Evaluation of prenatally diagnosed structural congenital anomalies.
To provide information to genetic counsellors, midwives, nurses, and physicians who are involved in the prenatal care of women dealing with prenatally diagnosed isolated or multiple structural congenital anomalies. To provide better counselling for women and families who are dealing with the diagnosis of a fetal structural anomaly. Published literature was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library for relevant articles using appropriate controlled vocabulary (e.g., structural congenital anomalies, prenatal ultrasound diagnosis of congenital anomalies, invasive testing results, and diagnosis of genetic syndromes; soft markers of aneuploidy were not included in this search) and key words. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no date or language restrictions. Searches were updated on a regular basis and material from between 1985 and 2008 incorporated in the guideline. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. The evidence obtained was reviewed by the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Recommendations were quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care. Findings of isolated or multiple fetal anomalies on prenatal ultrasound examination always lead to stressful times for women and families. Although a proportion of such anomalies can be explained by chromosomal abnormalities (aneuploidy, unbalanced translocation, deletions, or duplications), others may represent recognizable syndromes with another genetic basis (microdeletion or autosomal dominant, recessive, or X-linked inheritance). Providing accurate information and relevant reproductive genetic counselling to these women and families will allow them to make informed decisions. This is not easily accomplished because of the limited information available prenatally. This document does not provide an extensive description of every syndrome but rather a framework of reference. No cost-benefit analysis is provided. 1. When a fetal structural anomaly is identified, the pregnant woman should be offered a timely consultation with a trained genetic counsellor and with a maternal-fetal medicine specialist and/or a medical geneticist. The counselling should be unbiased and respectful of the patient's choice, culture, religion, and beliefs. (III-A) 2. Patients should be informed that prenatal ultrasound at 18 to 20 weeks can detect major structural anomalies in approximately 60% of such cases. (II-2A) 3. When a fetal structural anomaly is suspected or identified, a referral to a tertiary ultrasound unit should be made as soon as possible to optimize therapeutic options. (II-2A) 4. In ongoing pregnancies with fetal structural anomalies, ultrasound examination should be repeated (at a frequency depending on the anomaly) to assess the evolution of the anomaly and attempt to detect other anomalies not previously identified, as this may influence the counselling as well as the obstetrical or perinatal management. (II-2B) 5. Once a fetal structural anomaly is identified by 2-D ultrasound, other imaging techniques such as fetal echocardiography, 3-D obstetrical ultrasound, ultrafast fetal MRI, and, occasionally, fetal X-ray and fetal CT scan (using a low-dose protocol) may be helpful in specific cases. (II-2A) 6. Parental imaging should be considered in specific cases, depending on the fetal anomaly identified (e.g., potential dominant inheritance). (III-A) 7. Parental blood testing and invasive prenatal testing may also be required to clarify the diagnosis for a fetus with isolated or multiple structural anomalies. (II-2A) 8. Women should receive information regarding the abnormal ultrasound findings in a clear, sympathetic, and timely fashion, and in a supportive environment that ensures privacy. Referral to the appropriate pediatric or surgical subspecialist(s) should be considered to provide the most accurate information possible concerning the anomaly or anomalies and the associated prognosis. (II-2 B) 9. Parents should be informed that major or minor fetal structural anomalies, whether isolated or multiple, may be part of a genetic syndrome, sequence, or association, despite a normal fetal karyotype. (III-A) 10. If early or urgent postnatal management may be required, delivery at a centre that can provide the appropriate neonatal care should be considered. (III-A) 11. When any congenital structural anomaly has been identified prenatally, a comprehensive newborn assessment is essential for diagnosis and counselling on the etiology, prognosis, and recurrence risk for future pregnancies, especially when the etiology has not been clearly identified prenatally. (III-A) 12. In cases of termination of pregnancy, stillbirth, or neonatal death, the health professional should encourage the performance of a complete autopsy by a perinatal or pediatric pathologist to provide maximum information on the diagnosis and etiology of the structural fetal anomaly or anomalies. When a complete autopsy is refused, the health professional should encourage the performance of at least a partial or external autopsy (including X-rays and photographs). (III-A) VALIDATION: This committee opinion has been prepared by the Genetics Committee of the SOGC and approved by the Executive of the SOGC.


Mechanism-based probing, characterization, and inhibitor design of glycosidases and glycosyltransferases.
Recent structural and kinetic studies indicated that enzymes shift their peripheral structures of the catalytic sites dynamically to modify the substrate structures. Molecules which disturb such mechanism of specific enzymes may become potent candidates for therapeutic reagent. This article describes a versatile strategy to synthesize new class of mechanism-based inhibitors for glycosyltransferases and glycoside hydrolases. Combination of irreversible tagging and proteomic analysis of crucial amino acid residues using MALDI-TOF/TOF mass spectrometry allowed a promising method to probe such invisible transitional state in the enzymatic reactions. Feasibility of the fluorescence energy resonance transfer (FRET) is also documented as novel protocol for the real-time and continuous monitoring of glycosyltransferase catalyzed reactions. It was demonstrated that FRET method greatly facilitates discovery research of selective inhibitors in combination with click chemistry.


Computation of ancestry scores with mixed families and unrelated individuals.
The issue of robustness to family relationships in computing genotype ancestry scores such as eigenvector projections has received increased attention in genetic association, and is particularly challenging when sets of both unrelated individuals and closely related family members are included. The current standard is to compute loadings (left singular vectors) using unrelated individuals and to compute projected scores for remaining family members. However, projected ancestry scores from this approach suffer from shrinkage toward zero. We consider two main novel strategies: (i) matrix substitution based on decomposition of a target family-orthogonalized covariance matrix, and (ii) using family-averaged data to obtain loadings. We illustrate the performance via simulations, including resampling from 1000 Genomes Project data, and analysis of a cystic fibrosis dataset. The matrix substitution approach has similar performance to the current standard, but is simple and uses only a genotype covariance matrix, while the family-average method shows superior performance. Our approaches are accompanied by novel ancillary approaches that provide considerable insight, including individual-specific eigenvalue scree plots.


Hydroxytyrosol, the Major Phenolic Compound of Olive Oil, as an Acute Therapeutic Strategy after Ischemic Stroke.
Stroke is one of the leading causes of adult disability worldwide. After ischemic stroke, damaged tissue surrounding the irreversibly damaged core of the infarct, the penumbra, is still salvageable and is therefore a target for acute therapeutic strategies. The Mediterranean diet (MD) has been shown to lower stroke risk. MD is characterized by increased intake of extra-virgin olive oil, of which hydroxytyrosol (HT) is the foremost phenolic component. This study investigates the effect of an HT-enriched diet directly after stroke on regaining motor and cognitive functioning, MRI parameters, neuroinflammation, and neurogenesis. Stroke mice on an HT diet showed increased strength in the forepaws, as well as improved short-term recognition memory probably due to improvement in functional connectivity (FC). Moreover, mice on an HT diet showed increased cerebral blood flow (CBF) and also heightened expression of brain derived neurotrophic factor (Bdnf), indicating a novel neurogenic potential of HT. This result was additionally accompanied by an enhanced transcription of the postsynaptic marker postsynaptic density protein 95 (Psd-95) and by a decreased ionized calcium-binding adapter molecule 1 (IBA-1) level indicative of lower neuroinflammation. These results suggest that an HT-enriched diet could serve as a beneficial therapeutic approach to attenuate ischemic stroke-associated damage.


Evaluating Intellectual Disability after the Moore v. Texas Redux.
This article reviews the history of the U.S. Supreme Court's rulings on intellectual disability in capital cases, highlighting the difficulty states have had in devising a workable definition that meets constitutional standards. The Court's decisions in Penry v. Lynaugh (1989), Atkins v. Virginia (2002), and Hall v. Florida (2014) are briefly summarized. Next, the Texas Court of Criminal Appeals' ruling in Ex parte Briseno (2004) is discussed as a prelude to the Supreme Court's decision in Moore v. Texas I (2017). On remand, the Texas Court of Criminal Appeals interpreted the Supreme Court's Moore I ruling in a manner that resulted in finding Mr. Moore intellectually able, and therefore eligible for the death penalty, in Ex parte Moore II (2018). Finally, the importance of the Supreme Court's most recent ruling on intellectual disability in capital cases, Moore v. Texas II (2019), is explored in depth. The article concludes with recommendations for best practices among forensic evaluators who assess capital defendants for intellectual disability.


False Computed Tomography Findings in Bilateral Choanal Atresia.
Introduction Choanal atresia (CA) is a challenging surgical problem defined as a failure in the development of communication between the nasal cavity and nasopharynx. Objective The objective of this study is to describe computed tomography (CT) findings in cases with bilateral choanal atresia. Methods The study involved performing axial and coronal non-contrast CT scanning with 2-3 mm sections on14 neonates that had bilateral CA. We used fiberoptic nasal endoscopy to confirm the diagnosis. We evaluated coronal CT to study the skull base area in such neonates. Results This study included 14 neonates with bilateral CA; with mean age of 7 ± 3.5 days. Mixed atretic plates were found in 12 (85.7%) cases while two (14.3%) had pure bony atresia. Isolated CA was detected in 9 cases (64.3%) and 5 (35.7%) cases had associated anomalies. Coronal CT showed soft tissue density in the nasal cavity that appeared to extend through an apparent defect in the nasal roof (cribriform plate), falsely diagnosed by radiologists as associated encephalocele. At the time of surgical repair, all patients showed thick tenacious mucous secretions in both nasal cavities and revealed no encephalocele. Nasal roof remained intact in all cases. Conclusion The thick secretion of bilateral CA could give a false encephalocele appearance on the CT. It is highly recommended to perform proper suction of the nasal cavity of suspected CA cases just before CT scanning.


