Diarrhea in Crohn's disease: investigating the role of the ileal hormone fibroblast growth factor 19.
Bile acids [BA] are usually reabsorbed by the terminal ileum, but this process is frequently abnormal in Crohn's disease [CD]. BA malabsorption occurs, and excess colonic BA cause secretory diarrhea. Furthermore, the hormone fibroblast growth factor 19 [FGF19] is synthesized in the ileum in response to BA absorption and regulates BA synthesis. We hypothesized that reduced serum FGF19 levels will be associated with diarrheal symptoms and disease activity in both ileal resected[IR-CD] and non-resected CD [NR-CD] patients. Fasting serum FGF19 levels were measured in 58 patients [23 IR-CD patients and 35NR-CD patients]. Disease activity was assessed using the Harvey Bradshaw Index and C-reactive protein [CRP]. Stool frequency, Bristol Stool Form Scale and length of previous ileal resection were recorded. FGF19 levels were also compared with healthy and diarrhea control patients. FGF19 levels were inversely correlated with ileal resection length in IR-CD patients[r = -0.54, p = 0.02]. In NR-CD patients, median FGF19 levels were significantly lower in patients with active disease compared with inactive disease [103 vs. 158 pg/ml, p = 0.04] and in those with symptoms of diarrhea compared with those without [86 vs. 145 pg/ml, p = 0.035]. FGF19 levels were inversely correlated with stool frequency, Bristol stool form and CRP in NR-CD patients with ileal disease. Reduced FGF19 levels are associated with ileal resection, diarrhea and disease activity. FGF19 may have utility as a biomarker for functioning ileum in CD. This study supports a potential role of FGF19 in guiding treatments for diarrhea in Crohn's disease.


mRNA lipid nanoparticle-mediated pyroptosis sensitizes immunologically cold tumors to checkpoint immunotherapy.
Synergistically improving T-cell responsiveness is promising for favorable therapeutic outcomes in immunologically cold tumors, yet current treatments often fail to induce a cascade of cancer-immunity cycle for effective antitumor immunity. Gasdermin-mediated pyroptosis is a newly discovered mechanism in cancer immunotherapy; however, cleavage in the N terminus is required to activate pyroptosis. Here, we report a single-agent mRNA nanomedicine-based strategy that utilizes mRNA lipid nanoparticles (LNPs) encoding only the N-terminus of gasdermin to trigger pyroptosis, eliciting robust antitumor immunity. In multiple female mouse models, we show that pyroptosis-triggering mRNA/LNPs turn cold tumors into hot ones and create a positive feedback loop to promote antitumor immunity. Additionally, mRNA/LNP-induced pyroptosis sensitizes tumors to anti-PD-1 immunotherapy, facilitating tumor growth inhibition. Antitumor activity extends beyond the treated lesions and suppresses the growth of distant tumors. We implement a strategy for inducing potent antitumor immunity, enhancing immunotherapy responses in immunologically cold tumors.


[Pituitary spindle cell oncocytoma].
Spindle cell oncocytoma is an infrequent benign non-endocrine sellar neoplasm. Due to its similar morphology to pituitary adenomas, consideration of this differential diagnosis would conduce to a more careful surgical approach in order to avoid intraoperative bleeding and aiming to a complete resection, on which depends long-term outcomes. We present the case of a 60-year-old male who complained about visual abnormalities, with computerized visual field confirmation. On biochemistry, a panhypopituitarism was detected. The brain magnetic resonance images showed a sellar mass. A non-functioning pituitary macroadenoma was presumptively diagnosed and due to the visual impairment, surgical transesphenoidal treatment was indicated. The histological diagnosis was spindle cell oncocytoma. Five months after surgery, the control image demonstrated a lesion that was considered as remnant tumor, hence radiosurgery was performed. During the follow-up, the tumor reduced its size and four years after initial treatment, the sellar resonance imaging showed disappearance of the residual tumor. Communication of new cases of this rare entity will enlarge the existing evidence and will help to determinate the most effective treatment and prognosis.


Hemoadsorption by CytoSorb in septic patients: a case series.
Septic shock, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, is a highly lethal condition that causes substantial morbidity and mortality among critically ill patients. One of the hallmarks of sepsis is the excessive release of cytokines and other inflammatory mediators causing refractory hypotension, tissue damage, metabolic acidosis and ultimately multiple organ failure. In this context, cytokine reduction by hemoadsorption represents a new concept for blood purification, developed to attenuate the overwhelming systemic levels of pro-inflammatory and anti-inflammatory mediators released in the early phase of sepsis. In the present case series, we evaluated the impact of a new hemoadsorption device (CytoSorb) used as adjunctive therapy, on hemodynamics and clinically relevant outcome parameters in 26 critically ill patients with septic shock and in need of renal replacement therapy. We found that treatment of these patients with septic shock was associated with hemodynamic stabilization and a reduction in blood lactate levels. Actual mortality in the overall patient population was lower than mortality predicted by acute physiology and chronic health evaluation II (APACHE II). These effects seem to be more pronounced in patients in whom therapy started within 24 h of sepsis diagnosis, whereas a delay in the start of therapy was associated with a poor response to therapy in terms of reduction of catecholamine demand and survival. Moreover, from our patient population, medical patients seemed to benefit more than post-surgical patients in terms of survival. Treatment using the CytoSorb device was safe and well-tolerated with no device-related adverse events during or after the treatment sessions. Hemoadsorption using CytoSorb resulted in rapid hemodynamic stabilization and increased survival, particularly in patients in whom therapy was started early. Given the positive clinical experience of this case series, randomized controlled trials are urgently needed to define the potential benefits of this new treatment option.


Letterer-Siwe disease associated with chronic myelomyonocytic leukemia: a fortuitous association?
Langerhans cell histiocytosis (LCH) and malignancy occurring in the same individual is unusual and has generally been the subject of isolated case reports. LCH is a rare condition in adults. Its cause is uncertain but, with the recent demonstration of clonality and its association with malignant disease, there has been a renewal of interest. We report a singular case of Letterer-Siwe disease associated with a chronic myelomonocytic leukemia developing in an elderly woman. The simultaneous occurrence of both malignant disorders supports the hypothesis of a common genetic origin.


Combined effect of hygienic and polygenic risk scores in children with allergic rhinitis.
Although the development of allergic rhinitis (AR) is associated with multiple genetic and hygienic environmental factors, previous studies have focused mostly on the effect of a single factor on the development of AR. This study aimed to investigate the combined effect of multiple genetic and hygienic environmental risk factors on AR development in school children. We conducted a cross-sectional study, comprising 1,797 children aged 9-12 years. Weighted environmental risk score (ERS) was calculated by using four hygienic environmental factors, including antibiotic use during infancy, cesarean section delivery, breast milk feeding, and having older siblings. Weighted polygenic risk score (PRS) was calculated by using four single nucleotide polymorphisms (SNPs), including interleukin-13 (rs20541), cluster of differentiation 14 (rs2569190), toll-like receptor 4 (rs1927911), and glutathione S-transferase P1 (rs1695). Multivariable logistic regression analysis was used. More than three courses of antibiotic use during infancy increased the risk of current AR (adjusted odd ratio [aOR], 2.058; 95% confidence interval [CI]: 1.290-3.284). Having older siblings, especially > 2 (aOR, 0.526; 95%Cl: 0.303-0.913) had a protective effect. High ERS ( > median; aOR, 2.079; 95%Cl: 1.466-2.947) and PRS ( > median; aOR, 1.627; 95%Cl: 1.117-2.370) increased the risk of current AR independently. Furthermore, children who had both high ERS and PRS showed a higher risk of current AR (aOR, 3.176; 95%Cl: 1.787-5.645). Exposure to multiple hygienic risk factors during infancy increases the risk of AR in genetically susceptible children.


Neurobiology of coronaviruses: Potential relevance for COVID-19.
In the first two decades of the 21st century, there have been three outbreaks of severe respiratory infections caused by highly pathogenic coronaviruses (CoVs) around the world: the severe acute respiratory syndrome (SARS) by the SARS-CoV in 2002-2003, the Middle East respiratory syndrome (MERS) by the MERS-CoV in June 2012, and Coronavirus Disease 2019 (COVID-19) by the SARS-CoV-2 presently affecting most countries In all of these, fatalities are a consequence of a multiorgan dysregulation caused by pulmonary, renal, cardiac, and circulatory damage; however, COVID patients may show significant neurological signs and symptoms such as headache, nausea, vomiting, and sensory disturbances, the most prominent being anosmia and ageusia. The neuroinvasive potential of CoVs might be responsible for at least part of these symptoms and may contribute to the respiratory failure observed in affected patients. Therefore, in the present manuscript, we have reviewed the available preclinical evidence on the mechanisms and consequences of CoVs-induced CNS damage, and highlighted the potential role of CoVs in determining or aggravating acute and long-term neurological diseases in infected individuals. We consider that a widespread awareness of the significant neurotropism of CoVs might contribute to an earlier recognition of the signs and symptoms of viral-induced CNS damage. Moreover, a better understanding of the cellular and molecular mechanisms by which CoVs affect CNS function and cause CNS damage could help in planning new strategies for prognostic evaluation and targeted therapeutic intervention.


Estimation of heritability of familial hypercholesterolemia among 335 family members of five hypercholesterolemic probands of Pakistani population.
Familial hypercholesterolemia is an autosomal dominant disorder, caused by mutation in Low-density lipoprotein receptor (LDL-R) gene. Cross-sectional study conducted to recruit the population of Karachi-Pakistan, screened for familial hypercholesterolemia. A total of 1523 hypercholesterolemic individuals have taken part in the study, five were found to be familial hypercholesterolemia. Their lipids profile was estimated and a family pedigree was drawn. Parent-offspring correlation, coefficient of linear regression, and heritability is calculated by using SPSS 12.0. A significant positive correlation of cholesterol was found among parents and their offspring (r = 0.511, p = 0.01, n = 76). Coefficient of linear regression analysis also showed that parents-offspring relationship was highly significant at p < 0.01 with b = 0.438. Relationship between Father-Son, Father-Daughter, Mother-Son and Mother-Daughter were highly significant with b = 0.794, 0.41, 0.766 and 0.56 respectively. The heritability among the parents and their offspring showed that genetic factors are major determinant of the familial resemblance in serum cholesterol among the Pakistani population living in the metropolitan area of Karachi.


