Secretin potentiates, caffeine does not affect caerulein--stimulated pancreatic enzyme depletion and growth in newborn rats.
We studied the effect of two peptides, the intracellular Ca2(+)-mobilizing caerulein and the cAMP-mediated secretin, and also the phosphodiesterase inhibitor caffeine on pancreatic secretion and growth in newborn rats. To investigate the secretory response of these substances, and to construct dose-response curves 10-day-old conscious rats were given subcutaneously a single injection of caerulein, secretin, caffeine or the combination of these compounds (caerulein + secretin, caerulein + caffeine). Fifteen min after the injection pancreatic specific trypsin activities were measured in order to estimate depletion of enzymes from the pancreas. To study the pancreatic growth--promoting effect of these substances, newborn rats were treated three times daily for 10 days from the day of birth, using the same experimental groups as described above. Caerulein stimulated both enzyme depletion and pancreatic growth. Secretin stimulated enzyme depletion and increased the trophic effects of caerulein on the pancreas. Caffeine alone or in combination with caerulein did not affect pancreatic enzyme depletion and growth.


Paracoccidioidomycosis simulating brain tumor.
Paracoccidioidomycosis (PCM) is a systemic granulomatous disease caused by Paracoccidioides brasiliensis. Involvement of the central nervous system (CNS) occurs in about 10% of cases. A 57-year-old white man presented with the complaint of headache and an episode of focal seizure 1 month earlier. Magnetic resonance imaging (MRI) revealed a ring-enhancing lesion in the right parietal lobe with peri-lesional vasogenic edema suggestive of a primary neoplasm. The patient underwent craniotomy and the intraoperative finding was a yellowish, hard lesion with thick content and yellow inside. Anatomo-pathological findings were pathognomonic of PCM: large, thick-walled, spherical yeast cells with multiple peripheral buds. The patient tested negative for human immunodeficiency virus (HIV). Encephalitis and meningitis were ruled out by cerebrospinal fluid analysis. Culture confirmed the diagnosis of PCM and the patient was treated with amphotericin B. The patient responded well to treatment with resolution of the headache and clinical improvement, despite a bitemporal hemianopia. He was clinically stable and then discharged in good general condition. Radiographic findings of PCM with CNS involvement may suggest neoplasia, making diagnosis difficult. In endemic areas, the diagnosis of PCM should be promptly considered when a ring-enhancing mass associated with peri-lesional edema is observed on MRI.


A soluble form of alpha1,3-galactosyltransferase functions within cells to galactosylate glycoproteins.
It has been assumed that membrane-bound glycosyltransferases function within the Golgi apparatus to glycosylate glycoproteins. We now report, however, that a truncated, soluble recombinant form of the murine alpha1,3-galactosyltransferase expressed in human 293 cells is highly efficient and comparable to the full-length enzyme in alpha-galactosylating both newly synthesized membrane-associated and secreted glycoproteins. Although the soluble enzyme was secreted by cells as expected, we also found that the full-length, membrane-associated form was secreted. Unexpectedly, both secreted forms are cleaved identically at two primary sites within the stem region by endogenous protease(s) at the indicated positions in the sequence 73KDWW (downward arrow) FPS (downward arrow) WFKNG. These results demonstrate that the soluble alpha1,3-galactosyltransferase is functional within the cell and that specific proteolysis occurs in the stem region. The widespread occurrence of different soluble glycosyltransferases secreted by cells suggests that normal glycoconjugate biosynthesis may involve cooperation between membrane-bound and soluble enzymes.


Mitochondrial cross-compartmental signalling to maintain proteostasis and longevity.
Lifespan in eukaryotic species can be prolonged by shifting from cellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly and maintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.


Leveraging a Clinical Phase Ib Proof-of-Concept Study for the GPR40 Agonist MK-8666 in Patients With Type 2 Diabetes for Model-Informed Phase II Dose Selection.
GPR40 mediates free fatty acid-induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK-8666, a partial GPR40 agonist, after once-daily multiple dosing in type 2 diabetes patients. This double-blind, multisite, parallel-group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14-day treatment. The results showed no serious adverse effects or treatment-related hypoglycemia. One patient (150-mg group) showed mild-to-moderate transaminitis at the end of dosing. Median MK-8666 Tmax was 2.0-2.5 h and mean apparent terminal half-life was 22-32 h. On Day 15, MK-8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer-term assessment is projected at 500 mg based on exposure-response analysis. In conclusion, MK-8666 was generally well tolerated with robust glucose-lowering efficacy.


[Cytologic examination during operation of endometrial cancer (author's transl)].
In order to prevent vaginal recurrences after hysterectomy for endometrial cancer, a operation method is described which permits sampling of endometrial cells and enables cytologic examination, evaluation of sensitation response and radiation response and search for vital cancer cells after preoperative irradiation. In 84 endomentrial carcinomas operated upon using this procedure no vaginal reccurences have been met.


Differences in psychological readiness for return to sport after anterior cruciate ligament injury is evident in thigh musculature motor unit characteristics.
Following anterior cruciate ligament (ACL) injury, many athletes that undergo surgery and 6-9 months of rehabilitation struggle to return to sport. Evidence suggests that psychological factors contribute to this failure to return-to-sport. Determine the motor control relationship between thigh musculature motor unit characteristics and psychological readiness to return to sport between ACL-injured and healthy controls. A longitudinal cohort study. Athletes longitudinally completed the ACL Return to Sport after Injury (ACL-RSI) survey and isometric strength measures with a measurement of electromyography (EMG) of the vastus lateralis, vastus medialis, biceps femoris, and semitendinosus. A score cut-off of 61 on the ACL-RSI was used to divide ACL-injured groups. EMG was decomposed to provide each identified motor unit's characteristics (amplitude, average firing rate, etc). Data demonstrated increased average firing rate for hamstrings (p<0.001), decreased average firing rate for vastus lateralis (p<0.001) and decreased motor unit size for both the quadriceps and hamstrings at return-to-sport post-ACL reconstruction compared with sex-matched and age-matched healthy controls (p<0.001). Furthermore, there were marked differences in disparate ACL-RSI scores between ACL-injured athletes. At return to sport, ACL-injured athletes have major alterations of thigh musculature motor control, with smaller motor units used by those with low ACL-RSI scores. This study uniquely demonstrates objective thigh muscle motor unit characteristics that coincide with subjective reports of psychological readiness. This information will be important to address psychomotor complexes of injury for future rehabilitation protocols.


Malignant mixed mesodermal ovarian tumor treatment and prognosis: a 20-year experience.
Mixed mesodermal sarcoma of the ovary is a rare clinical entity. To review the epidemiology, prognostic factors, and treatment results related to primary ovarian sarcoma at our center, a retrospective chart review of all patients referred for ovarian cancer was carried out from 1974 to 1994. Cases with confirmed pathologic diagnosis of primary mixed mesodermal ovarian sarcomas were selected, forming the present study group. Thirty-six charts were identified. The median age at presentation was 67.5 years. Findings at laparotomy demonstrated extraovarian metastasis in 33/35 patients. Total abdominal hysterectomy and bilateral salpingo-oophorectomy +/- omentectomy were performed in 34 patients, with 22 patients left with macroscopic residual disease after surgery. Follow-up adjuvant chemotherapy consisting of cisplatin and doxorubicin was administered to 29/36 patients. Follow-ups ranged from 1 to 11 years with a median of 2 years. As with epithelial ovarian cancer, residual disease after initial surgery is an important prognostic factor. Thirteen patients had a second-look laparotomy. Five patients were positive for disease. Eight patients, one of whom recurred, were histologically negative. The patients with positive second-look findings, as well as all those who recurred clinically, subsequently died within 12 months despite trials with different second-line chemotherapeutic agents. Survival analysis showed a median survival of 3 years among patients treated with combination cytotoxic chemotherapy. Primary ovarian sarcomas make up about 2-3% of all ovarian cancer cases seen in our center. These are often very aggressive tumors with widespread metastasis at the time of presentation, making optimal tumor debulking difficult. The combination of cisplatin and doxorubicin appears to have activity resulting in a survival of 35% at 5 years. Second-look surgery offers little helpful information on the management of these tumors.


Magnetic impurity doping induced spin-glass state and short-range zigzag order in the honeycomb iridate Na2IrO3.
Based on the modified Heisenberg-Kitaev model, the effects of magnetic substitution on the magnetic properties of the honeycomb-lattice iridate [Formula: see text] [Formula: see text] are studied using Monte Carlo simulations. It is observed that the long-range zigzag state of the original system is rather fragile and can be replaced by a spin-glass state even for small substitution, well consistent with the experimental observation in Ru-substituted samples (Mehlawat et al 2015 Phys. Rev. B 92 134412). Both the disordered Heisenberg and Kitaev interactions caused by the magnetic ion-doping are suggested to be responsible for the magnetic phase transitions in the system. More interestingly, a short-range zigzag order is suggested to survive above the freezing temperature even at high magnetic impurity doping levels.


Large continuous, transparent and oriented self-supporting films of layered double hydroxides with tunable chemical composition.
Highly ordered transparent self-supporting films of layered double hydroxides (LDHs) with a size of the order of cm2 have been obtained by a simple method; the chemical composition of both the layers and interlayers can be readily tuned, as demonstrated by the preparation of [ZnAl-NO3] LDH, [NiAl-NO3] LDH and [Tb(EDTA)]- intercalated-ZnAl LDH films.


Serum uric acid: a new therapeutic target for nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is a major, worldwide public health problem. NAFLD is recognized as a major cause of liver-related morbidity and mortality. However, physicians are currently limited by available treatment options. Recently, numerous studies have reported a correlation between serum uric acid (SUA) and NAFLD with numerous clinical and experimental studies demonstrating a significant correlation. This review will focus on the role of SUA in the development of NAFLD and its potential role as a new target for therapeutic intervention. This review discusses SUA as a significant independent factor in the development of NAFLD. Moreover, we introduce the causal relationship between SUA, metabolic syndrome, and NAFLD. We discuss two major theories of insulin resistance and inflammasomes as potential explanations of the mechanistic link between SUA and NAFLD. In addition, we review current and emerging therapeutic medications to control appropriate SUA levels. There is an urgent need to develop novel, safe and effective therapies for the growing NAFLD epidemic. Reduction of SUA may be a promising potential treatment for patients with NAFLD. Clinical studies are required to determine the therapeutic effect of attenuation of hyperuricemia in humans with NAFLD.


