Bipolar disorder and comorbid alcoholism: prevalence rate and treatment considerations.
Classic Kraepelian observations and contemporary epidemiological studies have noted a high prevalence rate between bipolar disorder and alcoholism. The extent to which these two illnesses are comorbid (i.e., two distinct disease processes each with an independent course of illness), genetically linked, or different phenotypic expressions of bipolar illness itself continues to be investigated. It is increasingly clear that co-occurring alcohol abuse or dependence in bipolar disorder phenomenologically changes the illness presentation with higher rates of mixed or dysphoric mania, rapid cycling, increased symptom severity, and higher levels of novelty seeking, suicidality, aggressivity, and impulsivity. It is very encouraging that interest and efforts at evaluating pharmacotherapeutic compounds has substantially increased over the past few years in this difficult-to-treat patient population. This article will review the clinical studies that have evaluated the effectiveness of conventional mood stabilizers (lithium, carbamazepine, divalproex, and atypical antipsychotics) in the treatment of alcohol withdrawal and relapse prevention in patients with alcoholism and in the treatment of bipolar disorder with comorbid alcoholism. A number of add-on, adjunctive medications, such as naltrexone, acamprosate, topiramate, and the atypical antipsychotics quetiapine and clozapine, may be candidates for further testing.


G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial).
Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo. STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34+ cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment. The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals. Eudract 2014-002228-28.


Targeting STAT3 affects melanoma on multiple fronts.
As a point of convergence for numerous oncogenic signaling pathways, STAT3 is constitutively-activated at 50 to 90% frequency in diverse human cancers, including melanoma. A critical role of STAT3 in tumor cell survival, proliferation, angiogenesis, metastasis and immune evasion has been recently demonstrated. STAT3 contributes to tumor cell growth by regulating the expression of genes that are involved in cell survival and proliferation. STAT3 promotes metastasis and angiogenesis by inducing expression of the metastatic gene, MMP-2, and the potent angiogenic gene, VEGF. STAT3 participates in the regulation of tumor immune evasion by inhibiting expression of proinflammatory mediators while promoting expression of immune-suppressing factors, which in turn activates STAT3 signaling in dendritic cells leading to immune tolerance. Thus, targeting STAT3 for therapy assaults cancer on multiple fronts. Many of the studies that defined STAT3's role in oncogenesis were carried out in melanoma cells and tumor models. In this review, we summarize the key role of STAT3 in cancer in general and melanoma in particular. With the emergence of small-molecule drugs that directly inhibit STAT3 or the oncogenic signaling pathways upstream of STAT3 in melanoma, a promising novel approach for melanoma therapy is emerging.


Midwife-led versus other models of care for childbearing women.
Midwives are primary providers of care for childbearing women around the world. However, there is a lack of synthesised information to establish whether there are differences in morbidity and mortality, effectiveness and psychosocial outcomes between midwife-led and other models of care. To compare midwife-led models of care with other models of care for childbearing women and their infants. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (January 2008), Cochrane Effective Practice and Organisation of Care Group's Trials Register (January 2008), Current Contents (1994 to January 2008), CINAHL (1982 to August 2006), Web of Science, BIOSIS Previews, ISI Proceedings, (1990 to 2008), and the WHO Reproductive Health Library, No. 9. All published and unpublished trials in which pregnant women are randomly allocated to midwife-led or other models of care during pregnancy, and where care is provided during the ante- and intrapartum period in the midwife-led model. All authors evaluated methodological quality. Two authors independently checked the data extraction. We included 11 trials (12,276 women). Women who had midwife-led models of care were less likely to experience antenatal hospitalisation, risk ratio (RR) 0.90, 95% confidence interval (CI) 0.81 to 0.99), the use of regional analgesia (RR 0.81, 95% CI 0.73 to 0.91), episiotomy (RR 0.82, 95% CI 0.77 to 0.88), and instrumental delivery (RR 0.86, 95% CI 0.78 to 0.96) and were more likely to experience no intrapartum analgesia/anaesthesia (RR 1.16, 95% CI 1.05 to 1.29), spontaneous vaginal birth (RR 1.04, 95% CI 1.02 to 1.06), to feel in control during labour and childbirth (RR 1.74, 95% CI 1.32 to 2.30), attendance at birth by a known midwife (RR 7.84, 95% CI 4.15 to 14.81) and initiate breastfeeding (RR 1.35, 95% CI 1.03 to 1.76). In addition, women who were randomised to receive midwife-led care were less likely to experience fetal loss before 24 weeks' gestation (RR 0.79, 95% CI 0.65 to 0.97), and their babies were more likely to have a shorter length of hospital stay (mean difference -2.00, 95% CI -2.15 to -1.85). There were no statistically significant differences between groups for overall fetal loss/neonatal death (RR 0.83, 95% CI 0.70 to 1.00), or fetal loss/neonatal death of at least 24 weeks (RR 1.01, 95% CI 0.67 to 1.53). All women should be offered midwife-led models of care and women should be encouraged to ask for this option.


Assessing satisfaction with social care services among black and minority ethnic and white British carers of stroke survivors in England.
Overall satisfaction levels with social care are usually high but lower levels have been reported among black and minority ethnic (BME) service users in England. Reasons for this are poorly understood. This qualitative study therefore explored satisfaction with services among informal carer participants from five different ethnic groups. Fifty-seven carers (black Caribbean, black African, Asian Indian, Asian Pakistani and white British) were recruited from voluntary sector organisations and a local hospital in England, and took part in semi-structured interviews using cognitive interviewing and the critical incident technique. Interviews took place from summer 2013 to spring 2014. Thematic analysis of the interviews showed that participants often struggled to identify specific 'incidents', especially satisfactory ones. When describing satisfactory services, participants talked mostly about specific individuals and relationships. Unsatisfactory experiences centred on services overall. When rating services using cognitive interviewing, explicit comparisons with expectations or experiences with other services were common. Highest satisfaction ratings tended to be justified by positive personal characteristics among practitioners, trust and relationships. Lower level ratings were mostly explained by inconsistency in services, insufficient or poor care. Lowest level ratings were rare. Overall, few differences between ethnic groups were identified, although white British participants rated services higher overall giving more top ratings. White British participants also frequently took a more overall view of services, highlighting some concerns but still giving top ratings, while South Asian carers in particular focused on negative aspects of services. Together these methods provide insight into what participants mean by satisfactory and unsatisfactory services. Cognitive interviewing was more challenging for some BME participants, possibly a reflection of the meaningfulness of the concept of service satisfaction to them. Future research should include comparisons between BME and white participants' understanding of the most positive parts of satisfaction scales and should focus on dissatisfied participants.


Carcinogenesis Bioassay of Agar (CAS No. 9002-18-0) in F344 Rats and B6C3F1 Mice (Feed Study).
A carcinogenesis bioassay of agar isolated from Pterocladia, a gelling agent used in foods and pharmaceuticals, was conducted on groups of 50 F344 rats and 50 B6C3F1 mice of either sex which were fed diets containing 25,000 or 50,000 ppm of the test substance for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. Mean body weights of dosed and control male rats were comparable throughout the study. After week 80, mean body weights of dosed female rats were slightly lower than those of the controls. Mean body weights of dosed and control male mice were comparable throughout the study. The mean body weights of dosed female mice were lower than those of the controls at week 20 and remained lower throughout the study. No compound-related effects on survival, feed consumption, clinical signs of toxicity, or tumor incidence were observed. Although the rats of either sex and male mice might have been able to tolerate higher doses, 50,000 ppm was the administered high-dose level since that is the maximum concentration of a test substance in feed recommended in the guidelines of the BioassayProgram. A statistically significant trend (P=0.015) was observed for the increased incidence of cortical adenomas of the adrenal gland (control, 0/50; low-dose, 0/50; high-dose, 4/50) in female rats; the difference between control and high-dose groups was not significant. In male mice the incidence of hepatocellular adenomas (control, 0/49; low-dose, 3/50; high-dose, 7/50) was significantly (P=0.007) increased in the high-dose group when compared with controls; likewise, the overall trend was significant (P=0.005). The incidence of total liver tumors (control, 9/49; low-dose, 8/50; high-dose, 13/50) did not differ significantly among the groups. Neither of these increases (in cortical adenomas or in liver tumors) was considered to be compound related. Under the conditions of this bioassay, the agar isolated from Pterocladia was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative


The role of reactive oxygen species in triggering proliferation and IL-2 secretion in T cells.
This paper examines the hypothesis that reactive oxygen species (ROS) play an important role as second messengers in T cell activation. Activation of T cells with phorbol ester in combination with either calcium ionophore, or anti-CD3 antibody results in a large rapid flux of ROS activity. In contrast, co-stimulation with CD28 does not enhance ROS activity. The ROS signal was sensitive to ascorbic acid, desferrioxamine and dimethyl sulfoxide, suggesting that the major active species being generated was the hydroxyl radical, probably by iron-catalyzed decomposition of hydrogen peroxide. The generation of ROS in T cells was regulated by an accessory population within the peripheral blood. An anti-CD2 antibody induced a strong ROS flux, suggesting that the CD2/LFA-3 interaction may be important in this regulation. T cell activation was inhibited by the same panel of anti-oxidants as ROS generation, but much higher concentrations were required for inhibition of proliferation and IL-2 release than those required to block ROS generation. These data imply that ROS are not obligate second messengers for initiation of T cell activation. The results are compatible, however, with a role for activation-dependent T cell ROS generation in modulating the overall T cell response via autocrine and paracrine signalling pathways.