A novel genetic system based on zinc finger nucleases for the identification of interactions between proteins in vivo.
Yeast two-hybrid (Y2H) methods are powerful tools for detecting protein-protein interactions. The traditional Y2H method has been widely applied to screen novel protein interactions since it was established two decades ago. The high false-positive rate of the traditional method drove the development of modified Y2H systems. Here, we describe a novel Y2H system using zinc-finger nucleases (ZFNs). ZFNs contain two functional domains, a zinc-finger DNA-binding domain (ZFP) and a non-specific nuclease domain (FokI). In this system, the bait is expressed as a fusion protein with a specific ZFP, and the prey is fused to the FokI. A reporter vector is designed such that the ZFN target site disrupts the Gal4 open reading frame. By transforming the three plasmids into a yeast strain (AH109), the interaction between the bait and prey proteins reconstitutes ZFN function and generates the double-strand break (DSB) on its target site. The DNA DSB repair restores Gal4 function, which activates the expression of the four reporter genes. We used p53-SV40LT interacting proteins to prove the concept. In addition, 80% positive rate was observed in a cDNA screening test against WDSV orfA protein. Our results strongly suggested that this Y2H system could increase screening reliability and reproducibility, and provide a novel approach for interactomics research.


Distribution and antibiogram of Vibrio species from hospital wastewater in Southwest, Nigeria.
the continuous generation of wastewater and its release into the environment with little or no treatment remains a threat to the environment and public health. We examined the prevalence and antibiotic susceptibility profiles of Vibrio species isolated from untreated wastewater samples from Ondo State Specialist Hospital Okitipupa, Nigeria, as part of the global efforts to provide information for containing the spread of resistant infections. twelve hospital wastewater samples were collected aseptically and transported to the laboratory for analysis. The samples were processed on thiosulphate citrate bile salt sucrose agar and colonies typical of Vibrio species were selected for further identification. All isolates were confirmed by polymerase chain reaction (PCR) using Vibrio-specific primers and the PCR products were sequenced for species identification. The susceptibility profiles of the isolates were determined by the Kirby-Bauer disc diffusion method. twenty-nine (58%) of 38 presumptive isolates were confirmed as Vibrio by PCR, while 23 (60.5%) isolates were screened up to species level by sequencing. Six different species following the trend: 26.1% V. fortis and V. algivorus, 17.4% V. cholerae, 13.0% V. panuliri, 8.7% V. stylophorae and V. parahaemolyticus were identified. The isolates were commonly resistant (73.9%-91.3%) to doxycycline, tetracycline, erythromycin and meropenem. The least resistance rate (17.4%) was observed against amikacin and cotrimoxazole. All isolates were multidrug-resistant, with multiple antibiotic resistance (MAR) indices exceeding the 0.2 recommended limit. this study has shown that untreated hospital wastewater is a reservoir for diverse strains of multiply resistant Vibrio species. Therefore, it is essential to adequately treat hospital wastewater to eliminate these emerging pollutants and set up a monitoring scheme to evaluate the treatment plants' effectiveness to reduce the pollutants' impact on the environment and the population.


Mixing tests: diagnostic aides in the investigation of prolonged prothrombin times and activated partial thromboplastin times.
Mixing tests are a relatively simple procedure used in the hemostasis laboratory as a first-line investigation into the cause of an abnormal screening test, typically a prolonged activated partial thromboplastin time and/or a prolonged prothrombin time. The mixing test involves combining the test plasma with normal plasma, then repeating the screening test on the mixture to assess whether the clotting time becomes normal or remains prolonged. The primary purpose of a mixing test is to guide further investigations. When mixing test results "normalize," this suggests the test plasma is deficient in clotting factor(s) and thus specific factor assays can be performed to determine which are reduced. When the mixing test result does not "normalize," this suggests the presence of an inhibitor or other type of interference (e.g., the presence of an anticoagulant such as high-dose heparinoids), and so the laboratory needs to determine if this is a lupus anticoagulant or a specific coagulation factor inhibitor, or another type of inhibitor. Because these follow-up investigations are more costly and time-consuming than the basic screening tests, the appropriate performance and interpretation of mixing tests is advantageous for the laboratory. Moreover, the correct laboratory approach is also clinically relevant, as patient management is ultimately affected, and an incorrect interpretation may lead to inappropriate therapies being established. Components of a mixing test that can influence result interpretation include the sensitivity of the used screening reagents to various factor deficiencies and inhibitors, the source or composition of the normal plasma, and the setting of cutoffs for the formula used in expressing mixing test results. Numerous and differing criteria for mixing test interpretation have been suggested historically, which can lead to confusion as to which approach is the most appropriate. The use of differing criteria will also lead to differing interpretations regarding "normalization." For this pivotal reason, standardized mixing test procedures and a consistent set of validated interpretive criteria represent the most favorable approach to maximizing the utility of a mixing test, and ensure the most accurate diagnosis for investigated patients.


Suspension of bone marrow-derived undifferentiated mesenchymal stromal cells for repair of superficial digital flexor tendon in race horses.
It has been proven that mesenchymal stromal cells (MSCs) can differentiate into tenocytes. Attempts to repair tendon lesions have been performed, mainly using scaffold carriers in experimental settings. In this article, we describe the clinical use of undifferentiated MSCs in racehorses. Significant clinical recovery was achieved in 9 of 11 horses evaluated using ultrasound analysis and their ability to return to racing. Our results show that the suspension of a small number of undifferentiated MSCs may be sufficient to repair damaged tendons without the use of scaffold support. Ultrasound scanning showed that fibers were correctly oriented. By using undifferentiated cells, no ectopic bone deposition occurred. A sufficient number of cells was recovered for therapeutic purposes in all but 1 case. We suggest that the use of autologous MSCs is a safe therapeutic method for treating incompletely (i.e., not full-thickness) damaged tendons.


[Fetal ventriculomegaly: diagnosis using magnetic resonance imaging and its prognosis].
To evaluate the diagnostic value of magnetic resonance imaging (MRI) on fetal ventriculomegaly identified through prenatal ultrasonography and the outcomes of these newborns were followed up. From March 2006 to July 2008, MRI was performed on 135 pregnant women whose fetuses diagnosed as fetal ventriculomegaly at an average of 32 gestational weeks in Shengjing Hospital Affiliated to China Medical University. Mild ventriculomegaly was defined when the width of unilateral or bilateral fetal cerebral ventricle triangle was 10-15 mm, moderate ventriculomegaly 16-20 mm and severe ventriculomegaly >20 mm. We introduced the Denver developmental screening test (DDST) to follow-up the mild ventriculomegaly and normal babies, confirmed by MRI, at 6-12 months after birth and a case-control study was conducted. The intelligence and growth of these infants were analyzed. (1) Diagnostic rate of fetal ventriculomegaly through MRI: Among the 135 gravidas, 60 (44.4%) showed isolated ventriculomegaly, 5(3.7%) complicated with ventricular hemorrhage; 12 (8.9%) complicated with agenesis of corpus callosum (ACC) and 2 (1.5%) complicated with cerebellar hypoplasia, while 56 (41.5%) were normal. Seventy-nine cases had fetal ventriculomegaly on MRI and 15.2% (n = 12) of them complicated with ACC. (2) Degree of fetal ventriculomegaly on MRI: Among the 60 isolated ventriculomegaly cases, 55 (91.7%) were mild and 5 (8.3%) moderate ones. Among the 5 cases complicated with ventricular hemorrhage, one was mild ventriculomegaly, and 4 moderate or severe cases. Among the 12 cases with ACC, 8 (66.7%) were moderate ventriculomegaly and 4 (33.3%) severe cases. The 2 cases with cerebellar hypoplasia were both moderate ventriculomegaly fetuses. (3) Follow-up at 6-12 months after birth: thirty out (case group) of the 55 isolated ventriculomegaly cases, 38 out of the 56 normal babies and 42 babies with normal MRI results were followed up, and the later 80 cases were taken as control. Four infants (13.3%) in the case group and 10 (12.5%) in the control group showed abnormal or suspected results in DDST (P > 0.05), the rest babies were all normal. (4) Clinical outcomes of the 79 ventriculomegaly fetuses diagnosed by MRI: thirty mild ventriculomegaly babies and 5 moderate ones were born at term and showed normal at follow ups. However, 7 gravidas were not compliant, 6 pregnancies were terminated, and 12 were lost. Three of the 12 cases with ACC continued the pregnancy, and postnatal MRI of the babies showed the same with the prenatal MRI, 8 pregnancies were induced and one was lost. All of the 5 fetuses with ventricular hemorrhage were induced and the prenatal diagnosis was confirmed by autopsy. One of the 2 fetuses with cerebellar hypoplasia was term delivered and diagnosed as cerebral palsy at the age of 6 months, and the other one was induced. MRI is an indispensable complementary diagnostic method for fetal ventriculomegaly diagnosed through ultrasound. The development of intelligence and growth of babies born with mild isolated ventriculomegaly is the same as normal ones.


Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding.
Heavy menstrual bleeding (HMB) is an important cause of ill health in women and it accounts for 12% of all gynaecology referrals in the UK. Heavy menstrual bleeding is clinically defined as greater than or equal to 80 ml of blood loss per menstrual cycle. However, women may complain of excessive bleeding when their blood loss is less than 80 ml. Hysterectomy is often used to treat women with this complaint but medical therapy may be a successful alternative. The intrauterine coil device was originally developed as a contraceptive but the addition of uterine relaxing hormones, progestogens, to these devices resulted in a large reduction in menstrual blood loss. Case studies of two types of progesterone or progestogen-releasing systems, Progestasert and Mirena, reported reductions of up to 90% and that dysmenorrhoea may be improved. Insertion, however, may be regarded as invasive by some women, which affects its acceptability as a treatment. Frequent intermenstrual bleeding and spotting is also likely during the first few months. To determine the effectiveness and acceptability of progesterone or progestogen-releasing intrauterine devices in achieving a reduction in heavy menstrual bleeding. All studies which might describe randomised controlled trials of progesterone or progestagen-releasing intrauterine devices for the treatment of heavy menstrual bleeding were obtained by electronic searches of The Cochrane Library, MEDLINE (1966 to 2005) and EMBASE (1980 to 2005). Companies producing progestogen-releasing intrauterine devices and experts in the field were contacted for information on published and unpublished trials. Randomised controlled trials in women of reproductive age treated with progesterone or progestogen-releasing intrauterine devices versus no treatment, placebo, or other medical or surgical therapy for heavy menstrual bleeding within primary care, family planning or specialist clinic settings were eligible for inclusion. Women with postmenopausal bleeding, intermenstrual or irregular bleeding, or pathological causes of heavy menstrual bleeding were excluded. Potential trials were independently assessed by three review authors and nine trials met the criteria for inclusion in the review. The reviewers extracted the data independently and data were pooled where appropriate. Odds ratios (OR) were estimated from the data for dichotomous outcomes and weighted mean differences (WMD) for continuous outcomes. The primary outcome was reduction in menstrual blood loss but incidence of side effects, changes in quality of life, satisfaction and acceptability measures were also assessed. Progesterone or progestogen-releasing intrauterine systems have not been compared to placebo or no treatment. Progestasert has been compared to a number of different medical therapies in one small study but no conclusions can be made about its effectiveness. The levonorgestrel-releasing intrauterine device (LNG IUS) has been compared to oral cyclical norethisterone (NET) administered on days 5 to 26 of the menstrual cycle in one trial and was significantly more effective although there was a large reduction in loss from baseline in both groups. Some short term side effects were more common in the LNG IUS group but a significantly greater proportion of women in this group were satisfied and willing to continue with their treatment. In one trial of women awaiting hysterectomy, where the LNG IUS was compared with a control group taking their existing medical therapy, a higher proportion of the women in the intrauterine device group cancelled their planned surgery after six months of treatment. The LNG IUS has been compared to an endometrial ablation: either transcervical resection of the endometrium (TCRE) (two trials) or balloon ablation (three trials). There was a significantly greater mean reduction in menstrual bleeding in one trial in those undergoing balloon ablation (WMD -45.2 units, 95% CI -56.9 to -33.5), a lower score on the pictorial blood loss chart (PBAC) (WMD 33.2 units, 95% CI 27.2 to 39.2) and higher rates of successful treatment in 3 trials including both balloon and TCRE (OR 0.28, 95% CI 0.14 to 0.58) but the rates of satisfaction with treatment was were similar. There was no conclusive evidence of changes in quality of life between groups but women with the LNG IUS had a greater incidence of progestogenic side effects within one year. The LNG IUS has been compared to hysterectomy in one trial. There was no evidence of a change in quality of life scores but the LNG IUS treatment had lower costs than with hysterectomy, both at one and five-years follow up. The levonorgestrel-releasing intrauterine device (LNG IUS) is more effective than cyclical norethisterone (for 21 days) as a treatment for heavy menstrual bleeding. Women with an LNG IUS are more satisfied and willing to continue with treatment but experience more side effects, such as intermenstrual bleeding and breast tenderness. The LNG IUS results in a smaller mean reduction in menstrual blood loss (as assessed by the PBAC chart) than endometrial ablation but there is no evidence of a difference in the rate of satisfaction with treatment. Women with an LNG IUS experience more progestogenic side effects compared to women having TCRE for treatment of their heavy menstrual bleeding but there is no evidence of a difference in their perceived quality of life. The LNG IUS treatment costs less than hysterectomy but there is no evidence of a difference in quality of life measures between these groups. There are no data available from randomised controlled trials comparing progesterone-releasing intrauterine systems to either placebo or other commonly used medical therapies for heavy menstrual bleeding.


An overview of the role of cardiovascular reactivity to stressful challenges in the etiology of hypertension.
There is significant variability among individuals in the cardiovascular responses to both physical and psychologic stimuli, a phenomenon called cardiovascular reactivity. The magnitude of cardiovascular reactivity may distinguish those prone to develop cardiovascular disease or differentiate pathophysiologic states among individuals who have existing pathologies such as hypertension. This article describes the cardiovascular reactivity hypothesis as a proposed mechanism of hypertension development. Furthermore, proposed mechanisms underlying the pathophysiology of hyperreactivity are also discussed. The value of assessing stress-induced cardiovascular reactivity is evaluated with special regard to hypertension, and future avenues for nursing research are presented.


[A rare cardiac tumor: the malignant fibrous histiocytoma. Description of a case].
The present report describes the case of a 61-year-old woman with malignant fibrous histiocytoma of the left atrium originating from the left atrial free wall, operated on in emergency for a suspected large left atrial myxoma that, at the echo scan, was consistently protruding through the left atrioventricular orifice at each diastole and was almost completely occluding the left ventricular inflow, causing signs of congestive heart failure and severe dyspnea. Surgery was performed as radically as possible, but the histological examination of the specimen revealed the exact diagnosis of the neoplasm. About 75% of primary tumors are benign and 75% of these are atrial myxomas. The malignant tumors consist of various sarcomas: myxosarcoma, liposarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, osteosarcoma, synovial sarcoma, rhabdomyosarcoma, undifferentiated sarcoma, reticulum cell sarcoma, neurofibrosarcoma, and malignant fibrous histiocytoma. The long-term results for sarcomas are very poor and there are few survivors after several months from surgery due to the extent of local spread and invasion or because of the frequent distant metastases. Malignant fibrous histiocytoma constitutes about 2% of all cardiac malignancies, which might grow within several localized areas, occasionally in the heart. Echocardiography represents the best examination procedure for both diagnosis and follow-up of patients with cardiac tumors.


Future Directions in the Diagnosis and Treatment of APDS and IEI: a Survey of German IEI Centers.
The diagnosis and treatment of inborn errors of immunity (IEI) is a major challenge as the individual conditions are rare and often characterized by a variety of symptoms, which are often non disease-specific. Ideally, patients are treated in dedicated centers by physicians who specialize in the management of primary immune disorders. In this study, we used the example of Activated PI3Kδ syndrome (APDS), a rare IEI with an estimated prevalence of 1:1,000,000. We conducted surveys by questionnaire and interviewed physicians at different IEI centers in Germany. We queried structural aspects of IEI care in Germany, diagnostic procedures in IEI care (including molecular diagnostics), distribution of APDS patients, APDS symptoms and severity, treatment algorithms in APDS, the role of stem cell transplantation and targeted therapies in IEI with focus on APDS. We were especially interested in how genetic diagnostics may influence treatment decisions, e.g. with regard to targeted therapies. Most centers care for both pediatric and adult patients. A total of 28 APDS patients are currently being treated at the centers we surveyed. Patient journeys vary considerably, as does severity of disease. Genetic diagnosis continues to gain importance - whole genome sequencing is likely to become routine in IEI in the next few years. According to the experts interviewed, stem cell transplantation and - with new molecules being approved - targeted therapies, will gain in importance for the treatment of APDS and IEI in general.


Predictive model for the development of hypertensive cardiopathy: A prospective cohort study.
Predictive models of cardiovascular conditions are useful tools for risk stratification. The high morbidity and mortality resulting from hypertensive cardiopathy creates a need for the use of tools to predict the risk of cardiovascular disease. To evaluate the capacity of a model based on risk factors to predict the development of hypertensive cardiopathy after ten years in patients with a diagnosis of essential arterial hypertension. A prospective cohort study was carried out in hypertensive patients cared for at the specialized arterial hypertension physician's office of the Specialty Policlinic attached to "Carlos Manuel de Céspedes" Hospital, Bayamo Municipality, Granma Province, Cuba, from January 1, 2000 to December 31, 2009. A predictive model was constructed and validated through a process that included the random split of the whole sample in two parts: one for development (parameters estimation) and the other for validation. The binary regression model adjusted by the "step-by-step backward method," showed that in step six, 13 variables sufficed to estimate the risk of developing hypertensive cardiopathy. In the estimation sample, the area under the receiver operating characteristic curve obtained for the prediction of hypertensive heart disease was 0.985 (confidence interval: 0.980-0.990; p = <0.0005). In the validation sample the area under the receiver operating characteristic curve was 0.963 (confidence interval: 0.953-0, 0.973, p<0.0005). The calibration of the model was also adequate (p = 0.863). The model obtained proved is a clinical and epidemiological surveillance instrument, useful to identify subjects with greater likelihood to acquire hypertensive heart disease, and to stratify their risk in the following ten-year period.


One-year follow-up study of elderly group-home residents with dementia.
For the present research, a 1-year follow-up study was conducted on elderly group-home residents with dementia (n = 13). This research compared the cognitive function and behavioral disorders of the elderly group-home residents with dementia with a control group (n = 13) of elderly patients with dementia in a dementia care ward. Thirteen residents of a group home were observed for 1 year, following the establishment of the group home in January 2003. The subjects in the control group were matched for the sex and dementia type of the group-home residents. The present results suggest that cognitive function among elderly group-home residents was maintained in comparison with elderly patients in a dementia ward. In addition, behavioral and psychological symptoms of dementia were not observed in either group. Furthermore, these findings suggest that behavioral disorders significantly improved in the group-home residents because of the incorporation of activities combining basic and instrumental activities of daily living.


Reduced incidence of vagally induced atrial fibrillation and expression levels of connexins by n-3 polyunsaturated fatty acids in dogs.
This open-label canine study assessed whether n-3 polyunsaturated fatty acids (PUFAs) prevent vagally induced atrial fibrillation (AF) and influence atrial tissue expression levels of connexins (CXs). n-3 polyunsaturated fatty acids in fish oils protect against sudden cardiac death and reduce postoperative AF. Changes in spatial organization of gap junctions or cellular CX levels have been linked to arrhythmogenesis. Vagally induced AF was studied. Eight dogs were given fish oil daily for 14 days. Eight control dogs had reproducibly induced AF and were re-evaluated after intravenous administration of fish oil. Atrial fibrillation was compared, and n-3 PUFA, CX40, and CX43 protein levels were assessed in atrial biopsies. Atrial tissue n-3 PUFA levels increased in oral treatment dogs (5.78 +/- 0.71% vs. 2.49 +/- 0.46% in control animals, p < 0.001). No difference was observed for atrial refractory periods or hemodynamic or electrocardiographic parameters. Incidence of AF in oral treatment dogs decreased 79% with the extra stimulus technique (10.5% vs. 48.9%, p = 0.003) and 42% with burst induction (22.5% vs. 38.8%, p = 0.038). Both CX40 and CX43 levels were lower in oral treatment dogs (60% [p = 0.019] and 42% [p = 0.038] lower, respectively); protection against AF was mostly related to reduced CX40 expression levels (p = 0.02). In dogs that were given intravenous n-3 PUFAs, AF inducibility by the extra stimulus technique was reduced from 75.0% to 28.6% (p = 0.002). Oral treatment with fish oils increased atrial n-3 PUFA levels and reduced vulnerability to induction of AF in this dog model. Modulation of cardiac CX by n-3 PUFAs probably contributes to the antiarrhythmic effects of fish oils.