Precursor of rat liver alpha 2u-globulin: partial amino acid sequence determination of its signal peptide.
The biosynthesis of alpha 2 u-globulin, the major protein in rat urine, was studied in a cell-free system programmed with messenger RNA isolated from rat liver. Analysis of the primary translation product by SDS-polyacrylamide gel electrophoresis showed a molecular weight of approximatley 22,000 daltons as compared to 20,000 daltons for the mature form. When translation was carried out in the presence of dog pancreas microsomes, alpha 2u-globulin was cotranslationally processed and sequestered in the microsomal lumen. Automated sequencing to mature alpha 2u-globulin and the labeled precursor disclosed the presence of 19 additional amino acids at the amino-terminal end of the primary translation product of the urinary alpha 2u-globulin. The partial amino acid sequence of this extension was determined.


Dynamically Synthetic Images for Federated Learning of medical images.
To develop deep learning models for medical diagnosis, it is important to collect more medical data from several medical institutions. Due to the regulations for privacy concerns, it is infeasible to collect data from various medical institutions to one institution for centralized learning. Federated Learning (FL) provides a feasible approach to jointly train the deep learning model with data stored in various medical institutions instead of collected together. However, the resulting FL models could be biased towards institutions with larger training datasets. In this study, we propose the applicable method of Dynamically Synthetic Images for Federated Learning (DSIFL) that aims to integrate the information of local institutions with heterogeneous types of data. The main technique of DSIFL is to develop a synthetic method that can dynamically adjust the number of synthetic images similar to local data that are misclassified by the current model. The resulting global model can handle the diversity in heterogeneous types of data collected in local medical institutions by including the training of synthetic images similar to misclassified cases in local collections. In model performance evaluation metrics, we focus on the accuracy of each client's dataset. Finally, the accuracy of the model of DSIFL in the experiments can achieve the higher accuracy of the FL approach. In this study, we propose the framework of DSIFL that achieves improvements over the conventional FL approach. We conduct empirical studies with two kinds of medical images. We compare the performance by variants of FL vs. DSIFL approaches. The performance by individual training is used as the baseline, whereas the performance by centralized learning is used as the target for the comparison studies. The empirical findings suggest that the DSIFL has improved performance over the FL via the technique of dynamically synthetic images in training.


A direct repeat of N-type Ca2+ channel alpha1B gene functions as a negative regulatory element in HeLa cells.
The expression of the N-type voltage-gated calcium channel alpha1B gene is restricted to neurons by a 5'-upstream region (-3992 to -1788) that contains negative regulatory element(s) that are active in non-neuronal cells. A 39 bp DNA element, which is repeated nine times in a head-to-tail fashion, was found within the same region. To examine whether this direct repeat (DR) may function as a negatively acting cis-regulatory element, several fusion plasmids, DR-110alpha1BLUC (1X), DR-SV40LUC (IX, 2X), in which one or two copies of the DR fragment were subcloned upstream of the homologous and heterologous promoters, were transiently transfected into HeLa and NS20Y cells. The promoter activity of DR-110alpha1BLUC (1X) decreased to approximately 17% of the 110alph(a1B)LUC construct in HeLa cells. The expression of the DR-SV40LUC (1X) and DR-SV40LUC (2X) plasmids was also reduced to 50 to 23% of the levels that were observed in the pGL2-Promoter in the same cells. However, no repression of the DR constructs was observed in NS20Y cells. An electrophoretic mobility shift assay showed that two DR-specific complexes were detected in HeLa cells, but not in NS20Y cells. In addition, Southwestern blotting revealed the presence of approximately 33 and 43 kDa proteins in HeLa cells. Overall, these results suggest that a 39 bp DNA element might act as repressor in non-neuron cells through the specific interactions of the DNA-proteins.


Jmjd3 inhibits reprogramming by upregulating expression of INK4a/Arf and targeting PHF20 for ubiquitination.
Although somatic cell reprogramming to generate inducible pluripotent stem cells (iPSCs) is associated with profound epigenetic changes, the roles and mechanisms of epigenetic factors in this process remain poorly understood. Here, we identify Jmjd3 as a potent negative regulator of reprogramming. Jmjd3-deficient MEFs produced significantly more iPSC colonies than did wild-type cells, whereas ectopic expression of Jmjd3 markedly inhibited reprogramming. We show that the inhibitory effects of Jmjd3 are produced through both histone demethylase-dependent and -independent pathways. The latter pathway involves Jmjd3 targeting of PHF20 for ubiquitination and degradation via recruitment of an E3 ligase, Trim26. Importantly, PHF20-deficient MEFs could not be converted to fully reprogrammed iPSCs, even with knockdown of Jmjd3, Ink4a, or p21, indicating that PHF20 is required for reprogramming. Our findings demonstrate, to the best of our knowledge, a previously unrecognized role of Jmjd3 in cellular reprogramming and provide molecular insight into the mechanisms by which the Jmjd3-PHF20 axis controls this process.


Frontal lesions predict response to prism adaptation treatment in spatial neglect: A randomised controlled study.
Spatial neglect commonly follows right hemisphere stroke. It is defined as impaired contralesional stimulus detection, response, or action, causing functional disability. While prism adaptation treatment is highly promising to promote functional recovery of spatial neglect, not all individuals respond. Consistent with a primary effect of prism adaptation on spatial movements, we previously demonstrated that functional improvement after prism adaptation treatment is linked to frontal lobe lesions. However, that study was a treatment-only study with no randomised control group. The current study randomised individuals with spatial neglect to receive 10 days of prism adaptation treatment or to receive only standard care (control group). Replicating our earlier results, we found that the presence of frontal lesions moderated response to prism adaptation treatment: among prism-treated patients, only those with frontal lesions demonstrated functional improvements in their neglect symptoms. Conversely, among individuals in the standard care control group, the presence of frontal lesions did not modify recovery. These results suggest that further research is needed on how frontal lesions may predict response to prism adaptation treatment. Additionally, the results help elucidate the neural network involved in spatial movement and could be used to aid decisions about treatment.


Analysis of relationship between P wave dispersion and diagnosis of pulmonary arterial hypertension and risk stratification.
The aim of this study was to measure the P-wave dispersion(PWD) in the ECG of patients with pulmonary arterial hypertension(PAH). A total of 103 PAH patients were collected, including 55 patients related with congenital heart disease(CHD) and 44 patients with idiopathic pulmonary arterial hypertension(IPAH). In addition, 30 CHD patients without PAH (nPAH-CHD group) and 30 healthy controls (HCG group) were collected as control. Patients in the PAH group were categorized into the low-risk group (30 cases), moderate-risk group (53 cases) and high-risk group (20 cases), followed by comparison of PWD difference between groups. The ROC curve was used to evaluate the diagnostic efficacy of PWD on PAH-CHD and IPAH. The levels of PWD and maximum P wave duration(Pmax) in PAH-CHD and IPAH group were significantly higher than those in nPAH-CHD and HCG group (P < 0.05). PWD level was positively correlated with right ventricular end-diastolic diameter(RVD), right atrial end-systolic diameter(RAS), mean pulmonary arterial pressure(mPAP), pulmonary vascular resistance(PVR)(r = 0.407, 0.470, 0.477, 0.423, P < 0.001), and was negatively correlated with systolic displacement of tricuspid valve annulus(TAPSE) level (r = -0.551, P < 0.001). After risk quantification in 103 PAH patients, we found that PWD was significantly different among the low-risk, moderate-risk and high-risk groups (43.89 ± 9.91 vs. 51.29 ± 6.61, 62.15 ± 10.44, P < 0.001). CHD-PAH and IPAH were identified by PWD with a cut off value of 41.5 ms (P < 0.001), and a cut off value of 41.45 ms (P < 0.001), respectively. PWD might be an effective ECG indicator for PAH, which might be used as a relatively economical indicator for PAH patients to assist in early diagnosis, disease severity assessment and prognosis evaluation.


Status inconsistency in groups: How discrepancies between instrumental and expressive status result in symptoms of stress.
This study examines whether a mismatch between the positions that individuals hold in different status hierarchies results in symptoms of stress. Prior research has focused on inconsistencies between socioeconomic status dimensions (e.g., education and income) and did not find a significant relation between status inconsistency and stress. In this paper, we build on research on role differentiation and propose to study the effect of inconsistencies between instrumental status and expressive status in group contexts. We hypothesize that people with an inconsistency between these status dimensions experience feelings of uncertainty and frustration in their interactions with others and this manifests in stress-related symptoms. We test this hypothesis with data collected in a medium-sized Dutch childcare organization (N = 93). Polynomial regression analysis, visualized in response surface plots, suggests that status inconsistent employees report higher levels of stress.


Surface adhesive forces: a metric describing the drag-reducing effects of superhydrophobic coatings.
Nanomaterials with superhydrophobic properties are promising as drag-reducing coatings. However, debates regarding whether superhydrophobic surfaces are favorable for drag reduction require further clarification. A quantified water adhesive force measurement is proposed as a metric and its effectiveness demonstrated using three typical superhydrophobic coatings on model ships with in situ sailing tests.


The role of infinitival clauses in the dialogues of German-speaking children and adults.
The present study aims at analysing the role of infinitival clauses (INFCs) in German child-adult dialogue. In German subject-less INFCs are a grammatical sentence pattern. Extensive corpora of spontaneous speech between 6 children aged 1;5 to 2;10 and adults were analysed applying structural and contextual analyses. We extended Freudenthal, Pine and Gobet's (2010) model of lexically specific learning to include INFCs in adult input. Results show that frequencies of adult INFC and MOD+INF clauses are related to child INFCs. We interpret these results as reflecting shared verb vocabulary and, regarding INFCs, as an adaptation of adult CDS to child grammatical structure. While most child INFCs have modal meaning, some occur in non-modal contexts. The majority of child INFCs are subject-less clauses with final infinitives and therefore grammatical. Results are discussed in terms of the pragmatic function of child and adult INFCs and the role of adult INFCs in German CDS.