Comparative study of osteoarthritis of the contralateral knee joint of male amputees who do and do not play volleyball.
To assess the prevalence of osteoarthritis (OA) of the contralateral knee of men with traumatic amputation who do and do not participate in regular, vigorous physical activity. Three groups of patients were assessed. Group 1 consisted of 8 male amputee volleyball players. Group 2 consisted of 24 male amputees who do not play volleyball, and Group 3 was made up of 24 healthy controls matched by age and weight to Group 2. The prevalence of contralateral knee OA in Groups 1 and 2 was assessed by questionnaire, physical examination, and radiographs, and was compared with findings for Group 3. The rate of OA in all amputees (Groups 1 and 2 together) was 65.6%, which was significantly higher than among the controls (p < 0.05). The most common findings among the amputees were patellar and medial osteophytosis of the tibiofemoral joint, with a tendency to medial narrowing of the tibiofemoral joint space. Traumatic amputees have a higher prevalence of OA in the knee of the nonamputated leg than matched healthy controls.


Borrelia-induced cytokine production is mediated by spleen tyrosine kinase (Syk) but is Dectin-1 and Dectin-2 independent.
Although it is known that Borrelia species express sugar-like structures on their outer surface, not much is known about the role of these structures in immune recognition by host cells. Fungi, like Candida albicans, are mainly recognized by C-type lectin receptors, in specific Dectin-1 and Dectin-2. In this study we assessed the role of Dectin-1 and Dectin-2 in the recognition process of Borrelia spirochetes. Using specific inhibitors against these receptors on human cells did not influenced cytokine production. Individuals carrying a SNP leading to an early stop codon in the DECTIN-1 gene also did not lead to differential induction of Borrelia-dependent cytokines. After injection of live Borrelia into knee joints of Dectin-2 deficient mice a trend towards lower inflammation was observed. Inhibition of Syk in human cells resulted in lower cytokine production after Borrelia stimulation. In conclusion, Dectin-1 and Dectin-2 seem not to play a major role in Borrelia recognition or Borrelia-induced inflammation. However, Syk seems to be involved in Borrelia-induced cytokine production.


Mortality in HIV infection is independently predicted by host iron status and SLC11A1 and HP genotypes, with new evidence of a gene-nutrient interaction.
Iron-related genes and iron status may independently contribute to variable HIV outcomes. The nature of the biologically plausible gene-nutrient interaction remains unknown. The objectives were to investigate whether iron-related genotypes and clinically abnormal iron status independently predict mortality in HIV and whether a gene-nutrient interaction exists. Baseline plasma, DNA, and clinical data were obtained from 1362 HIV-seropositive Gambian adults followed for 11.5 y to ascertain all-cause mortality. Iron status was estimated on the basis of plasma iron, soluble transferrin receptor (sTfR), ferritin, transferrin, transferrin index, and log(sTfR/ferritin). One haptoglobin (HP) and 5 SLC11A1 (NRAMP1) polymorphisms were genotyped. SLC11A1-SLC3 and CAAA polymorphisms were the best independent genetic predictors of mortality [adjusted mortality rate ratio (95% CI)]: SLC3:G/C = 0.59 (95% CI: 0.45, 0.85), CAAA:del/ins = 1.51 (95% CI: 1.10, 2.07). In an adjusted model that included all polymorphisms, SLC1:199/199, SLC1:other/other, SLC6a:A/A, and CAAA:del/ins were associated with significantly greater mortality, whereas Hp 2-1 and SLC3:G/C were protective. In unadjusted analyses, all biomarker concentrations were significantly associated with mortality. In an extension of previous findings, both low and elevated iron states were associated with mortality, but the nature of the risk was variable, with linear, inversely linear, and U-shaped associations depending on the biomarker. Mortality was significantly lower in HIV-2 than in HIV-1 infection in the presence of abnormal (low or elevated) iron status. A gene-iron interaction was detected (likelihood-ratio test P = 0.018); however, subject numbers restricted category-specific interpretation. Iron-related genes, iron status, and their interaction predict mortality in HIV. These findings illustrate the complexity and uncertainty surrounding best practice for managing abnormal iron status and anemia during HIV infection and in regions with a high risk of infection.


Participatory indicator development: what can ecologists and local communities learn from each other?
Given the growing popularity of indicators among policy-makers to measure progress toward conservation and sustainability goals, there is an urgent need to develop indicators that can be used accurately by both specialists and nonspecialists, drawing from the knowledge possessed by each group. This paper uses a case study from the Kalahari, Botswana to show how participatory and ecological methods can be combined to develop robust indicators that are accessible to a range of users to monitor and enhance the sustainability of land management. First, potential environmental sustainability indicators were elicited from pastoralists in three study sites. This knowledge was then evaluated by pastoralists, before being tested empirically using ecological and soil-based techniques. Despite the wealth of local knowledge about indicators, this knowledge was thinly spread. The knowledge was more holistic than published indicator lists for monitoring rangelands, encompassing vegetation, soil, livestock, wild animal, and socioeconomic indicators. Pastoralist preferences for vegetation and livestock indicators match recent shifts in ecological theory suggesting that livestock populations reach equilibrium with key forage resources in semiarid environments. Although most indicators suggested by pastoralists were validated through empirical work (e.g., decreased grass cover and soil organic matter content, and increased abundance of Acacia mellifera and thatching grass), they were not always sufficiently accurate or reliable for objective degradation assessment, showing that local knowledge cannot be accepted unquestioningly. We suggest that, by combining participatory and ecological approaches, it is possible to derive more accurate and relevant indicators than either approach could achieve alone.


Enhanced antitumor activity of low-dose continuous administration schedules of topotecan in prostate cancer.
The objective of this study was to determine the antitumor effects of alternate dosing schedules of topotecan in prostate cancer. A concentration-dependent increase in cytotoxicity was observed in PC-3 and LNCaP cells after topotecan treatment using conventional and metronomic protocols. A significant increase in potency (2.4-18 fold, after 72 hr) was observed following metronomic dosing compared to conventional dosing administration in both cell lines. Metronomic dosing also increased the percentage of PC-3 cells in the G2/M, compared to control, but did not alter LNCaP cell cycle distribution. Metronomic dosing increased p21 protein expression in LNCaP and PC-3 cells compared to conventional dosing. The observed in vitro activity was confirmed using an in vivo model of human prostate cancer. Metronomic dosing and continuous infusion decreased tumor volume significantly (p < 0.05) compared to control and conventional topotecan treatment, but had no effect on tumor vascular staining. The cytotoxicity of topotecan after conventional or metronomic dosing was determined by examining cellular morphology, mitochondrial enzymatic activity (MTT), total cellular protein (SRB), annexin V and propidium iodine (PI) staining, cell cycle and western blot analysis in human prostate cancer cell lines (PC-3 and LNCaP) and the effects metronomic or continuous infusion on tumor growth in an in vivo tumor xenograft model. These data support the hypothesis that low-dose continuous administration of topotecan increases potency compared to conventional dosing in prostate cancer. These data also suggest the novel finding that the enhanced antitumor activity of topotecan following low-dose exposure correlates to alterations in cell cycle and increased p21 expression.


Myocardial ischaemia and post-systolic shortening.
The assessment of regional wall motion is useful to identify myocardial ischaemia because wall motion abnormalities occur relatively upstream in the ischaemic cascade. Echocardiography is widely used for this, but the subjectivity of visual observation may hamper accurate evaluation. The analysis of myocardial velocity and strain by tissue Doppler and speckle tracking echocardiography has allowed the quantitative assessment of regional wall motion and facilitated the detection of subtle myocardial deformation that is difficult to identify by conventional methods, such as post-systolic shortening (PSS). PSS is defined as myocardial shortening that occurs after end-systole (or aortic valve closure), and it is observed in the myocardium with regional contractile dysfunction. In experimental and clinical studies, it has been reported that the assessment of PSS is superior to that of conventional parameters such as wall thickening or peak systolic strain in detecting acute ischaemia and diagnosing coronary artery disease. Moreover, it has recently been found that PSS remains after recovery from brief ischaemia despite the rapid recovery of peak systolic strain. The assessment of PSS allows after-the-fact recognition of myocardial ischaemic insults and is expected to be used for ischaemic memory imaging. In this review, the usefulness of the assessment of PSS for the diagnosis of acute ischaemia and ischaemic memory is demonstrated, and issues that need to be resolved for the widespread use of this assessment in the echocardiographic laboratory are discussed.


The effectiveness of depression care management on diabetes-related outcomes in older patients.
Depression frequently occurs in combination with diabetes mellitus, adversely affecting the course of illness. To determine whether enhancing care for depression improves affective and diabetic outcomes in older adults with diabetes and depression. Preplanned subgroup analysis of the Improving Mood-Promoting Access to Collaborative Treatment (IMPACT) randomized, controlled trial. 18 primary care clinics from 8 health care organizations in 5 states. 1801 patients 60 years of age or older with depression; 417 had coexisting diabetes mellitus. A care manager offered education, problem-solving treatment, or support for antidepressant management by the patient's primary care physician; diabetes care was not specifically enhanced. Assessments at baseline and at 3, 6, and 12 months for depression, functional impairment, and diabetes self-care behaviors. Hemoglobin A(1c) levels were obtained for 293 patients at baseline and at 6 and 12 months. At 12 months, diabetic patients who were assigned to intervention had less severe depression (range, 0 to 4 on a checklist of 20 depression items; between-group difference, -0.43 [95% CI, -0.57 to -0.29]; P < 0.001) and greater improvement in overall functioning (range, 0 [none] to 10 [unable to perform activities]; between-group difference, -0.89 [CI, -1.46 to -0.32]) than did participants who received usual care. In the intervention group, weekly exercise days increased (between-group difference, 0.50 day [CI, 0.12 to 0.89 day]; P = 0.001); other self-care behaviors were not affected. At baseline, mean (+/-SD) hemoglobin A1c levels were 7.28% +/- 1.43%; follow-up values were unaffected by the intervention (P > 0.2). Because patients had good glycemic control at baseline, power to detect small but clinically important improvements in glycemic control was limited. Collaborative care improves affective and functional status in older patients with depression and diabetes; however, among patients with good glycemic control, such care minimally affects diabetes-specific outcomes.