Practice improvement, part II: update on patient communication technologies.
Patient portals (ie, secure web-based services for patient health record access) and secure messaging to health care professionals are gaining popularity slowly. Advantages of web portals include timely communication and instruction, access to appointments and other services, and high patient satisfaction. Limitations include inappropriate use, security considerations, organizational costs, and exclusion of patients who are uncomfortable with or unable to use computers. Attention to the organization's strategic plan and office policies, patient and staff expectations, workflow and communication integration, training, marketing, and enrollment can facilitate optimal use of this technology. Other communication technologies that can enhance patient care include automated voice or text reminders and brief electronic communications. Social media provide another method of patient outreach, but privacy and access are concerns. Incorporating telehealthcare (health care provided via telephone or Internet), providing health coaching, and using interactive health communication applications can improve patient knowledge and clinical outcomes and provide social support.


Exploring the use of the Psychological Characteristics of Developing Excellence (PCDEs) in younger age groups: First steps in the validation process of the PCDE Questionnaire for Children (PCDEQ-C).
Athletes who want to benefit most optimally and efficient from the Talent Development (TD) pathway, should start developing their psychological characteristics at a young age. The Psychological Characteristics Developing Excellence Questionnaire-Version 2 (PCDEQ2) can provide a full assessment of the mental characteristics athletes need. However, the PCDEQ2 has only been validated in adolescent athletes and as a consequence its does not contribute to the understanding of these psychological skills in a younger age group. The main purpose of this study was to take a first step in examining the factor structure and reliability of the Psychological Characteristics of Developing Excellence Questionnaire for Children (PCDEQ-C), a questionnaire based on the PCDEQ- 2. Firstly, the original questionnaire was translated to Dutch, age-adapted and redesigned for implementation in young athletes. Secondly, 774 participants (400 girls) from Flanders, Belgium, between 7 and 13 years (mean age of 10.61 ± 1.58) old filled out the questionnaire. After exploratory factor analysis, a new factor structure for the PCDEQ-C deemed an acceptable fit with 51 items in 5 factors. In the third stage, the reliability showed a good overall and internal consistency, with adequate relations between factors. The first steps in the validation process of the PCDEQ-C, suggest that this questionnaire could be a useful and reliable tool to assess the developmental psychological characteristics of 7-to-13-year-old athletes. The questionnaire is one of the first formative assessment tools to monitor and develop the psychological characteristics needed during the earliest talent development stages of a young athlete.


Thyroid Function and Cancer Risk: The Rotterdam Study.
In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results. We aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting. The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T4 (FT4) and/or TSH were available. Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically. Higher FT4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval [CI], 1.12-1.79), lung cancer (HR, 2.33; 95% CI, 1.39-3.92) and breast (HR, 1.77; 95% CI, 1.10-2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk. Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.


Loneliness and hypervigilance to social cues in females: an eye-tracking study.
The goal of the present study was to examine whether lonely individuals differ from nonlonely individuals in their overt visual attention to social cues. Previous studies showed that loneliness was related to biased post-attentive processing of social cues (e.g., negative interpretation bias), but research on whether lonely and nonlonely individuals also show differences in an earlier information processing stage (gazing behavior) is very limited. A sample of 25 lonely and 25 nonlonely students took part in an eye-tracking study consisting of four tasks. We measured gazing (duration, number of fixations and first fixation) at the eyes, nose and mouth region of faces expressing emotions (Task 1), at emotion quadrants (anger, fear, happiness and neutral expression) (Task 2), at quadrants with positive and negative social and nonsocial images (Task 3), and at the facial area of actors in video clips with positive and negative content (Task 4). In general, participants tended to gaze most often and longest at areas that conveyed most social information, such as the eye region of the face (T1), and social images (T3). Participants gazed most often and longest at happy faces (T2) in still images, and more often and longer at the facial area in negative than in positive video clips (T4). No differences occurred between lonely and nonlonely participants in their gazing times and frequencies, nor at first fixations at social cues in the four different tasks. Based on this study, we found no evidence that overt visual attention to social cues differs between lonely and nonlonely individuals. This implies that biases in social information processing of lonely individuals may be limited to other phases of social information processing. Alternatively, biased overt attention to social cues may only occur under specific conditions, for specific stimuli or for specific lonely individuals.


POU5F1 promotes the proliferation, migration, and invasion of gastric cancer cells by reducing the ubiquitination level of TRAF6.
POU5F1 plays an important role in maintaining the cancer stem cell (CSC) -like properties of gastric cancer (GC) cells. The impact of POU5F1 on the proliferation and metastasis of GC was examined, along with the potential of ATRA as a specific therapeutic agent for GC. The dysregulation of POU5F1 expression in GC tissues was analyzed using public databases and bioinformatics techniques, and the disparity in POU5F1 expression between normal gastric tissues and GC tissues was further assessed through western blot, RT-qPCR, and immunohistochemistry. The present study aimed to investigate the impact of POU5F1 on the proliferation, migration, and invasion of GC cells through both in vivo and in vitro experiments. Additionally, the effects of ATRA on the proliferation, migration, and invasion of GC cells were examined using in vivo and in vitro approaches. Our findings revealed a significant upregulation of POU5F1 in GC tissues, which was found to be associated with a poorer prognosis in patients with GC. Moreover, POU5F1 was observed to enhance the proliferation, migration, and invasion of GC cells in vitro, as well as promote subcutaneous tumor growth and lung metastasis of GC cells in vivo. The overexpression of POU5F1 mechanistically triggers the process of Epithelial-mesenchymal transition (EMT) by down-regulating E-Cadherin and up-regulating N-Cadherin and VIM. POU5F1 hinders the ubiquitination of TRAF6 through negative regulation of TRIM59, thereby facilitating the activation of the NF-κB pathway. Furthermore, the administration of ATRA effectively impedes the proliferation, migration, and invasion of GC cells by suppressing the expression of POU5F1. The upregulation of POU5F1 elicits EMT, fosters the initiation of the NF-κB signaling pathway in GC cells, and stimulates the proliferation, invasion, and metastasis of GC cells. All-trans retinoic acid (ATRA) can impede these POU5F1-induced effects, thereby potentially serving as an adjunctive therapeutic approach for GC.


[Increased hair growth during prolonged tocolytic therapy with fenoterol. Measurements of testosterone, androstandiol, cortisol and ACTH (author's transl)].
28 patients out of 30 treated with a longtime i.v. infusion of Fenoterol showed an intensive hair growth all-over the skin not especially showing the Linea alba and the beard. To investigate the normal hair growth during pregnancy we examined 384 volontiers just before delivery. 2,8% showed an android hair growth and 3,6% a more intensive hair growth all over the skin. To investigate the role of hormones in the excessive hair growth following i.v. tocolysis with Fenoterol, we measured Testosterone, 5 a-androstan-3 beta-17 beta-diol, Cortisol and ACTH. In contrast to the reports in literature we found a decrease in Testosterone during the treatment with Fenoterol. After an initial fall Androstandiol showed a slight rise in the 3rd week of therapy. ACTH and Cortisol remained unchanged. Contrary to the literature we did not see any augmentation of plasma Cortisol. We conclude, that androgen metabolites are not the reason for the intensive hair growth. The hair growth may be due to a more intensive metabolism within the hair follicle.


[Prophylactic syrups for population of environmentally polluted areas].
The formulas and manufacture technology of the prophylactic syrups for population living in zones of radioactive pollution were developed. The basic raw material for syrups were infusions of herb having various radioprotective properties. As additional raw material was used food supplement "Adaptin".


Assessment of Executive Functions in Methamphetamine-addicted Individuals: Emphasis on Duration of Addiction and Abstinence.
Several studies have conducted on impairments of executive functions in individuals with methamphetamine addiction; however, only a few have investigated the relationship between executive functions and duration of addiction or abstinence. This study was designed to assess the executive functions in methamphetamine-addicted individuals in relation to the duration of addiction or abstinence. A total of 161 subjects aged between 20 and 45 years were categorized into three subgroups: currently abusing (n=41), abstinent (n=60), and control healthy individuals (n=60). A battery of standardized executive function tasks, including Stroop test, Wisconsin Card Sorting test, and Tower of London task, were administered. Data were analyzed using Pearson correlation coefficient, analysis of variance, and post hoc Bonferroni test with SPSS16.0. Methamphetamine-addicted and abstinent subjects performed worse than the controls. Methamphetamine-abstinent subjects performed better than the currently methamphetamine abusers in most executive functions. Duration of addiction and abstinence were correlated with executive dysfunctions. This study revealed that although executive functions may be improved by protracted abstinence, executive dysfunctions are not completely relieved, and specific attention to planning and implementation of intervention programs are necessary.


Inhibitory effect of palmitate on the mitochondrial NADH:ubiquinone oxidoreductase (complex I) as related to the active-de-active enzyme transition.
Palmitate rapidly and reversibly inhibits the uncoupled NADH oxidase activity catalysed by activated complex I in inside-out bovine heart submitochondrial particles (IC50 extrapolated to zero enzyme concentration is equal to 9 microM at 25 degrees C, pH 8.0). The NADH:hexa-ammineruthenium reductase activity of complex I is insensitive to palmitate. Partial (approximately 50%) inhibition of the NADH:external quinone reductase activity is seen at saturating palmitate concentration and the residual activity is fully sensitive to piericidin. The uncoupled succinate oxidase activity is considerably less sensitive to palmitate. Only a slight stimulation of tightly coupled respiration with NADH as the substrate is seen at optimal palmitate concentrations, whereas complete relief of the respiratory control is observed with succinate as the substrate. Palmitate prevents the turnover-induced activation of the de-activated complex I (IC50 extrapolated to zero enzyme concentration is equal to 3 microM at 25 degrees C, pH 8.0). The mode of action of palmitate on the NADH oxidase is qualitatively temperature-dependent. Rapid and reversible inhibition of the complex I catalytic activity and its de-active to active state transition are seen at 25 degrees C, whereas the time-dependent irreversible inactivation of the NADH oxidase proceeds at 37 degrees C. Palmitate drastically increases the rate of spontaneous de-activation of complex I in the absence of NADH. Taken together, these results suggest that free fatty acids act as specific complex I-directed inhibitors; at a physiologically relevant temperature (37 degrees C), their inhibitory effects on mitochondrial NADH oxidation is due to perturbation of the pseudo-reversible active-de-active complex I transition.