Anticancer effect of PP31J isolated from Physalis pubescens L. in human cervical carcinoma cells.
Extracts derived from Physalis pubescens L. may function as cancer therapies. The pharmacological effects of PP31J on human cervical carcinoma cells (HeLa cells) were investigated in this study. HeLa cells were treated with PP31J, and then cell proliferation, apoptosis, and cell cycle distribution were measured using a cell counting kit-8 (CCK-8) assay and flow cytometry. Protein expression levels of regulators of cell apoptosis and cell cycle were also examined using western blotting. Our data show that PP31J inhibited the growth of HeLa cells. Significant growth inhibition compared to the vehicle-treated group was observed using a concentration of 5 μM PP31J at 24, 48, and 72 h. PP31J also selectively arrested cell cycle progression in the G1 phase at 40 μM (P < 0.05) and in the G2/M phase at 20 μM (P < 0.01) and 40 μM (P < 0.001). Our results further demonstrate a significant increase in cell apoptosis (P < 0.001) following PP31J treatment (10, 20, and 40 μM). Immunoblotting data show that PP31J downregulated (P < 0.01) the expression of Bcl-xL and decreased (P < 0.05) the expression of Survivin and Cyclin D1 at 20 and 40 μM. This study shows the anti-tumor activity of PP31J in HeLa cells and that the effects of PP31J on cell cycle distribution and apoptosis induction were partially attributed to the regulation of Cyclin D1, Survivin, and Bcl-xL.


The Role of Interleukin-17, Interleukin-23, and Transforming Growth Factor-β in Pregnancy Complicated by Placental Insufficiency.
The aim of the study was to evaluate the role of Interleukin-17 (IL-17), Interleukin-23 (IL-23), and transforming growth factor-β (TGF-β) in pregnancy complicated by placental insufficiency and in normal pregnancy. The study comprised 34 patients with pregnancy complicated by fetal growth restriction (FGR) associated with preeclampsia (PE), as well as 35 healthy pregnant women. The concentrations of IL-17, IL-23, and TGF-β in sera from maternal peripheral blood were determined by an immunoenzymatic assay. There were higher concentrations of IL-17 in the study group when compared to the controls. In the group of patients with placental insufficiency, the levels of IL-17 positively correlated with systolic blood pressure (R = 0.42, p < 0.01). The study obtained comparable concentrations of IL-23 in both studied groups. The concentrations of TGF-β were significantly lower in pregnancy complicated by the insufficiency of placenta when compared to the controls. It seems possible that the increased concentrations of IL-17 and the deficiency of TGF-β in pregnancy complicated by FGR and PE can be responsible for the activation of inflammatory response observed in PE cases.


Biomarkers of inflammation and coagulation are associated with mortality and hepatitis flares in persons coinfected with HIV and hepatitis viruses.
Hepatitis C virus (HCV) and/or hepatitis B virus (HBV) coinfection with human immunodeficiency virus (HIV) has a greater risk of mortality than either HCV or HBV infection alone and is frequently associated with hepatitis flares after antiretroviral therapy (ART) initiation. We performed a retrospective cohort study of 287 HIV-positive persons coinfected with HBV and/or HCV (70 had HBV coinfection only, 207 had HCV coninfection only, and 10 had HBV and HCV coinfections) who had pre-ART plasma samples evaluated for biomarkers associated with death (within 4 years) and/or hepatitis flare (within 4 months) after ART initiation. A predictive biomarker risk score was calculated. Forty-eight deaths and 50 hepatitis flares occurred. Nonsurvivors were older, had more prior AIDS-defining events, and had higher pre-ART triglycerides and aspartate transaminase levels. Detectable hyaluronic acid and higher d-dimer, interleukin 6, interleukin 8, and soluble CD14 levels were associated with death in univariate models and with a composite biomarker risk score. The risk of hepatitis flares was higher with HBV coinfection only (24.3%) and with HBV and HCV coinfection (50%) than with HCV coinfection only (13.5%). Higher levels of alanine transaminase and interleukin 10 were also associated with hepatitis flares. Among HIV-positive patients coinfected with HBV and/or HCV who are initiating ART, biomarkers of inflammation and coagulation are associated with an increased risk of death, whereas HBV coinfection and higher pre-ART interleukin 10 levels are associated with hepatitis flares.


Statistical prediction of drug stability based on nonlinear parameter estimation.
The classical approach in Arrhenius prediction of drug stability uses two sequential steps of linear regression involving (a) a function of drug content versus time to obtain the rate constants (k) at several elevated temperatures and (b) the relationship of logarithm of mean k versus reciprocal temperature to predict the room temperature rate constant and hence the shelf-life of the drug. Uncertainties in drug content determinations are often neglected in the second regression. The classical approach also provides a wide and unsymmetrical 95% confidence interval for the predicted shelf-life. We have developed equations which allow for direct statistical prediction of shelf-life using observed values of drug content, time, and temperature. Nonlinear regression analysis was employed to provide parameter estimates of drug shelf-life and the energy of activation. The developed approach was shown to provide good estimates of shelf-life with meaningful statistics of reactions over a wide range of stability and energetics, with various kinetic orders, with different levels of noise in the data, and with different types of data structure. Comparison between the nonlinear approach and the classical approach showed that the nonlinear approach provided better mean estimates of shelf-life with much smaller and more symmetrical 95% confidence intervals than the classical approach. The method appears sufficiently robust and wide-ranging as to be potentially applicable for the prediction of the drug stability of pharmaceutical products.


Enzymatic complexes across scales.
An unprecedented opportunity to integrate ~100 years of meticulous in vitro biomolecular research is currently provided in the light of recent advances in methods to visualize closer-to-native architectures of biomolecular machines, and metabolic enzymes in particular. Traditional views of enzymes, namely biomolecular machines, only partially explain their role, organization and kinetics in the cellular milieu. Enzymes self- or hetero-associate, form fibers, may bind to membranes or cytoskeletal elements, have regulatory roles, associate into higher order assemblies (metabolons) or even actively participate in phase-separated membraneless organelles, and all the above in a transient, temporal and spatial manner in response to environmental changes or structural/functional changes of their assemblies. Here, we focus on traditional and emerging concepts in cellular biochemistry and discuss new opportunities in bridging structural, molecular and cellular analyses for metabolic pathways, accumulated over the years, highlighting functional aspects of enzymatic complexes discussed across different levels of spatial resolution.


Embryonic platelet-activating factor: an indicator of embryo viability.
A definitive need exists to identify a biomarker of embryonic viability. Platelet-activating factor (PAF) production by human embryos is related to pregnancy potential. Conditioned embryo culture media were obtained following conventional IVF on day 3, with PAF levels and pregnancy outcomes correlated. Overall pregnancy rate was 68% (17/25) with a mean of 84.1 (+/- 8.5) pmol/l/embryo PAF level. PAF levels ranged from a 216.4 pmol/l/embryo (pregnant) to a 3.7 pmol/l/embryo (not pregnant). There was a significant difference (P < 0.05) in PAF content between pregnant (92.1 +/- 9.5 pmol/l/embryo) and non-pregnant groups (52.5 +/- 16.6 pmol/l/embryo). Patients were categorized into three groups based upon PAF levels: low (< or= 5 pmol/l/embryo); medium (51-100 pmol/l/embryo) and high (>100 pmol/l/embryo). The low (60%) group had a significantly (P < 0.05) lower pregnancy rate than either the medium (85%) or high (89%) groups. A receiver-operator characteristic curve predicted a cut-off limit of 45 pmol/l/embryo for PAF content in human embryo conditioned culture media. The data demonstrate a correlation between PAF levels in human embryo conditioned culture media and pregnancy outcome. Additionally, as embryonic PAF levels increase so does the corresponding pregnancy rate. Therefore, PAF may be used as an indicator of embryo viability and for predicting pregnancy outcome.


Cardiac energetic impairment in heart disease and the potential role of metabolic modulators: a review for clinicians.
Cardiac energetic impairment is a frequent finding in patients with both inherited and acquired diseases of heart muscle. In this review the mechanisms of energy generation in the healthy heart and their disturbances in heart muscle diseases are described. Therapeutic agents targeted at correcting cardiac energetic impairment are discussed.


[Thulium-holmium-chromium-doped YAG laser sclerostomy ab externo in uncontrollable glaucoma].
Laser sclerostomy ab externo, using thulium-holmium-chromium-doped YAG laser was performed in 40 eyes with refractory glaucoma. Preoperative intraocular pressure (IOP) ranged from 21 to 50 mmHg (mean +/- SD: 33 +/- 18.6) with maximum tolerable medications. In all cases, a full-thickness sclerostomy was performed and subsequently a filtering bleb was formed. Total energy levels to produce the sclerostomy ranged from 0.2 J to 12.9 J (3.9 +/- 2.4). Follow-up periods varied from 3 to 18 (9 +/- 4) months. IOP control rate calculated by a life-table method at 6 and 12 months after surgery was 54% and 46%, respectively. IOP for successful eyes ranged from 0 to 18 mmHg (12.3 +/- 2.4). As complications, corneal fold formation (all eyes), choroidal detachment (12 eyes), hyphema (10 eyes), and iris incarceration in the sclerostomy site (4 eyes) were found. Astigmatism caused by corneal fold formation disappeared spontaneously within 3 months. Iris incarceration causing IOP elevation was repaired by Nd-YAG laser treatment and IOP control was obtained in 2 of 4 eyes. No other complications were observed.


Plasma proteins in edematous white matter after intracerebral hemorrhage confound immunoblots: an ELISA to quantify contamination.
Intracerebral hemorrhage (ICH) and traumatic brain injury can induce brain tissue edema (i.e., interstitial and/or vasogenic), containing high concentrations of plasma proteins. To understand biochemical processes in edema development following these insults, it would be useful to examine alterations in various proteins (e.g., transcription factors, signaling). However, determining altered protein responses in edematous brain tissue using standard immunoblotting techniques is problematic due to contaminating plasma proteins. To solve this problem, we developed an enzyme-linked immunosorbent assay (ELISA) method to quantify the two major plasma proteins, albumin and immunoglobulin G (IgG), that comprise about 80% of the total plasma proteins. We tested our method on edematous white matter samples from our porcine ICH model. To induce ICH, we infused autologous arterial whole blood (3 mL) into frontal hemispheric white matter of pentobarbital- anesthetized pigs ( approximately 20 kg) over 15 min. We froze brains in situ at various times up to 24 h post- ICH and sampled white matter adjacent and contralateral to hematomas. We prepared cytoplasmic extracts that we subjected to ELISA and immunoblotting analyses. Our results demonstrate that this ELISA method is accurate, reproducible, and enables the concentrations of albumin and IgG in edematous brain tissue samples to be accurately determined. By using this correction method, equal amounts of cellular protein can be loaded onto gels during immunoblotting procedures. This method is applicable to edematous tissue samples in brain injury models in which high plasma protein concentrations result from interstitial or vasogenic edema development.