A bioengineered peripheral nerve construct using aligned peptide amphiphile nanofibers.
Peripheral nerve injuries can result in lifelong disability. Primary coaptation is the treatment of choice when the gap between transected nerve ends is short. Long nerve gaps seen in more complex injuries often require autologous nerve grafts or nerve conduits implemented into the repair. Nerve grafts, however, cause morbidity and functional loss at donor sites, which are limited in number. Nerve conduits, in turn, lack an internal scaffold to support and guide axonal regeneration, resulting in decreased efficacy over longer nerve gap lengths. By comparison, peptide amphiphiles (PAs) are molecules that can self-assemble into nanofibers, which can be aligned to mimic the native architecture of peripheral nerve. As such, they represent a potential substrate for use in a bioengineered nerve graft substitute. To examine this, we cultured Schwann cells with bioactive PAs (RGDS-PA, IKVAV-PA) to determine their ability to attach to and proliferate within the biomaterial. Next, we devised a PA construct for use in a peripheral nerve critical sized defect model. Rat sciatic nerve defects were created and reconstructed with autologous nerve, PLGA conduits filled with various forms of aligned PAs, or left unrepaired. Motor and sensory recovery were determined and compared among groups. Our results demonstrate that Schwann cells are able to adhere to and proliferate in aligned PA gels, with greater efficacy in bioactive PAs compared to the backbone-PA alone. In vivo testing revealed recovery of motor and sensory function in animals treated with conduit/PA constructs comparable to animals treated with autologous nerve grafts. Functional recovery in conduit/PA and autologous graft groups was significantly faster than in animals treated with empty PLGA conduits. Histological examinations also demonstrated increased axonal and Schwann cell regeneration within the reconstructed nerve gap in animals treated with conduit/PA constructs. These results indicate that PA nanofibers may represent a promising biomaterial for use in bioengineered peripheral nerve repair.


Emotions, Alexithymia, and Emotion Regulation in Patients With Psoriasis.
Psoriasis is a chronic dermatological condition that is frequently associated with problematic patterns of emotional reactivity (the way in which patients react to stimuli), alexithymia (their ability to recognize and label the emotional reaction), and emotion regulation (the ability to enhance or reduce their own emotional reaction). A research in the peer-reviewed scientific literature was conducted in order to identify articles describing the association of psoriasis and affective problems. In particular, we first evaluate studies that have investigated abnormal emotional reactivity (in terms of duration, frequency, or type of the experienced emotions) and its impact on patients' quality of life; next, we review the role of alexithymia and emotion regulation in modulating the relationship between emotional reactivity and quality of life in this population. From a critical analysis of the reviewed studies, we highlight that altered emotional processing might be particularly important in the characterization of this condition. In particular, we show that this condition is related to an emotional reactivity characterized by negative emotions that have a stronger impact on patients' quality of life when emotion regulation abilities are weak, especially if patients have alexithymia. Finally, we present suggestions for future directions in both clinical and research fields.


The paradox of music-evoked sadness: an online survey.
This study explores listeners' experience of music-evoked sadness. Sadness is typically assumed to be undesirable and is therefore usually avoided in everyday life. Yet the question remains: Why do people seek and appreciate sadness in music? We present findings from an online survey with both Western and Eastern participants (N = 772). The survey investigates the rewarding aspects of music-evoked sadness, as well as the relative contribution of listener characteristics and situational factors to the appreciation of sad music. The survey also examines the different principles through which sadness is evoked by music, and their interaction with personality traits. Results show 4 different rewards of music-evoked sadness: reward of imagination, emotion regulation, empathy, and no "real-life" implications. Moreover, appreciation of sad music follows a mood-congruent fashion and is greater among individuals with high empathy and low emotional stability. Surprisingly, nostalgia rather than sadness is the most frequent emotion evoked by sad music. Correspondingly, memory was rated as the most important principle through which sadness is evoked. Finally, the trait empathy contributes to the evocation of sadness via contagion, appraisal, and by engaging social functions. The present findings indicate that emotional responses to sad music are multifaceted, are modulated by empathy, and are linked with a multidimensional experience of pleasure. These results were corroborated by a follow-up survey on happy music, which indicated differences between the emotional experiences resulting from listening to sad versus happy music. This is the first comprehensive survey of music-evoked sadness, revealing that listening to sad music can lead to beneficial emotional effects such as regulation of negative emotion and mood as well as consolation. Such beneficial emotional effects constitute the prime motivations for engaging with sad music in everyday life.


Effects of hyperinsulinemia in the primate fetus.
Nonhuman primate models of gestational diabetes have produced fetopathies most similar to those of the human infant of the mother with gestational diabetes (IGDM). Fetal hyperglycemia, hyperinsulinemia, macrosomia, selective organomegaly, intrauterine death, and placental hyperplasia are hallmarks of the fetopathy of the IGDM. The chronic infusion of insulin into the fetus of a normal pregnant rhesus monkey results in fetal hyperinsulinemia with normal to low plasma metabolic substrate concentrations. Under these conditions, fetal hyperinsulinemia is sufficient to cause fetal growth and hormone changes observed in the human IGDM. Our studies provide evidence that the soft tissue hyperplasia in the fetal macrosomia syndromes in humans and nonhuman primates in which fetal hyperinsulinemia is observed is the direct result of that chronic in utero hyperinsulinemia.


Physical Activity During the Early Years: A Systematic Review of Correlates and Determinants.
Being physically active during the early years (age 0-6 years) is vital for healthy development. Identifying correlates and determinants of physical activity (PA) is crucial to guide effective interventions. This systematic review synthesized studies investigating potential correlates and determinants of PA during the early years, accounting for different types of PA assessment. Nine electronic databases were searched from inception year (1900) until September 2014; data were analyzed/interpreted in April 2015. The following inclusion criteria were used: written in English, published in peer-reviewed journals, participants not in statutory/school education, and an observational design investigating associations between an exposure/variable, and a quantitative measure of PA. Correlates/determinants of total, moderate to vigorous, and light PA were reported using an ecologic model. Of 22,045 identified studies, 130 were included. All took place in high-income countries and few (6%) were of high quality. Correlates of total PA were sex (male, ++); parental PA (+); parental support (+); and time outdoors (+). Determinants of total PA were sex (+) and time spent playing with parents (+). The only correlate of moderate to vigorous PA was sex (male, ++). No determinants of moderate to vigorous or light PA were found. PA correlates/determinants were relatively consistent between objective and subjective PA measures. Numerous studies investigated potential correlates and determinants of PA, but overall quality was low. A small number of demographic/biological and social/cultural factors were associated with PA. There is a need for high-quality studies exploring correlates/determinants across all domains of the ecologic model.


The effectiveness of choline citrate infusions monitored by lymphocyte transformation test (LTT) in multiple sclerosis. A new approach to the diagnosis and treatment of the disease.
The efficacy of intravenous choline citrate infusions was investigated in 34 patients with multiple sclerosis (MS) by clinical evaluation and by monitoring of lymphocyte proliferation in vitro against fragments of myelin basic protein (MOG-35-55, MBP15-31, PLP 39-15) over a period of 12 weeks. Patients have been diagnosed with MS at least one year before entering the study and suffered from mild relapsing/remitting course to long-term chronic progressive disease. Twenty one patients exhibited positive lymphocyte proliferation to myelin fragments prior to treatment and were therefore selected for further studies. Choline citrate was administered with a dosage of 1200mg/ 2x week for a period of 3 months. This treatment resulted in a significant decrease of lymphocyte proliferation to neural fragments (MOG- 35-55, MBP15-31) in lymphocyte transformation test (LTT). There was no significant SI change of PLP Peptide (PLP 39-15) LTT found after treatment with choline citrate. During the 3 mo observation period, patients remained stable and no side-effects of the treatment were observed. In addition, some patients reported long-lasting improvement (less paresthesia and increase of muscle strength in lower extremities) which was demonstrated up to 3 years later. In one spectacular case a commercial pilot was able to return to duty again after treatment. This pilot was allowed back in to his position as a commercial flying cockpit member and is on duty for more than 4 yrs now.


Efficient uranium capture by polysulfide/layered double hydroxide composites.
There is a need to develop highly selective and efficient materials for capturing uranium (normally as UO2(2+)) from nuclear waste and from seawater. We demonstrate the promising adsorption performance of S(x)-LDH composites (LDH is Mg/Al layered double hydroxide, [S(x)](2-) is polysulfide with x = 2, 4) for uranyl ions from a variety of aqueous solutions including seawater. We report high removal capacities (q(m) = 330 mg/g), large K(d)(U) values (10(4)-10(6) mL/g at 1-300 ppm U concentration), and high % removals (>95% at 1-100 ppm, or ∼80% for ppb level seawater) for UO2(2+) species. The S(x)-LDHs are exceptionally efficient for selectively and rapidly capturing UO2(2+) both at high (ppm) and trace (ppb) quantities from the U-containing water including seawater. The maximum adsorption coeffcient value K(d)(U) of 3.4 × 10(6) mL/g (using a V/m ratio of 1000 mL/g) observed is among the highest reported for U adsorbents. In the presence of very high concentrations of competitive ions such as Ca(2+)/Na(+), S(x)-LDH exhibits superior selectivity for UO2(2+), over previously reported sorbents. Under low U concentrations, (S4)(2-) coordinates to UO2(2+) forming anionic complexes retaining in the LDH gallery. At high U concentrations, (S4)(2-) binds to UO2(2+) to generate neutral UO2S4 salts outside the gallery, with NO3(-) entering the interlayer to form NO3-LDH. In the presence of high Cl(-) concentration, Cl(-) preferentially replaces [S4](2-) and intercalates into LDH. Detailed comparison of U removal efficiency of S(x)-LDH with various known sorbents is reported. The excellent uranium adsorption ability along with the environmentally safe, low-cost constituents points to the high potential of S(x)-LDH materials for selective uranium capture.