Highly Diastereo- and Enantioselective Synthesis of Trifluoromethyl-Substituted Cyclopropanes via Myoglobin-Catalyzed Transfer of Trifluoromethylcarbene.
We report an efficient strategy for the asymmetric synthesis of trifluoromethyl-substituted cyclopropanes by means of myoglobin-catalyzed olefin cyclopropanation reactions in the presence of 2-diazo-1,1,1-trifluoroethane (CF3CHN2) as the carbene donor. These transformations were realized using a two-compartment setup in which ex situ generated gaseous CF3CHN2 is processed by engineered myoglobin catalysts expressed in bacterial cells. This approach was successfully applied to afford a variety of trans-1-trifluoromethyl-2-arylcyclopropanes in high yields (61-99%) and excellent diastereo- and enantioselectivity (97-99.9% de and ee). Furthermore, mirror-image forms of these products could be obtained using myoglobin variants featuring stereodivergent selectivity. These reactions provide a convenient and effective biocatalytic route to the stereoselective synthesis of key fluorinated building blocks of high value for medicinal chemistry and drug discovery. This work expands the range of carbene-mediated transformations accessible via metalloprotein catalysts and introduces a potentially general strategy for exploiting gaseous and/or hard-to-handle carbene donor reagents in biocatalytic carbene transfer reactions.


Improving ecological inference using individual-level data.
In typical small-area studies of health and environment we wish to make inference on the relationship between individual-level quantities using aggregate, or ecological, data. Such ecological inference is often subject to bias and imprecision, due to the lack of individual-level information in the data. Conversely, individual-level survey data often have insufficient power to study small-area variations in health. Such problems can be reduced by supplementing the aggregate-level data with small samples of data from individuals within the areas, which directly link exposures and outcomes. We outline a hierarchical model framework for estimating individual-level associations using a combination of aggregate and individual data. We perform a comprehensive simulation study, under a variety of realistic conditions, to determine when aggregate data are sufficient for accurate inference, and when we also require individual-level information. Finally, we illustrate the methods in a case study investigating the relationship between limiting long-term illness, ethnicity and income in London.


Poly(carboxylic acid)-Cyclodextrin/Anionic Porphyrin Finished Fabrics as Photosensitizer Releasers for Antimicrobial Photodynamic Therapy.
In the development of new antibacterial therapeutic approaches to fight multidrug-resistant bacteria, antimicrobial photodynamic therapy (aPDT) represents a well-known alternative to treat local infections caused by different microorganisms. Here we present a polypropylene (PP) fabric finished with citrate-hydroxypropyl-βCD polymer (PP-CD) entrapping the tetra-anionic 5,10,15,20-tetrakis(4-sulfonatophenyl)-21H,23H-porphine (TPPS) as photosensitizer-eluting scaffold (PP-CD/TPPS) for aPDT. The concept is based on host-guest complexation of porphyrin in the cavities of CDs immobilized on the PP fibers, followed by its sustained and controlled delivery in release medium and simultaneous photoinactivation of microorganisms. Morphology of fabric was characterized by optical (OM) and scanning electron microscopies (SEM). Optical properties were investigated by UV-vis absorption, steady- and time-resolved fluorescence emission spectroscopy. X-ray photoelectron spectroscopy (XPS) and FT-IR revealed the surface chemical composition and the distribution map of the molecular components on the fabric, respectively. Direct 1O2 determination allowed to assess the potential photodynamic activity of the fabric. Release kinetics of TPPS in physiological conditions pointed out the role of the CD cavity to control the TPPS elution. Photoantimicrobial activity of the porphyrin-loaded textile was investigated against both Gram-positive Staphylococcus aureus ATCC 29213 (S. aureus) and Gram-negative Pseudomonas aeruginosa ATCC 27853 (P. aeruginosa). Optical microscopy coupled with UV-vis extinction and fluorescence spectra aim to ascertain the uptake of TPPS to S. aureus bacterial cells. Finally, PP-CD/TPPS fabric-treated S. aureus cells were photokilled of 99.98%. Moreover, low adhesion of S. aureus cells on textile was established. Conversely, no photodamage of fabric-treated P. aeruginosa cells was observed, together with their satisfying adhesion.


Treatment of patients with heart failure and preserved ejection fraction.
Of the more than 5 million Americans who have heart failure (HF), 30% to 50% have HF with preserved ejection fraction (HF-PEF). HF-PEF commonly occurs in elderly patients, especially women, with comorbidities of hypertension, left ventricular hypertrophy, diabetes, myocardial ischemia, and obesity. HF-PEF is associated with high morbidity and mortality. Although two large multicenter randomized, placebo-controlled trials evaluating an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) in patients with HF-PEF did not demonstrate any statistically significant benefit in their primary end points, they did suggest that these agents may have a modest role in reducing HF hospitalizations. Although calcium channel blockers and beta-blockers may be of benefit in patients with HF-PEF, large clinical trial data are not available to support their routine use in all patients with HF-PEF. Subgroup analysis does not support the use of digoxin in patients with HF-PEF in sinus rhythm. Current therapeutic recommendations for HF-PEF are aimed at 1) management of HF symptoms with sodium and fluid restriction along with diuretics for volume overload and 2) treatment of concomitant comorbidities, especially hypertension, rate and possibly rhythm control of atrial fibrillation, and evaluation and treatment of myocardial ischemia and anemia. ACEIs, ARBs, calcium channel blockers, and beta-blockers are recommended for HF-PEF patients who have other established indications for their use. Results are awaited from ongoing clinical trials with another ARB, irbesartan, and an aldosterone blocker, spironolactone.


Prevalence of HIV-1 infection among foreign applicant to residency in Shanghai, China, 2005-2016.
Shanghai is one of the largest cities in China and has the highest proportion of inbound travelers in the world. The HIV (human immunodeficiency virus) infection status of this population can reflect the global HIV epidemic trend to a certain extent. Therefore, we conducted a retrospective epidemic survey to clarify the prevalence and characteristics of HIV-1 infection among inbound travelers applying for Shanghai residency. The retrospective cohort analysis included a total of 50,830 inbound tourists/travelers who applied for Shanghai residency from 2005 to 2016. HIV-1 infection rates were determined based on HIV-1 antibody testing. Among all the recruited inbound travelers, 245 were HIV-1 positive, with an infection rate of 0.48%. The detection rate of HIV in males was significantly higher than in females (χ2 = 62.584, P < 0.0001). Those aged 18-30 years, 31-40 years, and >40 years accounted for 34.3%, 39.6%, and 26.1% of the infected population, respectively. Although the annual detection rates were different, the trend analysis results showed no increase in HIV-1 prevalence rates among the sampling years (Cochran-Armitage Z = 2.543, P = 0.111). Proportions of individuals infected through homosexual transmission increased over the study period (Cochran-Armitage Z = 5.41, P < 0.001), while the proportion infected through heterosexual declined over time (Cochran-Armitage Z = 3.38, P = 0.001). The rate and characteristics of HIV-1 infection among foreign applicants for residency in Shanghai were identified in the study. The results provide the necessary epidemiological data for monitoring the HIV-1 epidemic among international entry travelers and contribute to establishing relevant policies and regulations for HIV control and prevention.


Laryngeal abductor reinnervation with a phrenic nerve transfer after a 9-month delay.
Successful restoration of laryngeal abductor function, using the phrenic nerve, has been described in the cat model in the acute phase. However, in clinical practice there is usually a considerable delay between injury to the RLN and presentation for treatment. Delayed reinnervation therefore would be more suitable in clinical practice. To test the feasibility of delayed selective abductor reinnervation following transection of the recurrent laryngeal nerve (RLN). In 12 cats, the right RLN was severed. Nine months later, the phrenic nerve was anastomosed to the distal RLN stump with all its branches directed toward the posterior cricoarytenoid muscle. For 10 weeks after the reconstruction, electromyography and videolaryngoscopy were performed weekly. Finally, histological analysis of the RLN was performed. Evaluation was possible in 11 cats. Reinnervation of the right posterior cricoarytenoid muscle with the phrenic nerve occurred in 10 cats following nerve anastomosis, but results of videolaryngoscopy showed adequate to good abduction in only 4 cats. The main limiting factor was reduced mobility of the cricoarytenoid joint. Evidence of spontaneous subclinical reinnervation after the delay was observed in 7 cats but apparently did not impede the surgical reinnervation. Delayed selective laryngeal abductor reinnervation was feasible, but function recovery was less successful than if performed immediately. Future investigations should concentrate on early determinants of spontaneous restoration of function to allow early selection of patients who are eligible for reinnervation surgery.


Hematological and antifungal properties of temporin A and a cecropin A-temporin A hybrid.
Temporin A (TA) and a cecropin A-temporin A hybrid peptide (CATA) were synthesized and assayed for their hemolytic, anticoagulant, and antifungal properties. CATA retains significant antifungal activity, is less hemolytic than TA, and inhibits blood coagulation. These results recommend further studies of the biological activities of CATA.


Status epilepticus in a patient with fragile X syndrome: electro-clinical features and peri-ictal neuroimaging.
Fragile X syndrome (Fra-X) is a common cause of mental retardation that can be associated with partial epilepsy characterized by a variety of electro-clinical features. A wide spectrum of interictal activities are reported, although no data regarding ictal EEG activity have as yet been published. Drug-resistant seizures are uncommon, and the occurrence of clustering seizures or status epilepticus has only been reported anecdotally. We describe a Fra-X patient with refractory partial epilepsy related to a malformation of cortical development who experienced a partial status epilepticus that was well documented by video-EEG and MRI. We report the electro-clinical features and peri-ictal neuroimaging data.


Immunotherapy and neuropsychiatric toxicity. Nursing clinical management consideration.
Ensuring the safety of patients who receive immunotherapy is an essential element of nursing care. Communicating changes in mental status to the medical team is important feedback for modifying or discontinuing the cycle of immunotherapy. These observations are even more crucial if neuropsychiatric toxicity (NPT) has been exhibited in a previous cycle of treatment. If nurses are aware of associative factors of NPT they can be more alert for emerging cognitive dysfunction. Early intervention will also mean the nurse will take additional measures to ensure patient safety, such as suggesting possible pharmacological alternatives and closer observation, and encouraging family members to help with orientation. The nurse can further assist by helping alleviate the patient's or family's feelings of helplessness by assuring them that the NPT will begin to subside once treatment has been terminated.