Cordocentesis in the assessment of the small-for-gestational age fetus.
Fetal blood sampling by cordocentesis in a group of 239 severely small-for-gestational age fetuses revealed a high incidence of chromosomal anomalies (17%). Furthermore, some of the fetuses were hypoxemic and demonstrated abnormalities in carbohydrate, lipid and protein metabolism. There were significant correlations between the degree of fetal hypoxemia and abnormalities in Doppler measurements of impedance to flow in the maternal uterine arteries and in the fetal umbilical artery, and of mean blood velocity measured in the fetal descending thoracic aorta and in the common carotid artery. Maternal hyperoxygenation in some cases improved fetal oxygenation and corrected some of the abnormalities in the Doppler measurements of fetal circulation.


A syndrome of congenital retinal dystrophy and saccade palsy--a subset of Leber's amaurosis.
Three children who presented in infancy with a severe visual defect and absent or barely recordable electroretinograms, with relatively well preserved visually evoked cortical potentials, were subsequently found to have vertical and horizontal saccade palsies with head thrusts but relatively good visual acuity. These children, who were clearly different from other infants with congenital retinal dystrophy, were also developmentally delayed and had systemic motor and speech defects, but their visual prognosis was relatively good. The recognition of their saccade palsy was delayed because their poor visual attention in infancy was ascribed purely to the tapetoretinal degeneration. We consider these patients represent a clear subset of those patients who are diagnosed as having congenital retinal dystrophy or Leber's amaurosis.


Aberrant functional brain connectome in people with antisocial personality disorder.
Antisocial personality disorder (ASPD) is characterised by a disregard for social obligations and callous unconcern for the feelings of others. Studies have demonstrated that ASPD is associated with abnormalities in brain regions and aberrant functional connectivity. In this paper, topological organisation was examined in resting-state fMRI data obtained from 32 ASPD patients and 32 non-ASPD controls. The frequency-dependent functional networks were constructed using wavelet-based correlations over 90 brain regions. The topology of the functional networks of ASPD subjects was analysed via graph theoretical analysis. Furthermore, the abnormal functional connectivity was determined with a network-based statistic (NBS) approach. Our results revealed that, compared with the controls, the ASPD patients exhibited altered topological configuration of the functional connectome in the frequency interval of 0.016-0.031 Hz, as indicated by the increased clustering coefficient and decreased betweenness centrality in the medial superior frontal gyrus, precentral gyrus, Rolandic operculum, superior parietal gyrus, angular gyrus, and middle temporal pole. In addition, the ASPD patients showed increased functional connectivity mainly located in the default-mode network. The present study reveals an aberrant topological organisation of the functional brain network in individuals with ASPD. Our findings provide novel insight into the neuropathological mechanisms of ASPD.


A cap 0-dependent mRNA capture method to analyze the yeast transcriptome.
Analysis of the protein coding transcriptome by the RNA sequencing requires either enrichment of the desired fraction of coding transcripts or depletion of the abundant non-coding fraction consisting mainly of rRNA. We propose an alternative mRNA enrichment strategy based on the RNA-binding properties of the human IFIT1, an antiviral protein recognizing cap 0 RNA. Here, we compare for Saccharomyces cerevisiae an IFIT1-based mRNA pull-down with yeast targeted rRNA depletion by the RiboMinus method. IFIT1-based RNA capture depletes rRNA more effectively, producing high quality RNA-seq data with an excellent coverage of the protein coding transcriptome, while depleting cap-less transcripts such as mitochondrial or some non-coding RNAs. We propose IFIT1 as a cost effective and versatile tool to prepare mRNA libraries for a variety of organisms with cap 0 mRNA ends, including diverse plants, fungi and eukaryotic microbes.


Computer-assisted radiology reporting: quality of reports.
Automated medical communication systems for patient care usually enhance timeliness and retrievability. The effect of automated systems on communication quality has not been sufficiently measured. The radiology reports produced with the automated radiology reporting system at the Johns Hopkins Hospital were evalueate for quality and compared to reports produced by dictation. No differences in quality between computer-generated and dictated reports were detected by three consultant radiologists using a specially designed quality rating system.


NERF encodes a RING E3 ligase important for drought resistance and enhances the expression of its antisense gene NFYA5 in Arabidopsis.
NFYA5 is an important drought-stress inducible transcription factor gene that is targeted by miR169 in Arabidopsis. We show here that the cis-natural antisense transcript gene of NFYA5, NFYA5 Enhancing RING FINGER (NERF), can produce siRNAs from their overlapping region (OR) and affect NFYA5 transcripts by functioning together with miR169. The NERF protein functions as an E3 ligase for ubiquitination. Overexpression of NERF or OR cDNA leads to siRNANERF accumulation, miR169 repression, and NFYA5 transcript enhancement; knock-down of NERF transcripts by an artificial miRNA enhances miR169 abundance and reduces NFYA5 transcripts. Overexpression of NFYA5 does not affect the NERF mRNA level. Deep sequencing of the small RNA library from 35S::OR plants identifies 960 sequences representing 323 unique siRNAs that originate from OR; the sequences of some siRNANERF are similar/complementary to those of miR169. Overexpression of the 195- to 280-bp OR cDNA-containing siRNAs similar/complementary to miR169 also leads to the accumulation of NFYA5 transcripts. Analysis of NERF knock-down plants and NERF overexpression lines showed that, like NFYA5, NERF is important for controlling stomatal aperture and drought resistance. This regulatory model might apply to other natural antisense transcripts with positively correlated expression patterns.


Frequency dependency of the relationship between perceived auditory source width and the interaural cross-correlation coefficient for time-invariant stimuli.
Previous research has indicated that the relationship between the interaural cross-correlation coefficient (IACC) of a narrow-band sound and its perceived auditory source width is dependent on its frequency. However, this dependency has not been investigated in sufficient detail for researchers to be able to properly model it in order to produce a perceptually relevant IACC-based model of auditory source width. A series of experiments has therefore been conducted to investigate this frequency dependency in a controlled manner, and to derive an appropriate model. Three main factors were discovered in the course of these experiments. First, the nature of the frequency dependency of the perceived auditory source width of stimuli with an IACC of 1 was determined, and an appropriate mathematical model was derived. Second, the loss of perceived temporal detail at high frequencies, caused by the breakdown of phase locking in the ear, was found to be relevant, and the model was modified accordingly using rectification and a low-pass filter. Finally, it was found that there was a further frequency dependency at low frequencies, and a method for modeling this was derived. The final model was shown to predict the experimental data well.


Regulation of Rho GTPase activity at the leading edge of migrating cells by p190RhoGAP.
Cell migration, a key feature of embryonic development, immunity, angiogenesis, and tumor metastasis, is based on the coordinated regulation of actin dynamics and integrin-mediated adhesion. Rho GTPases play a major role in this phenomenon by regulating the onset and maintenance of actin-based protruding structures at cell leading edges (i.e. lamellipodia and filopodia) and contractile structures (i.e., stress fibers) at their trailing edge. While spatio-temporal analysis demonstrated the tight regulation of Rho GTPases at the migration front during cell locomotion, little is known about how the main regulators of Rho GTPase activity, such as GAPs, GEFs and GDIs, play a role in this process. In this review, we focus on a major negative regulator of RhoA, p190RhoGAP-A and its close isoform p190RhoGAP-B, which are necessary for efficient cell migration. Recent studies, including our, demonstrated that p190RhoGAP-A localization and activity undergo a complex regulatory mechanism, accounting for the tight regulation of RhoA, but also other members of the Rho GTPase family, at the cell periphery.


Expression of human telomerase reverse transcriptase (hTERT) in thyroid neoplasms.
Distinction of thyroid neoplasms that include papillary carcinoma (PC) and follicular carcinoma (FC) from benign thyroid neoplasms can be performed successfully by histopathologic examination in most of the cases. However, in some cases it may be difficult to distinct PC and FC as well as FC and follicular adenoma (FA) and also FA and the dominant nodule of multinodular goiter (MNG) histopathologically. In this study, we aimed to determine the role of expression of the human telomerase reverse transcriptase (hTERT) in the distinction of thyroid neoplasms and its relation with prognostic factors by immunohistochemical methods. This retrospective study included 138 cases histopathologically diagnosed with benign and malignant thyroid neoplasia. Sections obtained from formalin-fixed paraffin- embedded blocks were stained with hTERT antibody. Cases were divided into hTERT-positive and -negative categories according to hTERT expression score that included percentage and intensity of staining in neoplastic cells. hTERT expression was negative in 93 (67.4%) and positive in 45 (32.6%) patients. Twenty-three (46.0%) of 50 PC, 12 (36.0%) of 33 FA, 1 (10.0%) of 10 FC, 4 (13.0%) of 31 MNG, 2 (66.0%) of 3 medullary carcinoma (MC) patients were found hTERT (+), showing that the difference between PC and FC was significant (p=0.034). There was also a significant difference between FA and MNG (p=0.030). There was no difference between FA and FC (p=0.117). The high expression of hTERT can be useful for making a differential diagnosis between PC and FC, and between FA and MNG when histopathological findings are equivocal.


Congenital localized limb hypertrophy: macrodystrophia lipomatosa.
Congenital localized gigantism in children is rare and may be caused by a gamut of disorders. Family history, cutaneous and systemic manifestations and imaging together with histopathology assist in reaching the diagnosis. Macrodystrophia lipomatosa is one such rare non-hereditary congenital developmental anomaly causing localized overgrowth of a digit(s) or limb. Herein we report an interesting case of macrodystrophia lipomatosa in a child.