Hydrogen peroxide generation and biocompatibility of hydrogel-bound mussel adhesive moiety.
To decouple the extracellular oxidative toxicity of catechol adhesive moiety from its intracellular non-oxidative toxicity, dopamine was chemically bound to a non-degradable polyacrylamide hydrogel through photo-initiated polymerization of dopamine methacrylamide (DMA) with acrylamide monomers. Network-bound dopamine released cytotoxic levels of H2O2 when its catechol side chain oxidized to quinone. Introduction of catalase at a concentration as low as 7.5 U/mL counteracted the cytotoxic effect of H2O2 and enhanced the viability and proliferation rate of fibroblasts. These results indicated that H2O2 generation is one of the main contributors to the cytotoxicity of dopamine in culture. Additionally, catalase is a potentially useful supplement to suppress the elevated oxidative stress found in typical culture conditions and can more accurately evaluate the biocompatibility of mussel-mimetic biomaterials. The release of H2O2 also induced a higher foreign body reaction to catechol-modified hydrogel when it was implanted subcutaneously in rat. Given that H2O2 has a multitude of biological effects, both beneficiary and deleterious, regulation of H2O2 production from catechol-containing biomaterials is necessary to optimize the performance of these materials for a desired application.


Performing and processing FNA of anterior fat pad for amyloid.
Historically, heart, liver, and kidney biopsies were performed to demonstrate amyloid deposits in amyloidosis. Since the clinical presentation of this disease is so variable and non-specific, the associated risks of these biopsies are too great for the diagnostic yield. Other sites that have a lower biopsy risk, such as skin or gingival, are also relatively invasive and expensive. In addition, these biopsies may not always have sufficient amyloid deposits to establish a diagnosis. Fat pad aspiration has demonstrated good clinical correlation with low cost and minimal morbidity. However, there are no standardized protocols for performing this procedure or processing the aspirated specimen, which leads to variable and nonreproducible results. The most frequently utilized modality for detecting amyloid in tissue is an apple-green birefringence on Congo red stained sections using a polarizing microscope. This technique requires cell block preparation of aspirated material. Unfortunately, patients presenting in early stage of amyloidosis have minimal amounts of amyloid which greatly reduces the sensitivity of Congo red stained cell block sections of fat pad aspirates. Therefore, ultrastructural evaluation of fat pad aspirates by electron microscopy should be utilized, given its increased sensitivity for amyloid detection. This article demonstrates a simple and reproducible procedure for performing anterior fat pad aspiration for the detection of amyloid utilizing both Congo red staining of cell block sections and electron microscopy for ultrastructural identification.


Linkage disequilibrium and age of HLA region SNPs in relation to classic HLA gene alleles within Europe.
The HLA region on chromosome 6 is gene-rich and under selective pressure because of the high proportion of immunity-related genes. Linkage disequilibrium (LD) patterns and allele frequencies in this region are highly differentiated across broad geographical populations, making it a region of interest for population genetics and immunity-related disease studies. We examined LD in this important region of the genome in six European populations using 166 putatively neutral SNPs and the classical HLA-A, -B and -C gene alleles. We found that the pattern of association between classic HLA gene alleles and SNPs implied that most of the SNPs predated the origin of classic HLA gene alleles. The SNPs most strongly associated with HLA gene alleles were in some cases highly predictive of the HLA allele carrier status (misclassification rates ranged from <1 to 27%) in independent populations using five or fewer SNPs, a much smaller number than tagSNP panels previously proposed and often with similar accuracy, showing that our approach may be a viable solution to designing new HLA prediction panels. To describe the LD within this region, we developed a new haplotype clustering method/software based on r(2), which may be more appropriate for use within regions of strong LD. Haplotype blocks created using this proposed method, as well as classic HLA gene alleles and SNPs, were predictive of a northern versus southern European population membership (misclassification error rates ranged from 0 to 23%, depending on which independent population was used for prediction), indicating that this region may be a rich source of ancestry informative markers.


A BAYESIAN MARK INTERACTION MODEL FOR ANALYSIS OF TUMOR PATHOLOGY IMAGES.
With the advance of imaging technology, digital pathology imaging of tumor tissue slides is becoming a routine clinical procedure for cancer diagnosis. This process produces massive imaging data that capture histological details in high resolution. Recent developments in deep-learning methods have enabled us to identify and classify individual cells from digital pathology images at large scale. Reliable statistical approaches to model the spatial pattern of cells can provide new insight into tumor progression and shed light on the biological mechanisms of cancer. We consider the problem of modeling spatial correlations among three commonly seen cells observed in tumor pathology images. A novel geostatistical marking model with interpretable underlying parameters is proposed in a Bayesian framework. We use auxiliary variable MCMC algorithms to sample from the posterior distribution with an intractable normalizing constant. We demonstrate how this model-based analysis can lead to sharper inferences than ordinary exploratory analyses, by means of application to three benchmark datasets and a case study on the pathology images of 188 lung cancer patients. The case study shows that the spatial correlation between tumor and stromal cells predicts patient prognosis. This statistical methodology not only presents a new model for characterizing spatial correlations in a multitype spatial point pattern conditioning on the locations of the points, but also provides a new perspective for understanding the role of cell-cell interactions in cancer progression.


Analysis of Anticancer Activity and Chemical Sensitization Effects of Dendropanax morbifera and Commersonia bartramia Extracts.
Dendropanax morbifera (DM) and Commersonia bartramia (CB) are possible candidates for immunotherapy. In this study, the cytotoxicity and chemical sensitization of DM and CB extracts on gynecologic and colon cancers were evaluated. The malignant cell lines were cultured and analyzed for cytotoxicity and chemical sensitization. A mouse model was also constructed to make the condition similar to in vivo. Reverse transcription-polymerase chain reaction was conducted to determine alterations in drug-resistant genes. The extracts from DM and CB showed specific cytotoxicity to malignant cell lines. DM increased chemical sensitivity to cervical and ovarian cancer, while CB showed improved sensitization to endometrial cancer. The effects of the extracts were confirmed using a mouse model. The extracts induced differences in the expression levels of a number of genes related to drug resistance. DM and CB extracts could be novel agents for immunotherapy and chemical sensitization in gynecologic and colon cancers.


Kv3.1 channels stimulate adult neural precursor cell proliferation and neuronal differentiation.
Adult neural stem/precursor cells (NPCs) play a pivotal role in neuronal plasticity throughout life. Among ion channels identified in adult NPCs, voltage-gated delayed rectifier K(+) (KDR) channels are dominantly expressed. However, the KDR channel subtype and its physiological role are still undefined. We used real-time quantitative RT-PCR and gene knockdown techniques to identify a major functional KDR channel subtype in adult NPCs. Dominant mRNA expression of Kv3.1, a high voltage-gated KDR channel, was quantitatively confirmed. Kv3.1 gene knockdown with specific small interfering RNAs (siRNA) for Kv3.1 significantly inhibited Kv3.1 mRNA expression by 63.9% (P < 0.001) and KDR channel currents by 52.2% (P < 0.001). This indicates that Kv3.1 is the subtype responsible for producing KDR channel outward currents. Resting membrane properties, such as resting membrane potential, of NPCs were not affected by Kv3.1 expression. Kv3.1 knockdown with 300 nm siRNA inhibited NPC growth (increase in cell numbers) by 52.9% (P < 0.01). This inhibition was attributed to decreased cell proliferation, not increased cell apoptosis. We also established a convenient in vitro imaging assay system to evaluate NPC differentiation using NPCs from doublecortin-green fluorescent protein transgenic mice. Kv3.1 knockdown also significantly reduced neuronal differentiation by 31.4% (P < 0.01). We have demonstrated that Kv3.1 is a dominant functional KDR channel subtype expressed in adult NPCs and plays key roles in NPC proliferation and neuronal lineage commitment during differentiation.


Solvent-type-dependent polymorphism and charge transport in a long fused-ring organic semiconductor.
Crystalline polymorphism of organic semiconductors is among the critical factors in determining the structure and properties of the resultant organic electronic devices. Herein we report for the first time a solvent-type-dependent polymorphism of a long fused-ring organic semiconductor and its crucial effects on charge transport. A new polymorph of 5,11-bis(triethylsilylethynyl)anthradithiophene (TES ADT) is obtained using solvent-assisted crystallization, and the crystalline polymorphism of TES ADT thin films is correlated with their measured hole mobilities. The best-performing organic thin film transistors of the two TES ADT polymorphs show subthreshold slopes close to 1 V dec(-1), and threshold voltages close to zero, indicating that the density of traps at the semiconductor-dielectric interface is negligible in these devices and the observed up to 10-fold differences in hole mobilities of devices fabricated with different solvents are largely resultant from the presence of two TES ADT polymorphs. Moreover, our results suggest that the best-performing TES ADT devices reported in the literature correspond to the new polymorph identified in this study, which involves crystallization from a weakly polar solvent (such as toluene and chloroform).