The yexA gene product is required for phosphoribosylformylglycinamidine synthetase activity in Bacillus subtilis.
The yexA gene encodes an 84 amino acid reading frame; in Bacillus subtilis it is positioned between the purC and purQ genes of the purine biosynthetic operon. Disruption of yexA resulted in a purine-auxotrophic phenotype. When yexA was expressed in trans it was able to complement a yexA mutation. Growth experiments and enzyme analysis of yexA mutant strains revealed a defective phosphoribosylformylglycinamidine synthetase (FGAM synthetase). In the organisms in which FGAM synthetase has been studied a single polypeptide is responsible for activity. In some organisms two separate genes - in B. subtilis the purL and purQ genes - encode polypeptides with similarity to the N-terminal and the C-terminal region, respectively, of the single-polypeptide FGAM synthetase. Thus, active FGAM synthetase in B. subtilis requires the yexA gene product in addition to the purL and purQ gene products. Open reading frames with sequence similarity to yexA are found in other Gram-positive organisms, in a cyanobacterium and in methanogenic archaea. The designation purS is proposed for this novel function in purine biosynthesis in B. subtilis.


Perioperative neurocognitive and functional neuroimaging trajectories in older APOE4 carriers compared with non-carriers: secondary analysis of a prospective cohort study.
Cognitive dysfunction after surgery is a major issue in older adults. Here, we determined the effect of APOE4 on perioperative neurocognitive function in older patients. We enrolled 140 English-speaking patients ≥60 yr old scheduled for noncardiac surgery under general anaesthesia in an observational cohort study, of whom 52 underwent neuroimaging. We measured cognition; Aβ, tau, p-tau levels in CSF; and resting-state intrinsic functional connectivity in six Alzheimer's disease-risk regions before and 6 weeks after surgery. There were no significant APOE4-related differences in cognition or CSF biomarkers, except APOE4 carriers had lower CSF Aβ levels than non-carriers (preoperative median CSF Aβ [median absolute deviation], APOE4 305 pg ml-1 [65] vs 378 pg ml-1 [38], respectively; P=0.001). Controlling for age, APOE4 carriers had significantly greater preoperative functional connectivity than non-carriers between several brain regions implicated in Alzheimer's disease, including between the left posterior cingulate cortex and left angular gyrus (β [95% confidence interval, CI], 0.218 [0.137-0.230]; PFWE=0.016). APOE4 carriers, but not non-carriers, experienced significant connectivity decreases from before to 6 weeks after surgery between several brain regions including between the left posterior cingulate cortex and left angular gyrus (β [95% CI], -0.196 [-0.256 to -0.136]; PFWE=0.001). Most preoperative and postoperative functional connectivity differences did not change after controlling for preoperative CSF Aβ levels. Postoperative change trajectories for cognition and CSF Aβ, tau or p-tau levels did not differ between community dwelling older APOE4 carriers and non-carriers. APOE4 carriers showed greater preoperative functional connectivity and greater postoperative decreases in functional connectivity in key Alzheimer's disease-risk regions, which occur via Aβ-independent mechanisms.


Prognostic impact of peripelvic fat invasion in pT3 renal pelvic transitional cell carcinoma.
Renal pelvic transitional cell carcinoma (TCC), which invades beyond muscularis into peripelvic fat or the renal parenchyma, is diagnosed as stage pT3 despite its structural complexity. We evaluated the prognostic impact of peripelvic fat invasion in pT3 renal pelvic TCC. Between 1986 and 2004, the medical records on 128 patients who were surgically treated for renal pelvic TCC were retrospectively reviewed. Sixty patients with pT3 disease were eligible for the main analysis. The prognostic impact of various clinicopathological factors was analyzed using univariate and multivariate analyses. On univariate analysis, sex, age, concomitant bladder tumors, concomitant ureter tumors, lymphadenectomy, adjuvant chemotherapy, tumor grade, multiplicity, renal parenchymal invasion, and carcinoma in situ did not influence the disease-specific survival (p>0.05). By contrast, peripelvic fat invasion, lymph node invasion, and lymphovascular invasion were each significantly associated with disease-specific survival (p<0.05). Multivariate analysis showed that peripelvic fat invasion (p=0.012) and lymph node invasion (p=0.004) were independent prognostic factors. In conclusion, peripelvic fat invasion is a strong prognostic factor in pT3 renal pelvic TCC. Thus, systemic adjuvant therapy should be considered in the presence of peripelvic fat invasion, even if the lymph nodes are not involved.


Overdiagnosis in primary care: framing the problem and finding solutions.
Overdiagnosis, is defined as the diagnosis of a condition that, if unrecognized, would not cause symptoms or harm a patient during his or her lifetime, and it is increasingly acknowledged as a consequence of screening for cancer and other conditions. Because preventive care is a crucial component of primary care, which is delivered to the broad population, overdiagnosis in primary care is an important problem from a public health perspective and has far reaching implications. The scope of overdiagnosis as a result of services delivered in primary care is unclear, though overdiagnosis of indolent breast, prostate, thyroid, and lung cancers is well described and overdiagnosis of chronic kidney disease, depression, and attention-deficit/hyperactivity disorder is also recognized. However, overdiagnosis is a known consequence of all screening and can be assumed to occur in many more clinical contexts. Overdiagnosis can harm patients by leading to overtreatment (with associated potential toxicities), diagnosis related anxiety or depression, and labeling, or through financial burden. Many entrenched factors facilitate overdiagnosis, including the growing use of advanced diagnostic technology, financial incentives, a medical culture that encourages greater use of tests and treatments, limitations in the evidence that obscure the understanding of diagnostic utility, use of non-beneficial screening tests, and the broadening of disease definitions. Efforts to reduce overdiagnosis are hindered by physicians' and patients' lack of awareness of the problem and by confusion about terminology, with overdiagnosis often conflated with related concepts. Clarity of terminology would facilitate physicians' understanding of the problem and the growth in evidence regarding its prevalence and downstream consequences in primary care. It is hoped that international coordination regarding diagnostic standards for disease definitions will also help minimize overdiagnosis in the future.


RNA expression of the molecular signature genes for metastasis in colorectal cancer.
Colorectal cancer is an endemic disease in the western world. Search for molecular signatures present in primary tumors that predict tumor metastasis potential has been proposed and in particular, a 17-gene molecular signature is associated with poor survival in breast cancer, prostate cancer, meduloblastoma and lymphoma in a recent study. Using quantitative real-time PCR assay (qPCR), our study observed tumor-normal differential RNA expression in 15 of these 17 genes in a cohort of 52 stage III colorectal cancer patients (all p<0.05), which signified the importance of these 17 signature genes in colorectal cancer. Although no significant correlation was found between tumor RNA levels of these 17 genes and some of clinical features (age, gender, and location, all p>0.05), two distinct groups among these genes were observed with Spearman correlation scores>0.6 (p<0.01), suggesting co-expression/interaction within these genes. Of the 37 patients for whom complete follow-up data was available, 12 patients had recurrence and 25 had no recurrence. There was no significant difference in tumor RNA levels between recurrence and non-recurrence groups for the 17 genes (all p>0.05), but the recurrence group had more patients with mucinous tumors (9/12 vs. 7/25, p<0.05) and more lymph node involvement (median 7.2 vs. 2.5, p<0.05) compared to the non-recurrence group. Moreover, survival analysis revealed a significant difference in patient overall survival time between low and high tumor RNA levels for 1 of the 17 genes (PTTG1, p=0.024). Our qPCR validation study confirms the importance of most 17-gene molecular signature genes with differential RNA expression and suggests the relevance of PTTG1 for survival in colorectal cancers.


Iodine intake and status during pregnancy and lactation before and after government initiatives to improve iodine status, in Palmerston North, New Zealand: a pilot study.
Iodine deficiency during pregnancy and lactation may adversely affect fetal and infant development. Two initiatives were introduced in New Zealand to prevent deficiency: (1) mandatory fortification of bread with iodised salt; and (2) provision of a subsidised iodine supplement (150 μg) for all pregnant and breastfeeding women. The aim of this study was to assess iodine intake and status among a self-selecting sample of pregnant and lactating women in Palmerston North, both before and after the two initiatives. Pregnant and breastfeeding women were recruited before (n = 25 and 32; 2009) and after (n = 34 and 36; 2011) the initiatives. Iodine concentration was determined in 24-h urine and breast milk samples using inductively-coupled plasma mass spectrometry. Use of supplements and salt, knowledge of iodine deficiency, and awareness of the initiatives were determined by questionnaire. Median urine iodine concentration (UIC) was higher in 2011 compared with 2009 for both pregnant (85 and 47 μg L(-1) ) and breastfeeding (74 and 34 μg L(-1) ) participants; median UIC were below the cut-offs for adequate iodine status. However, in 2011, the estimated daily iodine intake during pregnancy was 217 μg day(-1) ; 74% of women achieved the Estimated Average Requirement. Knowledge of the initiatives was low, only 28-56% were aware of the need for iodine supplements and only 15-22% were aware of the mandatory addition of iodised salt to bread. Despite initiatives, UIC of these women indicates iodine deficiency, however, dietary intakes appear adequate. Ongoing surveillance of supplement use and iodine status among pregnant and lactating women throughout New Zealand is needed to fully assess the efficacy of the initiatives. Alternative strategies may require evaluation to ensure all women have adequate iodine during pregnancy and breastfeeding.