Uninsured Workers Have More Severe Hospitalizations: Examining the Texas Workers' Compensation System, 2012.
Texas' unique elective system of workers' compensation (WC) coverage is being discussed widely in the United States as a possible model to be adopted by other states. Texas is the only state that does not mandate that employers provide state-certified WC insurance. Oklahoma passed legislation for a similar system in 2013, but it was declared unconstitutional by the Oklahoma Supreme Court in 2016. This study examined 9523 work-related hospitalizations that occurred in Texas in 2012 using Texas Department of State Health Services data. We sought to examine work-related injury characteristics by insurance source. An unexpected finding was that among those with WC, 44.6% of the hospitalizations were not recorded as work related by hospital staff. These unrecorded cases had 1.9 (1.6-2.2) times higher prevalence of a severe risk of mortality compared to WC cases that were recorded as work related. Uninsured and publicly insured workers also had a higher prevalence of severe mortality risk. The hospital charges for one year were $615.2 million, including at least $102.8 million paid by sources other than WC, and with $29.6 million that was paid for by injured workers or by taxpayers. There is an urgent need for more research to examine how the Texas WC system affects injured workers.


Secondary Data Analysis of the 2012 Peru Demographic and Health Survey Examining Immunization Campaign Participation Among Children Aged 18 to 59 Months.
Objective. To evaluate the association between characteristics known to be associated with under-immunization and participation in immunization campaigns among Peruvian children. Methods. This is an analysis of data collected as part of the Peru 2012 Demographic and Health Survey. Analyses were conducted among children in 2 groups: children aged 18 to 29 months among whom core vaccine coverage is typically determined by the Peruvian authorities and children aged 30 to 59 months who may have received the core vaccines at older ages. The associations between relative wealth, location, maternal education, primary maternal language and the outcome, participation in an immunization campaign within the past 2 years were estimated using logistic regression models adjusted for survey design in each age group. Results. For children aged 18 to 29 months, campaign participation was higher if the mother had completed secondary school compared with those not having completed secondary school (27.4% vs 20.1% [prevalence odds ratio (POR) = 1.51 (1.08, 2.13)]). For children aged 30 to 59 months, campaign participation was higher if the mother had completed secondary school (40.4% vs 35.1% [POR = 1.23 (1.02, 1.49)], adjusted for residence) and if the child resided in Lima versus in other urban areas (46% vs 35.4% [POR = 1.52 (1.16, 2.01)], adjusted for maternal education). Relative wealth and mothers' primary language were not associated with campaign participation. Conclusions. This study suggests that children of mothers with higher education and those residing in Lima had higher prevalence odds of reporting that their children had participated in a vaccination campaign. This contrasts with the populations vaccination campaigns typically target (poor, rural, or indigenous) to improve vaccination coverage.


In vitro and in vivo assays of 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives against Trypanosoma cruzi.
Cytotoxicity assays of 24 new 3,5-disubstituted-tetrahydro-2H-1,3,5-thiadiazin-2-thione derivatives were performed. The 17 compounds with higher anti-epimastigote activity and lower cytotoxicity were, thereafter, screened against amastigote of Trypanosoma cruzi. Out of these 17 derivatives S-2d was selected to be assayed in vivo, because of its remarkable trypanocidal properties. To determine toxicity against J774 macrophages, a method based on quantification of cell damage, after 24 h, was used. Cell respiration, an indicator of cell viability, was assessed by the reduction of MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] to formazan. Anti-amastigote activity was estimated after 48 h by microscopic counts of May Grünwald-Giemsa-stained monolayers. Nifurtimox and benznidazole were used as reference drugs. For the in vivo experiences, mice were infected with 10(4) blood trypomastigotes and then treated during 15 days with S-2d or nifurtimox by oral route. All of the compounds were highly toxic at 100 micro g/ml for macrophages and a few of them maintained this cytotoxicity even at 10 microg/ml. Of the derivatives assayed against amastigotes 3k and S-2d showed an interesting activity, that was held even at 1microg/ml. It is demonstrated that the high anti-epimastigote activity previously reported is mainly due to the non-specific toxicity of these compounds. In vivo assays assessed a reduction of parasitemia after administration of S-2d to infected mice.


Atomic structures of multi-walled boron nitride nanohorns.
Boron nitride (BN) nanohorns were synthesized by an arc-melting method, and atomic structure models for BN nanohorns with tetragonal BN rings were proposed from high-resolution electron microscopy and image calculation. Stability and electronic structures of the BN nanohorns were investigated by molecular orbital calculations, comparing with carbon nanohorns. The calculation showed that multi-walled BN nanohorns would be stabilized by the stacking of BN nanohorns. An energy gap of BN nanohorn was calculated to be 0.80 eV, which is lower compared to those of BN clusters and nanotubes.


The measure of effectiveness of a short-term 2-week intensive Cardiac Rehabilitation program in decreasing levels of anxiety and depression.
Research on heart disease have found a strong and consistent evidence of association between some psychosocial risk factors, including depression, anxiety, self-efficacy, lack of social support and outcome of disease. Depression increases the risk of cardiac death and is highly predictive of reduced adherence to recommended treatments; anxiety appears to be linked to adverse cardiac outcomes. It was demonstrated that Cardiac Rehabilitation (CR) leads to substantial improvements and positive outcomes because combines the prescription of physical activity with the modification of risk factors and aims to reduce symptoms related to the disease and the risk of new cardiovascular events. The main objective of this study is to determine if a short and intense CR program can produce a positive impact on anxious and depressive symptoms revealed in cardiac patients, confirming results of previous researches. The protocol was proposed to all patients referred for an outpatient CR after an acute event who attended the short 2-week intensive rehabilitation program. A total of 157 patients recruited at the operating unit of Cardiology, in the Hospital of Cittadella (Italy), was included in the analysis. The Beck Depression Inventory-II and the State-Trait Anxiety Inventory-Y were administered to the patients. SPSS 17.0 was used for statistical analysis. T-tests for paired samples were used to evaluate differences between the beginning and the end of the CR program. There was a statistically significant difference between the beginning and the end of the CR program. Results for paired samples showed significant differences in all factors of the BDI-II and in the total score. In addition, a statistically significant difference was found even in the state - anxiety subscale. No significant difference was detected for the trait anxiety. According to recent studies, this research shows that the CR program has a significant impact on levels of anxiety and depression, because all activities focus their commitment on changing the patient's personal beliefs and perception of illness, promoting the exchange of information and sharing of concerns and fears, increasing the patient's resilience with the aim of enabling him/her to reorganize positively his/her personal, family and professional sphere.


Interval between endoscopic surgery and decreased intracranial pressure related to putaminal hemorrhage prognosis.
Endoscopic evacuation of a putaminal hemorrhage is effective and minimally invasive; however, it may not result in sufficient brain decompression. While monitoring postoperative intracranial pressure (ICP) is likely useful, specific ICP data in patients with a putaminal hemorrhage are limited. The aim of this study was to determine the association between postoperative ICP and the prognosis of patients with putaminal hemorrhage after endoscopic surgery. We retrospectively analyzed 24 consecutive patients with a putaminal hemorrhage in whom ICP monitoring after endoscopic surgery was performed. Clinical data regarding hematoma volume, evacuation rate, onset-to-treatment time, operation time, ICP max, ICP peak out time (T peak out), and neurological outcomes on discharge were investigated. From August 2011 to October 2015, 24 patients with a putaminal hemorrhage were analyzed. Consciousness on admission and hemorrhage volume were associated with poor outcomes after endoscopic surgery for putaminal hemorrhage. The hematoma volume, operation time, and evacuation rate of hemorrhage were correlated to early peak out of ICP. Furthermore, a T peak out ≤24 h was significantly associated with good neurological outcomes on discharge. Our data suggest that early peak out (≤24 h) of ICP after endoscopic surgery is predictive of a good prognosis following putaminal hemorrhage. Operation time and evacuation rate of hemorrhage could hasten peak out of ICP and improve outcomes in patients with a putaminal hemorrhage after endoscopic surgery.


Persistence-Driven Durotaxis: Generic, Directed Motility in Rigidity Gradients.
Cells move differently on substrates with different rigidities: the persistence time of their motion is higher on stiffer substrates. We show that this behavior-in and of itself-results in a net flux of cells directed up a soft-to-stiff gradient. Using simple random walk models with varying persistence and stochastic simulations, we characterize the propensity to move in terms of the durotactic index also measured in experiments. A one-dimensional model captures the essential features and highlights the competition between diffusive spreading and linear, wavelike propagation. Persistence-driven durokinesis is generic and may be of use in the design of instructive environments for cells and other motile, mechanosensitive objects.


The Glare Effect Test and the Impact of Age on Luminosity Thresholds.
The glare effect (GE) is an illusion in which a white region appears self-luminous when surrounded by linearly decreasing luminance ramps. It has been shown that the magnitude of the luminosity effect can be modulated by manipulating the luminance range of the gradients. In the present study we tested the thresholds for the GE on two groups of adults: young (20-30 years old) and elderly (60-75 years old). Purpose of our perspective study was to test the possibility of transforming the GE into a test that could easily measure thresholds for luminosity and discomfort glare. The Glare Effect Test (GET) consisted in 101 printed cards that differed from each other for the range of luminance ramps. Participants were assessed with GET and a battery of visual tests: visual acuity, contrast sensitivity, illusion of length perception, and Ishihara test. Specifically in the GET, participants were required to classify cards on the basis of two reference cards (solid black-no gradient; full range black to white gradient). PSEs of the GE show no correlation with the other visual tests, revealing a divergent validity. A significant difference between young and elderly was found: contrary to our original expectations, luminosity thresholds of GE for elderly were higher than those for young, suggesting a non-direct relationship between luminosity perception and discomfort glare.


