Wnt-5a is a synaptogenic factor with neuroprotective properties against Aβ toxicity.
We have recently found that Wnt-5a regulates the synaptic structure and function in hippocampal neurons. This ligand is expressed in the hippocampus, stimulates dendritic spine morphogenesis and increases glutamatergic neurotransmission. Moreover, we have also shown that Wnt-5a induces the clustering of PSD-95. To explore the role of Wnt-5a in the formation of synaptic contacts. Primary rat hippocampal neurons were exposed to a formylated hexapeptide (Foxy-5) derived from the sequence of Wnt-5a to study synapse formation and function. In short-term experiments, Wnt-5a only induced the clustering of PSD-95 but had no effect on the density of presynaptic puncta, while in long-term experiments, it induced both pre- and postsynaptic protein clustering and the number of synaptic contacts, in agreement with electrophysiological studies. In long-term experiments, Foxy-5 increased miniature excitatory postsynaptic current amplitude and frequency. Our findings indicate that Wnt-5a induces synapse formation in hippocampal neurons. In addition, we discuss recent findings indicating a neuroprotective action of Wnt-5a against Aβ neurotoxicity.


IFITM1 plays an essential role in the antiproliferative action of interferon-gamma.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine involved in antiproliferative and anti-virus responses, immune surveillance and tumor suppression. These biological responses to IFN-gamma are mainly mediated by the regulation of gene expression. It has been reported that growth-inhibitory role of IFN-gamma is dependent on activation of signal transducers and activators of transcription 1 (STAT1); however, the molecular basis downstream of STAT1 remains unclear. Here, we report that an IFN-gamma-induced gene, interferon-induced transmembrane protein 1 (IFITM1), plays a key role in the antiproliferative action of IFN-gamma. Overexpression of IFITM1 negatively regulated cell growth, whereas suppression of IFITM1 blocked the antiproliferative effect of IFN-gamma, accelerated the cell growth rate and conferred tumorigenicity to a non-malignant hepatocyte in nude mice. Further, IFITM1 could inhibit the activity of extracellular signal-regulated kinase, enhance the transcriptional activity of p53 and stabilize the p53 protein by inhibiting p53 phosphorylation on Thr55. Suppression of p53 reduced the growth-inhibitory capacity of both IFITM1 and IFN-gamma. Therefore, these findings indicated that the antiproliferative action of IFN-gamma requires the induction of IFITM1, and provided a crosstalk between two well-known signaling mediators, STAT1 and p53, both of which play critical roles in tumor suppression.


NF-kappaB in liver diseases: a target for drug therapy.
There are five nuclear factor-kappaB (NF-kappaB) transcription factors with important roles in innate immunity, liver inflammation, fibrosis and apoptosis prevention. Several inhibitors of NF-kappaB, like caffeic acid, captopril, curcumin, pyrrolidine dithiocarbamate, resveratrol, silymarin and thalidomide, have demonstrated antinecrotic, anticholestatic, antifibrotic and anticancer activities in the liver. A link between inflammation and hepatocellular carcinoma through the NF-kappaB pathway has been observed, providing ample experimental support for the tumor-promoting function of NF-kappaB in various models of cancer. NF-kappaB has been associated with the induction of proinflammatory gene expression and has attracted interest as a target for the treatment of inflammatory disease. However, despite much attention being focused on the deleterious effects of NF-kappaB, activation of this factor during the resolution of inflammation is associated with the production of antiinflammatory molecules like interleukin (IL)-10 and the onset of apoptosis. This suggests that NF-kappaB has an antiinflammatory role in vivo involving the regulation of the resolution of inflammation. Also, NF-kappaB promotes liver regeneration by upregulating IL-6 and other molecules like hepatocyte growth factor. It has been postulated that the beneficial properties of NF-kappaB are due to p50 homodimers, whose activation prevents cholestatic and chronic liver injury. More basic understanding on the function of the diverse NF-kappaB factors is urgently needed in different physiological and pathological conditions, because depending on the subunit composition of the dimmer, the disease and the stage of the illness, inhibition of the factor may result in a beneficial or in a deleterious response.


Prefrontal connections of the parabelt auditory cortex in macaque monkeys.
In the present study, we determined connections of three newly defined regions of auditory cortex with regions of the frontal lobe, and how two of these regions in the frontal lobe interconnect and connect to other portions of frontal cortex and the temporal lobe in macaque monkeys. We conceptualize auditory cortex as including a core of primary areas, a surrounding belt of auditory areas, a lateral parabelt of two divisions, and adjoining regions of temporal cortex with parabelt connections. Injections of several different fluorescent tracers and wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) were placed in caudal (CPB) and rostral (RPB) divisions of the parabelt, and in cortex of the superior temporal gyrus rostral to the parabelt with parabelt connections (STGr). Injections were also placed in two regions of the frontal lobe that were labeled by a parabelt injection in the same case. The results lead to several major conclusions. First, CPB injections label many neurons in dorsal prearcuate cortex in the region of the frontal eye field and neurons in dorsal prefrontal cortex of the principal sulcus, but few or no neurons in orbitofrontal cortex. Fine-grain label in these same regions as a result of a WGA-HRP injection suggests that the connections are reciprocal. Second, RPB injections label overlapping prearcuate and principal sulcus locations, as well as more rostral cortex of the principal sulcus, and several locations in orbitofrontal cortex. Third, STGr injections label locations in orbitofrontal cortex, some of which overlap those of RPB injections, but not prearcuate or principal sulcus locations. Fourth, injections in prearcuate and principal sulcus locations labeled by a CPB injection labeled neurons in CPB and RPB, with little involvement of the auditory belt and no involvement of the core. In addition, the results indicated that the two frontal lobe regions are densely interconnected. They also connect with largely separate regions of the frontal pole and more medial premotor and dorsal prefrontal cortex, but not with the extensive orbitofrontal region which has RPB and STGr connections. The results suggest that both RPB and CPB provide the major auditory connections with the region related to directing eye movements towards stimuli of interest, and the dorsal prefrontal cortex for working memory. Other auditory connections to these regions of the frontal lobe appear to be minor. RPB has connections with orbitofrontal cortex, important in psychosocial and emotional functions, while STGr primarily connects with orbital and polar prefrontal cortex.


