, this is done by means of a technique that simultaneously estimates the order and the parameters of a multidimensional model using relevant regression matrix factorization. Doing so, the proposed method specifically fits ultrasound imaging and provides an estimated envelope. Moreover, an expression that links the theoretical image resolution to both the image acquisition features (such as the point spread function) and a postprocessing feature (the AR model) order is derived. The overall contribution of this work is threefold. First, it allows for automatic resolution improvement. Through a simple model and without any specific manual algorithmic parameter tuning, as is used in common methods, the proposed technique simply and exclusively uses the ultrasound RF signal as input and provides the improved B-mode as output. Second, it allows for the a priori prediction of the improvement in resolution via the knowledge of the parametric model order before actual processing. Finally, to achieve the previous goal, while classical parametric methods would first estimate the model order and then the model parameters, our approach estimates the model parameters and the order simultaneously. The effectiveness of the methodology is validated using two-dimensional synthetic and in vivo data. We show that, compared to other techniques, our method provides better results from a qualitative and a quantitative viewpoint.


Characteristics of Cognitive Behavioral Therapy for Older Adults Living in Residential Care: Protocol for a Systematic Review.
The prevalence rates of depressive and anxiety disorders are high in residential aged care settings. Older adults in such settings might be prone to these disorders because of losses associated with transitioning to residential care, uncertainty about the future, as well as a decline in personal autonomy, health, and cognition. Cognitive behavioral therapy (CBT) is efficacious in treating late-life depression and anxiety. However, there remains a dearth of studies examining CBT in residential settings compared with community settings. Typically, older adults living in residential settings have higher care needs than those living in the community. To date, no systematic reviews have been conducted on the content and the delivery characteristics of CBT for older adults living in residential aged care settings. The objective of this paper is to describe the systematic review protocol on the characteristics of CBT for depression and/or anxiety for older adults living in residential aged care settings. This protocol was developed in compliance with the recommendations of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). Studies that fulfill the inclusion criteria will be identified by systematically searching relevant electronic databases, reference lists, and citation indexes. In addition, the PRISMA flowchart will be used to record the selection process. A pilot-tested data collection form will be used to extract and record data from the included studies. Two reviewers will be involved in screening the titles and abstracts of retrieved records, screening the full text of potentially relevant reports, and extracting data. Then, the delivery and content characteristics of different CBT programs of the included studies, where available, will be summarized in a table. Furthermore, the Downs and Black checklist will be used to assess the methodological quality of the included studies. Systematic searches will commence in May 2018, and data extraction is expected to commence in July 2018. Data analyses and writing will happen in October 2018. In this section, the limitations of the systematic review will be outlined. Clinical implications for treating late-life depression and/or anxiety, and implications for residential care facilities will be discussed. PROSPERO 42017080113; https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=80113 (Archived by WebCite at http://www.webcitation.org/70dV4Qf54). RR1-10.2196/9902.


A Novel Platinum(II)-Based Bifunctional ADC Linker Benchmarked Using 89Zr-Desferal and Auristatin F-Conjugated Trastuzumab.
Greater control is desirable in the stochastic conjugation technology used to synthesize antibody-drug conjugates (ADC). We have shown recently that a fluorescent dye can be stably conjugated to a mAb using a bifunctional platinum(II) linker. Here, we describe the general applicability of this novel linker technology for the preparation of stable and efficacious ADCs. The ethylenediamine platinum(II) moiety, herein called Lx, was coordinated to Desferal (DFO) or auristatin F (AF) to provide storable "semifinal" products, which were directly conjugated to unmodified mAbs. Conjugation resulted in ADCs with unimpaired mAb-binding characteristics, DAR in the range of 2.5 to 2.7 and approximately 85% payload bound to the Fc region, presumably to histidine residues. To evaluate the in vivo stability of Lx and its effect on pharmacokinetics and tumor targeting of an ADC, Lx-DFO was conjugated to the HER2 mAb trastuzumab, followed by radiolabeling with 89Zr. Trastuzumab-Lx-DFO-89Zr was stable in vivo and exhibited pharmacokinetic and tumor-targeting properties similar to parental trastuzumab. In a xenograft mouse model of gastric cancer (NCI-N87) or an ado-trastuzumab emtansine-resistant breast cancer (JIMT-1), a single dose of trastuzumab-Lx-AF outperformed its maleimide benchmark trastuzumab-Mal-AF and FDA-approved ado-trastuzumab emtansine. Overall, our findings show the potential of the Lx technology as a robust conjugation platform for the preparation of anticancer ADCs. Cancer Res; 77(2); 257-67. ©2016 AACR.