Chronic hypoxia suppresses the CO2 response of solitary complex (SC) neurons from rats.
We studied the effect of chronic hypobaric hypoxia (CHx; 10-11% O(2)) on the response to hypercapnia (15% CO(2)) of individual solitary complex (SC) neurons from adult rats. We simultaneously measured the intracellular pH and firing rate responses to hypercapnia of SC neurons in superfused medullary slices from control and CHx-adapted adult rats using the blind whole cell patch clamp technique and fluorescence imaging microscopy. We found that CHx caused the percentage of SC neurons inhibited by hypercapnia to significantly increase from about 10% up to about 30%, but did not significantly alter the percentage of SC neurons activated by hypercapnia (50% in control vs. 35% in CHx). Further, the magnitudes of the responses of SC neurons from control rats (chemosensitivity index for activated neurons of 166+/-11% and for inhibited neurons of 45+/-15%) were the same in SC neurons from CHx-adapted rats. This plasticity induced in chemosensitive SC neurons by CHx appears to involve intrinsic changes in neuronal properties since they were the same in synaptic blockade medium.


Ca2+-dependent cytoprotective effects of ursodeoxycholic and tauroursodeoxycholic acid on the biliary epithelium in a rat model of cholestasis and loss of bile ducts.
Chronic cholestatic liver diseases are characterized by impaired balance between proliferation and death of cholangiocytes, as well as vanishing of bile ducts and liver failure. Ursodeoxycholic acid (UDCA) is a bile acid widely used for the therapy of cholangiopathies. However, little is known of the cytoprotective effects of UDCA on cholangiocytes. Therefore, UDCA and its taurine conjugate tauroursodeoxycholic acid (TUDCA) were administered in vivo to rats simultaneously subjected to bile duct ligation and vagotomy, a model that induces cholestasis and loss of bile ducts by apoptosis of cholangiocytes. Because these two bile acids act through Ca2+ signaling, animals were also treated with BAPTA/AM (an intracellular Ca2+ chelator) or Gö6976 (a Ca2+-dependent protein kinase C-alpha inhibitor). The administration of UDCA or TUDCA prevented the induction of apoptosis and the loss of proliferative and functional responses observed in the bile duct ligation-vagotomized rats. These effects were neutralized by the simultaneous administration of BAPTA/AM or Gö6976. UDCA and TUDCA enhanced intracellular Ca2+ and IP3 levels, together with increased phosphorylation of protein kinase C-alpha. Parallel changes were observed regarding the activation of the MAPK and PI3K pathways, changes that were abolished by addition of BAPTA/AM or Gö6976. These studies provide information that may improve the response of cholangiopathies to medical therapy.


Temperature-Controlled Delivery of Radiofrequency Energy in Fecal Incontinence: A Randomized Sham-Controlled Clinical Trial.
Controlled delivery of radiofrequency energy has been suggested as treatment for fecal incontinence. The aim of this study was to determine whether the clinical response to the radiofrequency energy procedure is superior to sham in patients with fecal incontinence. This was a randomized sham-controlled clinical trial from 2008 to 2015. This study was conducted in an outpatient clinic. Forty patients with fecal incontinence in whom maximal conservative management had failed were randomly assigned to receiving either radiofrequency energy or sham procedure. Fecal incontinence was measured using the Vaizey incontinence score (range, 0-24). The impact of fecal incontinence on quality of life was measured by using the fecal incontinence quality-of-life score (range, 1-4). Measurements were performed at baseline and at 6 months. Anorectal function was evaluated using anal manometry and anorectal endosonography at baseline and at 3 months. At baseline, Vaizey incontinence score was 16.8 (SD 2.9). At t = 6 months, the radiofrequency energy group improved by 2.5 points on the Vaizey incontinence score compared with the sham group (13.2 (SD 3.1), 15.6 (SD 3.3), p = 0.02). The fecal incontinence quality-of-life score at t = 6 months was not statistically different. Anorectal function did not show any alteration. Patients with severe fecal incontinence were included in the study, thus making it difficult to generalize the results. Both radiofrequency energy and sham procedure improved the fecal incontinence score, the radiofrequency energy procedure more than sham. Although statistically significant, the clinical impact for most of the patients was negligible. Therefore, the radiofrequency energy procedure should not be recommended for patients with fecal incontinence until patient-related factors associated with treatment success are known. See Video Abstract at http://links.lww.com/DCR/A373.


The law on artificial insemination: an italian anomaly.
The law on medically assisted procreation in Italy, from its entering into force, has undergone numerous amendments. This has been due to the fact that those citizens, directly affected by its imposed prohibitions, have not given in, bringing their requests before the courts, both nationally and internationally. Over the years, the courts through numerous rulings have significantly changed a law clearly incapable of protecting the rights of those involved. Currently Italy has an acceptable law on M.A.P. which is the result of the strong willing of citizens affected by problems of sterility or infertility. The aim of this paper is to present an historical summary of the troubled path which the issue, from every perspective, has faced and is still facing today. As well, it will document how, in Italy, the case-law and, therefore, the law's interpretation and application by the judges have contributed, in the end, to shaping a positive legislation.


Division of labour and the evolution of extreme specialization.
Division of labour is a common feature of social groups, from biofilms to complex animal societies. However, we lack a theoretical framework that can explain why division of labour has evolved on certain branches of the tree of life but not others. Here, we model the division of labour over a cooperative behaviour, considering both when it should evolve and the extent to which the different types should become specialized. We found that: (1) division of labour is usually-but not always-favoured by high efficiency benefits to specialization and low within-group conflict; and (2) natural selection favours extreme specialization, where some individuals are completely dependent on the helping behaviour of others. We make a number of predictions, several of which are supported by the existing empirical data, from microbes and animals, while others suggest novel directions for empirical work. More generally, we show how division of labour can lead to mutual dependence between different individuals and hence drive major evolutionary transitions, such as those to multicellularity and eusociality.


Magnesium metabolism: a case report and literature review.
Magnesium has been shown to play an important role in the body. In the critical care setting of particular concern is the role of Mg++ in the treatment of malignant tachydysrhythmias such as ventricular tachycardia and ventricular fibrillation. Research is being conducted to determine appropriate methods of assessing Mg++ status, the relationship of altered Mg++ states to clinical manifestations, and the treatment of the abnormalities associated with Mg++ deficiency. Safe and effective forms of parenteral and oral Mg++ supplements are currently available.


HANAC Col4a1 Mutation in Mice Leads to Skeletal Muscle Alterations due to a Primary Vascular Defect.
Collagen IV is a major component of basement membranes (BMs). The α1(IV) chain, encoded by the COL4A1 gene, is expressed ubiquitously and associates with the α2(IV) chain to form the α1α1α2(IV) heterotrimer. Several COL4A1 mutations affecting a conformational domain containing integrin-binding sites are responsible for the systemic syndrome of hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC). To analyze the pathophysiology of HANAC, Col4a1 mutant mice bearing the p.Gly498Val mutation were generated. Analysis of the skeletal muscles of Col4a1G498V mutant animals showed morphologic characteristics of a muscular dystrophy phenotype with myofiber atrophy, centronucleation, focal inflammatory infiltrates, and fibrosis. Abnormal ultrastructural aspects of muscle BMs was associated with reduced extracellular secretion of the mutant α1α1α2(IV) trimer. In addition to muscular dystrophic features, endothelial cell defects of the muscle capillaries were observed, with intracytoplasmic accumulation of the mutant α1α1α2(IV) molecules, endoplasmic reticulum cisternae dilation, and up-regulation of endoplasmic reticulum stress markers. Induction of the unfolded protein response in Col4a1 mutant muscle tissue resulted in an excess of apoptosis in endothelial cells. HANAC mutant animals also presented with a muscular functional impairment and increased serum creatine kinase levels reflecting altered muscle fiber sarcolemma. This extensive description of the muscular phenotype of the Col4a1 HANAC murine model suggests a potential contribution of primary endothelial cell defects, together with muscle BM alterations, to the development of COL4A1-related myopathy.


Nitrogen fertilizer rate and crop management effects on nitrate leaching from an agricultural field in central Pennsylvania.
Eighteen pan lysimeters were installed at a depth of 1.2 m in a Hagerstown silt loam soil in a corn field in central Pennsylvania in 1988. In 1995, wick lysimeters were also installed at 1.2 m depth in the same access pits. Treatments have included N fertilizer rates, use of manure, crop rotation (continuous corn, corn-soybean, alfalfa-corn), and tillage (chisel plow-disk, no-till). The leachate data were used to evaluate a number of nitrate leaching models. Some of the highlights of the 11 years of results include the following: 1) growing corn without organic N inputs at the economic optimum N rate (EON) resulted in NO3--N concentrations of 15 to 20 mg l(-1) in leachate; 2) use of manure or previous alfalfa crop as partial source of N also resulted in 15 to 20 mg l(-1) of NO3--N in leachate below corn at EON; 3) NO3--N concentration in leachate below alfalfa was approximately 4 mg l(-1); 4) NO3--N concentration in leachate below soybeans following corn was influenced by fertilizer N rate applied to corn; 5) the mass of NO3--N leached below corn at the EON rate averaged 90 kg N ha(-1) (approx. 40% of fertilizer N applied at EON); 6) wick lysimeters collected approximately 100% of leachate vs. 40-50% collected by pan lysimeters. Coefficients of variation of the collected leachate volumes for both lysimeter types were similar; 7) tillage did not markedly affect nitrate leaching losses; 8) tested leaching models could accurately predict leachate volumes and could be calibrated to match nitrate leaching losses in calibration years, but only one model (SOILN) accurately predicted nitrate leaching losses in the majority of validation treatment years. Apparent problems with tested models: there was difficulty estimating sizes of organic N pools and their transformation rates, and the models either did not include a macropore flow component or did not handle macropore flow well.