Core/shell structured CdS/polydopamine/TiO2 ternary hybrids as highly active visible-light photocatalysis.
Core/shell structured CdS/polydopamine/TiO2 (CdS/PDA/TiO2) ternary hybrids were fabricated by sequentially coating of PDA and TiO2 on CdS nanospheres through dopamine self-polymerization and TBOT hydrolysis and hydrothermal processes. The reaction rate constants of CdS/PDA/TiO2 ternary hybrids toward the degradation of RhB, MB and phenol were more than 3 times higher than those of CdS/TiO2 hybrids. The remarkably improved photocatalytic activity was attributed to enhanced light absorption and charge carrier separation efficiency associated with the introduction of PDA.


Changes in lymphocyte accumulation and proliferation in the lymph nodes draining the pregnant uterus.
Changes in weight, lymphocyte accumulation and cellular proliferation have been measured in the lymph nodes draining the uterus during inter- and intra-strain pregnancies and compared with similar effects after other antigenic stimuli. From the data obtained it was concluded that "paternal" antigenic stimulation from the conceptus initiated an immune response in these nodes. The mechanisms of the subsequent suppression of this response are discussed.


Mice with Established Diabetes Show Increased Susceptibility to Renal Ischemia/Reperfusion Injury: Protection by Blockade of Jnk or Syk Signaling Pathways.
Patients with diabetes are at an increased risk for acute kidney injury (AKI) after renal ischemia/reperfusion injury (IRI). However, there is a lack preclinical models of IRI in established diabetes. The current study characterized renal IRI in mice with established diabetes and investigated potential therapies. Diabetes was induced in C57BL/6J mice by low-dose streptozotocin injection. After 7 weeks of sustained diabetes, mice underwent 13 minutes of bilateral renal ischemia and were euthanized after 24 hours of reperfusion. Age-matched, nondiabetic controls underwent the same surgical procedure. Renal IRI induced two- and sevenfold increases in plasma creatinine level in nondiabetic and diabetic mice, respectively (P < 0.001). Kidney damage, as indicated by histologic damage, tubular cell death, tubular damage markers, and inflammation, was more severe in the diabetic IRI group. The diabetic IRI group showed greater accumulation of spleen tyrosine kinase (Syk)-expressing cells, and increased c-Jun N-terminal kinase (Jnk) signaling in tubules compared to nondiabetic IRI. Prophylactic treatment with a Jnk or Syk inhibitor substantially reduced the severity of AKI in the diabetic IRI model, with differential effects on neutrophil infiltration and Jnk activation. In conclusion, established diabetes predisposed mice to renal IRI-induced AKI. Two distinct proinflammatory pathways, JNK and SYK, were identified as potential therapeutic targets for anticipated AKI in patients with diabetes.


Activin A induction of murine and ovine follicle-stimulating hormone β transcription is SMAD-dependent and TAK1 (MAP3K7)/p38 MAPK-independent in gonadotrope-like cells.
Activins stimulate follicle-stimulating hormone (FSH) β subunit (Fshb) gene transcription in pituitary gonadotrope cells. Previous studies suggest that activins signal via homolog of Drosophila mothers against decapentaplegic (SMAD) proteins to stimulate murine or porcine Fshb promoter activity in the gonadotrope-like cell line, LβT2. In contrast, activins were suggested to regulate the ovine Fshb promoter via a SMAD-independent pathway involving TGFβ associated kinase 1 (TAK1, MAP3K7) and p38 mitogen activated protein kinase (MAPK). Here, we examined roles for TAK1 and p38 in activin A-stimulated murine and ovine Fshb transcription. The TAK1 inhibitor 5Z-7-Oxozeanol (Oxo) significantly impaired fold activin A induction of murine and ovine Fshb promoter-reporters (Fshb-luc) in LβT2 cells, but only at concentrations 50-100 fold greater than its IC(50) for TAK1. Moreover, Oxo failed to inhibit activin A induction of endogenous Fshb mRNA levels or fold induction of Fshb-luc activity by a constitutively active form of the activin type I receptor (ALK4). Oxo, at a concentration 5-10 fold greater than its IC(50) for TAK1, attenuated TAK1/TAB2 stimulation of a p38-dependent reporter in the same cells. A Map3k7 siRNA impaired TAK1/TAB2-stimulated p38-dependent reporter activity, but failed to antagonize activin A-stimulated Fshb-luc. Though TAK1 was previously suggested to act via p38 to stimulate the ovine Fshb promoter, activin A failed to stimulate p38 phosphorylation in LβT2 cells. In apparent contrast, however, the p38 inhibitors SB203580 and SB202190 concentration-dependently attenuated activin A-induced Fshb-luc activity. Given the lack of p38 activation, we postulated that the inhibitors might non-selectively antagonize ALK4 activity. Indeed, both attenuated activin A-stimulated SMAD2 phosphorylation, consistent with direct antagonism of ALK4 kinase activity. Finally, we observed that RNA-mediated suppression of Smad4, and to a lesser extent Smad3, attenuated activin A induction of both murine and ovine Fshb promoter-reporters. Collectively, these data suggest that activin A signals via SMAD proteins, but not TAK1 or p38, to regulate murine and ovine Fshb transcription in gonadotrope-like cells.


The dispersion of cholesterol with phospholipids and glycolipids.
Of the polar lipids studied (phospholipids and glycolipids), only phosphatidylcholine and sphingomyelin can disperse in water with up to 2 mol cholesterol/mol polar lipid. However, mixtures of phosphatidylethanolamine with small amounts of phosphatidylcholine and mixed lipids from mitochondria and myelin will also form sterol-rich dispersions. Steroids in which the 3beta-OH group is replaced by an oxo function do not form such steroid-rich dispersions. Electron microscopy and optical rotatory dispersion (ORD) show that sterols disperse with cerebrosides and gangliosides to form cylindrical structures with the regions around C atoms 3 and 7 of the sterol in less polar environments than those they occupy in phospholipid liposomes. It is proposed that choline-containing phospholipids facilitate entry of sterol molecules into the outer leaflet of cell surface membranes but that the phospholipid composition itself will not give rise to an asymmetric distribution of sterol in membranes with a high cholesterol content.