Thrombolysis for acute ischemic stroke in Joint Commission-certified and -noncertified hospitals in Michigan.
The Joint Commission (JC) for Accreditation of Healthcare Organizations has devised disease specific certification programs for hospitals, including stroke. JC certification as a primary stroke center (PSC) suggests that the hospital has critical measures in place to ensure improving stroke outcomes over the long term. In this study, we focused on the delivery of care for patients with acute ischemic and compared differences in JC-certified and -noncertified centers in Michigan. We performed a systematic chart review of patients with acute ischemic stroke from 10 Michigan hospitals, half of whom were JC-certified PSCs. Sixty charts were randomly chosen from 1 calendar year from each hospital. An experienced nurse performed the data abstraction, and data analysis was performed with the Fisher exact test. A total of 602 charts--of which 302 were from JC-certified PSCs--were chosen for the study. The 2 groups were similar with regard to stroke risk factors except that there were significantly more patients with atrial fibrillation in noncertified centers and there were more African American patients in JC-certified PSCs. Significantly more patients were considered for thrombolytic therapy in JC-certified PSCs compared to noncertified centers (90.4% v 66%; P = .0001). Overall, 3.8% of patients had received thrombolytic therapy without any significant difference between JC-certified PSCs and noncertified centers (4.6% v 3%; adjusted odds ratio 1.64; 95% confidence interval 0.64-4.19; P = .87). However, thrombolysis rates among eligible patients was significantly higher in the JC-certified PSCs (48.2% v 8.8%; P = .0001). The most common reason documented for not giving thrombolytic therapy was late arrival outside the therapeutic window, which was more common in JC-certified PSCs (72.8% v 55.6%; P = .0001) compared to noncertified centers. Seventy-four percent of patients from JC-certified PSCs were discharged home or to inpatient rehabilitation facility compared to 71% (P = .38) from noncertified hospitals. The mean length of stay was marginally shorter in JC-certified PSCs compared to noncertified centers (5.53 v 6.25 days; P = .08). Rates of thrombolysis administration for acute stroke patients across Michigan were low in both JC-certified and noncertified hospitals, although better processes were in place in JC-certified PSCs. While there was no overall difference in the administration of thrombolytic treatment, a greater number of the eligible patients received thrombolysis in the certified centers. There was a tendency to shorter lengths of stay at JC-certified PSCs, but there was no significant difference in discharge to home, inpatient rehabilitation, or inpatient mortality in this study.


Multi-omics examination of Q fever fatigue syndrome identifies similarities with chronic fatigue syndrome.
Q fever fatigue syndrome (QFS) is characterised by a state of prolonged fatigue that is seen in 20% of acute Q fever infections and has major health-related consequences. The molecular mechanisms underlying QFS are largely unclear. In order to better understand its pathogenesis, we applied a multi-omics approach to study the patterns of the gut microbiome, blood metabolome, and inflammatory proteome of QFS patients, and compared these with those of chronic fatigue syndrome (CFS) patients and healthy controls (HC). The study population consisted of 31 QFS patients, 50 CFS patients, and 72 HC. All subjects were matched for age, gender, and general geographical region (South-East part of the Netherlands). The gut microbiome composition was assessed by Metagenomic sequencing using the Illumina HiSeq platform. A total of 92 circulating inflammatory markers were measured using Proximity Extension Essay and 1607 metabolic features were assessed with a high-throughput non-targeted metabolomics approach. Inflammatory markers, including 4E-BP1 (P = 9.60-16 and 1.41-7) and MMP-1 (P = 7.09-9 and 3.51-9), are significantly more expressed in both QFS and CFS patients compared to HC. Blood metabolite profiles show significant differences when comparing QFS (319 metabolites) and CFS (441 metabolites) patients to HC, and are significantly enriched in pathways like sphingolipid (P = 0.0256 and 0.0033) metabolism. When comparing QFS to CFS patients, almost no significant differences in metabolome were found. Comparison of microbiome taxonomy of QFS and CFS patients with that of HC, shows both in- and decreases in abundancies in Bacteroidetes (with emphasis on Bacteroides and Alistiples spp.), and Firmicutes and Actinobacteria (with emphasis on Ruminococcus and Bifidobacterium spp.). When we compare QFS patients to CFS patients, there is a striking resemblance and hardly any significant differences in microbiome taxonomy are found. We show that QFS and CFS patients are similar across three different omics layers and 4E-BP1 and MMP-1 have the potential to distinguish QFS and CFS patients from HC.


Maintaining Genome Integrity during Seed Development in Phaseolus vulgaris L.: Evidence from a Transcriptomic Profiling Study.
The maintenance of genome integrity is crucial in seeds, due to the constant challenge of several endogenous and exogenous factors. The knowledge concerning DNA damage response and chromatin remodeling during seed development is still scarce, especially in Phaseolus vulgaris L. A transcriptomic profiling of the expression of genes related to DNA damage response/chromatin remodeling mechanisms was performed in P. vulgaris seeds at four distinct developmental stages, spanning from late embryogenesis to seed desiccation. Of the 14,001 expressed genes identified using massive analysis of cDNA ends, 301 belong to the DNA MapMan category. In late embryogenesis, a high expression of genes related to DNA damage sensing and repair suggests there is a tight control of DNA integrity. At the end of filling and the onset of seed dehydration, the upregulation of genes implicated in sensing of DNA double-strand breaks suggests that genome integrity is challenged. The expression of chromatin remodelers seems to imply a concomitant action of chromatin remodeling with DNA repair machinery, maintaining genome stability. The expression of genes related to nucleotide excision repair and chromatin structure is evidenced during the desiccation stage. An overview of the genes involved in DNA damage response and chromatin remodeling during P. vulgaris seed development is presented, providing insights into the mechanisms used by developing seeds to cope with DNA damage.


Lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive of Gerstmann-Sträussler-Scheinker disease Pro102Leu.
Gerstmann-Sträussler-Scheinker disease Pro102Leu (GSS102) is a rare autosomal dominant inherited prion disease due to a substitution of proline for leucine at codon 102 in the Prion Protein gene, and characterized by early walking difficulties and much later occurring dementia. We report clinical, electrophysiological and neuroradiological features of seven novel Italian cases of GSS102. The findings in our series support the thesis that early signs of GSS102 (including areflexia, ataxia, lower limb weakness, and painful dysesthesias) are likely due to a caudal myelopathic process, and suggest that GSS102 should be included among the causes of ataxia with areflexia. Moreover, our observations show that in patients with GSS102, as opposed to Friedreich's ataxia and other forms of ataxia with areflexia, nerve conduction studies and somato-sensory evoked potentials are normal, despite the presence of lower limb areflexia. Hence, in subjects with walking difficulties, the presence of lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive or possibly pathognomonic of GSS102, and can easily guide the clinicians to make the diagnosis of this rare neurodegenerative disease.


The influence of aging on poststroke depression using a rat model via middle cerebral artery occlusion.
Poststroke depression (PSD) is the most frequent psychological sequela following stroke. While previous studies describe the impact of age on brain infarct volume, brain edema, and blood-brain barrier (BBB) breakdown following ischemia, the role of age on PSD has yet to be described. Here, we examine the influence of age on PSD progression in a rat model of PSD by middle cerebral artery occlusion (MCAO). One hundred forty-three rats were divided into three groups. 48 rats 20 weeks of age underwent a sham procedure, 51 rats 20 weeks of age had MCAO, and 44 rats 22-26 months of age had MCAO. Groups were further divided into two subgroups. The first subgroup was used to measure infarct lesion volume, brain edema, and BBB breakdown at 24 h. In the second subgroup at 3 weeks after MCAO, rats were subjected to a sucrose preference test, two-way shuttle avoidance task, forced swimming test, and a brain-derived neurotrophic factor (BDNF) protein level measurement. Total and striatal infarct volume, brain edema, and BBB breakdown in the striatum were increased in older rats, as compared with younger rats. While both old and young rats exhibited depressive-like behaviors on each of the behavioral tests and lower BDNF levels post-MCAO, as compared with control rats, there were no differences between old and young rats. Although older rats suffered from larger infarct volumes, increased brain edema and more BBB disruption following MCAO, the lack of behavioral differences between young and old rats suggests that there was no effect of rat age on the incidence of PSD.


The response of dual-species bacterial biofilm to 2% and 5% NaOCl mixed with etidronic acid: A laboratory real-time evaluation using optical coherence tomography.
The addition of etidronic acid (HEDP) to sodium hypochlorite (NaOCl) could increase the antibiofilm potency of the irrigant, whilst maintaining the benefits of continuous chelation. Studies conducted so far have shown that mixing HEDP with NaOCl solutions of relatively low concentration does not compromise the antibiofilm efficacy of the irrigant. However, the working lifespan of NaOCl may decrease resulting in a reduction of its antibiofilm efficacy over time (efficiency). In this regard, continuous irrigant replenishment needs to be examined. This study investigated the response of a dual-species biofilm when challenged with 2% and 5% NaOCl mixed with HEDP for a prolonged timespan and under steady laminar flow. Dual-species biofilms comprised of Streptococcus oralis J22 and Actinomyces naeslundii T14V-J1 were grown on human dentine discs in a constant depth film fermenter (CDFF) for 96 h. Biofilms were treated with 2% and 5% NaOCl, alone or mixed with HEDP. Irrigants were applied under steady laminar flow for 8 min. Biofilm response was evaluated by means of optical coherence tomography (OCT). Biofilm removal, biofilm disruption, rate of biofilm loss and disruption as well as bubble formation were assessed. One-way anova, Wilcoxon's signed-rank test and Kruskal-Wallis H test were performed for statistical analysis of the data. The level of significance was set at a ≤.05. Increasing NaOCl concentration resulted in increased biofilm removal and disruption, higher rate of biofilm loss and disruption and increased bubble formation. Mixing HEDP with NaOCl caused a delay in the antibiofilm action of the latter, without compromising its antibiofilm efficacy. NaOCl concentration dictates the biofilm response irrespective of the presence of HEDP. The addition of HEDP resulted in a delay in the antibiofilm action of NaOCl. This delay affects the efficiency, but not the efficacy of the irrigant over time.