Diagnostic electrocardiography in epidemiological studies of Chagas' disease: multicenter evaluation of a standardized method.
An electrocardiographic recording method with an associated reading guide, designed for epidemiological studies on Chagas' disease, was tested to assess its diagnostic reproducibility. Six cardiologists from five countries each read 100 electrocardiographic (ECG) tracings, including 30 from chronic chagasic patients, then reread them after an interval of 6 months. The readings were blind, with the tracings numbered randomly for the first reading and renumbered randomly for the second reading. The physicians, all experienced in interpreting ECGs from chagasic patients, followed printed instructions for reading the tracings. Reproducibility of the readings was evaluated using the kappa (kappa) index for concordance. The results showed a high degree of interobserver concordance with respect to the diagnosis of normal vs. abnormal tracings (kappa = 0.66; SE 0.02). While the interpretations of some categories of ECG abnormalities were highly reproducible, others, especially those having a low prevalence, showed lower levels of concordance. Intraobserver concordance was uniformly higher than interobserver concordance. The findings of this study justify the use by specialists of the recording of readings method proposed for epidemiological studies on Chagas' disease, but warrant caution in the interpretation of some categories of electrocardiographic alterations.


Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia by linkage analysis.
Prenatal diagnosis of X-linked hypohidrotic ectodermal dysplasia was previously performed by the direct histological analysis of fetal skin obtained by late second trimester fetoscopy. The recent gene mapping of the locus for the disorder to the region of Xq11-21.1 now permits the indirect prenatal diagnosis of the disorder by the method of linkage analysis, based on closely linked marker loci, during the first trimester of pregnancy. We report the prenatal diagnosis of a male fetus with a high probability of the disorder by a linkage analysis utilizing restriction fragment length polymorphisms at the DXS159, PGK1, and DXS72 loci, from a DNA sample obtained by a chorionic villus biopsy at 9 weeks gestation. After further counseling, the pregnancy was terminated but the diagnosis could not be confirmed by histological analysis, even though analysis of skin samples by light and electron microscopy showed lack of hair germs, primary dermal ridges, and sweat gland primordia, due to the early developmental stage of the fetus. The use of DNA-based linkage analysis now offers the opportunity for an earlier diagnosis of X-linked hypohidrotic ectodermal dysplasia by a method other than fetal skin sampling. However, families must also fully understand the present limitations of the method prior to undertaking the procedure.


Latin America and the Caribbean SARS-CoV-2 Surveillance: Longitudinal Trend Analysis.
The COVID-19 pandemic has placed unprecedented stress on economies, food systems, and health care resources in Latin America and the Caribbean (LAC). Existing surveillance provides a proxy of the COVID-19 caseload and mortalities; however, these measures make it difficult to identify the dynamics of the pandemic and places where outbreaks are likely to occur. Moreover, existing surveillance techniques have failed to measure the dynamics of the pandemic. This study aimed to provide additional surveillance metrics for COVID-19 transmission to track changes in the speed, acceleration, jerk, and persistence in the transmission of the pandemic more accurately than existing metrics. Through a longitudinal trend analysis, we extracted COVID-19 data over 45 days from public health registries. We used an empirical difference equation to monitor the daily number of cases in the LAC as a function of the prior number of cases, the level of testing, and weekly shift variables based on a dynamic panel model that was estimated using the generalized method of moments approach by implementing the Arellano-Bond estimator in R. COVID-19 transmission rates were tracked for the LAC between September 30 and October 6, 2020, and between October 7 and 13, 2020. The LAC saw a reduction in the speed, acceleration, and jerk for the week of October 13, 2020, compared to the week of October 6, 2020, accompanied by reductions in new cases and the 7-day moving average. For the week of October 6, 2020, Belize reported the highest acceleration and jerk, at 1.7 and 1.8, respectively, which is particularly concerning, given its high mortality rate. The Bahamas also had a high acceleration at 1.5. In total, 11 countries had a positive acceleration during the week of October 6, 2020, whereas only 6 countries had a positive acceleration for the week of October 13, 2020. The TAC displayed an overall positive trend, with a speed of 10.40, acceleration of 0.27, and jerk of -0.31, all of which decreased in the subsequent week to 9.04, -0.81, and -0.03, respectively. Metrics such as new cases, cumulative cases, deaths, and 7-day moving averages provide a static view of the pandemic but fail to identify where and the speed at which SARS-CoV-2 infects new individuals, the rate of acceleration or deceleration of the pandemic, and weekly comparison of the rate of acceleration of the pandemic indicate impending explosive growth or control of the pandemic. Enhanced surveillance will inform policymakers and leaders in the LAC about COVID-19 outbreaks.


A canonical correlation analysis-based dynamic bayesian network prior to infer gene regulatory networks from multiple types of biological data.
One of the challenging and important computational problems in systems biology is to infer gene regulatory networks (GRNs) of biological systems. Several methods that exploit gene expression data have been developed to tackle this problem. In this study, we propose the use of copy number and DNA methylation data to infer GRNs. We developed an algorithm that scores regulatory interactions between genes based on canonical correlation analysis. In this algorithm, copy number or DNA methylation variables are treated as potential regulator variables, and expression variables are treated as potential target variables. We first validated that the canonical correlation analysis method is able to infer true interactions in high accuracy. We showed that the use of DNA methylation or copy number datasets leads to improved inference over steady-state expression. Our results also showed that epigenetic and structural information could be used to infer directionality of regulatory interactions. Additional improvements in GRN inference can be gleaned from incorporating the result in an informative prior in a dynamic Bayesian algorithm. This is the first study that incorporates copy number and DNA methylation into an informative prior in dynamic Bayesian framework. By closely examining top-scoring interactions with different sources of epigenetic or structural information, we also identified potential novel regulatory interactions.


Transient B12-dependent methyltransferase complexes revealed by small-angle X-ray scattering.
In the Wood-Ljungdahl carbon fixation pathway, protein-protein interactions between methyltransferase (MeTr) and corrinoid iron-sulfur protein (CFeSP) are required for the transfer of a methyl group. While crystal structures have been determined for MeTr and CFeSP both free and in complex, solution structures have not been established. Here, we examine the transient interactions between MeTr and CFeSP in solution using anaerobic small-angle X-ray scattering (SAXS) and present a global analysis approach for the deconvolution of heterogeneous mixtures formed by weakly interacting proteins. We further support this SAXS analysis with complementary results obtained by anaerobic isothermal titration calorimetry. Our results indicate that solution conditions affect the cooperativity with which CFeSP binds to MeTr, resulting in two distinct CFeSP/MeTr complexes with differing oligomeric compositions, both of which are active. One assembly resembles the CFeSP/MeTr complex observed crystallographically with 2:1 protein stoichiometry, while the other best fits a 1:1 CFeSP/MeTr arrangement. These results demonstrate the value of SAXS in uncovering the rich solution behavior of transient protein interactions visualized by crystallography.


Probing the ATP hydrolysis cycle of the ABC multidrug transporter LmrA by pulsed EPR spectroscopy.
Members of the ATP binding cassette (ABC) transporter superfamily translocate various types of molecules across the membrane at the expense of ATP. This requires cycling through a number of catalytic states. Here, we report conformational changes throughout the catalytic cycle of LmrA, a homodimeric multidrug ABC transporter from L. lactis. Using site-directed spin labeling and pulsed electron-electron double resonance (PELDOR/DEER) spectroscopy, we have probed the reorientation of the nucleotide binding domains and transmembrane helix 6 which is of particular relevance to drug binding and part of the dimerization interface. Our data show that LmrA samples a very large conformational space in its apo state, which is significantly reduced upon nucleotide binding. ATP binding but not hydrolysis is required to trigger this conformational change, which results in a relatively fixed orientation of both the nucleotide binding domains and transmembrane helices 6. This orientation is maintained throughout the ATP hydrolysis cycle until the protein cycles back to its apo state. Our data present strong evidence that switching between two dynamically and structurally distinct states is required for substrate translocation.


Klossiella quimrensis (Apicomplexa: Klossiellidae) causes renal coccidiosis in western barred bandicoots Perameles bougainville (Marsupialia: Peramelidae) in Western Australia.
Previous studies have described a range of Klossiella species parasitic in marsupial hosts. Klossiella quimrensis is the etiologic agent of renal coccidiosis in the peramelid marsupial hosts Isoodon obesulus and Perameles gunnii in Eastern Australia, but there is no previous report of klossiellosis in Western Australian peramelids. This study describes klossiellosis diagnosed by histology of renal tissue sections collected during necropsy of 20 Perameles bougainville between 2000 and 2005. Sporonts, sporoblasts, and macrogametes were identified within parasitophorous vacuoles of epithelial cells located near the renal corticomedullary junction. The prevalence of renal coccidiosis in P. bougainville diagnosed by renal histology is estimated at 30%. Only a single unsporulated sporocyst was detected by examination of cystocentesis-collected urine, indicating that microscopic evaluation of urine samples is an insensitive diagnostic test for detection of K. quimrensis in P. bougainville. This infection in P. bougainville is indirectly associated with mild multifocal interstitial lymphohistiocytic nephritis and is likely to be only minimally pathogenic in otherwise healthy individuals. Our study also extends the host and geographic range of K. quimrensis to include P. bougainville and Western Australia.