Transitions in mental health and addiction care for youth and their families: a scoping review of needs, barriers, and facilitators.
Transitional-aged youth (TAY) with mental health and/or addictions (MHA) concerns and their families experience significant challenges finding, accessing, and transitioning through needed MHA care. To develop appropriate supports that assist TAY and their families in navigating MHA care, their experiences of transitions in the MHA care system must be better understood. This scoping review identifies and explores the needs, barriers, and facilitators for TAY and their families when transitioning through MHA care. This scoping review commenced with a search of five relevant databases. Three research team members were involved in title, abstract, and full-text scanning and data extraction. Sources focusing on TAY anywhere between the ages of 12-29 years and meeting the study objectives were included. Extractions compiled background and narrative information about the nature and extent of the data. Analysis and synthesis of findings involved numerical description of the general information extracted (e.g., numbers of sources by country) and thematic analysis of narrative information extracted (e.g., family involvement in TAY help-seeking). A total of 5894 sources were identified. Following title and abstract scanning, 1037 sources remained for full-text review. A total of 66 sources were extracted. Findings include background information about extracted sources, in addition to five themes that emerged pertaining to barriers and facilitators to access and transitions through care and the needs and roles of TAY and families in supporting help-seeking and care transitions: holistic supports, proactive preparation, empowering TAY and families, collaborative relationships, and systemic considerations. These five themes demonstrate approaches to care that can ensure TAY and families' needs are met, barriers are mitigated, and facilitators are enhanced. This review provides essential contextual information regarding TAY with MHA concerns and their families' needs when seeking care. Such findings lend to an enhanced understanding of how MHA programs can support this population's needs, involve family members as appropriate, reduce the barriers experienced, and work to build upon existing facilitators.


Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS).
The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian-German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.


Anopheles (Cellia) epiroticus (Diptera: Culicidae), a new malaria vector species in the Southeast Asian Sundaicus Complex.
Anopheles sundaicus species A of the Southeast Asian A. sundaicus complex is formally named Anopheles epiroticus Linton & Harbach based on DNA sequence differentiation of the whole nuclear ITS2 region and a portion of both the cytochrome b and cytochrome c oxidase I mitochondrial genes. Detailed comparative morphological studies of the adult, larval and pupal stages did not reveal any differential or diagnostic differences that reliably distinguish A. epiroticus from A. sundaicus s.s. Information is provided on the bionomics and systematics of the new species.


How Should Risk-Based Regulation Reflect Current Public Opinion?
Risk-based regulation of novel agricultural products with public choice manifest via traceability and labelling is a more effective approach than the use of regulatory processes to reflect public concerns, which may not always be supported by evidence.


Molecular epidemiology of human rabies viruses in Sri Lanka.
Rabies is a lethal zoonotic disease caused by the rabies virus, which is transmitted by rabid animals to humans. Rabies is prevalent in all continents, with over 60% of human deaths occurring in Asia. Sri Lanka is a rabies-endemic country. This study shows that rabies afflicted more older individuals than children in Sri Lanka between 2008 and 2010. This novel finding indicates that older people in Sri Lanka should be more aware of the risk of rabies. Phylogenetic analyses of the rabies N and G genes showed that the Sri Lankan rabies viruses are distinct and probably originated from a single clone. The G-L noncoding region is highly diverse, and is suitable for the analysis of virus evolution within a country. A phylogenetic analysis of this region showed high diversity in the currently circulating Sri Lankan rabies viruses, which can be divided into seven clades. Some clades are unique to a specific geographic region, whereas others occur at multiple locations. This indicates that the movement of dogs, the main rabies-transmitting animal in Sri Lanka, is restricted in some areas but less limited in others. These data may help to formulate a more efficient rabies control program in Sri Lanka.


Sharpen your communication skills. Here comes generation Y.
Generation Y (those born 1980-2000) is now entering the workplace, making four generations of co-workers with potentially clashing characteristics, including different styles and expectations of communication. Because the "generation gap" can also be a "communication gap," the author explores how traditionalists, baby boomers, Generation X and Generation Y operate and converse in the workplace.


A behavior-genetic study of the legacy of early caregiving experiences: academic skills, social competence, and externalizing behavior in kindergarten.
A critique of research examining whether early experiences with primary caregivers are reflected in adaptation is that relevant longitudinal studies have generally not employed genetically informed research designs capable of unconfounding shared genes and environments. Using the twin subsample (N = 485 pairs) of the Early Childhood Longitudinal Study-Birth Cohort, the current study provides evidence that early parental support (derived from observations at 24 months and around age 4, in prekindergarten) is associated with academic skills (r = .32), social competence (r = .15), and externalizing behavior (r = -.11) in kindergarten. Crucially, the shared environment accounted for virtually all of the correlation between parenting and academic skills, roughly half of the association between parenting and social competence, and approximately one fourth of the correlation between parenting and externalizing behavior.


Effects of metastatic cascades on metastatic patterns: studies on colon-26 carcinomas in mice.
The present studies are based on autopsy data showing that in upper esophageal and lower rectal carcinomas, hematogenous metastasis occurs mainly first to the lungs, and cancer cells from pulmonary metastases generate arterial metastases. In lower esophageal and upper rectal carcinomas, hematogenous metastases occur first in the liver, then in the lungs, and are further disseminated by the arterial route. The arterial metastatic patterns are different in the 2 groups. One possible explanation for these differences in pattern is that liver "residence" is associated with different metastatic behavior; this has been tested in a model system. Experiments with the transplantable colon-26 carcinoma in mice reveal that, when cancer cells from common s.c. transplant sites are grown in the liver, lungs or liver-and-lungs, and then injected into the bloodstream of fresh recipients via the left ventricle, the portal vein or the tail vein, different patterns and degrees of colonization of 11 different target sites are observed. These results are consistent with the hypothesis that growth of cancers in different anatomic sites may modify the subsequent arterial metastatic patterns, due to site-induced changes occurring in cancer cell populations, which influence metastasis from metastases or so-called "cascade" processes.


Interactions of acridine orange with nucleic acids. Properties of complexes of acridine orange with single stranded ribonucleic acid.
Interactions between acridine orange (AO) and nucleic acids (calf thymus DNA, and homoribo- and homodeoxyribo-polynucleotides) were studied in solutions containing ethanol as a cosolvent. Light absorption, scattering and luminescence were measured as a function of AO concentration at different dye/phosphate (D/P) ratios, and the data were analyzed using the McGhee-von Hippel probabilistic model of the polymer-ligand interactions. The absorption spectra of AO complexes with four homoribopolymers are presented. The intrinsic association constants and cooperativity coefficients of the formation of the complexes were calculated. The effects of ethanol (up to 35%, v/v) on these interactions were concentration dependent and may be extrapolated to zero concentration of this cosolvent. The possibility of destabilization of the double helix of nucleic acids by AO at high D/P ratios is discussed in light of the available thermodynamic data.


A rare presentation of neurosyphilis mimicking a unilateral Adie's tonic pupil.
We describe a case of a female patient who presented with anisocoria and was initially diagnosed with a right acute Adie's pupil on the basis of a right tonic pupil with absent oculomotor or neurological findings and hyper-responsiveness to dilute Pilocarpine. Two months later, the patient returned with bilateral tonic pupils and limitation of extraocular movement in the right eye. Subsequent laboratory testing revealed neurosyphilis. Our case, only the second ever reported, emphasizes the importance of considering the diagnosis of neurosyphilis in patients presenting with an isolated acute tonic pupil.