Can alveolar hypoventilation due to kyphoscoliosis be a contraindication to driving?
Road accidents are among the main fatalities worldwide and drowsy driving is a significant cause of road deaths where drivers are at fault. There are well known diseases which impair sensory and cognitive functions and can cause sleepiness during driving. Such diseases can be an important contraindication to driving because they may have an adverse effect on its safety. Thus, medical examinations for drivers should also be directed at identifying any possible conditions posing risks for driving safety. Occupational medicine specialists should look for symptoms of locomotor and sleep-related breathing disorders as these are medical conditions which could preclude a person from driving. In this case report, the authors describe a professional driver with chest deformity and present a pioneering attempt at assessing his medical fitness to drive. It is also explained why scoliosis can impair driving ability and how it should be diagnosed and treated. Finally, the authors describe how they used driving simulator tests as part of their diagnosis and suggest a relevant treatment regimen. Int J Occup Med Environ Health. 2019;32(5):735-45.


Crystal structure of human mitochondrial NAD(P)(+)-dependent malic enzyme: a new class of oxidative decarboxylases.
Background: Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate and CO(2) with the concomitant reduction of NAD(P)(+) to NAD(P)H. They are widely distributed in nature and have important biological functions. Human mitochondrial NAD(P)(+)-dependent malic enzyme (mNAD-ME) may have a crucial role in the metabolism of glutamine for energy production in rapidly dividing cells and tumors. Moreover, this isoform is unique among malic enzymes in that it is a cooperative enzyme, and its activity is controlled allosterically. Results: The crystal structure of human mNAD-ME has been determined at 2.5 Å resolution by the selenomethionyl multiwavelength anomalous diffraction method and refined to 2.1 Å resolution. The structure of the monomer can be divided into four domains; the active site of the enzyme is located in a deep cleft at the interface between three of the domains. Three acidic residues (Glu255, Asp256 and Asp279) were identified as ligands for the divalent cation that is required for catalysis by malic enzymes. Conclusions: The structure reveals that malic enzymes belong to a new class of oxidative decarboxylases. The tetramer of the enzyme appears to be a dimer of dimers. The active site of each monomer is located far from the tetramer interface. The structure also shows the binding of a second NAD(+) molecule in a pocket 35 Å away from the active site. The natural ligand for this second binding site may be ATP, an allosteric inhibitor of the enzyme.


Azidation of β-keto esters and silyl enol ethers with a benziodoxole reagent.
The efficient azidation of β-keto esters and silyl enol ethers using a benziodoxole-derived azide transfer reagent is reported. The azidation of cyclic β-keto esters could be achieved in up to quantitative yields in the absence of any catalyst. In the case of less reactive linear β-keto esters and silyl enol ethers, complete conversion and good yields could be obtained by using a zinc catalyst.


Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator.
A human plasma protein binds to cell-bound C3b, the major cleavage product of the third component of complement. Consequent upon this binding, C3b no longer functions in either the classical or alternative pathways. This C3b inhibitory activity is a property of a protein previously designated beta 1H on the basis of its electrophoretic mobility.


Observations on the Solubility of Skeletal Carbonates in Aqueous Solutions.
Carbonate skeletal materials of marine organisms exhibit a wide range of solubilities in aqueous solutions. In most cases, the dissolution of the carbonate mineral is irreversible and therefore the material can have no true equilibrium solubility. Relative solubilities have been measured in distilled water and in sea water. The least soluble mineral appears to be calcite with low magnesium content; the most soluble is calcite containing 20 to 30 percent MgCO(3) in solid solution. Aragonite has an intermediate solubility.


Reactive hyperemia following one-beat coronary occlusions in the awake dog.
This study was performed to examine the effect of alterations of cardiac activity during brief coronary artery occlusions on the subsequent reactive hyperemic response. Reactive hyperemia following coronary occlusions equal in duration to one cardiac cycle were examined in 12 chronically instrumented awake dogs while heart rate was maintained constant by cardiac pacing. During continuous pacing, one-beat coronary occlusions resulted in reactive hyperemia with excess flow equal to 220 +/- 23% blood flow debt repayment. When coronary occlusions of identical duration were performed while a single cycle of pacing was omitted during the interval of occlusion, the subsequent reactive hyperemia was decreased. Conversely, when coronary occlusion was produced during the first potentiated beat following a single cycle of paired ventricular stimulation, the reactive hyperemia was increased. Since, in the absence of coronary occlusion, omitting a single paced beat caused a transient decrease in coronary flow, while a single cycle of paired ventricular stimulation caused a brief increase in coronary flow, the reactive hyperemic responses were corrected for these perturbations in flow. Despite these corrections, the influence of alterations of myocardial activity during the interval of occlusion persisted, with the decreased reactive hyperemia when occlusion occurred during an omitted beat and increased hyperemia when occlusion was performed during a potentiated beat. These data indicate substantial coupling between myocardial activity during coronary occlusions as brief as one cardiac cycle in duration and the subsequent reactive hyperemic response.


COVID-19-Related Social Isolation Predispose to Problematic Internet and Online Video Gaming Use in Italy.
COVID-19 pandemic and its related containment measures have been associated with increased levels of stress, anxiety and depression in the general population. While the use of digital media has been greatly promoted by national governments and international authorities to maintain social contacts and healthy lifestyle behaviors, its increased access may also bear the risk of inappropriate or excessive use of internet-related resources. The present study, part of the COVID Mental hEalth Trial (COMET) study, aims at investigating the possible relationship between social isolation, the use of digital resources and the development of their problematic use. A cross sectional survey was carried out to explore the prevalence of internet addiction, excessive use of social media, problematic video gaming and binge watching, during Italian phase II (May-June 2020) and III (June-September 2020) of the pandemic in 1385 individuals (62.5% female, mean age 32.5 ± 12.9) mainly living in Central Italy (52.4%). Data were stratified according to phase II/III and three groups of Italian regions (northern, central and southern). Compared to the larger COMET study, most participants exhibited significant higher levels of severe-to-extremely-severe depressive symptoms (46.3% vs. 12.4%; p < 0.01) and extremely severe anxiety symptoms (77.8% vs. 7.5%; p < 0.01). We also observed a rise in problematic internet use and excessive gaming over time. Mediation analyses revealed that COVID-19-related general psychopathology, stress, anxiety, depression and social isolation play a significant role in the emergence of problematic internet use, social media addiction and problematic video gaming. Professional gamers and younger subjects emerged as sub-populations particularly at risk of developing digital addictions. If confirmed in larger and more homogenous samples, our findings may help in shedding light on possible preventive and treatment strategies for digital addictions.


Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations.
Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876).


Rapid adjustment of bird community compositions to local climatic variations and its functional consequences.
The local spatial congruence between climate changes and community changes has rarely been studied over large areas. We proposed one of the first comprehensive frameworks tracking local changes in community composition related to climate changes. First, we investigated whether and how 12 years of changes in the local composition of bird communities were related to local climate variations. Then, we tested the consequences of this climate-induced adjustment of communities on Grinnellian (habitat-related) and Eltonian (function-related) homogenization. A standardized protocol monitoring spatial and temporal trends of birds over France from 2001 to 2012 was used. For each plot and each year, we used the spring temperature and the spring precipitations and calculated three indices reflecting the thermal niche, the habitat specialization, and the functional originality of the species within a community. We then used a moving-window approach to estimate the spatial distribution of the temporal trends in each of these indices and their congruency with local climatic variations. Temperature fluctuations and community dynamics were found to be highly variable in space, but their variations were finely congruent. More interestingly, the community adjustment to temperature variations was nonmonotonous. Instead, unexplained fluctuations in community composition were observed up to a certain threshold of climate change intensity, above which a change in community composition was observed. This shift corresponded to a significant decrease in the relative abundance of habitat specialists and functionally original species within communities, regardless of the direction of temperature change. The investigation of variations in climate and community responses appears to be a central step toward a better understanding of climate change effects on biodiversity. Our results suggest a fine-scale and short-term adjustment of community composition to temperature changes. Moreover, significant temperature variations seem to be responsible for both the Grinnellian and Eltonian aspects of functional homogenization.


Epigenetic silencing of miR-126 contributes to tumor invasion and angiogenesis in colorectal cancer.
microRNAs (miRNAs) have been reported to play a crucial role in regulating a variety of genes pivotal for tumor metastasis. miR-126 is well known as one of the angiogenesis regulatory miRNAs. Recent studies have reported controversial roles of miR-126 in tumor progression. In this study, we sought to investigate the potential roles of miR-126 in colorectal cancer (CRC). By real-time PCR, miR-126 was shown to be downregulated in primary CRC tissues and cell lines. Restoration of miR-126 in CRC cells inhibited cell growth, migration and invasion. Using both in silico prediction and immunoblotting, we found that vascular endothelial growth factor (VEGF) was a target of miR-126. The interaction of miR-126 on the 3'UTR of VEGF mRNA was validated by luciferase reporter assay. Mechanistically, we found that the silencing of miR-126 was induced by promoter methyl-ation of its host gene, EGFL7. Treatment with 5-aza-CdR restored miR-126 expression and thereby led to a decline in VEGF expression. Functionally, due to suppression of VEGF, enhanced miR-126 expression inhibited tumor neovasculature triggered by CRC cells. In conclusion, our findings suggest that DNA methylation-induced silencing of miR-126 contributes, at least in part, to tumor invasion and angiogenesis in CRC, through upregulation of VEGF expression. miR-126 may be a potential target for the therapeutic strategy against CRC.