Addition of bone morphogenetic protein type 2 to ascorbate and β-glycerophosphate supplementation did not enhance osteogenic differentiation of human adipose-derived stem cells.
Bone morphogenetic protein type 2 (BMP-2) is a potent local factor, which promotes bone formation and has been used as an osteogenic supplement for mesenchymal stem cells. This study evaluated the effect of a recombinant BMP-2 as well as the endogenous BMP-4 and BMP-7 in the osteogenic differentiation of adipose-derived stem cells (ASCs) in medium supplemented with ascorbate and β-glycerophosphate. Human ASCs were treated with osteogenic medium in the presence (ASCs+OM+BMP-2) or absence (ASCs+OM) of BMP-2. The alkaline phosphatase (ALP) activity was determined and the extracellular matrix mineralization was evaluated by Von Kossa staining and calcium quantification. The expressions of BMP-4, BMP-7, Smad1, Smad4, and phosphorylated Smad1/5/8 were analyzed by western blotting. Relative mRNA expressions of Smad1, BMP receptor type II (BMPR-II), osteonectin, and osteocalcin were evaluated by qPCR. ASCs+OM demonstrated the highest expression of BMP-4 and BMP-7 at days 21 and 7, respectively, the highest levels of BMPR-II mRNA expression at day 28, and the highest levels of Smad1 mRNA at days 14 and 28. ASCs+OM+BMP-2 demonstrated the highest levels of Smad1 mRNA expression at days 1, 7, and 21, the highest expression of Smad1 at day 7, the highest expression of Smad4 at day 14, the highest ALP activity at days 14 and 21, and expression of phosphorylated Smad1/5/8 at day 7. ASCs+OM and ASCs+OM+BMP2 showed similar ALP activity at days 7 and 28, similar osteonectin and osteocalcin mRNA expression at all time periods, and similar calcium depositions at all time periods. We concluded that human ASCs expressed endogenous BMP-4 and BMP-7. Moreover, the supplementation of ASCs with BMP-2 did not increase the level of osteogenic markers in the initial (ALP activity), intermediate (osteonectin and osteocalcin), or final (calcium deposition) phases, suggesting that the exogenous addition of BMP-2 did not improve the in vitro osteogenesis process of human ASCs.


[A table of senile forms of cataract. Clinical picture, prognosis, biochemistry and etiology].
The three important types of age-related senile cataract, namely deep supranuclear cortical cataract, superficial subcapsular cortical cataract (sometimes associated with secondary nuclear cataract), and primary nuclear cataract, are arranged in a table which may be used for quick reference with regard to clinical features - slit lamp findings, age at onset of opacification, rate of progression, and related biochemistry (e.g., ATP content, glutathione content, and the cation pump (K+ greater than Na+] - as well as etiological features. The significance of the table is illustrated on the basis of an important example from the literature ("Sunlight and Human Cataracts").


The role of pain acceptance on function in individuals with disabilities: a longitudinal study.
Having higher levels of pain acceptance has been shown to be associated positively with quality of life in patients with chronic pain, but its role in adjustment to chronic pain among individuals with physical disabilities living in the community is not known. Moreover, issues related to item overlap between measures of pain acceptance and measures of patient function have limited the conclusions that can be drawn from previous research in this area. To better understand the role that pain acceptance plays in patient function, we administered measures of pain acceptance, pain intensity, depressive symptoms, and function to 392 individuals with physical disabilities, and the pain, symptom, and function measures were readministered 3.5 years later. Analyses evaluated the main and interaction effects of initial pain acceptance on subsequent changes in pain and function. Having higher levels of pain acceptance-in particular as reflected by a willingness to engage in activities despite pain-resulted in less increase in pain intensity and more improvements in pain interference, physical function, depressive symptoms, and sleep quality. The findings indicate that previous research supporting the importance of pain acceptance to function in patients from health care settings extends to individuals with chronic pain living in the community. Moreover, they indicate that pain acceptance may have long-lasting (up to 3.5 years) beneficial effects on subsequent pain and function and on the association between change in pain and depression. Research to examine the potential benefits of community-based treatments that increase pain acceptance is warranted.


Bulk conductivity of soft surface layers: experimental measurement and electrokinetic implications.
Conductivity measurements were carried out on a family of polyacrylamide-co-sodium acrylate gels cross-linked with N,N'-methylenebisacrylamide in a homemade electrokinetic cell. The conductivity data allowed the equilibrium Donnan potential difference between the bulk gel and the bulk electrolyte solution to be estimated at various ionic strengths. The data were fit to a simple model assuming full dissociation of functional groups as well as to a more complete model (Dukhin, S. S.; Zimmerman, R.; Werner, C. J. Colloid Interface Sci. 2004, 274, 309) that accounts for the weak electrolyte nature of the acrylate groups fixed within the gel structure. The conductivity of the gel layers was observed to be significantly larger than the conductivity of the bulk electrolyte solutions at low ionic strengths. The increased conductivity reflects the enhanced concentration of ions within the gel structure due to Donnan equilibrium and the mobility of ions within the high water content gel layers. The electrokinetic implications of the bulk conductivity of gel-like soft surface layers are discussed in terms of the influence of the gel conductance on the resulting streaming potential.


Matrix stiffness regulates the proliferation, stemness and chemoresistance of laryngeal squamous cancer cells.
Increasing evidence shows that matrix stiffness plays a critical role in affecting the phenotype and behavior of tumor cells. We report that matrix stiffness significantly regulated the proliferation and chemotherapeutic response of Hep-2 cells. Increasing substrate stiffness promotes the proliferation of Hep-2 cells. When cultured on soft gels, Hep-2 cells expressed higher level of stem cell markers. Following treatment with cisplatin or 5-FU, we observed reduced apoptosis in Hep-2 cells cultured on soft supports. Sox2 is essential for the chemoresistance of Hep-2 cells cultured in soft stiffness. Our results demonstrated that Sox2 promotes chemoresistance of Hep-2 cells in soft stiffness via upregulating the expression of ABCG2. Our findings will provide a new platform for the future design of anticancer drugs based on the biophysical properties of the tumor site.


Clinical performance of a quantitative pan-genus Leishmania Real-time PCR assay for diagnosis of cutaneous and visceral leishmaniasis.
Leishmaniasis is a complex vector-borne disease caused by various Leishmania species, affecting humans and animals. Current diagnostic methods have limitations, leading to potential misdiagnosis. Therefore, there is an urgent need for specific and sensitive diagnostic tools. We evaluated the sensitivity of a quantitative real-time PCR (qPCR) assay targeting the 18S gene in diverse clinical sample matrices. The assay showed a wide dynamic range and a limit of detection (LoD) of 1 parasite equivalent per milliliter (eq-p/mL) for all tested species. It exhibited high specificity for Leishmania DNA, with no amplification against other microorganisms. When applied to samples from patients with visceral and cutaneous leishmaniasis, the qPCR assay provided results that matched the reference methods and allowed estimation of parasite burdens. This assay holds promise for diagnosing and monitoring leishmaniasis by offering high sensitivity, specificity, and the ability to estimate parasitemia. Further studies are needed to enhance Leishmania molecular diagnostics and expand their coverage for improved clinical impact.


Antioxidant and ACE-Inhibitory Activity of Protein Hydrolysates Produced from Atlantic Sea Cucumber (Cucumaria frondosa).
Atlantic sea cucumber is a benthic marine echinoderm found in Northwest Atlantic waters and is harvested mainly for its body wall. The body wall, along with internal organs and aquaphyrangeal bulb/flower, is a rich source of proteins, where the latter parts are often considered as processing discards. The objective of this research was to produce protein hydrolysates from sea cucumber tissues (body wall, flower, and internal organs) with bioactive properties associated with antioxidants, DNA and LDL cholesterol oxidation inhibition, and angiotensin-I-converting enzyme (ACE) inhibitory effects. The protein hydrolysates were prepared using food-grade commercial enzymes, namely Alcalase, Corolase, and Flavourzyme, individually and in combination, and found that the combination of enzymes exhibited stronger antioxidant potential than the individual enzymes, as well as their untreated counterparts. Similar trends were also observed for the DNA and LDL cholesterol oxidation inhibition and ACE-inhibitory properties of sea cucumber protein hydrolysates, mainly those that were prepared from the flower. Thus, the findings of this study revealed potential applications of sea cucumber-derived protein hydrolysates in functional foods, nutraceuticals, and dietary supplements, as well as natural therapeutics.


Studies on the pH value of abomasal contents in dairy cows during the first 3 weeks after calving.
The pH value of the abomasal contents in adult cattle is normally constant and has a value of 2. Abomasal contents with pH values of 5.5 and higher could give rise to bacterial fermentation with subsequent gas production. The accumulation of gas is thought to form a key event in the pathogenesis of abomasal displacement. The aim of the present study was to determine the pH values of abomasal contents of dairy cows in the first 3 weeks after calving. The pH of the abomasal contents was, over several days. higher than the pH value of the abomasal juice in mid-lactation cows. The highest pH values were measured on day 14 after calving, thereafter the pH declined. Possible explanations for the rise in the pH value of the abomasal contents are discussed.


Estimating under-observation and the full size of the 2016 Zika epidemic in Rio de Janeiro.
The 2015-16 Zika epidemic spread quickly from north to south in Brazil. Two striking features were the much higher incidence in young adult women due to sexual transmission, and the serious congenital malformations and miscarriages associated to Zika infection in pregnant women. In this paper we use case reporting data along with live-birth records to reconstruct the full size of the epidemic through a Bayesian probabilistic graph model representing the Zika transmission probabilities of observation (case reporting) and of birth loss (through miscarriage or abortion). We find that the probability of observing (reporting) a Zika case is different between men and women and ranges between 10 to 13%. From these estimates we reconstruct the full size of the Zika epidemic in Rio de Janeiro in 2015-16.


The non-estrogenic alternative for the treatment of climacteric complaints: Black cohosh (Cimicifuga or Actaea racemosa).
In postmenopausal women estrogens in combination with progestins have beneficial effects on climacteric complaints and on osteoporosis but this hormone replacement therapy (HRT) bears the risk of increased mammary carcinomas and cardiovascular diseases. Phytoestrogens at low doses have little or no effects on climacteric complaints, at high doses they mimic the effects of estrogens. Therefore other plant derived substances are currently intensively investigated. Extracts of the rhizome of black cohosh (Cimicifuga racemosa=CR) did not bind to estrogen receptors and were shown to be devoid of estrogenic effects on mammary cancer cells in vitro and on mammary gland and uterine histology in ovariectomized rats. In addition in this rat model the special extract CR BNO 1055 inhibited the occurrence of hot flushes and development of osteoporosis. In postmenopausal women CR BNO 1055 reduced major climacteric complaints as effectively as conjugated estrogens and significantly more than placebo. Similar data were published for other European CR preparations whereas 2 US American preparations were ineffective. This was most likely due to the too high doses or due to the adulteration with Asian Cimicifuga preparations. In all European studies neither effects in the uterus nor in mammary glands were observed. The effective compounds in CR are most likely neurotransmitter-mimetic in nature: dopaminergic, noradrenergic, serotoninergic and GABAergic effects were demonstrated and some have been structurally identified. We conclude that CR extracts at low doses are effective to ameliorate climacteric complaints but are devoid of adverse estrogenic effects. These finding strengthens the role of CR extracts as substitutes for HRT. This article is part of a special issue entitled: Special Issue on Phytoestrogens.