Steric and interactive barrier properties of intestinal mucus elucidated by particle diffusion and peptide permeation.
The mucus lining of the gastrointestinal tract epithelium is recognized as a barrier to efficient oral drug delivery. Recently, a new in vitro model for assessment of drug permeation across intestinal mucosa was established by applying a biosimilar mucus matrix to the surface of Caco-2 cell monolayers. The aim of the present study was to gain more insight into the steric and interactive barrier properties of intestinal mucus by studying the permeation of peptides and model compounds across the biosimilar mucus as well as across porcine intestinal mucus (PIM). As PIM disrupted the Caco-2 cell monolayers, a cell-free mucus barrier model was implemented in the studies. Both the biosimilar mucus and the PIM reduced the permeation of the selected peptide drugs to varying degrees illustrating the interactive properties of both mucus matrices. The reduction in peptide permeation was decreased depending on the cationicity and H-bonding capacity of the permeant clearly demonstrated by using the biosimilar mucus, whereas the larger inter sample variation of the PIM matrix obstructed similarly clear conclusions. Thus, for mechanistic studies of permeation across mucus and mucosa the biosimilar mucus offers a relevant and reproducible alternative to native mucus.


Inherited deficiency of the Mac-1, LFA-1, p150,95 glycoprotein family and its molecular basis.
Leukocyte surface glycoproteins that share a common beta subunit have been found to be congenitally deficient in three unrelated patients with recurring bacterial infection. The glycoproteins, Mac-1, LFA-1, and p150,95, have the subunit compositions alpha M beta, alpha L beta, and alpha X beta, respectively. Using subunit-specific monoclonal antibodies, both the alpha M and beta subunits of Mac-1, the alpha L and beta subunits of LFA-1, and at the least the beta subunit of p150,95, were found to be deficient at the cell surface by the techniques of immunofluorescence flow cytometry, radioimmunoassay, and immunoprecipitation. A latent pool of Mac-1 that can be expressed on granulocyte surfaces in response to secretory stimuli, such as f-Met-Leu-Phe, was also lacking in patients. Deficiency was found on all leukocytes tested, including granulocytes, monocytes, and T and B lymphocytes. Quantitation by immunofluorescence cytometry of subunits on granulocytes from parents of these patients and of a fourth deceased patient showed approximately half-normal surface expression, and, together with data on other siblings and a family with an affected father and children, demonstrate autosomal recessive inheritance. Deficiency appears to be quantitative rather than qualitative, with two patients expressing approximately 0.5% and one patient approximately 5% of normal amounts. The latter patient had alpha beta complexes on the cell surface detectable by immunoprecipitation. Biosynthesis experiments showed the presence of normal amounts of alpha'L intracellular precursor in lymphoid lines of all three patients. Together with surface deficiency of three molecules that share a common beta subunit but have differing alpha subunits, this suggests the primary deficiency is of the beta subunit. The lack of maturation of alpha'L to alpha L and the deficiency of the alpha subunits at the cell surface and in latent pools suggests that association with the beta subunit is required for alpha subunit processing and transport to the cell surface or to latent pools. The molecular basis of this disease is discussed in light of adhesion-related functional abnormalities in patients' leukocytes and the blockade of similar functions in healthy cells by monoclonal antibodies.