Alteration in sleep architecture and electroencephalogram as an early sign of Alzheimer's disease preceding the disease pathology and cognitive decline.
The present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD). Sleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease. Sleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD. Based on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage. Our data suggested that AβPPswe/PS1ΔE9 transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology. Future experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow-up studies in high-risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated. Studies on human participants with early stage of AD, especially the follow-up studies on the presymptomatic elderly in a large population, are difficult and time-consuming. Our hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression.


RNA synthesis dependence of action potential development in spinal cord neurones.
The role of transcription in the development of electrical properties of neuronal membranes has been largely unexplored. To study the molecular events which result in the expression of these properties it is useful to describe the timing of the underlying RNA synthetic events. For example, the timing of the transcription involved in denervation-induced action potentials in frog slow muscle fibres and brain extract-induced sodium channels in chick muscle cells has been investigated. Previous studies of Xenopus laevis spinal neurones have established that the timing of the development of the neuronal action potential ionic dependence in dissociated cell cultures parallels that seen in vivo. This culture system, therefore, allows the determination of transcription-dependent periods necessary for the development of membrane properties known to have in vivo relevance. In the study described here, actinomycin D was used to examine the timing of the RNA synthetic events necessary for (1) neurite outgrowth and (2) development of the ionic dependence of the action potential. I report that inhibition of transcription at an early stage specifically blocks the appearance of the mature sodium-dependent action potential without affecting either neurite outgrowth or the development of delayed rectification.


A facile aqueous route to synthesize highly ordered mesoporous polymers and carbon frameworks with Ia3d bicontinuous cubic structure.
By employing an organic-organic self-assembly in a dilute aqueous solution, novel ordered bicontinuous cubic mesoporous polymers and carbons with Iad symmetry are directly synthesized.


Plants as sources of antimalarial drugs, Part 6: Activities of Simarouba amara fruits.
Extracts prepared from Simarouba amara fruits collected in Panama have been found to be active against Plasmodium falciparum in vitro and against Plasmodium berghei in mice. Four active quassinoids have been identified as ailanthinone, 2'-acetylglaucarubinone, glaucarubinone and holacanthone.


Electro-metabolic coupling in multi-chambered vascularized human cardiac organoids.
The study of cardiac physiology is hindered by physiological differences between humans and small-animal models. Here we report the generation of multi-chambered self-paced vascularized human cardiac organoids formed under anisotropic stress and their applicability to the study of cardiac arrhythmia. Sensors embedded in the cardiac organoids enabled the simultaneous measurement of oxygen uptake, extracellular field potentials and cardiac contraction at resolutions higher than 10 Hz. This microphysiological system revealed 1 Hz cardiac respiratory cycles that are coupled to the electrical rather than the mechanical activity of cardiomyocytes. This electro-mitochondrial coupling was driven by mitochondrial calcium oscillations driving respiration cycles. Pharmaceutical or genetic inhibition of this coupling results in arrhythmogenic behaviour. We show that the chemotherapeutic mitoxantrone induces arrhythmia through disruption of this pathway, a process that can be partially reversed by the co-administration of metformin. Our microphysiological cardiac systems may further facilitate the study of the mitochondrial dynamics of cardiac rhythms and advance our understanding of human cardiac physiology.


High cholesterol affects platelet APP processing in controls and in AD patients.
Alzheimer disease (AD) is characterised by a decrease of platelet Amyloid Precursor Protein forms ratio (APPr), which parallels symptoms' severity. Recent studies have suggested that cholesterol might play a role in the pathophysiology of AD by modulating Abeta production. Aim of this study was to evaluate the relationship between serum cholesterol levels and platelet APP processing in controls and AD. Sixty AD patients and 45 age-matched controls (CTRL) were investigated. Neuropsychological assessment, cholesterol dosage and APP forms' evaluation were performed on each subject. CTRL showed lower serum cholesterol levels compared to AD (P<0.01) and higher mean APPr scores (P<0.0001). Hypercholesterolaemic AD patients showed lower APPr scores compared to normocholesterolaemic AD patients matched for disease severity (0.31+/-0.16 versus 0.45+/-0.28; P<0.05), since the early stage of the disease. In AD, cholesterol levels influence APPr independently of disease severity. These findings confirm the association between cholesterol and AD, and suggest that in vivo cholesterol affects APP processing by interfering with its maturation.


18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Assessing Tumor Response to Immunotherapy in Solid Tumors: Melanoma and Beyond.
The complexity of the immune response and diversity of targets challenges conventional conceptual frameworks used in selecting and monitoring treatment with immune check-point inhibitors. The limitations of anatomic imaging in assessing response have been recognized. Varying patterns of response have been recognized. These patterns have different implications for the continuation and duration of therapy. Evidence supporting the role of 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography as a prognostic biomarker and in characterizing response is presented. An added benefit of this approach is the ability to detect immune-related inflammatory reactions, often in advance of severe or life-threatening clinical manifestations.


Slow freezing versus vitrification technique for human ovarian tissue cryopreservation: An evaluation of histological changes, WNT signaling pathway and apoptotic genes expression.
This study compared slow freezing and vitrification of ovarian tissue by evaluation of histological changes, WNT signaling pathway and apoptotic genes expression. Ovarian tissue was obtained from women aging 27-38 years old. Ovarian cortex from each patient was divided into three pieces and randomly grouped as slow freezing, vitrification and control groups for investigation of WNT signaling gene expression and β-CATENIN presence as well as histological studies. The stromal structure of all ovaries were preserved. The number of secondary follicles decreased in vitrified group (P < 0.05). WNT-3, β-CATENIN, FZD-2 and GSK-3β expressions were significantly higher in slow frozen and vitrified groups, compared to control group (P < 0.05). On the contrary, AXIN1 expression in slow frozen samples were significantly lower than that of the vitrified and control group. The expression of apoptotic genes, excluding CASP3, was significantly decreased in slow-frozen samples (P < 0.05). Conversely, BAX:BCL-2 percentage significantly increased in vitrification versus slow freezing and control(P < 0.05). Follicles in slow frozen samples displayed nuclear and cytoplasmic β-CATENIN staining, while control and vitrification groups only showed β-CATENIN protein in the cytoplasm. The presented data show that slow freezing results in a better preservation regardless of the type of follicle. Therefore, it is concluded that slow freezing is still an ideal method for ovary cryopreservation.