Atypical choroid plexus papilloma: clinicopathological and neuroradiological features.
Background Atypical choroid plexus papilloma (APP) is a rare, newly introduced entity with intermediate characteristics. To date, few reports have revealed the magnetic resonance (MR) findings. Purpose To analyze the clinicopathological and MR features of APP. Material and Methods The clinicopathological data and preoperative MR images of six patients with pathologically proven APP were retrospectively reviewed. The MR features including tumor location, contour, signal intensity, degree of enhancement, intratumoral cysts, and necrosis; and flow voids, borders, peritumoral edema, and associated hydrocephalus were analyzed. Results The APP were located in the ventricle (n = 4) and cerebellopontine angle (CPA, n = 2). Tumor dissemination along the spinal subarachnoid space was found in one patient. The tumors appeared as milt-lobulated (n = 5) or round mass (n = 1), with slightly heterogeneous signals (n = 5) or mixed signals (n = 1) on T1-weighted and T2-weighted images. Heterogeneous and strong enhancement were found in five cases on contrast-enhanced images. Three of four intraventricular tumors had a partly blurred border with ventricle wall. Four tumors had mild to moderate extent of surrounding edema signals. A slight hydrocephalus was seen in four patients. Incomplete capsule was seen in four tumors at surgery. Histopathologically, mild nuclear atypia was seen in all tumors with a mitotic rate of 2-5 per 10 high-power fields. Conclusion APP should be included in the differential diagnosis when an intraventricular or CPA tumor appearing as a multi-lobulated solid mass with slight heterogeneity, heterogeneous strong enhancement, partly blurred borders, mild to moderate peritumoral edema, or slight hydrocephalus are present.


Virological Mechanisms in the Coinfection between HIV and HCV.
Due to shared transmission routes, coinfection with Hepatitis C Virus (HCV) is common in patients infected by Human Immunodeficiency Virus (HIV). The immune-pathogenesis of liver disease in HIV/HCV coinfected patients is a multifactorial process. Several studies demonstrated that HIV worsens the course of HCV infection, increasing the risk of cirrhosis and hepatocellular carcinoma. Also, HCV might increase immunological defects due to HIV and risk of comorbidities. A specific cross-talk among HIV and HCV proteins in coinfected patients modulates the natural history, the immune responses, and the life cycle of both viruses. These effects are mediated by immune mechanisms and by a cross-talk between the two viruses which could interfere with host defense mechanisms. In this review, we focus on some virological/immunological mechanisms of the pathogenetic interactions between HIV and HCV in the human host.


One Versatile Route to Three-Dimensional Graphene Wrapped Metal Cyanide Aerogels for Enhanced Sodium Ion Storage.
Facile and controllable integration of metal cyanides (MCs) into three-dimensional graphene (3DG) with advantageous structures is of fundamental importance for the development of superior MC-based electrode materials for electrochemical energy storage and catalysis. Here a facile and versatile spatially-confined Ostwald ripening strategy was developed to synthesize a series of 3DG wrapped MC aerogels with different compositions, size, and structure based on the chemical instability of MC in the reaction system. Remarkably, the integration of Prussian blue (PB) into 3DG, with such unique architecture, largely improves the rate performance and long-term cycling stability of PB as a cathode material for sodium ion batteries.


Computational studies on metathetical and redox processes of HOCl in gas phase. III. Its self-reaction and interactions with HNOx (x = 1-3).
The gas-phase redox reactions of HOCl with its self and HNO(x) (x = 1-3) have been studied theoretically by ab initio quantum chemical and statistical mechanical theories. The structures of reactants, intermediate complexes, products, and transition states were optimized at the MPW1PW91/6-311+G(3df,2p) level of theory. The potential energy surface of each reaction was refined at the CCSD(T)/6-311+G(3df,2p) level of theory. The most favorable products are predicted to be ClClO + H(2)O and ClOCl + H(2)O for the HOCl self-reaction (A), H(2)O + Cl + NO for the HOCl + HNO reaction (B), H(2)O + ClNO(2) for the HOCl + HONO-t reaction (C), H(2)O + cis-ClONO for the HOCl + HONO-c reaction (D). For the HOCl + HONO(2) reaction (E), only one dehydration reaction channel was considered to produce H(2)O + ClONO(2). The rate constants of all above five reactions have been predicted at 300-3000 K by the VTST/RRKM theory. The calculation shows that the theoretical rate constants are within the upper limits of experimental results. In addition, we calculated the equilibrium constant for the Cl(2)O + H(2)O --> HOCl + HOCl reaction, which is also in reasonable agreement with experimental data within the error of the available experimental enthalpy change.


Intrinsic cues and hormones control mouse mammary epithelial tree size.
Organ size control is a long-standing question in biology. In mammals, using conditional cell ablation, two mutually exclusive mechanisms involving either intrinsic or extrinsic programs have been described to control organ size. The mammary gland is an ideal model for such studies, since it undergoes size and morphological changes during puberty and pregnancy. The role of stem cells in controlling mammary epithelial tree size is unclear, although mammary stem cells are able to reconstitute a functional organ on transplantation. Here, we show that mammary gland cellularity was strictly dependent on mammary stem cell number, even following a 20-fold expansion of the mammary stem cell pool at puberty and transient 3-fold expansions with each pregnancy. In addition, the expansion of the mammary stem cell pool was hormone dependent, as demonstrated by female bilateral ovariectomies during puberty and transplants of male-derived cells into female recipients. In these transplants, apart from a mammary stem cell expansion, we also observed the donor cells reconstituting functional mammary glands, developing alveolar structures, and secreting milk after the recipient's parturition. Taken together, these data suggest that in the mammary gland, there is a third organ size control mechanism, combining intrinsic cues throughout the organism's lifetime, with extrinsic hormone signals at particular developmental windows (puberty, pregnancy), where an expansion of the mammary stem cell pool occurs. This mechanism might have strong implications for the understanding of mammary tumorigenesis, since the expansion of the mammary stem cell pool precedes the generation of breast tumors.


Development and validation of a liquid chromatography-tandem mass spectrometry method for CPUL1, a novel antitumor candidate compound, and its application to pharmacokinetic studies.
An active substance of pyrano[3,2-a]phenazine, also called CPUL1, is a synthesized phenazine derivative and displays broad-spectrum anticancer activities. Quantitative assessment of CPUL1 in biological samples has not been well established, hindering pharmaceutical development and application. According to international guidelines, a sensitive and selective liquid chromatography-tandem mass spectrometry method in negative ion mode was developed and validated for quantification of CPUL1 in human plasma, colorectal cancer cell lines, and rat plasma, whereby linearity and accuracy were demonstrated for the range of 1-1000 ng/ml. The validated liquid chromatography-tandem mass spectrometry method was successfully employed in pharmacokinetic studies of CPUL1 in vitro and in vivo. Notably, the cellular pharmacokinetic behavior of CPUL1 varies in colorectal cancer cell lines. Regarding the pharmacokinetic processes in vivo, oral absorption was less effective than an injection, with a bioavailability of 23.66%. CPUL1 was linearly eliminated after a single administration; however, it could accumulate in tissues (heart, liver, spleen, lung, and kidney) after multiple injections. In summary, this study established a capable bioanalytical method for CPUL1 and provided exploratory pharmacokinetic data, paving the way for use of this promising derivative in disease models.


Human DNA helicase, RuvBL1 and its Chlamydomonas homologue, CrRuvBL1 plays an important role in ciliogenesis.
Several nuclear and nucleic acid-binding proteins were detected in the proteomic analyses of ciliary fractions from various organisms. Yet very little is known about the role of these proteins in ciliogenesis and ciliary signaling. In an attempt to characterize the role of these nuclear proteins, we identified a hypothetical protein from Chlamydomonas reinhardtii, CrRuvBL1, which is homologous to human DNA helicase, HsRuvBL1. CrRuvBL1 localizes to flagella and nucleus in vegetative Chlamydomonas cells. It accumulates in the nucleus specifically during initial stages of flagellar assembly and cell division indicating its role in these processes. Mammalian counterpart of this protein, HsRuvBL1, was found to be present at the basal bodies and in the primary cilium of quiescent Retinal Pigment Epithelial (RPE1) cells. In interphase cells, HsRuvBL1 is present at centrioles while the protein localizes on spindle fibers, spindle poles and midbodies, which are important structures formed during different phases of cell division. Depletion of HsRuvBL1 by using siRNAs leads to complete loss of primary cilia in RPE1 cells. Together these results suggest that nuclear proteins play an important role in ciliogenesis.


The effect of non-pharmacological interventions on sleep quality in people with sleep disturbances: A systematic review and a meta-analysis.
Sleep is the elixir of life. Both healthy populations and patients with chronic diseases experience sleep disturbances in their lifetime. Pharmacological agents to induce sleep in individuals with sleep disturbances pose side effects like tolerance and dependence, warranting the development of alternative non-pharmacological interventions with less or no adverse effects. However, deciphering comprehensive evidence on the translational potential of these alternative therapies remains difficult. In the current paper, we systematically reviewed the recent literature on the effect of non-pharmacological interventions (NPIs) on improving sleep quality in both healthy and diseased populations experiencing sleep disturbances. We searched PubMed, Science Direct, Cochrane Controlled Trials, and Web of Science databases from inception to June 2022 for randomized controlled trials and cohort studies evaluating the sleep quality of individuals. We performed a meta-analysis using the random effects model with Pittsburgh Sleep Quality Index (PSQI) as an outcome measure to evaluate the effect of five distinct NPIs on sleep quality in normal and people with different medical conditions. Subgroup analyses and sensitivity analyses were done for heterogeneity analysis and to check the consistency of results, respectively. In 16 trials reporting on 1885 subjects, that all NPIs like Resistance Training (SMD -0.29, 95% CI -0.64 to 0.05; p = 0.09); Yoga (SMD -0.48, 95% CI -0.72 to -0.25; p < 0.0001); Cognitive Behavioral Therapy (SMD -1.69, 95% CI -2.70 to -0.68; p = 0.001); Music (SMD -1.42, 95% CI -1.99 to -0.85; p < 0.00001); Light (SMD -0.43, 95% CI -0.77 to -0.09; p = 0.01) have substantially decreased the global PSQI scores. The findings of the randomized studies and a cohort study included in qualitative synthesis demonstrated that the global PSQI scores improved significantly as compared to the placebo groups. Despite the limitations of clinical heterogeneity in subjects, our results demonstrate a positive impact of the studied NPIs on sleep quality in individuals experiencing sleep disturbances. However, comprehensive double-blinded controlled trials are indispensable in the future, emphasizing the objective sleep quality and inter-individual differences in response to the intervention.