JAK1-dependent transphosphorylation of JAK2 limits the antifibrotic effects of selective JAK2 inhibitors on long-term treatment.
Janus kinase 2 (JAK2) has recently been described as a novel downstream mediator of the pro-fibrotic effects of transforming growth factor-β. Although JAK2 inhibitors are in clinical use for myelodysplastic syndromes, patients often rapidly develop resistance. Tumour cells can escape the therapeutic effects of selective JAK2 inhibitors by mutation-independent transactivation of JAK2 by JAK1. Here, we used selective JAK2 inhibition as a model to test the hypothesis that chronic treatment may provoke resistance by facilitating non-physiological signalling pathways in fibroblasts. The antifibrotic effects of long-term treatment with selective JAK2 inhibitors and reactivation of JAK2 signalling by JAK1-dependent transphosphorylation was analysed in cultured fibroblasts and experimental dermal and pulmonary fibrosis. Combined JAK1/JAK2 inhibition and co-treatment with an HSP90 inhibitor were evaluated as strategies to overcome resistance. The antifibrotic effects of selective JAK2 inhibitors on fibroblasts decreased with prolonged treatment as JAK2 signalling was reactivated by JAK1-dependent transphosphorylation of JAK2. This reactivation could be prevented by HSP90 inhibition, which destabilised JAK2 protein, or with combined JAK1/JAK2 inhibitors. Treatment with combined JAK1/JAK2 inhibitors or with JAK2 inhibitors in combination with HSP90 inhibitors was more effective than monotherapy with JAK2 inhibitors in bleomycin-induced pulmonary fibrosis and in adTBR-induced dermal fibrosis. Fibroblasts can develop resistance to chronic treatment with JAK2 inhibitors by induction of non-physiological JAK1-dependent transactivation of JAK2 and that inhibition of this compensatory signalling pathway, for example, by co-inhibition of JAK1 or HSP90 is important to maintain the antifibrotic effects of JAK2 inhibition with long-term treatment.


Body side and predominant motor features at the onset of Parkinson's disease are linked to motor and nonmotor progression.
Patients with Parkinson's disease most often have asymmetric motor features at onset, and specific motor signs (ie, tremor versus bradykinesia and rigidity) frequently characterize the first few years of disease evolution. Some previous clinical evidence has suggested that body side and a predominance of motor manifestations at disease onset are linked to long-term evolution and disease progression. We prospectively analyzed 206 patients with Parkinson's disease according to the most affected side and predominant motor signs at onset. Patients were divided into left-side rigid-akinetic (n = 71), right-side rigid-akinetic (n = 59), left-side tremor (n = 41), and right-side tremor (n = 35) subgroups. These subgroups were compared in terms of motor and cognitive functions, mean motor deterioration per year (calculated as the motor score divided by disease duration), total equivalent doses of dopaminergic drugs, and the presence of hallucinations and rapid eye movement sleep behavior disorder. Disease duration was similar in all groups. Motor fluctuations were more likely to occur in rigid-akinetic patients. In a multiple model analysis adjusted for potential confounders, faster disease progression was associated with right-side (P = 0.045) and rigid-akinetic onset (P = 0.001). With respect to nonmotor symptoms, the rigid-akinetic type was associated with increased risk of cognitive decline (P = 0.004) compared with the tremor type. A trend was noticed toward an increased risk of developing visual hallucinations in rigid-akinetic patients and toward an increased frequency of rapid eye movement sleep behavior disorder in those who had left-sided onset of symptoms. Our findings corroborate that body side and type of motor signs at the time of diagnosis affect the evolution of motor severity and may also have an impact on some nonmotor manifestations.


Pharmacology and toxicity of intracarotid adriamycin administration following osmotic blood-brain barrier modification.
The effect of reversible blood-brain barrier modification on the delivery of Adriamycin to the brain was studied in a rodent and canine model. Pharmacokinetic and physiological studies were done in these animals after a wide range of doses of Adriamycin (0.1 to 1.0 mg/kg) were administered into the carotid artery following osmotic barrier modification with mannitol. In the absence of barrier modification, no immunoreactive Adriamycin was detected in the cerebrum; whereas, following barrier modification, up to 4.5 micrograms of drug and/or metabolites per g of brain were found. Optimum tissue levels of Adriamycin and metabolites were achieved following barrier modification when the drug was administered by either bolus or slow continuous (15-min) infusion. Immunoreactive drug was identified in brain for up to 6 hr after administration. Significant functional neurotoxicity occurred at all dose levels, even at 0.1 mg/kg, a level at which Adriamycin concentration in the brain was below the level of detectability. Neuropathological examination revealed the presence of necrosis and hemorrhagic infarcts. Thus, these pharmacological and toxicity studies suggest that Adriamycin (or its metabolites) may produce significant clinical neurotoxicity when even small amounts penetrate the blood-brain barrier.