Structure of the Proteus vulgaris HigB-(HigA)2-HigB toxin-antitoxin complex.
Bacterial toxin-antitoxin (TA) systems regulate key cellular processes to promote cell survival during periods of stress. During steady-state cell growth, antitoxins typically interact with their cognate toxins to inhibit activity presumably by preventing substrate recognition. We solved two x-ray crystal structures of the Proteus vulgaris tetrameric HigB-(HigA)2-HigB TA complex and found that, unlike most other TA systems, the antitoxin HigA makes minimal interactions with toxin HigB. HigB adopts a RelE family tertiary fold containing a highly conserved concave surface where we predict its active site is located. HigA does not cover the solvent-exposed HigB active site, suggesting that, in general, toxin inhibition is not solely mediated by active site hindrance by its antitoxin. Each HigA monomer contains a helix-turn-helix motif that binds to its own DNA operator to repress transcription during normal cellular growth. This is distinct from antitoxins belonging to other superfamilies that typically only form DNA-binding motifs upon dimerization. We further show that disruption of the HigB-(HigA)2-HigB tetramer to a HigBA heterodimer ablates operator binding. Taken together, our biochemical and structural studies elucidate the novel molecular details of the HigBA TA system.


Administration of fatty acids and gonadotrophin secretion in the mature ram.
The addition of lupin grain to a maintenance diet increases circulating concentrations of volatile fatty acids and gonadotrophin secretion in mature rams. The experiments reported in this paper tested whether these responses were linked causally. The first experiment used 24 rams, of which 16 had two intra-ruminal cannulae inserted each, one for infusion of buffer and the other for infusion of volatile fatty acids. The treated rams (n = 8) were infused for 10 h each day with 1 litre of a solution of volatile fatty acids containing 1.93 moles acetate, 1.89 moles propionate and 0.68 moles butyrate, and 2 litres of a buffer solution containing 14.78 moles sodium bicarbonate, 6.39 moles potassium bicarbonate and 2.06 moles sodium chloride. The eight negative control rams were fed to maintenance and four of them were infused intra-ruminally each day with 3 litres of buffer containing the same mass of salts as the treated rams were given. The eight positive control rams were fed the maintenance diet plus a daily supplement of 900 g lupin grain and four of them were also infused with buffer salts. Blood was sampled before treatment, on Day 3 and at the end of the treatment period (Day 10) for measurement of the plasma concentrations of gonadotrophins (LH and FSH), glucose, insulin and cortisol. In the second experiment, another 24 mature rams were fed to maintain constant live weight and, for 12 of them, sodium acetate (127 g), sodium propionate (64 g) and vegetable oil (60 g) were added to the diet every day for 11 days. Blood was sampled before, and at the end of the treatment period for measurement of the plasma concentrations of gonadotrophins, inhibin, glucose and insulin. In Experiment 1, intraruminal infusion of buffer alone did not affect any of the endocrine variables measured. The infusion of fatty acids and buffer did not alter gonadotrophin secretion, but depressed food intake and increased the plasma concentrations of glucose, insulin and cortisol. When the fatty acids were added to the diet (Experiment 2), the pulsatile secretion of LH was stimulated and FSH and inhibin concentrations were increased. Lupin feeding increased LH pulse frequency on Days 5 and 10, but did not affect FSH concentrations. There were no changes in the circulating concentrations of glucose or insulin. The effects of intra-ruminal infusion of fatty acids on cortisol concentrations and appetite, which were completely absent when similar amounts of fatty acids were fed, suggest that such infusions have undesirable, perhaps stressful, side-effects that prevent expression of the reproductive endocrine responses. On the other hand, the stimulation of gonadotrophin secretion following addition of fatty acids to the diet possibly suggests that changes in the plane of nutrition or rams, for example with lupin supplements, stimulates the reproductive centres of the brain via pathways associated with the synthesis or utilisation of fatty acids. These pathways do not seem to involve changes in glucose homeostasis.


Global life-long health benefits of repression of hypothalamic NPY system by central leptin gene therapy.
A minute-to-minute crosstalk between the hypothalamic neuropeptide Y (NPY) network and the hormone leptin is essential for energy homeostasis. Leptin insufficiency i.e. lack of leptin restraint due to genetic and environmental factors on the hypothalamic NPY system confers obesity, a cluster of metabolic afflictions and shorter lifespan. A state-of-the-art gene transfer technology using recombinant adeno-associated viral vector to overcome hypothalamic leptin insufficiency was employed in rodent models of obesity, metabolic syndrome and shorter lifespan. Our findings show that life-long tonic repression of NPY system with a stable increase in leptin availability in the hypothalamus prevented the age-related and high fat-diet-induced obesity, hyperinsulinemia and diabetes and extended lifespan. Additional health benefits include increased energy expenditure and normalization of neuroendocrine control on reproduction, and promotion of brain and bone growth. We propose that central leptin gene therapy or novel long-acting leptin mimetics should be tested clinically to decelerate the worldwide epidemic of obesity, diabetes and shortened lifespan.


MRSA nares swab is a more accurate predictor of MRSA wound infection compared with clinical risk factors in emergency department patients with skin and soft tissue infections.
Skin and soft tissue infections (SSTI) caused by methicillin-resistant Staphylococcus aureus (MRSA) are prevalent in the emergency department (ED). We determined whether MRSA nasal carriage better identifies patients with MRSA wound infection than clinical risk factors or emergency medicine (EM) provider's choice of discharge prescriptions. Adult patients presenting to a large academic medical centre ED in the USA with SSTI between May 2010 and November 2011 were screened. Research assistants administered a questionnaire regarding MRSA risk factors, and MRSA nares swab PCR testing, wound culture results and information on antibiotics prescribed at discharge were collected. Measures of classification accuracy for nares swab, individual risk factors and physician's prescription for MRSA coverage were compared with gold standard wound culture. During the study period, 116 patients with SSTI had both wound cultures and nares swabs for MRSA. S. aureus was isolated in 59.5%, most often MRSA (75.4%). Thirty patients (25.9%) had a positive MRSA nares swab and culture for a sensitivity of 57.7% and specificity of 92.2%. Positive predictive value (PPV) for MRSA nares swab was 85.7% and positive likelihood ratio was 7.4, while negative predictive value was 72.8% and negative likelihood ratio 0.5. None of the individual risk factors nor EM provider's prescription for MRSA coverage had a PPV or positive likelihood ratio higher than nares swabs. MRSA nares swab is a more accurate predictor of MRSA wound infection compared with clinical risk factors or EM provider's choice of antibiotics. MRSA nares swab may be a useful tool in the ED.


Lamellar corneal transplantation in the horse.
Surgical correction of corneal opacities in horses has rarely been documented in detail and is still reported to be in the experimental stage. For this reason, studies of lamellar keratoplasty were conducted on the equine eye using a modified trephine with an adjustable inside quard for grafting of identical discs from the donor and the recipient cornea. Fourteen transplantations, seven with homografts and seven with heterografts, 15 and 9 mm in diameter, were performed. Sharp-edged, vertical, and regular outlined wound margins of the graft and host are essential for good adaptation and healing without tension. The details of instruments used, preoperative preparation, surgical technique, and postoperative care are described. Results indicated that this method is a feasible tool for the repair of corneal defects in the horse and may be usefully employed in an intention to restore vision.


Disability identity development: A systematic review of the literature.
The purpose of this systematic review was to synthesize existing empirical research on disability identity development. This review is organized to present the demographics of participants and types of disabilities represented in the existing data, measures of disability identity development and theoretical models of disability identity development. Electronic databases (EBSCO, PsycINFO, ERIC, and Sociological Abstracts) were searched for all peer reviewed empirical studies published between 1980 and 2017. Articles were excluded if they were theoretical and/or did not include participants with disabilities, or focused on a disability-specific community identity rather than general disability identity. Empirical articles (N = 41) were included in the final review. An overwhelming majority (75.6%) were qualitative in nature, with only 22% of the articles reviewed being quantitative and only 1 that utilized a mixed methods design. The results suggest that disability identity can be considered a unique phenomenon that shapes persons' ways of seeing themselves, their bodies, and their way of interacting with the world. Disability identity development has the potential to become an important factor in developing effective interventions and/or therapies. Identity development is a fundamentally social process, and identities are formed through mirroring, modeling, and recognition through available identity resources, and so it is imperative that able-bodied professionals (i.e., rehabilitation professionals, therapists, teachers and caregivers) working with individuals with disabilities become aware of this developmental process to be able to better support individuals along this journey. (PsycINFO Database Record


A Physiologically Informed Strategy to Effectively Open, Stabilize, and Protect the Acutely Injured Lung.
Acute respiratory distress syndrome (ARDS) causes a heterogeneous lung injury and remains a serious medical problem, with one of the only treatments being supportive care in the form of mechanical ventilation. It is very difficult, however, to mechanically ventilate the heterogeneously damaged lung without causing secondary ventilator-induced lung injury (VILI). The acutely injured lung becomes time and pressure dependent, meaning that it takes more time and pressure to open the lung, and it recollapses more quickly and at higher pressure. Current protective ventilation strategies, ARDSnet low tidal volume (LVt) and the open lung approach (OLA), have been unsuccessful at further reducing ARDS mortality. We postulate that this is because the LVt strategy is constrained to ventilating a lung with a heterogeneous mix of normal and focalized injured tissue, and the OLA, although designed to fully open and stabilize the lung, is often unsuccessful at doing so. In this review we analyzed the pathophysiology of ARDS that renders the lung susceptible to VILI. We also analyzed the alterations in alveolar and alveolar duct mechanics that occur in the acutely injured lung and discussed how these alterations are a key mechanism driving VILI. Our analysis suggests that the time component of each mechanical breath, at both inspiration and expiration, is critical to normalize alveolar mechanics and protect the lung from VILI. Animal studies and a meta-analysis have suggested that the time-controlled adaptive ventilation (TCAV) method, using the airway pressure release ventilation mode, eliminates the constraints of ventilating a lung with heterogeneous injury, since it is highly effective at opening and stabilizing the time- and pressure-dependent lung. In animal studies it has been shown that by "casting open" the acutely injured lung with TCAV we can (1) reestablish normal expiratory lung volume as assessed by direct observation of subpleural alveoli; (2) return normal parenchymal microanatomical structural support, known as alveolar interdependence and parenchymal tethering, as assessed by morphometric analysis of lung histology; (3) facilitate regeneration of normal surfactant function measured as increases in surfactant proteins A and B; and (4) significantly increase lung compliance, which reduces the pathologic impact of driving pressure and mechanical power at any given tidal volume.