Modified vaccinia virus Ankara-infected dendritic cells present CD4+ T-cell epitopes by endogenous major histocompatibility complex class II presentation pathways.
CD4(+) T lymphocytes play a central role in the immune system and mediate their function after recognition of their respective antigens presented on major histocompatibility complex II (MHCII) molecules on antigen-presenting cells (APCs). Conventionally, phagocytosed antigens are loaded on MHCII for stimulation of CD4(+) T cells. Certain epitopes, however, can be processed directly from intracellular antigens and are presented on MHCII (endogenous MHCII presentation). Here we characterized the MHCII antigen presentation pathways that are possibly involved in the immune response upon vaccination with modified vaccinia virus Ankara (MVA), a promising live viral vaccine vector. We established CD4(+) T-cell lines specific for MVA-derived epitopes as tools for in vitro analysis of MHCII antigen processing and presentation in MVA-infected APCs. We provide evidence that infected APCs are able to directly transfer endogenous viral proteins into the MHCII pathway to efficiently activate CD4(+) T cells. By using knockout mice and chemical inhibitory compounds, we further elucidated the molecular basis, showing that among the various subcellular pathways investigated, proteasomes and autophagy are key players in the endogenous MHCII presentation during MVA infection. Interestingly, although proteasomal processing plays an important role, neither TAP nor LAMP-2 was found to be involved in the peptide transport. Defining the molecular mechanism of MHCII presentation during MVA infection provides a basis for improving MVA-based vaccination strategies by aiming for enhanced CD4(+) T-cell activation by directing antigens into the responsible pathways. This work contributes significantly to our understanding of the immunogenic properties of pathogens by deciphering antigen processing pathways contributing to efficient activation of antigen-specific CD4(+) T cells. We identified autophagosome formation, proteasomal activity, and lysosomal integrity as being crucial for endogenous CD4(+) T-cell activation. Since poxvirus vectors such as MVA are already used in clinical trials as recombinant vaccines, the data provide important information for the future design of optimized poxviral vaccines for the study of advanced immunotherapy options.


Commonalities between Disaster and Climate Change Risks for Health: A Theoretical Framework.
Disasters and climate change have significant implications for human health worldwide. Both climate change and the climate-sensitive hazards that result in disasters, are discussed in terms of direct and indirect impacts on health. A growing body of literature has argued for the need to link disaster risk reduction and climate change adaptation. However, there is limited articulation of the commonalities between these health impacts. Understanding the shared risk pathways is an important starting point for developing joint strategies for adapting to, and reducing, health risks. Therefore, this article discusses the common aspects of direct and indirect health risks of climate change and climate-sensitive disasters. Based on this discussion a theoretical framework is presented for understanding these commonalities. As such, this article hopes to extend the current health impact frameworks and provide a platform for further research exploring opportunities for linked adaptation and risk reduction strategies.


Determination of a limiting nutrient regulating algal biomass using in situ experiments of nutrient enrichment bioassay (NEB) and empirical relations of nutrients and chlorophyll-a.
Long-term nutrient contents and nutrient ratios indicated that phosphorus was a potential limiting element for algal growth. In situ experiments of nutrient enrichment bioassay supported the evidence of P-limitation. However, regression analyses of log10-transformed chlorophyll-a (CHL) against TP (R2 values < 0.25) showed that seasonal CHL was not closely related to flux of phosphorus during all seasons. Also, two dimensional graphical approach of Trophic State Index (TSI) showed that most values of TSI (CHL) -TSI (TP) and TSI (CHL) -TSI (SD) were less than zero, indicating factors other than phosphorus limited algal biomass (CHL -TP < 0), and that non-algal particles dominated light attenuation (CHL -SD < 0). The weak empirical relations and trophic deviations were explained well by the experiment of NEB-II that was conduced during a period of high inorganic turbidity. Overall results suggest that phosphorus is the primary element regulating the system productivity, but the system also were highly influenced by rapid flushing and high inorganic turbidity.


Cost savings of patients with a MACIS score lower than 6 when radioactive iodine is not given.
To assess the cost savings if the current policy of treating patients with a MACIS (metastases, age, completeness of resection, invasion, and size) score lower than 6 using radioactive iodine (RAI) was changed to reflect the findings of recent studies. Retrospective medical record review. Mount Sinai Hospital, Toronto, Ontario. Between January 1, 2002, and July 1, 2005, 199 consecutive patients with a MACIS score lower than 6 who received RAI treatment after total thyroidectomy. Patient demographics were analyzed. Costs for the dose of RAI, hospital stay, and health insurance claims were included in the calculations. For 199 consecutive patients, the cost for sodium iodide 131 treatment totaled Can$161 588, and the required 2-day stay in isolation totaled Can$764 558. The overall cost to the health care system was Can$934 106, which translates into approximately Can$4694 per patient. By following the recommendations of recent evidence-based studies and by ceasing to treat patients with a MACIS score lower than 6 after total thyroidectomy using RAI, cost savings can be accrued for health care systems involved in the treatment of thyroid cancer. Alternate strategies, such as treating patients who need RAI therapy on an outpatient basis and reducing the dose of RAI, can lower costs as well.


DprA from Neisseria meningitidis: properties and role in natural competence for transformation.
DNA processing chain A (DprA) is a DNA-binding protein that is ubiquitous in bacteria and expressed in some archaea. DprA is active in many bacterial species that are competent for transformation of DNA, but its role in Neisseriameningitidis (Nm) is not well characterized. An Nm mutant lacking DprA was constructed, and the phenotypes of the wild-type and ΔdprA mutant were compared. The salient feature of the phenotype of dprA null cells is the total lack of competence for genetic transformation shown by all of the donor DNA substrates tested in this study. Here, Nm wild-type and dprA null cells appeared to be equally resistant to genotoxic stress. The gene encoding DprANm was cloned and overexpressed, and the biological activities of DprANm were further investigated. DprANm binds ssDNA more strongly than dsDNA, but lacks DNA uptake sequence-specific DNA binding. DprANm dimerization and interaction with the C-terminal part of the single-stranded binding protein SSBNmwere demonstrated. dprA is co-expressed with smg, a downstream gene of unknown function, and the gene encoding topoisomerase 1, topA.


Using a Network Physiology Approach to Prescribe Exercise for Exercise Oncology.
Current American College of Sports Medicine (ACSM) exercise guidelines for exercise oncology survivors are generic one-size fits all recommendations, which assume ideal or prototypic health and fitness state in order to prescribe. Individualization is based on the objective evaluation of the patient's baseline physiological status based on a linear dose response relationship of endpoints. This is only a partial snapshot of both the acute and chronic responses exercise can provide. Each acute exercise session represents a unique challenge to whole-body homeostasis and complex acute and adaptive responses occur at the cellular and systemic levels. Additionally, external factors must be considered when prescribing exercise. Network physiology views the human organism in terms of physiological and organ systems, each with structural organization and functional complexity. This organizational approach leads to complex, transient, fluctuating and nonlinear output dynamics which should be utilized in exercise prescription across health states. Targeting health outcomes requires a multi-system approach as change doesn't happen in only one system at a time or in one direction Utilizing a multi-system or person-centered approach, allows for targeting and personalization and understands and targets non-linear dynamics of change. Therefore, the aims of this review are to propose a paradigm shift towards a Network Physiology approach for exercise prescription for cancer survivors. Cancer treatment affects multiple systems that interact to create symptoms and disruptions across these and therefore, prescribing exercise utilizing both external daily factors and internal physiological networks is of the highest order.


A modified sequential algebraic algorithm applied to identify rough acoustic impedance profiles in slender structures.
This paper develops and examines a modified technique for identifying damage in slender structures. An algorithm, called modified sequential algebraic algorithm, is presented to solve the longitudinal acoustic wave propagation problem in inhomogeneous media. This method accurately predicts the echo generated by the inhomogeneities when the acoustic impedance variation profile in the damaged part of the structure is non-smooth. For these cases, the available algorithms fail to provide the actual regressive wave component. In the following, a stochastic optimization scheme, the differential evolution method, is applied to solve the inverse problem. Numerical examples with smooth and non-smooth impedance profiles are considered. It is shown that, for smooth profiles, both the available techniques and the modified algorithm succeed in identifying the actual damage. Nevertheless, in situations where a rough profile is to be reconstructed, only the modified algorithm succeeds. The technique is found to be robust with respect to additive noise in the signals.


Unfolding times for proteins in a force clamp.
The escape process from the native valley for proteins subjected to a constant stretching force is examined using a model for a beta barrel. For a wide range of forces, the unfolding dynamics can be treated as one-dimensional diffusion, parametrized in terms of the end-to-end distance. In particular, the escape times can be evaluated as first passage times for a Brownian particle moving on the protein free-energy landscape, using the Smoluchowski equation. At strong forces, the unfolding process can be viewed as a diffusive drift away from the native state, while at weak forces thermal activation is the relevant mechanism. An escape-time analysis within this approach reveals a crossover from an exponential to an inverse Gaussian escape-time distribution upon passing from weak to strong forces. Moreover, a single expression valid at weak and strong forces can be devised both for the average unfolding time as well as for the corresponding variance. The analysis offers a possible explanation of recent experimental findings for the proteins ddFLN4 and ubiquitin.


Case report of nivolumab-related pneumonitis.
We report a case with suggestive antiprogrammed death-1 inhibitor-related pneumonitis in an endometrial cancer patient. This case presented with fever and cough after three dosages of nivolumab. Computed tomography initially showed centrilobular nodularities in a unilateral lung, which was compatible with aspiration pneumonia. However, diffuse ground-glass opacities (GGO) rapidly developed in the unilateral lung over 4 days despite the use of broad-spectrum antibiotics. Development of GGO was considered to be related to a nivolumab-mediated immune reaction. Corticosteroid was administered and the GGO subsequently disappeared. The present report focuses on the computed tomography diagnostic features of nivolumab-related pneumonitis. The accumulation of knowledge regarding various types of antiprogrammed death-1-related pneumonitis will lead to appropriate treatment for this newly emerging adverse event.