A new dynamometer measuring concentric and eccentric muscle strength in accelerated, decelerated, or isokinetic movements. Validity and reproducibility.
A new computerized dynamometer (the SPARK System) is described. The system can measure concentric and eccentric muscle strength (torque) during linear or nonlinear acceleration or deceleration, isokinetic movements up to 400 degrees.s-1, and isometric torque. Studies were performed to assess: I. validity and reproducibility of torque measurements; II. control of lever arm position; III. control of different velocity patterns; IV. control of velocity during subject testing; and, V. intra-individual reproducibility. No significant difference was found between torque values computed by the system and known torque values (p greater than 0.05). No difference was present between programmed and external measurement of the lever arm position. Accelerating, decelerating and isokinetic velocity patterns were highly reproducible, with differences in elapsed time among 10 trials being never greater than 0.001 s. Velocity during concentric and eccentric isokinetic quadriceps contractions at 30 degrees.s-1, 120 degrees.s-1 and 270 degrees.s-1 never varied by more than 3 degrees.s-1 among subjects (N = 21). Over three days of testing, the overall error for concentric and eccentric quadriceps contraction peak torque values for 5 angular velocities between 30 degrees.s-1 and 270 degrees.s-1 ranged from 5.8% to 9.0% and 5.8% to 9.6% respectively (N = 25). The results indicate that the SPARK System provides valid and reproducible torque measurements and strict control of velocity. In addition, the intra-individual error is in accordance with those reported for other similar devices.


Rapid label-free detection of intact pathogenic bacteria in situ via surface plasmon resonance imaging enabled by crossed surface relief gratings.
The unique plasmonic energy exchange occurring within metallic crossed surface relief gratings (CSRGs) has recently motivated their use as biosensors. However, CSRG-based biosensing has been limited to spectroscopic techniques, failing to harness their potential for integration with ubiquitous portable electronics. Here, we introduce biosensing via surface plasmon resonance imaging (SPRi) enabled by CSRGs. The SPRi platform is fully integrated including optics and electronics, has bulk sensitivity of 613 Pixel Intensity Unit (PIU)/Refractive Index Unit (RIU), a resolution of 10-6 RIU and a signal-to-noise ratio of ∼33 dB. Finite-Difference Time-Domain (FDTD) simulations confirm that CSRG-enabled SPRi is supported by an electric field intensity enhancement of ∼30 times, due to plasmon resonance at the metal-dielectric interface. In the context of real-world biosensing applications, we demonstrate the rapid (<35 min) and label-free detection of uropathogenic E. coli (UPEC) in PBS and human urine samples for concentrations ranging from 103 to 109 CFU mL-1. The detection limit of the platform is ∼100 CFU mL-1, three orders of magnitude lower than the clinical detection limit for diagnosis of urinary tract infection. This work presents a new avenue for CSRGs as SPRi-based biosensing platforms and their great potential for integration with portable electronics for applications requiring in situ detection.


Optical time-of-flight and absorbance imaging of biologic media.
Imaging the interior of living bodies with light may assist in the diagnosis and treatment of a number of clinical problems, which include the early detection of tumors and hypoxic cerebral injury. An existing picosecond time-of-flight and absorbance (TOFA) optical system has been used to image a model biologic system and a rat. Model measurements confirmed TOFA principles in systems with a high degree of photon scattering; rat images, which were constructed from the variable time delays experienced by a fixed fraction of early-arriving transmitted photons, revealed identifiable internal structure. A combination of light-based quantitative measurement and TOFA localization may have applications in continuous, noninvasive monitoring for structural imaging and spatial chemometric analysis in humans.


Composition and flavor of milk and butter from cows fed unsaturated dietary fat and receiving bovine somatotropin.
Composition and flavor of milk and butter were evaluated from cows divided into four treatments including a control, control with bST, added dietary fat from sunflower seeds with bST, or added dietary fat from safflower seeds with bST. Feeding added unsaturated dietary fat resulted in lower concentrations of short-and medium-chain and higher concentrations of long-chain fatty acids in milk fat and butter. Milk fat unsaturated fatty acid concentrations were 25.0, 28.4, 39.6, and 37.9%, and butter unsaturated fatty acid concentrations were 23.0, 26.9, 37.8, and 36.2% for control, control with bST, sunflower seeds with bST, and safflower seeds with bST, respectively. Sensory evaluations indicated that butters from the bST with sunflower seed and bST with safflower seed treatments were equal or superior in flavor to the control butter. Milk from cows receiving bST or fed added unsaturated dietary fat and receiving bST was no more susceptible to oxidized off-flavors than control milk. Butters from sunflower seed and safflower seed treatments with bST contained higher concentrations of unsaturated fatty acids, were softer at 4 and 20 degrees C, and possessed acceptable flavor and processing characteristics compared with butters from control and control with bST.