Optimizing power to track brain degeneration in Alzheimer's disease and mild cognitive impairment with tensor-based morphometry: an ADNI study of 515 subjects.
Tensor-based morphometry (TBM) is a powerful method to map the 3D profile of brain degeneration in Alzheimer's disease (AD) and mild cognitive impairment (MCI). We optimized a TBM-based image analysis method to determine what methodological factors, and which image-derived measures, maximize statistical power to track brain change. 3D maps, tracking rates of structural atrophy over time, were created from 1030 longitudinal brain MRI scans (1-year follow-up) of 104 AD patients (age: 75.7+/-7.2 years; MMSE: 23.3+/-1.8, at baseline), 254 amnestic MCI subjects (75.0+/-7.2 years; 27.0+/-1.8), and 157 healthy elderly subjects (75.9+/-5.1 years; 29.1+/-1.0), as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). To determine which TBM designs gave greatest statistical power, we compared different linear and nonlinear registration parameters (including different regularization functions), and different numerical summary measures derived from the maps. Detection power was greatly enhanced by summarizing changes in a statistically-defined region-of-interest (ROI) derived from an independent training sample of 22 AD patients. Effect sizes were compared using cumulative distribution function (CDF) plots and false discovery rate methods. In power analyses, the best method required only 48 AD and 88 MCI subjects to give 80% power to detect a 25% reduction in the mean annual change using a two-sided test (at alpha=0.05). This is a drastic sample size reduction relative to using clinical scores as outcome measures (619 AD/6797 MCI for the ADAS-Cog, and 408 AD/796 MCI for the Clinical Dementia Rating sum-of-boxes scores). TBM offers high statistical power to track brain changes in large, multi-site neuroimaging studies and clinical trials of AD.


[Stress related to administrative tasks in nursing].
According to several studies, nursing, especially in hospital settings, is one of the most stressful professions. The objective of this study was to identify the sources of stress related to the administrative tasks of nurses working in a hospital, as well as the main health changes that stress caused these professionals. The quantitative survey was carried out in 1996 with a sample of 207 nurses at a university hospital in the city of Porto Alegre, in the state of Rio Grande do Sul, Brazil. A questionnaire was used to collect data on stress sources and symptoms. The questionnaire also gathered demographic data, as well as information on the nurses' feelings about their working conditions. The average age of the study participants was 35.8 years, and the average time working at the hospital was 8.5 years. Among participants, 48% were considered to be stressed. Work overload was the stress source that best predicted relative risk of stress (6.1). In terms of stress symptoms, the most commonly reported ones were cardiovascular changes. However, gastrointestinal changes were related to a higher risk of stress (5.3). Managing other staff was the stress source that had the greatest number of significant correlations with stress symptoms. On the other hand, immunologic changes were the symptoms that had the highest correlation with stress sources. Our results suggest that stress related to administrative tasks in nursing may trigger changes in nurses' health.


Comparison of granisetron and metoclopramide in the treatment of pain and emesis in migraine patients: A randomized controlled trial study.
One of the irritating features of migraine is emesis that can compromise taking oral medications. We designed this study to compare the effectiveness of granisetron and metoclopramide in reducing pain and treating emesis in migraine patients. We included a total of 148 patients with migraine headache presenting to two referral hospitals in a prospective, double-blinded randomized controlled trial. We compared the effect of granisetron (2 mg intravenous) with metoclopramide (10 mg intravenous). Pain intensity and emesis episodes were recorded before drug administration, one, two and four 4 h after drug administration. Of the 148 patients, 47 were male and 101 were female. 75 patients received granisetron and 73 metoclopramide. Mean pain intensity before the administration of the medications was 7.67 ± 1.30 in granisetron group and 7.68 ± 1.13 in metoclopramide group with an insignificant difference. Mean pain intensity at one, two, and 4 h after drug administration was 3.20 ± 1.37, 2.39 ± 1.28, and 1.31 ± 0.52 in granisetron group and 5.04 ± 1.77, 4.1 ± 1.8, and 1.56 ± 0.68 in metoclopramide group (P = 0.03). Mean emesis episodes before drug administration were 1.85 ± 0.81 and 1.80 ± 0.77 in granisetron and metoclopramide groups, respectively. These episodes were 1.33 ± 0.66, 0.25 ± 0.49, and 0.04 ± 0.19 in granisetron group and 1.38 ± 0.73, 0.21 ± 0.47, and 0.41 ± 0.19 in metoclopramide group at one, two, and 4 h after the drug administration (P = 0.7). To came in conclusion, compared to metoclopramide, granisetron is a better choice in acute migraine ATTACK because it decreases the patients' pain as well as their emesis.


Definition and Implications of the Preventable Stroke.
Although patients with acute stroke are routinely evaluated for potential treatment (ie, treatability of the stroke), preventability of the presenting stroke is generally not seriously considered. To systematically analyze stroke preventability. We evaluated medical records of 274 consecutive patients discharged with a diagnosis of ischemic stroke between December 2, 2010, and June 11, 2012, at the University of California Irvine Medical Center. Mean (SE) patient age was 67.2 (0.8) years. Data analysis was conducted from July 3, 2014, to August 4, 2015. Medical records were systematically examined for demographic information, stroke risk factors, stroke severity, and acute stroke treatment. We defined stroke preventability as the degree to which the patient's presenting stroke was preventable. Using variables easily determined at onset of stroke, we developed a 10-point scale (0, not preventable; 10, most preventable) to classify the degree of stroke preventability. Our focus was effectiveness of treatment of hypertension (0-2 points), hyperlipidemia (0-2 points), and atrial fibrillation (0-4 points), as well as use of antithrombotic treatment for known prior cerebrovascular and cardiovascular disease (0-2 points). Total risk scores ranged from 0 to 8 (mean [SE], 2.2 [0.1]), with 207 patients (75.5%) exhibiting some degree of preventability (score of 1 or higher). Seventy-one patients (25.9%) had scores of 4 or higher, indicating that the stroke was highly preventable. Severity of stroke as determined by the National Institutes of Health Stroke Scale score was not related to preventability of stroke. However, 21 of 71 patients (29.6%) whose stroke was highly preventable were treated with intravenous or intra-arterial acute stroke therapy while these treatments were provided for only 13 of 67 patients (19.4%) with scores of 0 (no preventability) and 19 of 136 patients (14.0%) with scores of 1 to 3 (low preventability) (P = .03). Most patients with acute stroke exhibited some degree of preventability. Preventability and treatment of stroke were significantly associated, indicating that the most preventable strokes paradoxically were more likely to receive acute treatment.


Electrical and Network Neuronal Properties Are Preferentially Disrupted in Dorsal, But Not Ventral, Medial Entorhinal Cortex in a Mouse Model of Tauopathy.
The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal-ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30-80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.


Transcathether aortic valve implantation with the new repositionable self-expandable Evolut R versus CoreValve system: A case-matched comparison.
Despite promising results following transcatheter aortic valve implantation (TAVI), several relevant challenges still remain. To overcome these issues, new generation devices have been developed. The purpose of the present study was to determine whether TAVI with the new self-expanding repositionable Evolut R offers potential benefits compared to the preceding CoreValve, using propensity matching. Between June 2007 and November 2015, 2148 consecutive patients undergoing TAVI either CoreValve (n=1846) or Evolut R (n=302) were prospectively included in the Italian TAVI ClinicalService® project. For the purpose of our analysis 211 patients treated with the Evolut R were matched to 211 patients treated with the CoreValve. An independent core laboratory reviewed all angiographic procedural data and an independent clinical events committee adjudicated all events. Patients treated with Evolut R experienced higher 1-year overall survival (log rank test p=0.045) and a significantly lower incidence of major vascular access complications, bleeding events and acute kidney injury compared to patients treated with the CoreValve. Recapture manoeuvres to optimize valve deployment were performed 44 times, allowing a less implantation depth for the Evolut R. As a consequence, the rate of more than mild paravalvular leak and new permanent pacemaker was lower in patients receiving the Evolut R. In this matched comparison of high surgical risk patients undergoing TAVI, the use of Evolut R was associated with a significant survival benefit at 1year compared with the CoreValve. This was driven by lower incidence of periprocedural complications and higher rates of correct anatomic positioning.


Cancer screening - United States, 2010.
Each year, approximately 350,000 persons are diagnosed with breast, cervical, or colorectal cancer in the United States, and nearly 100,000 die from these diseases. The U.S. Preventive Services Task Force (USPSTF) recommends screening tests for each of these cancers to reduce morbidity and mortality. Healthy People 2020 sets national objectives for use of the recommended cancer screening tests and identifies the National Health Interview Survey (NHIS) as the means to measure progress. Data from the 2010 NHIS were analyzed to assess use of the recommended tests by age, race, ethnicity, education, length of U.S. residence, and source and financing of health care to identify groups not receiving the full benefits of screening and to target specific interventions to increase screening rates. Overall, the breast cancer screening rate was 72.4% (below the Healthy People 2020 target of 81.1%), cervical cancer screening was 83.0% (below the target of 93.0%), and colorectal cancer screening was 58.6% (below the target of 70.5%). Screening rates for all three cancer screening tests were significantly lower among Asians than among whites and blacks. Hispanics were less likely to be screened for cervical and colorectal cancer. Higher screening rates were positively associated with education, availability and use of health care, and length of U.S. residence. Continued monitoring of screening rates helps to assess progress toward meeting Healthy People 2020 targets and to develop strategies to reach those targets.


Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern.
AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1-3, 2-4, 5-6 disulfide bonding pattern; an unexpected Cys3-4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases.