Does eccentric-exercise-induced jaw muscle soreness influence brainstem reflexes?
To investigate the effects of soreness evoked by eccentric jaw exercises on two types of brainstem reflexes: the short-latency stretch reflex and the longer-latency exteroceptive suppression (ES), and to test for possible relationships between magnitude of soreness and reflex responses. The brainstem reflexes of jaw-closing muscles were recorded before (Baseline), immediately after (Post-task), and 1 day after (1-day-after) a 30-min eccentric exercise in 15 healthy men. All subjects participated in a control session without exercise. Soreness sensations at rest and during maximum biting were significantly elevated until 1-day-after the eccentric exercise (P<0.014). The ES responses tended to be increased (more inhibition) at Post-task and 1-day-after. There was a significant correlation between the ES response and the soreness sensation during maximum biting (P<0.04). The jaw-stretch reflex did not show significant change after the eccentric exercise. Muscle soreness associated with eccentric jaw exercises has a differential impact on the jaw-stretch reflex and the ES response. Experimentally induced acute muscle pain has previously been shown to influence both the ES and the jaw-stretch reflex, thus, different types of muscle pain and symptoms can be speculated to have different effects on a variety of brainstem reflexes.


An evaluation of 'confirmatory' medical opinion given to English courts in 14 cases of alleged child sexual abuse.
Fourteen cases of alleged child sexual abuse, where the medical opinion rated a high degree of concordance with the history or suspicion of abuse given to the doctor, were reviewed to evaluate the objectivity and reliability of the medical evidence. It was common practice for physicians conducting the medical examination to form conclusions that the child had been sexually abused on the basis of the examiner's willingness to accept statements by the child, the adolescent, the caregiver or the investigator without determining if this information was accurate and obtained through the use of appropriate interviewing techniques. In the prepubertal children, evaluation of the examination findings revealed anatomical descriptions that were normal or non-specific, rather than supportive of abuse. In the teenagers, inadequate consideration was made of the behavioural and physical differences that occur with adolescence. The physical findings were not interpreted using research derived knowledge concerning the variations of "normal" and the particular conditions that may be mistaken as abuse. The medical reports of these examinations suggest to this author a possibility of the significance and relevance of physical findings being unduly and unwittingly over-emphasised, despite the cases all having occurred post the Cleveland Inquiry [Butler Sloss E. Report into the Child Abuse Enquiry in Cleveland, 1987. London, HMSO] and some as recently as 2005. This may reflect emotional involvement in the case and the doctor taking on a role of advocacy for the child. It is sometimes difficult for physicians to step out of the medical role where they do have the responsibility to diagnose and into a role where their information is only a piece of the puzzle and it is the work of the court to determine if sexual abuse has occurred. The role confusion between medicine and forensics must be sorted out in order for physicians to provide an objective assessment. The main conclusion of this paper is that it identifies significant training needs among doctors undertaking child examinations for suspected sexual abuse.


Fiber connectivity between the striatum and cortical and subcortical regions is associated with temperaments in Chinese males.
The seven-factor biopsychosocial model of personality distinguished four biologically based temperaments and three psychosocially based characters. Previous studies have suggested that the four temperaments-novelty seeking (NS), reward dependence (RD), harm avoidance (HA), and persistence (P)-have their respective neurobiological correlates, especially in the striatum-connected subcortical and cortical networks. However, few studies have investigated their neurobiological basis in the form of fiber connectivity between brain regions. This study correlated temperaments with fiber connectivity between the striatum and subcortical and cortical hub regions in a sample of 50 Chinese adult males. Generally consistent with our hypotheses, results showed that: (1) NS was positively correlated with fiber connectivity from the medial and lateral orbitofrontal cortex (mOFC, lOFC) and amygdala to the striatum; (2) RD was positively correlated with fiber connectivity from the mOFC, posterior cingulate cortex/retrosplenial cortex (PCC), hippocampus, and amygdala to the striatum; (3) HA was positively linked to fiber connectivity from the dorsolateral prefrontal cortex (dlPFC) and PCC to the striatum; and (4) P was positively linked to fiber connectivity from the mOFC to the striatum. These results extended the research on the neurobiological basis of temperaments by identifying their anatomical fiber connectivity correlates within the subcortical-cortical neural networks.


The Impact of Lung Carcinoma Histology on the Frequency of Bone Metastases.
Objective Lung cancer is the leading cause of death by cancer, and the bones are one of the most common sites of metastasis from this condition. This study aimed to evaluate the influence of lung carcinoma histology on the frequency of bone metastases. Methods This retrospective study evaluated the medical records of 407 patients diagnosed with lung cancer between 2003 and 2012. The prevalence of bone metastases and their association with histological subtypes were evaluated using chi-squared tests, odds ratios (ORs) and 95% confidence intervals (CIs). The overall survival was evaluated using the Kaplan-Meier method. Results The prevalence of bone metastases was 28.2% ( n = 115), and the spine was the most frequently affected site (98 metastases; 32.1%). Adenocarcinoma was the most common histological subtype of lung carcinoma (46.7%), and it was significantly more frequent among patients with bone metastases (58.3% versus 42.1%; p = 0.003; OR = 1.92; 95% CI: 1.29-2.97). Squamous cell carcinoma was significantly less frequent among patients with bone metastases (13.0% versus 29.8%; p = 0.0004; OR = 0.35; 95% CI: 0.19-0.64). The median survival time after the first bone metastasis diagnosis was 4 months. Conclusion Adenocarcinoma was the most common histological subtype of lung carcinoma, and it was significantly associated with a higher risk of developing bone metastases.


Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication.
The hepatitis C virus (HCV) induces alterations of host cells to facilitate its life cycle. Fatty acid synthase (FASN) is a multidomain enzyme that plays a key role in the biosynthesis of fatty acids and is upregulated during HCV infection. Herein, we applied activity-based protein profiling (ABPP) that allows for the identification of differentially active enzymes in complex proteomic samples, to study the changes in activity of FASN during HCV replication. For this purpose, we used an activity-based probe based on the FASN inhibitor Orlistat, and observed an increase in the activity of FASN in the presence of a subgenomic and a genomic HCV replicon as well as in chimeric SCID/Alb-uPA mice infected with HCV genotype 1a. To study the molecular basis for this increase in FASN activity, we overexpressed individual HCV proteins in Huh7 cells and observed increased expression and activity of FASN in the presence of core and NS4B, as measured by western blots and ABPP, respectively. Triglyceride levels were also elevated in accordance with FASN expression and activity. Lastly, immunofluorescence and ABPP imaging analyses demonstrated that while the abundance and activity of FASN increases significantly in the presence of HCV, its localization does not change. Together these data suggest that the HCV-induced production of fatty acids and neutral lipids is provided by an increase in FASN abundance and activity that is sufficient to allow HCV propagation without transporting FASN to the replication complexes.