Metal-film subwavelength-grating polarizer with low insertion losses and high extinction ratios in the terahertz region.
A metal-film subwavelength-grating polarizer with high performance in the terahertz region is presented. The polarizer was obtained by depositing a thin Au film on a resin grating with a triangular cross section duplicated from a metal mold by using the imprinting method. Microstructural parameters were investigated in detail. Measured insertion losses were less than 0.5 dB in the frequency range of 0.5-3 THz, while extinction ratios were 50 dB in the range of 0.5-2.3 THz. The proposed fabrication method is suited to mass production of large-aperture robust polarizers.


Beyond PrP9res) type 1/type 2 dichotomy in Creutzfeldt-Jakob disease.
Sporadic Creutzfeldt-Jakob disease (sCJD) cases are currently subclassified according to the methionine/valine polymorphism at codon 129 of the PRNP gene and the proteinase K (PK) digested abnormal prion protein (PrP(res)) identified on Western blotting (type 1 or type 2). These biochemically distinct PrP(res) types have been considered to represent potential distinct prion strains. However, since cases of CJD show co-occurrence of type 1 and type 2 PrP(res) in the brain, the basis of this classification system and its relationship to agent strain are under discussion. Different brain areas from 41 sCJD and 12 iatrogenic CJD (iCJD) cases were investigated, using Western blotting for PrP(res) and two other biochemical assays reflecting the behaviour of the disease-associated form of the prion protein (PrP(Sc)) under variable PK digestion conditions. In 30% of cases, both type 1 and type 2 PrP(res) were identified. Despite this, the other two biochemical assays found that PrP(Sc) from an individual patient demonstrated uniform biochemical properties. Moreover, in sCJD, four distinct biochemical PrP(Sc) subgroups were identified that correlated with the current sCJD clinico-pathological classification. In iCJD, four similar biochemical clusters were observed, but these did not correlate to any particular PRNP 129 polymorphism or western blot PrP(res) pattern. The identification of four different PrP(Sc) biochemical subgroups in sCJD and iCJD, irrespective of the PRNP polymorphism at codon 129 and the PrP(res) isoform provides an alternative biochemical definition of PrP(Sc) diversity and new insight in the perception of Human TSE agents variability.


New York's Blue Cross and Blue Shield, 1934-1990: the complicated politics of nonprofit regulation.
The story of New York Blue Cross is one of complex interaction with state and federal regulators and also with hospitals, the medical profession, commercial insurers, and the public, who make up the regulatory environment. Negotiation, cooperation, and adaptation among parties whose goals and assumptions were partly parallel characterize the relationships. As we can see from New York Blue Cross's origins and its role in the development and administration of certificate-of-need legislation, Medicare, insurance practice and regulation, and hospital rate setting, this story does not represent the capture of government by a special interest, nor the gradual souring of a public interest organization, nor disinterested and distant government regulation.


The Optimal Imaging Window for Dysplastic Colorectal Polyp Detection Using c-Met-Targeted Fluorescence Molecular Endoscopy.
Fluorescence molecular endoscopy (FME) is an emerging technique that has the potential to improve the 22% colorectal polyp detection miss-rate. We determined the optimal dose-to-imaging interval and safety of FME using EMI-137, a c-Met-targeted fluorescent peptide, in a population at high risk for colorectal cancer. Methods: We performed in vivo FME and quantification of fluorescence by multidiameter single-fiber reflectance/single-fiber fluorescence spectroscopy in 15 patients with a dysplastic colorectal adenoma. EMI-137 was intravenously administered (0.13 mg/kg) at a 1-, 2- or 3-h dose-to-imaging interval (n = 3 patients per cohort). Two cohorts were expanded to 6 patients on the basis of target-to-background ratios. Fluorescence was correlated to histopathology and c-Met expression. EMI-137 binding specificity was assessed by fluorescence microscopy and in vitro experiments. Results: FME using EMI-137 appeared to be safe and well tolerated. All dose-to-imaging intervals showed significantly higher fluorescence in the colorectal lesions than in surrounding tissue, with a target-to-background ratio of 1.53, 1.66, and 1.74 for the 1-, 2-, and 3-h cohorts, respectively, and a mean intrinsic fluorescence of 0.035 vs. 0.023 mm-1 (P < 0.0003), 0.034 vs. 0.021 mm-1 (P < 0.0001), and 0.033 vs. 0.019 mm-1 (P < 0.0001), respectively. Fluorescence correlated with histopathology on a macroscopic and microscopic level, with significant c-Met overexpression in dysplastic mucosa. In vitro, a dose-dependent specific binding was confirmed. Conclusion: FME using EMI-137 appeared to be safe and feasible within a 1- to 3-h dose-to-imaging interval. No clinically significant differences were observed among the cohorts, although a 1-h dose-to-imaging interval was preferred from a clinical perspective. Future studies will investigate EMI-137 for improved colorectal polyp detection during screening colonoscopies.