From phenomenology to neurophysiological understanding of hallucinations in children and adolescents.
Typically reported as vivid, multisensory experiences which may spontaneously resolve, hallucinations are present at high rates during childhood. The risk of associated psychopathology is a major cause of concern. On the one hand, the risk of developing further delusional ideation has been shown to be reduced by better theory of mind skills. On the other hand, ideas of reference, passivity phenomena, and misidentification syndrome have been shown to increase the risk of self-injury or heteroaggressive behaviors. Cognitive psychology and brain-imaging studies have advanced our knowledge of the mechanisms underlying these early-onset hallucinations. Notably, specific functional impairments have been associated with certain phenomenological characteristics of hallucinations in youths, including intrusiveness and the sense of reality. In this review, we provide an update of associated epidemiological and phenomenological factors (including sociocultural context, social adversity, and genetics, considered in relation to the psychosis continuum hypothesis), cognitive models, and neurophysiological findings concerning hallucinations in children and adolescents. Key issues that have interfered with progress are considered and recommendations for future studies are provided.


The antiangiogenic efficacy of NGR-modified PEG-DSPE micelles containing paclitaxel (NGR-M-PTX) for the treatment of glioma in rats.
Aminopeptidase N (APN), recognized by Asn-Gly-Arg (NGR) peptides, is expressed in the pericytes associated with the BBB, and the main objective of this study is to confirm the hypothesis that NGR-modified DSPE-PEG micelles containing paclitaxel (NGR-M-PTX) can bind to and kill brain tumor angiogenic blood vessels and penetrate into the brain tumor interstitial space, resulting in direct cell death. NGR-M-PTX is prepared by a thin-film hydration method. The in vitro targeting characteristics of NGR-modified micelles on BMEC (murine brain microvascular endothelial cells) were investigated. The effect of NGR-M-PTX on BMEC proliferation and the cytotoxicity of NGR-M-PTX in C6 glioma cells were also tested. The antitumor activity NGR-M-PTX was evaluated in C6 glioma tumor-bearing rats in vivo. The particle size of NGR-M-PTX was approximately 54.2 nm. The drug encapsulation efficiency of NGR-M-PTX was 82.11 ± 2.82%. The cellular coumarin-6 level of NGR-M-coumarin-6 in the BMEC was about 2.2-fold higher than that of M-coumarin-6. BMEC proliferation was significantly inhibited by NGR-M-PTX. NGR-M-PTX had a much lower IC(50) value than M-PTX and free drug. The growth of C6 glioma tumor was markedly inhibited by NGR-M-PTX compared with Taxol. In conclusion, our results show that antiangiogenic therapy using NGR-M-PTX exhibits potent in vivo antitumor activity in a C6 glioma-bearing animal model.


A tool to identify recent or present rheumatoid arthritis flare from both patient and physician perspectives: the 'FLARE' instrument.
There is a lack of consensus about the definition of flare of rheumatoid arthritis (RA) and a measurement tool. To develop a self-administered tool integrating the perspectives of the patient and the rheumatologist, enabling the detection of present or recent-past RA flare. The patient perspective was explored by semistructured individual interviews of patients with RA. Two health psychologists conducted a content analysis to extract items best describing flare from the interviews. The physician's perspective was explored through a Delphi exercise conducted among a panel of 13 rheumatologists. A comprehensive list of items produced in the first round was reduced in a four-round Delphi process to select items cited by at least 75% of the respondents. The identified elements were assembled in domains-each converted into a statement-to constitute the final self-administered Flare Assessment in Rheumatoid Arthritis (FLARE) questionnaire. The content of 99 patient interviews was analysed, and 10 domains were identified: joint swelling or pain, night pain, fatigue and different emotional consequences, as well as analgesic intake. The Delphi process for physicians identified eight domains related to objective RA symptoms and drug intake, of which only four were common to domains for patients. Finally, 13 domains were retained in the FLARE questionnaire, formulated as 13 statements with a Likert-scale response modality of six answers ranging from 'absolutely true' to 'completely untrue'. Two different methods, for patient and physician perspectives, were used to develop the FLARE self-administered questionnaire, which can identify past or present RA flare.


In situ activation of a doxorubicin prodrug using imaging-capable nanoparticles.
A general strategy for image-guided prodrug activation using fluorescently-labeled magnetic iron oxide nanoparticles is described. It is based on a recently developed concept in bio-orthogonal inverse-electron demand Diels-Alder chemistry, which is termed 'click-to-release'. To illustrate a potential new biomedical application of the chemistry, the nanoparticles were modified with tetrazine, as well as near infrared fluorescent (NIRF) cy5.5 dye, while doxorubicin was converted into a prodrug. The nanoparticles taken up by the MDA-MB-231 breast cancer cells efficiently converted the prodrug of doxorubicin into the biologically active chemotherapeutic doxorubicin form.


[Development of diagnostic test system based on fluorescent polarization immunoassay method for detection of antibodies to HCV nucleocapsid protein].
The antigen activity of the synthetic fluorescently labeled peptides, overlapping immunoresponsive epitops a.a. 7-19, 20-34 from N-end part and a.a. 73-85 from the central area of the nucleocapsid protein of C hepatitis virus, was tested using the method of fluorescent polarization immunoassay (FPIA) with 40 samples of the blood serum of patients with viral C hepatitis. A comparative study of analytic characteristics of FPIA method was performed, based on the application of synthesized peptides, as well as of the commercial ELISA test system (BEST anti-HCV-test 4, Vector Best Ltd.). The performed research revealed that the developed method has a high specificity and sensitivity level. The comparability of summary FPIA results with the commercial ELISA test system was 85%, which evidences the prospects of further research in this direction. The principal possibility of the application of the polarization fluorescent immunoassay for the determination of antibodies to the nucleocapsid protein of the C hepatitis virus in clinical serum samples was demonstrated.


Report on five cases of tularaemic pneumonia in a tularaemia outbreak in Spain.
A report is given on five cases of atypical tularaemic pneumonia selected from among 140 cases of tularaemic infection in a previously reported outbreak occurring in 1997. Prior to this outbreak no human cases of tularaemia had been reported in Spain. All cases were diagnosed serologically. All five patients reported on here had a mild form of the disease, which was treated successfully with streptomycin in four cases and ciprofloxacin in one case. Tularaemic pneumonia should be considered in the differential diagnosis of atypical pneumonia in Spain, especially in hunters and other persons who handle animal carcasses.


Clinical interpretation of reference intervals and reference limits. A plea for assay harmonization.
Reference intervals for healthy subjects and diseased populations are important benchmarks for the clinical interpretation of laboratory test values. It is important that the testing conditions used to collect the reference data be closely matched with the testing conditions used for patient data. Interlaboratory differences and intralaboratory changes, especially changes in analytic set-points, can markedly affect the clinical interpretation of tests. If laboratory testing methods could be harmonized, laboratories could potentially share reference data to make these data more reliable. This chapter illustrates the use of reference intervals for healthy subjects and reference data from diseased populations for medical decisions. One example illustrates the effects of age differences on test result interpretation. Other examples illustrate use of thyroid-stimulating hormone (TSH) and combinations of TSH with free thyroxine measurements for diagnosing thyroid diseases. Both univariate and multivariate reference intervals are discussed. Model systems for using disease prevalence and cost utility functions are provided to illustrate optimization of medical decisions.


Complete sequence of a cryptic virus from hemp (Cannabis sativa).
Hemp (Cannabis sativa) was found to be a useful propagation host for hop latent virus, a carlavirus. However, when virus preparations were analysed by electron microscopy, along with the expected filamentous particles, spherical particles with a diameter of around 34 nm were found. RNA from virus preparations was purified, and cDNA was prepared and cloned. Sequence information was used to search databases, and the greatest similarity was found with Primula malacoides virus 1, a putative new member of the genus Partitivirus. The full sequences of RNA 1 and RNA 2 of this new hemp cryptic virus were obtained.


[MHC-multimers and their application in studies of antiviral immune response].
Application of main histocompatibility complex tetrames (MHC-tetramers) for antigen specific T-cells detection and analysis coupled with flow cytometry opened new opportunities for T-cell response analysis. MHC-multimers allow the detection of T-cells against viral, cancer and vaccine antigens with exceptional sensitivity and specificity. This approach has become the "gold standard" for quantative analysis of T-cell immune response. Certain aspects of analysis using MHC-tetramer are examined, and importance of this approach in T-cell response efficacy evaluation in anti-HIV vaccine trials as well as in HIV positive patients are discussed.


Evaluation of cerebral oxygenation in patients undergoing long-term hemodialysis.
Patients undergoing hemodialysis (HD) have higher occurrence rates of cerebral diseases, including uremic encephalopathy, cognitive impairment, dementia, and cerebrovascular disease, than the general population. During HD, ultrafiltration is performed to maintain an adequate fluid condition and is associated with subsequent blood volume (BV) reduction. We aimed to (1) monitor changes in cerebral oxygenation and BV reduction during HD, and (2) clarify the mechanism that influences cerebral oxygenation in HD patients. Eighteen HD patients and 12 healthy controls were recruited. Regional saturation of oxygen (rSO2) was continuously monitored in the frontal cortex using INVOS 5100C before, during, and after HD, and in healthy controls. Relative change in BV (%ΔBV) was simultaneously monitored during HD using a BV monitor. Before HD, patients had significantly lower rSO2 values than controls (56.1 ± 1.4 vs. 70.4 ± 2.5%, p < 0.001). Although %ΔBV significantly decreased from 20 min to the end of HD (20 min: -3.3 ± 0.3%, p < 0.05; end of HD: -12.0 ± 1.0%, p < 0.01), changes in rSO2 values during HD were not significant. No relationship existed between rSO2 values and blood pressure levels, hemoglobin levels, oxygen pressure, HCO3(- ), oxygen saturation, and arterial O2 content before and after HD. Furthermore, changes in rSO2 were not correlated with changes in these parameters. rSO2 values before HD were significantly lower in HD patients than in healthy controls. rSO2 values were maintained during HD and were not influenced by BV reduction.