Synthesis and structure-activity studies in vivo of liposomal phospholipid-N4-palmitoyl- and N4-hexadecyl-1-beta-D-arabinofuranosylcytosine conjugates.
N4-Hexadecyl-1-beta-D-arabinofuranosylcytosine (hxd4araC), a new cytostatic derivative of the antileukemic drug 1-beta-D-arabinofuranosylcytosine (araC), was linked in gram-scale syntheses to phospholipids containing differently substituted glycerol residues. All phospholipid-araC conjugates which were condensed via a phosphotriester linkage were shown to be ineffective in the in vivo treatment of L1210 murine leukemia. The transformation of the triesters into phosphodiester-linked conjugates by cleavage of the 2-chlorophenyl protecting group resulted in conjugates which were highly active against L1210 leukemia. These conjugates form stable liposomes with matrix lipids which exert antileukemic effects depending on the number and characteristics of the lipophilic residues of the conjugates. By treatment of L1210 leukemic mice with 100 mumol/kg body wt as total dose given by i.p. injection on days 2 and 6 after tumor inoculation with liposomal hxd4araC or 1-O-octadecyl-rac-glycero-3-phosphoryl-(3-->5')-1- beta-D-arabino-furanosylcytosine (Ocd1GroP-araC) the fraction of 60-day survivors was 100%. Corresponding curative effects were observed after treatment with 200 mumol/kg of 1,2-O-dipalmitoyl-rac-glycero-3-phosphoryl-(3-->5')-N4-palmitoyl-1-beta- D-arabinofuranosylcytosine (Pam1pam2GroP-pam4araC); 1,2-O-dioctadecyl-rac-glycero-3-phosphoryl- (3-->5')-N4-palmitoyl-1-beta-D-arabinofuranosylcytosine (Ocd1ocd2GroP-pam4araC) or 1-O-octadecyl-rac-glycero-3-phosphoryl-(3-->5')-hxd4araC (Ocd1GroP-hxd4araC). Four other conjugates with differently combined palmitoyl-, octadecyl- and hexadecyl residues were significantly less active or inactive. A distinct relationship between the chemical structures and the antileukemic activity of the nine investigated compounds was not found.


Characterization of the rnpB gene and RNase P RNA in the order Chlamydiales.
The sequence of the RNase P RNA gene (rnpB) was determined for 60 strains representing all nine species in the family Chlamydiaceae and for the related Chlamydiales species, Parachlamydia acanthamoebae and Simkania negevensis. These sequences were used to infer evolutionary relationships among the Chlamydiaceae. The analysis separated Chlamydophila and Chlamydia into two lineages, with Chlamydophila forming three distinct clusters: the Chlamydophila pneumoniae strains; the Chlamydophila pecorum strains; and a third cluster comprising the species Chlamydophila psittaci, Chlamydophila abortus, Chlamydophila caviae and Chlamydophila felis. The Chlamydia line of descent contained two clusters, with the Chlamydia suis strains distinctly separated from strains of Chlamydia trachomatis and Chlamydia muridarum. This analysis indicated that the rnpB sequence and structure are distinctive markers for species in the Chlamydiaceae. It was also demonstrated that the RNase P RNA derived from Chlamydia trachomatis is able to cleave a tRNA precursor in the absence of protein. These findings are discussed in relation to the structure of Chlamydia RNase P RNA.


The role of the dorsal intercarpal ligament in dynamic and static scapholunate instability.
Scapholunate instability (SLI) is the most common carpal instability. Recent studies have suggested that the dorsal intercarpal (DIC) and the dorsal radiocarpal ligaments play an important role in stabilization of the scaphoid and lunate. Differences between dynamic SLI and static SLI with a dorsal intercalated segment instability (DISI) are clearly described in the clinical literature; however, there has never been a clear explanation of the anatomic differences. This study describes the role of the DIC in the development of dynamic and static SLI with DISI in a cadaver model. Five fresh cadavers were studied radiographically and by 3-dimensional digitization. Six increasing stages of instability were developed by sectioning progressively the following structures: the dorsal capsule, the palmar and proximal (membranous) portion of the scapholunate interosseous ligament, the DIC from its insertion on the scaphoid and trapezium, the dorsal scapholunate interosseous ligament from the scaphoid, the DIC ligament from its attachment on the lunate, and the lunotriquetral interosseous ligament. The scaphoid position and the scapholunate gap changed significantly after sectioning the entire scapholunate interosseous ligament and DIC from the scaphoid when a 5-kg load was applied. The lunate position was unchanged in both the loaded and the unloaded conditions. After detaching the DIC from the lunate, both the scaphoid and lunate moved and the scapholunate gap increased significantly in both loaded and unloaded conditions and showed a DISI deformity. This study describes an anatomic difference between dynamic and static scapholunate instability. Complete disruption of the scapholunate ligament did not result in the development of a static collapse of the lunate. The DIC had an important role in stabilizing the scaphoid and lunate and preventing DISI deformity. This study suggests that in the clinical setting the DIC ligament should be assessed intraoperatively and consideration should be given to repair and/or reconstruction of the DIC ligament attachments to both the scaphoid and the lunate.


Swelling pressure of the lumbar intervertebral discs: influence of age, spinal level, composition, and degeneration.
The fluid content of the intervertebral disc is important in determining its mechanical response and also its transport and biologic properties. Fluid content depends on the proteoglycan content of the tissue and on the relationship of the external load to the disc's swelling pressure. The influence of proteoglycan content and external load on the hydration of nuclei from 32 human lumbar discs was measured. Swelling pressure of the same specimens was measured by equilibrium dialysis. The influence of age (14-91 years) and spinal level was noted. Proteoglycan content of the discs fell with age, and for all spines tested, proteoglycan content was lowest in the L5-S1 disc; no systematic change in collagen content was found. The hydration of the discs, as received, also fell with increase in age; in each complete lumbar spine tested, the L1-L2 and the L5-S1 discs had the lowest hydration at postmortem examination. As the stress applied to the discs was increased, hydration decreased. Although a stress of 0.10-0.23 MPa maintained the disc slices at their postmortem hydration, under a stress of about 0.6-0.8 MPa, most discs lost 40-60% of their initial fluid. The relationship between change in hydration and swelling pressure was found to depend on the composition of the disc rather than on age or degree of degeneration; the relationship between equilibrium hydration and swelling pressure could be predicted satisfactorily for a disc of known collagen and proteoglycan content.


Facial emotion processing in schizophrenia: a non-specific neuropsychological deficit?
Identification of facial emotions has been found to be impaired in schizophrenia but there are uncertainties about the neuropsychological specificity of the finding. Twenty-two patients with schizophrenia and 20 healthy controls were given tests requiring identification of facial emotion, judgement of the intensity of emotional expressions without identification, familiar face recognition and the Benton Facial Recognition Test (BFRT). The schizophrenia patients were selected to be relatively intellectually preserved. The patients with schizophrenia showed no deficit in identifying facial emotion, although they were slower than the controls. They were, however, impaired on judging the intensity of emotional expression without identification. They showed impairment in recognizing familiar faces but not on the BFRT. When steps are taken to reduce the effects of general intellectual impairment, there is no deficit in identifying facial emotions in schizophrenia. There may, however, be a deficit in judging emotional intensity. The impairment found in naming familiar faces is consistent with other evidence of semantic memory impairment in the disorder.


A randomized controlled trial studying the effect of maternal hyperoxygenation on fetal heart rate in suspected fetal distress.
To investigate the effect of maternal hyperoxygenation on fetal heart rate (FHR) when applied for suspected fetal distress during the second stage of term labor. A single-center randomized controlled trial was conducted in a tertiary care hospital in The Netherlands. Participants were included during the second stage of labor in case of an intermediary or abnormal FHR pattern. Patients were randomized to receive either 100% oxygen at 10 l/min until delivery, or conventional care without additional oxygen. The primary outcome was the change in FHR pattern before and after the onset of the study, measured as the change in depth and duration of FHR decelerations. Secondary outcome measures were features based on phase-rectified signal averaging (PRSA), baseline assignability, and deceleration characteristics of the FHR pattern. Between March 2016 and April 2018, 117 women were included. The FHR pattern could be analyzed for 71 participants, the other 46 women delivered before the end of the post time-frame. A 2.3% reduction in depth and duration of FHR decelerations was found after maternal hyperoxygenation, compared to a 10% increase in the control group (p = 0.24). Maternal hyperoxygenation had a significantly positive effect on PRSA metrics, with a decrease in PRSA-acceleration capacity (p = 0.03) and PRSA-deceleration capacity (p = 0.02) in the intervention group compared to the control group. The difference in depth and duration of decelerations after the start of the study was not significantly different between both study groups. A statistically significant positive effect on PRSA-deceleration capacity and PRSA-acceleration capacity was found after maternal hyperoxygenation, which might be associated with a positive effect on neonatal outcome.


Antibody response to a sterile filtered PPD tuberculin in M. bovis infected and M. bovis sensitized cattle.
Bovine tuberculosis, caused by Mycobacterium bovis, afflicts approximately 50 million cattle worldwide and is detected by the tuberculin skin test (TST). While it has long been recognized that purified protein derivative (PPD) tuberculin is composed of a mixture of M. bovis derived protein components, little is known about the quality, relative quantity and identity of the proteins that make up PPD tuberculin. We manufactured a sterile filtered PPD tuberculin (SF-PPD) from a nine-week-old M. bovis culture supernatant in order to characterise the culture filtrate proteins (CFP) which make up M. bovis PPD tuberculin and to compare the antibody response of M. bovis infected versus M. bovis sensitized cattle. SF-PPD resolved into approximately 200 discrete spots using two-dimensional polyacrylamide gel electrophoresis (2-DE) while fewer than 65 spots could be discerned from 2-DE gels of tuberculin derived from autoclaved culture supernatant. Two dimensional Western blot analyses indicated that sera from M. bovis sensitized cattle recognized additional SF-PPD antigens as compared to M. bovis infected cattle at seven weeks post infection/sensitization. However, application of a comparative tuberculin skin test resulted in an antibody boosting response to the same set of M. bovis CFPs in both the M. bovis infected and M. bovis sensitized cattle. We concluded that it is the heat sterilization of the M. bovis CFPs that causes severe structural changes to the M. bovis proteins. This work suggests that M. bovis infected cattle and cattle artificially sensitized to M. bovis with an injection of heat killed cells exhibit similar antibody responses to M. bovis antigens.


Human CCR6+ Th Cells Show Both an Extended Stable Gradient of Th17 Activity and Imprinted Plasticity.
Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6+ cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to yield the unusual plasticity ascribed to type 17 cells.