Inherently multimodal nanoparticle-driven tracking and real-time delineation of orthotopic prostate tumors and micrometastases.
Prostate cancer is the most common cancer among men and the second cause of male cancer-related deaths. There are currently three critical needs in prostate cancer imaging to personalize cancer treatment: (1) accurate intraprostatic imaging for multiple foci and extra-capsular extent; (2) monitoring local and systemic treatment response and predicting recurrence; and (3) more sensitive imaging of occult prostate cancer bone metastases. Recently, our lab developed porphysomes, inherently multimodal, all-organic nanoparticles with flexible and robust radiochemistry. Herein, we validate the first in vivo application of (64)Cu-porphysomes in clinically relevant orthotopic prostate and bony metastatic cancer models. We demonstrate clear multimodal delineation of orthotopic tumors on both the macro- and the microscopic scales (using both PET and fluorescence) and sensitively detected small bony metastases (<2 mm). The unique and multifaceted properties of porphysomes offers a promising all-in-one prostate cancer imaging agent for tumor detection and treatment response/recurrence monitoring using both radionuclide- and photonic-based strategies.


Role of mesenchymal stem cells in tissue engineering of meniscus.
Tissue engineering is a promising approach for the treatment of tissue defects. Mesenchymal stem cells are of potential use as a source of repair cells or of important growth factors for tissue engineering. The purpose of this study was to examine the role of mesenchymal stem cells in meniscal tissue repair. This was tested using several cell and biomaterial-based treatment options for repair of defects in the avascular zone of rabbit menisci. Circular meniscal punch defects (2 mm) were created in the avascular zone of rabbit menisci and left empty or filled with hyaluronan-collagen composite matrices without cells, loaded with platelet-rich plasma, autologous bone marrow, or autologous mesenchymal stem cells. In some experiments, matrices with stem cells were precultured in chondrogenic medium for 14 days before implantation. Rabbits were then allowed free cage movement after surgery for up to 12 weeks. Untreated defects and defects treated with cell-free implants had muted fibrous healing responses. Neither bone marrow nor platelet-rich plasma loaded in matrices produced improvement in healing compared with cell-free implants. The implantation of 14 days precultured chondrogenic stem cell-matrix constructs resulted in fibrocartilage-like repair tissue, which was only partially integrated with the native meniscus. Non-precultured mesenchymal stem cells in hyaluronan-collagen composite matrices stimulated the development of completely integrated meniscus-like repair tissue. The study shows the necessity of mesenchymal stem cells for the repair of meniscal defects in the avascular zone. Mesenchymal stem cells seem to fulfill additional repair qualities besides the delivery of growth factors.


Citrate synthase from the liver fluke Fasciola hepatica.
Citrate synthase catalyses the first step of the Krebs' tricarboxylic acid cycle. A sequence encoding citrate synthase from the common liver fluke, Fasciola hepatica, has been cloned. The encoded protein sequence is predicted to fold into a largely α-helical protein with high structural similarity to mammalian citrate synthases. Although a hexahistidine-tagged version of the protein could be expressed in Escherichia coli, it was not possible to purify it by nickel-affinity chromatography. Similar results were obtained with a version of the protein which lacks the putative mitochondrial targeting sequence (residues 1 to 29). However, extracts from bacterial cells expressing this version had additional citrate synthase activity after correcting for the endogenous, bacterial activity. The apparent K m for oxaloacetate was found to be 0.22 mM, which is higher than that observed in mammalian citrate synthases. Overall, the sequence and structure of F. hepatica citrate synthase are similar to ones from other eukaryotes, but there are enzymological differences which merit further investigation.