Successful bone marrow transplantation in a case of Griscelli disease which presented in accelerated phase with neurological involvement.
Griscelli disease (GD) is a rare disorder characterized by pigment dilution, immunodeficiency and occurrence of accelerated phase consisting of hemophagocytosis, pancytopenia and neurological manifestations. Allogeneic BMT in the early period is an important modality of treatment for GD. We carried out an alloBMT from an HLA-identical sibling donor on a 4-year-old girl who presented in accelerated phase with neurological manifestations including convulsions, strabismus, severe dysarthria, ataxia and clonus. She was treated with etoposide, methylprednisolone and intrathecal methotrexate for 8 weeks and underwent alloBMT after receiving a conditioning regimen including ATG (rabbit, 10 mg/kg x 5 days), Bu/Cy. 8 x 108/kg nucleated bone marrow cells were given. Engraftment occurred early and the post-BMT period was uneventful. Currently, she is at 18 months post BMT with sustained engraftment and with a normal neurological examination except for minimal clonus. Long-term follow-up will determine the prognosis regarding the neurological findings.


Concentrations and distributions of metals in tissues of stranded green sea turtles (Chelonia mydas) from the southern Atlantic coast of Brazil.
Silver (Ag), cadmium (Cd), copper (Cu), lead (Pb) and zinc (Zn) concentrations were analyzed in tissues of juvenile green sea turtles (Chelonia mydas) found stranded along the southern Atlantic coast in Brazil. Green sea turtles were collected (n=29), measured (curved carapace length: CCL) and had their muscle, liver, and kidney dissected for metal concentration measurements. Sex was identified in 18 individuals (10 females and 8 males) through gonad histology. No gender differences in CCL and tissue metal concentrations were observed. In the muscle, there was a negative correlation between CCL and Cd and Cu concentrations. Metal concentrations were lower in the muscle than in the liver and kidney. Zn concentration in the muscle was the highest of all metals analyzed (16.6 mg/kg). The kidney showed the highest concentrations of Pb, Cd and Zn (5.4, 28.3 and 54.3 mg/kg, respectively), while the liver had the highest values of Ag and Cu (0.8 and 100.9 mg/kg, respectively). Tissue Ag, Zn and Cd concentrations were similar to those found in green sea turtles from other regions while Cu and Pb values were elevated, likely due to the metal-rich water and sediment reported in the collection area. In the liver and kidney, concentrations of non-essential (Ag, Cd and Pb) and essential (Cu or Zn) metals were positively correlated, likely due to an induced metallothionein synthesis to protect tissue against the toxic effect of metals. This is the first study to report and correlate the concentrations of essential and non-essential metals in tissues of green sea turtles in the Brazilian southern Atlantic coast, an important feeding and developing area for this turtle species.


Peroxisome proliferator-activated receptor-gamma agonists and diabetes: current evidence and future perspectives.
Since their initial availability in 1997, the thiazolidinediones (TZDs) have become one of the most commonly prescribed classes of medications for type 2 diabetes. In addition to glucose control, the TZDs have a number of pleiotropic effects on myriad traditional and non-traditional risk factors for diabetes. TZDs may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function and fibrinolytic state. In this review, we summarise the experimental, preclinical and clinical data regarding the effects of the TZDs in conditions for which they are indicated and discuss their potential in the treatment of other conditions.


Previously unrecognized vaccine candidates control Trypanosoma cruzi infection and immunopathology in mice.
Trypanosoma cruzi is the etiologic agent of Chagas' disease, a major health problem in Latin America and an emerging infectious disease in the United States. Previously, we screened a T. cruzi sequence database by a computational-bioinformatic approach and identified antigens that exhibited the characteristics of good vaccine candidates. In this study, we tested the vaccine efficacy of three of the putative candidate antigens against T. cruzi infection and disease in a mouse model. C57BL/6 mice vaccinated with T. cruzi G1 (TcG1)-, TcG2-, or TcG4-encoding plasmids and cytokine (interleukin-12 and granulocyte-macrophage colony-stimulating factor) expression plasmids elicited a strong Th1-type antibody response dominated by immunoglobulin G2b (IgG2b)/IgG1 isotypes. The dominant IgG2b/IgG1 antibody response was maintained after a challenge infection and was associated with 50 to 90% control of the acute-phase tissue parasite burden and an almost undetectable level of tissue parasites during the chronic phase, as determined by a sensitive T. cruzi 18S rRNA gene-specific real-time PCR approach. Splenocytes from vaccinated-and-infected mice, compared to unvaccinated-and-infected mice, exhibited decreased (approximately 50% lower) proliferation and gamma interferon (IFN-gamma) production when stimulated in vitro with T. cruzi antigens, thus suggesting that protection from challenge infection was not provided by an active T-cell response. Subsequently, the serum and cardiac levels of IFN-gamma and tumor necrosis factor alpha and infiltration of inflammatory infiltrate in the heart were decreased in vaccinated mice during the course of infection and chronic disease development. Taken together, these results demonstrate the identification of novel vaccine candidates that provided protection from T. cruzi-induced immunopathology in experimental mice.


[Bad or mad? Thinking in terms of 'bad or mad' and the (possible) prosecution of offenses committed by the mentally ill].
Psychiatrists working for the outreach emergency services of mental health institutions are regularly asked to assess whether a suspect being held at a police station should be charged and later prosecuted or be admitted to a mental institution. In other words, is the suspect 'suited for detention'. Often the representative of the judicial system and the psychiatrist from the emergency services then discuss whether the suspect would be better served by care under the mental healthcare system or under the criminal judicial system. Compulsorily admission to a mental health institution often leads to exemption from prosecution. To determine what procedure (prison or clinic) will provide the suspect with appropriate care; to find out how to ensure that mentally-ill perpetrators of offences are not assigned erroneously to psychiatric care (i.e. they are 'psychiatricised') and thereby exempted from prosecution, and to determine whether the term 'suited for detention' is applicable to such a person. Data were derived from semi-structured interviews with experts from the acute mental health services, the forensic psychiatric services and the criminal justice system. All topics were based on a literature review and on study of case histories. A decision by the emergency services to admit a suspect to a mental health institution influences the views of the representative of a criminal judicial system with regards to the possible imprisonment of the suspect. Thinking in terms of 'bad or mad' can influence the judicial system to give a psychiatric slant to offences or crimes committed by psychiatric patients. Psychiatrists' interpretation of proper care and often their lack of knowledge about the current care facilities available in prisons meant that psychiatrists were more likely than their forensic colleagues to assign suspects to mental health care. According to forensic psychiatrists, their colleagues from mental health care services should not be concerned about whether a suspect is 'suited' or 'unsuited' for detention; their main concern should be what kind of care and treatment the suspect urgently requires. The role of the representative of the emergency services present at the police station is to decide what type of care is required at that particular moment. Care within the judicial system is an important option; that type of care can be obtained by involving forensic colleagues in the decision. Awareness of the importance of a dual track policy (conviction/punishment or care) should help to prevent unjustified 'psychiatrisation', of both minor and serious offenses.


Atmospheric Spectroscopy and Photochemistry at Environmental Water Interfaces.
The air-water interface is ubiquitous in nature, as manifested in the form of the surfaces of oceans, lakes, and atmospheric aerosols. The aerosol interface, in particular, can play a crucial role in atmospheric chemistry. The adsorption of atmospheric species onto and into aerosols modifies their concentrations and chemistries. Moreover, the aerosol phase allows otherwise unlikely solution-phase chemistry to occur in the atmosphere. The effect of the air-water interface on these processes is not entirely known. This review summarizes recent theoretical investigations of the interactions of atmosphere species with the air-water interface, including reactant adsorption, photochemistry, and the spectroscopy of reactants at the water surface, with an emphasis on understanding differences between interfacial chemistries and the chemistries in both bulk solution and the gas phase. The results discussed here enable an understanding of fundamental concepts that lead to potential air-water interface effects, providing a framework to understand the effects of water surfaces on our atmosphere.


Impact of Comorbid Affective Disorders on Longitudinal Clinical Outcomes in Individuals at Ultra-high Risk for Psychosis.
Diagnoses of anxiety and/or depression are common in subjects at Ultra-High Risk for Psychosis (UHR) and associated with extensive functional impairment. Less is known about the impact of affective comorbidities on the prospective course of attenuated psychotic symptoms (APS). Latent class mixed modelling identified APS trajectories in 331 UHR subjects assessed at baseline, 6, 12, and 24 months follow-up. The prognostic value of past, baseline, and one-year DSM-IV depressive or anxiety disorders on trajectories was investigated using logistic regression, controlling for confounders. Cox proportional hazard analyses investigated associations with transition risk. 46.8% of participants fulfilled the criteria for a past depressive disorder, 33.2% at baseline, and 15.1% at one-year follow-up. Any past, baseline, or one-year anxiety disorder was diagnosed in 42.9%, 37.2%, and 27.0%, respectively. Participants were classified into one of three latent APS trajectory groups: (1) persistently low, (2) increasing, and (3) decreasing. Past depression was associated with a higher risk of belonging to the increasing trajectory group, compared to the persistently low (OR = 3.149, [95%CI: 1.298-7.642]) or decreasing group (OR = 3.137, [1.165-8.450]). In contrast, past (OR = .443, [.179-1.094]) or current (OR = .414, [.156-1.094]) anxiety disorders showed a trend-level association with a lower risk of belonging to the increasing group compared to the persistently low group. Past depression was significantly associated with a higher risk of transitioning to psychosis (HR = 2.123, [1.178-3.828]). A past depressive episode might be a particularly relevant risk factor for an unfavorable course of APS in UHR individuals. Early affective disturbances may be used to advance detection, prognostic, and clinical strategies.