Goals of treatment in diabetes: a comparison of doctors and parents of children with diabetes.
Treatment failure is usually understood as a problem of patient compliance. This paper suggests another approach: to see this problem as resulting from a difference in the goals of the two parties involved, the doctor and the patient. Comparison was made between the goals of doctors and those of parents in treating children with diabetes. Significant differences emerged between the goals. Parents' goals of treatment were governed more by avoidance of the short-term threat of diabetes (hypoglycemia); doctors' goals more by the long-term threat of diabetes (diabetic complications). The outcome of treatment (diabetic control) was more closely related to parents' than doctors' goals of control. These results indicate that doctors and patients do not always share the same goals in treatment. It is suggested that a more effective clinical alliance would result if the goals of the clinical team were at least made explicit, even if they were not always shared.


ELISA based quantification of Pax6 expression in the developing Zebrafish embryos.
Transcription factors are the key regulators of metabolic pathways in the cells, tissues and organ development during embryogenesis. Pax6 is a transcription factor involved in vertebrate eye, brain and central nervous system formation during development. A reliable and sensitive assay for the spatiotemporal expression, quantification and detection of Pax6 is not available so far in zebrafish as a developmental model, hence the objective of this work is to develop quantitative assay in zebrafish embryos. The Pax6 transcription factor was purified by heparin agarose affinity chromatography and DEAE cellulose chromatography techniques from the developing zebrafish embryos. The purity was confirmed by SDS-PAGE and western blotting using Pax6 mouse monoclonal antibody. The standard graph was plotted for Pax6 and the expressions in seventeen developmental stages were quantified by indirect ELISA. The maximum expression of Pax6 was detected at 8 hpf (hours post fertilization) and it was quantified as 179 ng/embryo from the average total protein of 9.5 µg/embryo. The zebrafish Pax6 protein was detected as 48 kDa and confirmed by western blotting. This study paves way to quantify the level of expression of proteins or transcription factors during early embryonic and larval development or embryogenesis using zebrafish as model system.


Comparison of the prognosis of primary vs. progressive muscle invasive bladder cancer after radical cystectomy: Results from a large multicenter study.
To assess whether progressive and primary muscle invasive bladder cancer (MIBC) have different prognosis after radical cystectomy or not. To date only a few data are available on this topic with conflicting results. Further studies on large cohort are needed to clarify these outcomes that may influence bladder cancer management for these patients. A multicentre retrospective study was conducted on patient treated for MIBC at 5 centres between 2005 and 2015 by radical cystectomy. Patients' outcomes were compared between patients with primary MIBC vs. progressive MIBC subsequent to a history of non-muscle invasive bladder cancer (NMIBC). A total of 1197 patients were included. Median (IQ) age was 65 (58-72) years and median follow-up was 65 months. Baseline characteristics were similar between the groups as well as the Tumour pT stage, N status and positive surgical margins. Patients with progressive MIBC had worse overall survival (OS) (hazard ratio [HR] 1.36, [95%CI 1.10-1.76]; P = 0.004), cancer specific survival (CSS) (HR 1.41 [1.13-1.78]; P = 0.002), and recurrence-free survival (RFS) (HR 1.21 [1.01-1.49]; P = 0.05). Pathological stage ≥pT3, positive surgical margins, and positive lymph nodes status (pN+) were also found as predictors of OS, CSS, and RFS. Our results suggest that patient having a progressive BC have a worse prognosis in terms of OS, PFS, and CSS than patient with primary disease. These 2 groups may require different management and patients with high risk NMIBC should be assessed properly to avoid progression and be offered early cystectomy.


31P NMR spectroscopy and HbO2 cryospectrophotometry in prediction of tumor radioresistance caused by hypoxia.
The aim of this study was to search for possible relationships between the fraction of radiobiologically hypoxic cells in tumors and their 31P NMR spectral parameters and intracapillary HbO2 saturations. Four different tumor lines, two murine sarcomas (KHT, RIF-1) and two human ovarian carcinoma xenografts (MLS, OWI), were used. When tumor volume increased from about 200 mm3 to about 2000 mm3, hypoxic fraction increased from 12 to 23% for the KHT line, from 0.9 to 1.7% for the RIF-1 line, and from 9 to 28% for the MLS line. The OWI line showed similar hypoxic fractions at 200 (17%) and 2000 mm3 (15%). Tumor bioenergetic status decreased, that is, the inorganic phosphate (Pi) resonance increased and the phosphocreatine (PCr) and nucleoside triphosphate beta (NTP beta) resonances decreased, with increasing tumor volume for the KHT, RIF-1, and MLS lines, whereas the OWI line did not show any changes in the 31P NMR spectral parameters during tumor growth. Similarly, tumor HbO2 saturation status, that is, the fraction of vessels with HbO2 saturation above 30%, decreased with increasing tumor volume for the KHT, RIF-1, and MLS lines, but remained unchanged during tumor growth for the OWI line. Although the data indicated a relationship between hypoxic fraction and tumor bioenergetic status as well as tumor HbO2 saturation status within a specific line during tumor growth, there was no correlation between hypoxic fraction and tumor bioenergetic status or tumor HbO2 saturation status across the four tumor lines. This may have occurred because cell survival time under hypoxic stress as well as fraction of non-clonogenic, but metabolically active hypoxic cells differed among the tumor lines. This indicates that 31P NMR spectroscopy and HbO2 cryospectrophotometry data have to be supplemented with other data to be useful in prediction of tumor radioresistance caused by hypoxia.


Association of low oleic acid intake with diabetic retinopathy in type 2 diabetic patients: a case-control study.
The objective of this study was to describe the intake of macronutrient, especially fatty acids, and explore their possible effect on diabetic retinopathy (DR) in patients with type 2 diabetes mellitus. In this case-control study, we included a total of 146 patients with DR and 148 without DR. The intake of macronutrient was evaluated using a validated food frequency questionnaire. We used logistic regression adjusted for sex, age, diabetes duration, energy intake, educational level, physical activity, waist circumference, systolic blood pressure, high-density lipoprotein cholesterol and diabetes treatment, to estimate odds ratio (ORs) of DR. Patients with DR had significantly lower intake of fibre, monounsaturated fatty acids (MUFA), and palmitic and oleic acid. Inverse associations were observed between MUFA and oleic acid intake in DR. Subjects with intermediate and high MUFA intake were less likely to have DR than those with lower MUFA intake, with ORs of 0.46 (95 % CI: 0.22-0.93) and 0.42 (95 % CI: 0.18-0.97), respectively. Similarly, intermediate and high oleic acid intake were associated with reduced DR frequency compared with low oleic acid intake, with OR values of 0.48 (95 % CI: 0.23-0.97) and 0.37 (95 % CI: 0.16-0.85), respectively. These associations were stronger in patients with a longer diabetes duration. In type 2 diabetes mellitus, MUFA and oleic acid intake were inversely associated with DR.