Chilblains in Southern California: two case reports and a review of the literature.
Chilblains or perniosis is an acrally located cutaneous eruption that occurs with exposure to cold. Chilblains can be classified into primary and secondary forms. The primary or idiopathic form is not associated with an underlying disease and is clinically indistinguishable from the secondary form. The secondary form is associated with an underlying condition such as connective tissue disease, monoclonal gammopathy, cryoglobulinemia, or chronic myelomonocytic leukemia. Histopathology cannot accurately help distinguish the primary from secondary forms of chilblains. This article will raise the awareness of chilblains by presenting two unusual case reports of chilblains in men from Southern California with discussion of the appropriate evaluation and treatment of this condition. Case 1: A 56-year-old Caucasian man presented in January to a Southern California primary care clinic with a report of tingling and burning in both feet, followed by bluish discoloration and swelling as well as blistering. He had no unusual cold exposure prior to the onset of his symptoms. He had a history of "white attacks" in his hands consistent with Raynaud's phenomenon. His symptoms gradually resolved over a 3-week period. Case 2: A 53-year-old Caucasian man also presented to a Southern California clinic in January with a 3-week history of painful tingling in his toes, and subsequent purplish-black discoloration of the toes in both feet. His symptoms occurred 1 week after a skiing trip. He had partial improvement with warming measures. His symptoms resolved 2 weeks after his initial presentation. Chilblains is a relatively uncommon entity in warmer climates but can present during the winter months. Primary care providers in warmer climates such as Southern California in the USA may be unfamiliar with its presentation. It can be diagnosed clinically by the appearance of typical lesions during the cold damp season. Through a thorough history, physical examination and selected laboratory evaluation, underlying connective tissue disease or a mimic such as vasculitis or cutaneous leukemia can be excluded.


Older Adults' Needs for Assistance as a Function of Living Environment.
As the older adult population grows and becomes more diverse, so will their needs and preferences for living environments. Many adults over 65 years of age require assistance in their living environment (Administration on Aging, 2009), however it is important for their feelings of well-being that the assistance does not restrict their autonomy (e.g., Barkay & Tabak, 2002). Moreover, autonomy enhancement may improve older adults' functionality (e.g., Greiner et al., 1996). This paper provides an overview of older adults' diverse living situations and an assessment of their needs for assistance with activities of daily living (ADLs) and instrumental activities of daily living (IADLs) when living in the community or in a long-term care residence, such as assisted living or skilled nursing. We also examine older adults' residential mobility patterns to understand potential unmet needs for assistance. This needs assessment highlights the specific areas that could benefit from human factors interventions to support older adults in making choice-driven decisions about where they live.


Targeting of lanthanide(III) chelates of DOTA-type glycoconjugates to the hepatic asyaloglycoprotein receptor: cell internalization and animal imaging studies.
The characterization of a new class of hydrophilic liver-targeted agents for gamma-scintigraphy and MRI, consisting, respectively, of [(153)Sm](3+) or Gd(3+) complexes of DOTA monoamide or bisamide linked glycoconjugates (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), is reported. In vitro studies show high uptake of radiolabeled [(153)Sm]-DOTAGal(2) by the human hepatocyte carcinoma cell line Hep G2 containing the asialoglycoprotein receptor (ASGP-R), which is decreased to less than 50% by the presence of its high-affinity ligand asialofetuin (ASF). In vivo biodistribution, gamma-imaging and pharmacokinetic studies on Wistar rats using the [(153)Sm](3+)-labeled glycoconjugates show a high uptake in the receptor-rich organ liver of the radiolabeled compounds containing terminal galactosyl groups, but very little uptake for those compounds with terminal glycosyl groups. Blocking the receptor in vivo reduced liver uptake by 90%, strongly suggesting that the liver uptake of these compounds is mediated by their binding to the asyaloglycoprotein receptor (ASGP-R). This study also demonstrated that the valency increase improves the targeting capability of the glycoconjugates, which is also affected by their topology. However despite the specific liver uptake of the radiolabeled galactose-bearing multivalent compounds, the animal MRI assessment of the corresponding Gd(3+) chelates shows liver-to-kidney contrast effects which are not significantly better than those shown by GdDTPA. This probably results from the quick wash-out from the liver of these highly hydrophilic complexes, before they can be sufficiently concentrated within the hepatocytes via receptor-mediated endocytosis.


Variation in the replication loci of Streptomyces linear plasmids.
Streptomyces linear plasmids start replication at centrally located loci, usually consisting of iterons and adjacent rep genes. Here, we identified four new replication loci from Streptomyces linear plasmids. A discontinuous locus, consisting of two genes and iterons separated by two nonessential genes, was required for replication of pRL2 in both linear and circular modes. A temperature-sensitive plasmid, pRL4, contained a replication locus, a noncoding sequence and a SAP1.35-like gene. A telomere-adjacent locus, another noncoding sequence and SAP1.1-like gene, was identified for replication of the large plasmid pFRL2. The replication locus of pSHK1 consisted of SCP1-rep-like genes and iterons. These results indicate an unexpected variety of components, positions and combinations of replication loci among Streptomyces linear plasmids.


Gastrin-Releasing Peptide Receptor Targeting in Cancer Treatment: Emerging Signaling Networks and Therapeutic Applications.
Growth factors of the bombesin/gastrin releasing peptide (BN/GRP) family play a critical role in proliferation and progression of malignancies. Inhibitors targeting GRP signalling have been developed and tested as anticancer compounds showing promising preclinical and early phase clinical results. In this review, we will discuss the molecular signaling, expression and the functional role of BN/GRP-GRPR in different cancer models and will focus on the available strategies to target BN/GRP-GRPR in cancer treatment as well as in tumour diagnosis and follow up.


Sensitivity of Saturation Transfer Electron Spin Resonance Extended to Extremely Slow Mobility in Glassy Materials
A novel extension of the saturation transfer (ST) ESR technique that enables the determination of extremely long rotational correlation times of nitroxide spin labels up to values around 10(4) s is proposed. The method is based on the observation that the integral of ST-ESR spectra is sensitive to the spin-lattice relaxation time of the electron of the spin label, which in turn is directly dependent upon the rotational correlation time. The method is applied to the spin label TEMPOL (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl) in glycerol. From the known viscosity data and the related rotational correlation times of the TEMPOL spin label in glycerol, the rotational correlation times of unknown samples can be determined. The method is especially applicable to systems with a very high viscosity, such as glassy materials. The method is applied to a 20 wt% glucose-water mixture in the glassy state, giving a value for the highest limiting rotational correlation time of about 10(3) s at a temperature of 45 K below the glass transition temperature of this system. This is an extension by six decades for the rotational correlation time, as compared to the current application of ST-ESR. Copyright 1998 Academic Press.


Causes of hypercalcemia in a population of military veterans in the United States.
To determine the various causes of hypercalcemia in a population of US veterans at the San Diego Veterans Affairs Medical Center. A retrospective analysis of medical records was performed on 212 US veterans encountered between 1998 and 2002 with serum calcium measurements between 10.5 and 10.9 mg/dL on multiple readings or 11.0 mg/dL (or greater) on any single determination. Data were collected from the clinical records for each patient and used to determine the cause of each patient's hypercalcemia. Patients undergoing hemodialysis were excluded from this study. The study population consisted of 201 men (95%) and 11 women (5%), with a median age of 63 years (range, 25 to 95). Of the 212 patients, 59 (28%) had a diagnosis of malignant disease, 38 (18%) had primary hyperparathyroidism, and 114 (54%) had hypercalcemia due to a range of other causes. The mean total serum calcium concentration for all patients in this study was 11.69 mg/dL. Lung carcinoma was the most prevalent malignant condition (in 17 patients or 29% of those with cancer). A single parathyroid adenoma (in 20 of 22 patients who underwent surgical intervention) accounted for the majority of cases of primary hyperparathyroidism. Among the other identified causes of hypercalcemia, acute renal failure was the most common (in 37 patients or 17% of all patients). In 37 patients, no specific cause for the hypercalcemia was identified. To our knowledge, this is the first study to focus on hypercalcemia within the US veterans population. Although the 2 most common causes of hypercalcemia, hyperparathyroidism and malignant disease, were represented in this study, the majority of cases of hypercalcemia in this population of US veterans related to other etiologic factors.


[Dynamic changes of intestinal 16S rDNA metagenome in 5 infants].
To investigate the dynamic changes of intestinal 16S rDNA metagenome in healthy infants. Seventeen fecal samples were collected at ages of 3 days, 1 month, 6 months and 1 year in 5 infants. Total bacterial DNAs were extracted and submitted high throughout sequencing on the V6 viable region of 16S rDNA. Tags and Operational Taxonomic Units (OTU) were then obtained and analysis of taxonomy, abundance and alpha diversity were performed. In total 2,190.66 Mbp raw data in 17 samples were produced. The OTU numbers ranged from 36 to 308. The dominate phylum included Proteobacteria, Firmicutes and Bacteroidetes and Actinobacteria. The bacterial families>1% increased from only 2-4 per sample on day 3 to 7 at 1 or 6 months, 10 at 12 months. The average npShannon and Simpson index on day 3, at 1 month, 6 months and 1 year were 1.117, 1.460, 2.088, 2.50 and 0.443, 0.408, 0.229, 0.143 respectively. Infants' intestines harbor abounding bacterial genomes. Distinct individual differences exist in infants in terms of intestinal bacterial abundance and composition. The abundance and diversity of gut bacteria increase over time.


Using Internet search behavior to assess public awareness of protected wetlands.
Improving public awareness of protected wetlands facilitates sustainable wetland management, which depends on public participation. One way of gauging public interest is by tracking Internet search behavior (ISB). We assessed public awareness of issues related to protected wetland areas (PWAs) in South Korea by examining the frequencies of specific queries (PWAs, Ramsar, Upo wetland, Sunchon Bay, etc.) using relative search volumes (RSVs) obtained from an Internet search engine. RSV shows how many times a search term is used relative to a second search term during a specific period. Public awareness of PWAs changed from 2007 to 2013. Initially the majority of Internet searches were related to the most well-known tidal and inland wetlands Sunchon Bay and Upo wetlands, which are the largest existing wetlands in Korea with the greatest historical exposure. Public awareness, as reflected in RSVs, of wetlands increased significantly following PWA designation for the wetlands in 2008, which followed the Ramsar 10th Conference of Contracting Parties to the Convention on Wetlands (COP10) meeting. Public interest was strongly correlated to the number of news articles in the popular media, as evidenced by the increase in Internet searches for specific wetlands and words associated with specific wetlands. Correspondingly, the number of visitors to specific wetlands increased. To increase public interest in wetlands, wetland aspects that enhance wetland conservation should be promoted by the government and enhanced via public education. Our approach can be used to gauge public awareness and participation in a wide range of conservation efforts.