Ceritinib in patients with advanced, crizotinib-treated, anaplastic lymphoma kinase-rearranged NSCLC: Japanese subset.
Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer is sensitive to tyrosine kinase inhibitors; however, resistance can develop. Data are presented from the phase II trial (ASCEND-2) evaluating efficacy and safety in a subset of Japanese patients with ALK-rearranged non-small cell lung cancer previously treated with platinum-based chemotherapy, who experienced disease progression on crizotinib. Patients with advanced ALK-rearranged non-small cell lung cancer, including those with asymptomatic or neurologically stable baseline brain metastases, received oral ceritinib 750 mg/day. Whole-body and intracranial responses were assessed by investigator and Blinded Independent Review Committee (RECIST v1.1). Safety and tolerability were also investigated. All 24 Japanese patients had received ≥2 previous treatment regimens, with crizotinib the last therapy received prior to ceritinib. Median duration of ceritinib exposure was 8.1 (range: 0.2-12.5) months. Overall response rate was 45.8% (95% confidence interval: 25.6-67.2). Other efficacy endpoints included disease control rate (79.2% [95% confidence interval: 57.8-92.9]), time to response (median 1.9 months [range: 1.7-3.5]), duration of response (median 9.2 months [95% confidence interval: 4.0-not estimable]) and progression-free survival (median 6.6 months [95% confidence interval: 3.7-9.3]). Of the four patients with active baseline target brain lesions, two achieved an intracranial partial response (50%). The most commonly reported adverse events (majority grade 1/2) were nausea (91.7%), diarrhea (83.3%) and vomiting (83.3%). This study demonstrates the clinical activity and manageable tolerability of ceritinib in a Japanese subset of chemotherapy- and crizotinib-pretreated patients with ALK-rearranged non-small cell lung cancer who progressed on crizotinib, as was shown in the whole ASCEND-2 study population. ClinicalTrials.gov identifier: NCT01685060.


Skin Tissue Substitutes and Biomaterial Risk Assessment and Testing.
Tremendous progress has been made over the past few decades to develop skin substitutes for the management of acute and chronic wounds. With the advent of tissue engineering and the ability to combine advanced manufacturing technologies with biomaterials and cell culture systems, more biomimetic tissue constructs have been emerged. Synthetic and natural biomaterials are the main constituents of these skin-like constructs, which play a significant role in tissue grafting, the body's immune response, and the healing process. The act of implanting biomaterials into the human body is subject to the body's immune response, and the complex nature of the immune system involves many different cell types and biological processes that will ultimately determine the success of a skin graft. As such, a large body of recent studies has been focused on the evaluation of the performance and risk assessment of these substitutes. This review summarizes the past and present advances in in vitro, in vivo and clinical applications of tissue-engineered skins. We discuss the role of immunomodulatory biomaterials and biomaterials risk assessment in skin tissue engineering. We will finally offer a roadmap for regulating tissue engineered skin substitutes.


The MAPK Signaling Pathways as a Novel Way in Regulation and Treatment of Parasitic Diseases.
Few major advances in fighting parasitic diseases have been made in China since the development of new methods for prevention, control, and elimination. However, the proportion of immunocompromised individuals has increased due to the growth of chronic diseases, population aging, and more frequent cases of patients with AIDS and cancer. All these problems can promote development of parasitic infections, which is commonly associated with manipulation of host signaling pathways and the innate immune system. Mitogen-activated protein kinase (MAPK) signaling pathways are evolutionarily conserved in metazoan organisms, which play critical roles in the cell cycle, gene expression, growth, differentiation, apoptosis, and parasite⁻host interactions. Recent discoveries of the MAPK components involved in activation, regulation, and signal transduction appeared to be promising for the diagnosis, prevention, and treatment of parasitic diseases in the future. This review summarizes the involvement and critical role of the MAPK family in parasitic disease development and maintenance in the host. Moreover, it highlights recent studies concerning the mechanisms and novel drug development for inhibition and regulation of MAPK pathways in order to prevent parasitic disease. In addition, we discuss some antigenic proteins as prospective inhibitory molecules or vaccines for the regulation and control of MAPK signaling involved in parasite physiological activity.


Obesity associated disease risk: the role of inherent differences and location of adipose depots.
Obesity and associated metabolic co-morbidities are a worldwide public health problem. Negative health outcomes associated with obesity, however, do not arise from excessive adiposity alone. Rather, deleterious outcomes of adipose tissue accumulation are a result of how adipocytes are distributed to individual regions in the body. Due to our increased understanding of the dynamic relationship that exists between specific adipose depots and disease risk, an accurate characterization of total body adiposity as well as location is required to properly evaluate a population's disease risk. Specifically, distinctive tissue depots within the body include the lower body, upper body and abdominal (deep and superficial) subcutaneous regions, as well as visceral (mesenteric and omental) regions. Upper body and visceral adipose tissues are highly associated with metabolic dysfunction and chronic disease development, whereas lower body gluteofemoral subcutaneous adipose tissue imparts protection against diet-induced metabolic derangement. Each adipose depot functions distinctly as an endocrine organ hence it has a different level of impact on health outcomes. Effluent from adipose tissue can modulate the functions of other tissues, whilst receiving differential communication from the rest of the body via central nervous system innervation, metabolites and other signaling molecules. More so, adipose depots contain a diverse reservoir of tissue-resident immune cells that play an integral part in both maintaining tissue homeostasis, as well as propagating metabolically-induced inflammation. Overall, the conceptualization of obesity and associated risks needs updating to reflect the complexities of obesity. We review adipose tissue characteristics that are linked to deleterious or beneficial adipose tissue distributions.


Coexistence of three hemoglobins with different alpha-chains in two unrelated children (with family studies indicating polymorphism in the number of alpha-globin genes in the Sardinian population).
In each of two families from Sardinia, Italy, we have found segregation for two alpha-chain hemoglobin variants, which we have identified as G Philadelphia [alpha 68 (E17) Asn leads to Lys] and J Sardinia [alpha 50 (CE8) His leads to Asp], respectively. One family also shows segregation for the beta-thalassemia trait. One subject in one family and two subjects in the other family have in their red cells both hemoglobin variants, G and J, in addition to HbA. One of the subjects, a newborn baby, has six major hemoglobin components; alpha 2A beta 2, alpha 2A gamma 2, alpha 2G beta 2, alpha 2G gamma 2, alpha 2J beta 2, alpha 2J gamma 2. These three cases are to be added to three previous cases in the literature in whom three different alpha-chains have been found in the same blood. These findings prove that the alpha-chain locus is duplicated in the Sardinian population, as it is in other populations. The relative amounts of the various hemoglobin species found in members of our two families, through three and four generations respectively, suggest that chromosomes with and without duplication may coexist in the same population.


Helicobacter pylori infection and systemic sclerosis-is there a link?
Over the last 20 years, increasing evidence has accumulated to implicate infectious agents in the etiology of systemic sclerosis (SSc) and Raynaud's phenomenon. Infection rates in patients with SSc compared with those in control populations do not provide clear support for any specific pathogen. However, increased antibody titers, a preponderance of specific strains in patients with SSc, and evidence of molecular mimicry inducing autoimmune responses suggest mechanisms by which infectious agents may contribute to the development and progression of SSc. Helicobacter pylori (H. pylori) has been associated with diseases such as autoimmune gastritis, Sjögren's syndrome, atherosclerosis, immune thrombocytopenia purpura, inflammatory bowel diseases and autoimmune pancreatitis, in each of which it seems to play a pathogenetic, but it has also been suggested that it may help to protect against the development of autoimmune gastritis, multiple sclerosis, systemic lupus erythemathosus and inflammatory bowel diseases. A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and ACR/EULAR meeting abstracts. We hypotheses that H. pylori infection might play a critical role in the pathogenesis of SSc. Here we review studies examining the potential involvement of H. pylori infection in SSc.


Kin selection: its components.
Change in gene frequency under kin selection is the sum of two components, namely, [See equation in the PDF file], a change in gene frequency caused by individual selection, and [See equation in the PDF file], a change caused by group selection. For the evolution of altruistic traits by kin selection, [See equation in the PDF file] is always negative-that is, individual selection operates against altruism-and [See equation in the PDF file] is always positive, so that selection between groups favors altruism. Hamilton's rule specifies the conditions under which [See equation in the PDF file]-that is, the conditions necessary for intergroup selection to override individual selection.


Validation of Dual-energy X-Ray Absorptiometry to Predict Body Composition of Channel Catfish, Ictalurus punctatus.
Dual-energy X-ray absorptiometry (DXA) provides a noninvasive way to determine lean tissue mass (LTM), fat mass (FM), bone mineral content (BMC), and bone mineral density (BMD) in humans and small mammals. Live channel catfish (n=74, 78g - 1200 g) were anesthetized and scanned in both a lateral position and a dorsa-ventral position. Six individual fish (300g - 600g) were scanned five times each to determine precision by the coefficient of variation. Precision was good for LTM (0.75-1.06%) and for BMC and BMD (2-2.6%). Precision for FM was not good (27-34%), which was due to the very low FM (0-1g) recorded by the DXA. However, using the predicted values, FM precision improved to 5-5.5%. DXA values for LTM, FM, and BMC were significantly different from chemical analysis (P< 0.001). DXA overestimated LTM and underestimated FM and BMC. However, all three compartments were strongly correlated with carcass values (P <0.0001). Using the prediction equations and the jackknife procedure, predicted values of LTM, FM, and BMC were not significantly different from the carcass values (P >0.05). DXA may also be a valuable tool for evaluating body condition longitudinally in commercial or in threatened or endangered fish species, where non-invasive procedures would be invaluable.


Shugoshin: guardian spirit at the centromere.
A recently emerging protein family, shugoshin, plays a crucial role in the centromeric protection of cohesin, which is responsible for sister chromatid cohesion. This is especially important at the first meiotic division, where cohesin is cleaved by separase only along chromosome arms while the centromeric cohesin must be preserved. In vertebrate cells, arm cohesion is largely lost during prophase and prometaphase in order to facilitate sister chromatid resolution, whereas centromeric cohesion is preserved until the bipolar attachment of sister chromatids is established. Vertebrate shugoshin plays an essential role in protecting centromeric cohesin from prophase dissociation. In yeast, shugoshin also has a crucial role in sensing the loss of tension at kinetochores and in generating the spindle checkpoint signal.


Primary immunodeficiency diseases and malignancy in Japan.
Twenty-two cases out of a total of 683 patients (3.2%) with primary immunodeficiency diseases registered in the All-Japan Immunodeficiency Registry were reported to have developed malignant diseases. In the childhood patients with ataxia-telangiectasia the incidence of death due to malignancy was approximately 625 times higher than that of the normal Japanese childhood population. The incidence of lymphoproliferative disorders, such as malignant lymphoma, in Chediak-Higashi syndrome and the incidence of non-Hodgkin lymphoma and various carcinomas in ataxia-telangiectasia were both high, 37.5% and 13.7%, respectively. Only one case out of 45 with Wiskott-Aldrich syndrome was reported to have malignant lymphoma. The data obtained were compared with international statistics reported by the Immunodeficiency Cancer Registry.