Interobserver agreement of interstitial lung fibrosis Reporting and Data System (ILF-RADS) at high-resolution CT.
To assess the interobserver agreement of interstitial lung fibrosis Reporting and Data System (ILF-RADS) in interpretation and categorization of interstitial lung disease (ILD) at high-resolution CT (HRCT). Retrospective analysis was performed on 65 consecutive patients (36 male and 29 female), median age 53 years, who were referred to the Radiology Department, Mansoura University, in the period from July 2016 to February 2020. They were expected clinically to have diffuse lung disease and underwent HRCT of the chest. Patients had some investigations like serology, and when required surgical lung biopsy. Image analysis was done by two independent and blinded readers for the pulmonary and extra-pulmonary finding of ILF-RADS. The pulmonary findings were 13 items and extrapulmonary findings were 5 items. The score was 5 types according to ILF-RADS: ILF-RADS 0 (incomplete assessment), ILF-RADS 1 (typical UIP), ILF-RADS 2 (probable UIP), ILF-RADS 3 (indeterminate UIP), ILF-RADS 4 (CT features most consistent with non-UIP diagnosis). There was an excellent interobserver agreement of both reviewers for overall ILF-RADS (K = 0.88, P = 0.001) with 95.4% agreement. There was an excellent interobserver agreement for overall pulmonary findings (K = 0.901, 95% CI = 0.877-0.926, P = 0.001), excellent interobserver agreement for seven items including lung volume, traction bronchiectasis, nodules, cysts, consolidation, emphysema, and complications and moderate interobserver agreement for six items including reticulations, honeycomb, ground glass, mosaic attenuation, and axial and zonal distribution. There was excellent interobserver agreement for overall extra-pulmonary findings (K = 0.902, 95% CI = 0.852-0.952, P = 0.001), excellent interobserver agreement for four items including mediastinum, pleura, visible abdomen, and soft tissue and bone and moderate interobserver agreement for trachea and main bronchi. There was excellent interobserver agreement for ILF-RADS score: ILF-RADS 1 (K = 0.84, P = 0.001), ILF-RADS 3 (K = 0.881, P = 0.001), and ILF-RADS 4 (K = 0.878, 95% CI = 0.743-1.0, P = 0.001) and moderate interobserver agreement for ILF-RADS 2 (K = 0.784, P = 0.001). ILF-RADS is a reliable reporting system which can be routinely performed for standard interpretation of ILD.


[Sensitivity of nanoparticlized cefazolin sodium to the bacteria in vitro].
To investigate whether the in vitro sensitivity of cefazolin sodium to the bacteria was altered after nanoparticlization. The minimal inhibitory concentrations (MIC) of cefazolin sodium before and after nanoparticlization to S. aureaus and E. coli. were determined by microdilution. The MIC of nanoparticlized cefazolin sodium to S. aureaus and E. coli. had no significant change compared with that of non-nanoparticlized one. Nanoparticlization will not decrease the sensitivity of cefazolin sodium to the bacteria.


The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration.
Microglia are implicated in neurodegeneration, potentially by phagocytosing neurons, but it is unclear how to block the detrimental effects of microglia while preserving their beneficial roles. The microglial P2Y6 receptor (P2Y6R) - activated by extracellular UDP released by stressed neurons - is required for microglial phagocytosis of neurons. We show here that injection of amyloid beta (Aβ) into mouse brain induces microglial phagocytosis of neurons, followed by neuronal and memory loss, and this is all prevented by knockout of P2Y6R. In a chronic tau model of neurodegeneration (P301S TAU mice), P2Y6R knockout prevented TAU-induced neuronal and memory loss. In vitro, P2Y6R knockout blocked microglial phagocytosis of live but not dead targets and reduced tau-, Aβ-, and UDP-induced neuronal loss in glial-neuronal cultures. Thus, the P2Y6 receptor appears to mediate Aβ- and tau-induced neuronal and memory loss via microglial phagocytosis of neurons, suggesting that blocking this receptor may be beneficial in the treatment of neurodegenerative diseases.


Safety and efficacy of propranolol for treatment of familial cerebral cavernous malformations (Treat_CCM): a randomised, open-label, blinded-endpoint, phase 2 pilot trial.
Observations in people with cerebral cavernous malformations, and in preclinical models of this disorder, suggest that the β-blocker propranolol might reduce the risk of intracerebral haemorrhage. We aimed to evaluate the safety and efficacy of prolonged treatment with propranolol to reduce the incidence of symptomatic intracerebral haemorrhage or focal neurological deficit in people with familial cerebral cavernous malformations. We conducted a randomised, open-label, blinded-endpoint, phase 2 pilot trial (Treat_CCM) at six national reference centres for rare diseases in Italy. People aged 18 years or older with symptomatic familial cerebral cavernous malformation were eligible for enrolment. Participants were randomly assigned (2:1) to receive either oral propranolol (20-320 mg daily) plus standard care (intervention group), or standard care alone (control group), for 24 months. Participants, caregivers, and investigators were aware of treatment group assignment. Participants had clinical assessments and 3 T brain MRI at baseline and at 12 and 24 months. The primary outcome was new occurrence of symptomatic intracerebral haemorrhage or focal neurological deficit attributable to cerebral cavernous malformation over 24 months. Outcome assessors were masked to treatment group assignment. The primary analysis was done in the intention-to-treat population. Because of the pilot study design, we chose a one-sided 80% CI, which could either exclude a clinically meaningful effect or show a signal of efficacy. This trial is registered with EudraCT, 2017-003595-30, and ClinicalTrials.gov, NCT03589014, and is closed to recruitment. Between April 11, 2018, and Dec 5, 2019, 95 people were assessed for eligibility and 83 were enrolled, of whom 57 were assigned to the propranolol plus standard care group and 26 to the standard care alone group. The mean age of participants was 46 years (SD 15); 48 (58%) were female and 35 (42%) were male. The incidence of symptomatic intracerebral haemorrhage or focal neurological deficit was 1·7 (95% CI 1·4-2·0) cases per 100 person-years (two [4%] of 57 participants) in the propranolol plus standard care group and 3·9 (3·1-4·7) per 100 person-years (two [8%] of 26) in the standard care alone group (univariable hazard ratio [HR] 0·43, 80% CI 0·18-0·98). The univariable HR showed a signal of efficacy, according to predefined criteria. The incidence of hospitalisation did not differ between groups (8·2 cases [95% CI 7·5-8·9] per 100 person-years in the propranolol plus standard care group vs 8·2 [95% CI 7·1-9·3] per 100 person-years in the standard care alone group). One participant in the standard care alone group died of sepsis. Three participants in the propranolol plus standard care group discontinued propranolol due to side-effects (two reported hypotension and one reported weakness). Propranolol was safe and well tolerated in this population. Propranolol might be beneficial for reducing the incidence of clinical events in people with symptomatic familial cerebral cavernous malformations, although this trial was not designed to be adequately powered to investigate efficacy. A definitive phase 3 trial of propranolol in people with symptomatic familial cerebral cavernous malformations is justified. Italian Medicines Agency, Associazione Italiana per la Ricerca sul Cancro, Swedish Science Council, Knut and Alice Wallenberg Foundation, CARIPLO Foundation, Italian Ministry of Health.