Twelve Antioxidant Peptides From Protein Hydrolysate of Skipjack Tuna (Katsuwonus pelamis) Roe Prepared by Flavourzyme: Purification, Sequence Identification, and Activity Evaluation.
For using aquatic by-products to manufacture high-value products, Skipjack tuna (Katsuwonus pelamis) roes were degreased, pretreated with microwave, and hydrolyzed using five proteases. The protein hydrolysate (TRPH) generated using Flavourzyme displayed the strongest 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Twelve antioxidative peptides were prepared from TRPH by ultrafiltration and chromatography methods and determined to be SGE, VDTR, AEM, QDHKA, TVM, QEAE, YEA, VEP, AEHNH, QEP, QAEP, and YVM with molecular weights of 291.24, 489.50, 349.41, 597.59, 349.44, 475.42, 381.36, 343.37, 606.58, 372.35, 443.42, and 411.49 Da, respectively. AEM, QDHKA, YEA, AEHNH, and YVM presented the strongest scavenging activity on DPPH radical (EC50 values of 0.250±0.035, 0.279±0.017, 0.233±0.012, 0.334±0.011, and 0.288±0.015 mg/ml, respectively), hydroxyl radical (EC50 values of 0.456±0.015, 0.536±0.021, 0.476 ± 0.051, 0.369 ± 0.052, and 0.413 ± 0.019 mg/ml, respectively), and superoxide anion free radical (EC50 values of 0.348 ± 0.018, 0.281 ± 0.013, 0.305 ± 0.022, 0.198 ± 0.011, and 0.425 ± 0.021 mg/ml, respectively). Moreover, AEM, QDHKA, YEA, AEHNH, and YVM presented high lipid peroxidation inhibition ability, Ferric-reducing power, and significant protective function on H2O2-induced Chang liver cells. Therefore, AEM, QDHKA, YEA, AEHNH, and YVM could be natural antioxidant ingredients used in pharmaceutical and functional products.


Systematic review and meta-analysis of case-crossover and time-series studies of short term outdoor nitrogen dioxide exposure and ischemic heart disease morbidity.
Nitrogen dioxide (NO2) is a pervasive urban pollutant originating primarily from vehicle emissions. Ischemic heart disease (IHD) is associated with a considerable public health burden worldwide, but whether NO2 exposure is causally related to IHD morbidity remains in question. Our objective was to determine whether short term exposure to outdoor NO2 is causally associated with IHD-related morbidity based on a synthesis of findings from case-crossover and time-series studies. MEDLINE, Embase, CENTRAL, Global Health and Toxline databases were searched using terms developed by a librarian. Screening, data extraction and risk of bias assessment were completed independently by two reviewers. Conflicts between reviewers were resolved through consensus and/or involvement of a third reviewer. Pooling of results across studies was conducted using random effects models, heterogeneity among included studies was assessed using Cochran's Q and I2 measures, and sources of heterogeneity were evaluated using meta-regression. Sensitivity of pooled estimates to individual studies was examined using Leave One Out analysis and publication bias was evaluated using Funnel plots, Begg's and Egger's tests, and trim and fill. Thirty-eight case-crossover studies and 48 time-series studies were included in our analysis. NO2 was significantly associated with IHD morbidity (pooled odds ratio from case-crossover studies: 1.074 95% CI 1.052-1.097; pooled relative risk from time-series studies: 1.022 95% CI 1.016-1.029 per 10 ppb). Pooled estimates for case-crossover studies from Europe and North America were significantly lower than for studies conducted elsewhere. The high degree of heterogeneity among studies was only partially accounted for in meta-regression. There was evidence of publication bias, particularly for case-crossover studies. For both case-crossover and time-series studies, pooled estimates based on multi-pollutant models were smaller than those from single pollutant models, and those based on older populations were larger than those based on younger populations, but these differences were not statistically significant. We concluded that there is a likely causal relationship between short term NO2 exposure and IHD-related morbidity, but important uncertainties remain, particularly related to the contribution of co-pollutants or other concomitant exposures, and the lack of supporting evidence from toxicological and controlled human studies.


A rare cytological diagnosis of primary non-Hodgkin lymphoma of the parotid gland.
Primary lymphoma of the parotid gland is relatively rare and constitutes about 4-5% of extranodal lymphomas. The majority of them is non-Hodgkin lymphoma (NHL) and is B cell in nature. We report a case of primary diffuse large B-cell lymphoma (DLBCL) of the parotid gland in an elderly male. The case was diagnosed on fine needle aspiration cytology (FNAC) of the right parotid gland as high grade B-cell NHL and confirmed on histopathology as DLBCL. In correlation with the clinicoradiological findings, the case was diagnosed as primary parotid DLBCL. The case highlights the role of FNAC as a timely and useful diagnostic tool.


The effect of changing thyroid function on cyclic affective illness in a human subject.
Thyroid function abnormalities are common in persons with rapid-cycling bipolar affective illness. Some women who cycle rapidly respond to thyroxine, but there is scant evidence that the people who have thyroid abnormalities are the ones who respond to thyroid treatment. The authors report successful thyroxine treatment of a man whose rapid cycling began and resolved after changes in his thyroid status. The period of his affective cycle was altered by both lithium and thyroxine. The authors suggest that CNS thyroid status may determine the clinical course of some persons with a fixed cycle of affective episodes.


Effect of robotic-assisted ankle training on gait in stroke participants: A case series study.
Robotic rehabilitation therapy has grown rapidly during the last two decades allowing researchers and clinicians to deliver high-intensity training to persons with sensorimotor disorders caused by neurological injuries and diseases. This case series reports the effect of robot-assisted, impairment-oriented training for persons recovering from stroke on impairment of the paretic ankle as well as on the kinematic and spatiotemporal parameters of gait. Five persons with chronic stroke (>6 months post-stroke) participated in a 10-week training protocol, receiving three, 30-min sessions per week of a robot-assisted therapy. The robot-assisted intervention cyclically induced dorsiflexion and plantarflexion to the ankle at 5 degrees/s through ±15 degrees while the participants assisted with the imposed movement. Concurrently, participants received visual feedback of their active, assistive torque as well as targeted mechanical vibration of the ankle tendons when lengthened by the applied motion. Walking speed, cadence, step length of the non-paretic leg, percentage of paretic single limb support during the gait cycle, and ankle strength were assessed just before training began (baseline), after the last training session (post-training), and 3 months post-training (follow-up). Robot-assisted training that provided assisted movement, biofeedback, and proprioceptive stimulation reduced ankle impairment and improved kinematic and spatiotemporal gait parameters, suggesting that impairment-oriented therapy applied to the paretic ankle may provide a valuable adjunct to locomotor therapies in persons with chronic gait disorders due to stroke.


Appearance of three dimensionality in wall-bounded MHD flows.
We characterize experimentally how three dimensionality appears in wall-bounded magnetohydrodynamic flows. Our analysis of the breakdown of a square array of vortices in a cubic container singles out two mechanisms: first, a form of three dimensionality we call weak appears through differential rotation in individual 2D vortices. Second, strong three dimensionality characterized by vortex disruption leads on the one hand to a remarkable vortex array that is both steady and 3D, and, on the other hand, to scale-selective breakdown of two dimensionality in chaotic flows. Most importantly, these phenomena are entirely driven by inertia, so they are relevant to other flows with a tendency to two dimensionality, such as rotating, or stratified flows in geophysics and astrophysics.


[Rationale for a trial of prevention of perinatal transmission of hepatitis C via specific immunoglobulins].
Vertical transmission of the HCV infection is asymptomatic, occurring in 0-25% of infants born to viremic mothers in Europe. Nowadays, the only preventive measure in to advise against breastfeeding. Favourable conditions for a seroprophylaxis trial in neonates at risk are the low viral charge and the absence of former replication or integration. Several impediments to a randomized-controlled trial should be considered: Epidemiological: paucity of recruitment; low risk of transmission; possible antenatal transmission in cases of high maternal viremia; risk for intrafamilial transmission. Methodological: complex randomization of the study groups (genotyping, quantitative PCR, activity of mothers' diseases, modes/durations of delivery and feeding). Ethical: a direct individual benefit is not clearly established; should viremic mothers be allowed to breast feed their babies in the absence of prophylaxis? the risk of the emergence of mutants or quasi-species of the transmitted hepatitis C virus in neonates; the origin and selection of seropositive plasma donors.


Reactivation of Occult Hepatitis B Virus Infection During Long-Term Entecavir Antiviral Therapy.
Up to now, it has not been clear whether occult hepatitis B virus (HBV) infection (OBI) can be treated with antiviral therapy whether OBI can develop drug resistance gene mutation or not. We report a middle-aged female patient with OBI who showed HBV reactivation (HBVr) during more than 3 years of intermittent entecavir (ETV) antiviral therapy: seropositive HBV surface antigen (HBsAg), increased e antigen (HBeAg), and repeatedly elevated serum HBV DNA. Genotype analysis showed that the patient was infected with HBV type B. Genetic sequencing of HBV showed the mutants of S143T, D144G, and G145R in the S gene region, and the mutant of site 1896 in the pre-Core region coexisted with the wild type (G1896A/G). No mutation was found in other HBV gene segments. Drug resistance gene analysis found RtL229W mutant, resistant to lamivudine but sensitive to ETV and other nucleoside analogs. This case of OBI provides us with the following clinical experiences: Firstly, it is necessary to detect HBV genotype, mutation, and drug-resistant genes at the initial diagnosis, which can be helpful for reasonable treatment. Secondly, identifying the risk factors and mechanisms associated with HBVr could help quantify the risk of HBVr and manage the clinical consequences. Thirdly, the OBI patients with hepatitis B e antigen-positive, HBV DNA > 1 × 103 IU/ml should be recommended regular and continuous antiviral therapy as soon as possible to prevent the occurrence of hepatocirrhosis and hepatocellular carcinoma (HCC).


Shoulder apprehension: A multifactorial approach.
Shoulder apprehension is related to changes in functional cerebral networks induced by dislocations, peripheral neuromuscular lesions and persistent mechanical glenohumeral instability consisting of micro-motion.All the damage to the osseous and soft-tissue stabilizers of the shoulder, as well as neurologic impairment persisting even after stabilization, must be properly identified in order to offer the best possible treatment to the patient.There is growing evidence supporting the use of a global multimodal approach, involving, on the one hand, shoulder 'reafferentation', including proprioception, mirror therapy and even cognitive behavioural approaches, and, on the other hand, surgical stabilization techniques and traditional physical therapy in order to minimize persistent micro-motion, which may help brain healing. This combined management could improve return to sport and avoid dislocation arthropathy in the long term. Cite this article: EFORT Open Rev 2018;3:550-557. DOI: 10.1302/2058-5241.3.180007.


[Modern treatment of rupturted abdominal aortic aneurysms with the use of synthetic endovascular prostheses].
We analyzed the case of two patients with ruptured aortic aneurysm treated with the usage of the endowascular method. Treatment of ruptured abdominal aortic aneurysms is burdened with a high mortality rate during the perioperative period. The implantation of forked stent-grafts and uni-grafts significantly reduced the mortality rate in this group of patients. Usage of this treatment requires the hybrid operating room. An essential element is to have the appropriate amount of equipment available to find a suitable intravascular prostheses. Uni-grafts are a good alternative for smaller divisions and for physicians with less experience in endovascular surgery. Endowascular procedures have a great chance to became a golden treatment standard.


[Neuroleptic malignant syndrome].
This is a review article on neuroleptic malignant syndrome. Clinical manifestations and differential diagnosis are discussed. Treatment is based on suppression of the drug and administration of bromocriptine and dantrolene. After recovery, neuroleptics should be withheld or a drug with low dopaminergic blocking effect would be selected.


Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse.
A characteristic phenotype of congenital generalized lipodystrophy 2 (CGL2) that is caused by loss-of-function of seipin gene is mental retardation. Seipin is highly expressed in hippocampal pyramidal cells and astrocytes. Neuronal knockout of seipin in mice (seipin-KO mice) reduces the hippocampal peroxisome proliferator-activated receptor gamma (PPARγ) level without the loss of pyramidal cells. The down-regulation of PPARγ has gained increasing attention in neuroinflammation of Alzheimer's disease (AD). Thus, the present study focused on exploring the influence of seipin depletion on β-amyloid (Aβ)-induced neuroinflammation and Aβ neurotoxicity. Adult male seipin-KO mice were treated with a single intracerebroventricular (i.c.v.) injection of Aβ25-35 (1.2 nmol/mouse) or Aβ1-42 (0.1 nmol/mouse), generally a non-neurotoxic dose in wild-type (WT) mice. Spatial cognitive behaviors were assessed by Morris water maze and Y-maze tests, and hippocampal CA1 pyramidal cells and inflammatory responses were examined. The Aβ25-35/1-42 injection in the seipin-KO mice caused approximately 30-35 % death of pyramidal cells and production of Hoechst-positive cells with the impairment of spatial memory. In comparison with the WT mice, the number of astrocytes and microglia in the seipin-KO mice had no significant difference, whereas the levels of IL-6 and TNF-α were slightly increased. Similarly, the Aβ25-35/1-42 injection in the seipin-KO mice rather than the WT mice could stimulate the activation of astrocytes or microglia and further elevated the levels of IL-6 and TNF-α. Treatment of the seipin-KO mice with the PPARγ agonist rosiglitazone (rosi) could prevent Aβ25-35/1-42-induced neuroinflammation and neurotoxicity, which was blocked by the PPARγ antagonist GW9962. In the seipin-KO mice, the level of glycogen synthase kinase-3β (GSK3β) phosphorylation at Tyr216 was elevated, while at Ser9, it was reduced compared to the WT mice, which were corrected by the rosi treatment but were unaffected by the Aβ25-35 injection. Seipin deficiency in astrocytes increases GSK3β activity and levels of IL-6 and TNF-α through reducing PPARγ, which can facilitate Aβ25-35/1-42-induced neuroinflammation to cause the death of neuronal cells and cognitive deficits.


Re-organisation of the management of patients affected with chronic pathologies in Lombardy Region: critical points associated with the management of HIV positive patients.
The Regional Council of Lombardy Region published in 2017 two resolutions related to a re-organisation of the management pathway of patients affected with chronic pathologies, to meet the changing needs of the users. The objective of this document is to provide recommendations to the Regional Health Service of Lombardy Region to manage the implementation of the resolutions considering peculiar aspects related to the management of HIV positive patients. These resolutions are a concrete answer to the changing needs of health care users within the regional context. The design of the new approach is coherent with the objectives stated, allowing a tighter integration between hospital services, primary care services and social services, however it should be adapted to each of the 62 chronic pathologies considered. In the case of HIV, not considering antiretroviral treatments within the tariff might limit the cost management capability of the case manager. The full implementation of the resolutions with the inclusion of social services will allow a complete management of chronic patients with positive consequences on their quality of life.


Diagnostic and Therapeutic Challenges of Hereditary Tyrosinemia Type 1 in Lebanon: A 12-Year Retrospective Review.
Background: Hereditary tyrosinemia type 1 is a rare genetic disorder leading to liver cirrhosis and hepatocellular carcinoma. Few decades ago, dietary measures and ultimately liver transplant constituted the only treatment modalities. Nowadays, early diagnosis and therapy with nitisinone can reverse the clinical picture. In developing countries, diagnostic and therapeutic challenges may affect the outcome of this disease. The choice of the treatment modality may depend on the economic status of each country. Few reports on the long-term outcome of hereditary tyrosinemia type 1 are available from developing and Arab countries. Methods: A retrospective study of charts of Lebanese patients diagnosed with tyrosinemia type 1 and followed, at the American University of Beirut, during a 12-year period was performed. Clinical presentation and liver biochemical profile at diagnosis were analyzed, along with therapeutic modalities and long-term outcome. Results: Twenty-two children were diagnosed and followed during the study period. Median age at diagnosis was 7 months (range: one day to 35 months). Most of the patients presented with hepatomegaly and jaundice. Four patients were referred for atypical presentations with developmental delay and seizures, secondary to undiagnosed hypoglycemia episodes. Around half of the patients presented with failure to thrive. Transaminitis, cholestasis and increased α-fetoprotein level were variably present at diagnosis (36% to 50%). All patients had elevated plasma tyrosine and urinary succinylacetone levels. Genetic testing was performed in 9%. Only one third could be treated with nitisinone. Liver transplant was electively performed in 9% of cases, to overcome the long-term cost of nitisinone. One third of the patients died between the age of 1 month and 11 years. Surviving patients are still candidates for liver transplant. Conclusion: Our experience reflects the challenges of diagnosis and treatment of hereditary tyrosinemia type 1 in a developing country. In the absence of specific neonatal screening, early diagnosis relies mostly on the clinical awareness of the physician. Long-term nitisinone use may be deterred by its high cost and liver transplantation carries risks of surgical complications. New, effective, and less expensive treatments are needed, especially for developing countries.


Influence of geographical origin and ethnicity on mortality in patients on antiretroviral therapy in Canada, Europe, and the United States.
Our objective was to assess differences in all-cause mortality, as well as AIDS and non-AIDS death rates, among patients started on antiretroviral therapy (ART) according to their geographical origin and ethnicity/race in Europe, Canada, and the United States. This was a collaboration of 19 cohort studies of human immunodeficiency virus-positive subjects who have initiated ART (ART Cohort Collaboration) between 1998 and 2009. Adjusted mortality hazard ratios (AHRs) were estimated using Cox regression. A competing risk framework was used to estimate adjusted subdistribution hazard ratios for AIDS and non-AIDS mortality. Of 46 648 European patients, 16.3% were from sub-Saharan Africa (SSA), 5.1% Caribbean and Latin America, 1.6% North Africa and Middle East, and 1.7% Asia/West; of 1371 patients from Canada, 14.9% were First Nations and 22.4% migrants, and of 7742 patients from North America, 55.5% were African American and 6.6% Hispanic. Migrants from SSA (AHR, 0.79; 95% confidence interval [CI], .68-.92) and Asia/West (AHR, 0.62; 95% CI, .41-.92) had lower mortality than Europeans; these differences appeared mainly attributable to lower non-AIDS mortality. Compared with white Canadians, mortality in Canadian First Nations people (AHR, 1.48; 95% CI, .96-2.29) was higher, both for AIDS and non-AIDS mortality rates. Among US patients, when compared with whites, African Americans had higher AIDS and non-AIDS mortality, and hazard ratios for all-cause mortality increased with time on ART. The lower mortality observed in migrants suggests "healthy migrant" effects, whereas the higher mortality in First Nations people and African Americans in North America suggests social inequality gaps.


Failure of Ca2+-activated, CREB-dependent transcription in astrocytes.
Astrocytes participate in signaling via Ca(2+) transients that spread from cell to cell across a multicellular syncytium. The effect, if any, of these Ca(2+) waves on the transcription of Ca(2+)/cAMP-regulatory element binding protein (CREB)-dependent genes is not known. We report here that, unlike neurons, increasing intracellular Ca(2+) in cultured mouse cortical astrocytes failed to activate CREB-dependent transcription, even though CREB was phosphorylated at serine 133. In contrast, both CREB phosphorylation and CREB-dependent transcription were robustly stimulated by increasing cAMP. The failure of Ca(2+)-activated transcription in astrocytes was correlated with the absence of CaMKIV, a Ca(2+)-dependent protein kinase required for Ca(2+)-stimulated gene transcription in neurons. The inability of Ca(2+) to signal via CaMKIV may insulate CREB-dependent gene transcription in astrocytes from activation by Ca(2+) waves.


When Elder Care Is Viewed as Child Care: Significance of Elders' Cognitive Impairment and Caregiver Burden.
Family caregivers to frail parents often report that care of elderly parents is much like care of children. Predictors of such judgments regarding parent care were explored in a sample of adult caregiver-daughters (N = 426). Elders' cognitive impairment and perceived burden in caregiving were the strongest predictors of this likening of elder care to child care. The first factor is a response to elders' incompetencies that force caregivers to assume a directive, parental role. The second factor may reflect criticism of parents; for example, highly burdened caregivers view parent care as child care even in the absence of elders' cognitive impairment. The evidence suggests that family caregivers think of parent care as child care when parents fail to demonstrate competencies associated with adulthood. Thus, "role violation," and not "role-reversal," seems to underlie this judgment.