A Review of the Epidemiology of Invasive Meningococcal Disease and Vaccination Strategies in North Africa.
This narrative review considers the epidemiology of invasive meningococcal disease (IMD) in North Africa and the adequacy of current preventive measures to provide guidance for future vaccination strategies. Literature searches were conducted using PubMed for articles published from 1998 onwards to identify publications on IMD in North Africa. Additional relevant articles not included within the search results and data sources were identified from the reference lists of identified publications, authors' personal files, and publicly available government or regional surveillance data. Although IMD is an endemic and notifiable disease in several North African countries, inadequacies exist regarding each country's surveillance, vaccination strategies, and disease understanding. Studies showed bacterial meningitis in North Africa caused by Neisseria meningitidis mostly affects young children (aged <5 years), with meningococcal serogroup B (MenB) being the most frequently identified serotype. Importantly, MenB isolates were genetically heterogeneous. Serogroup A incidence and meningococcal outbreaks decreased over time in Morocco and Egypt, possibly because of their nationwide or school-based vaccination programs. Within the region, meningococcal vaccines are only included in the national immunization program of Egypt. Improving IMD diagnosis and surveillance would provide a reliable estimate of IMD burden, leading to better vaccination strategies.


Rifle bullet deflection through a soft tissue simulant.
Trajectory deflections of 5.56 NATO and 7.62×39mm rifle bullets, fired through 7.5, 15 and 22.5cm of gelatine, were studied. The magnitude of the deflections from the bullets' original trajectories after perforation are related to the length and the profile of the (wound) channels through gelatine. After 7.5cm of penetration depth, deflection was less than 1°. With the longer channel lengths, bullet instability set in and subsequently, deflection was much larger. Deflection was highest with fragmented 5.56 NATO bullets after perforating 22.5cm of gelatine. The data from this study can be used to assess the degree of bullet deflection in trajectory reconstructions after incidents where human bodies were perforated with rifle bullets of the respective calibres and cartridge types.


Pathogenic potentials of Aeromonas species isolated from aquaculture and abattoir environments.
The present study elucidated the presence of antibiotics resistance, virulence genes and biofilm potentials among Aeromonas species isolated from abattoir and aquaculture environments in Benin City, Nigeria. A total of 144 wastewater samples were obtained from two independent aquaculture and abattoir environments between May and October 2016. Aeromonas species were isolated on Glutamate Starch Phenol Red (GSP) agar and confirmed using API 20NE kits. Antimicrobial susceptibility profile of the isolates was carried out using standard disc diffusion assay while biofilm potentials were detected by the microtitre plate method and PCR technique was used to detect antibiotics resistance and virulence gene markers. Overall, 32 and 26 Aeromonas species were isolated from the abattoir and aquaculture environments respectively. Isolates from both environments were completely resistant (100%) to penicillin G, ertapenem and tetracycline; whereas aquaculture isolates exhibited absolute sensitivity (100%) towards cefepime. All the virulence gene markers (aerA, hlyA, alt, ast, laf, ascF-G, fla, lip, stx1, and stx2) investigated in this study (except laf) were detected in isolates from both environments. The laf genes were only detected in isolates from abattoir environments. Antibiotics resistant genes including pse, blaTEM and class 1 integron were detected in isolates from both environments. Majority of the isolates (53/58 91.4%) from both environments; demonstrated capacity for biofilm potential. The detection of antibiotic resistance and virulence gene markers as well as biofilm forming ability in Aeromonas species isolated from aquaculture and abattoir environments raise serious public health concern worthy of further investigation.


Seven years of clinical experience with teleconsultation in craniomaxillofacial surgery.
In this work the experiences from 50 telemedically supported treatments in craniomaxillofacial surgery are summarized and different setups for their technical realization are described. Furthermore, for the first time the innovative UMTS (universal mobile telecommunication system) is applied for the transmission of arthroscopic videos of the temporomandibular joint and other craniomaxillofacial structures. The combination of computer-assisted navigation technology in augmented reality environments with telecommunication is used for execution of interactive stereotaxic teleconsultation. Furthermore, treatments without navigation are telemedically supported. This study is composed of 4 technical system configurations: 1) integrated services digital network (ISDN)-based videoconferencing without remote control of the navigation computer; 2) transmission control protocol/internet protocol (TCP/IP)-based interactive teleconsultation via bundled ISDN lines (including remote control of the navigation computer); 3) TCP/IP-based interactive teleconsultation via network; 4) combination of TCP/IP-connection and ISDN-based videoconferencing. The telemedically supported treatments are: orbitozygomatic osteotomies, positioning of the mandibular condyle in orthognathic surgery, insertion of implants, positioning of the maxilla in orthognathic surgery, distraction osteogenesis, arthroscopies of the temporomandibular joint, and operation simulations on stereolithographic models. The surgical interventions are evaluated on a 5-level system performance scale from the technical point of view. In a separate trial 20 videosequences of arthroscopies of the temporomandibular joint are transmitted via UMTS cellular phones and independently evaluated by 3 experts (ie, a total of 60 streamings) to investigate feasibility of this technology in the field of craniomaxillofacial surgery. In the years from 1996 to 2002 a total of 50 treatments were telemedically supported. All intraoperative applications were successfully finished; 48 of 60 UMTS transmissions were finished without any interruptions in constant quality, slight interruptions were observed in 8 tests, and a complete breakdown was observed during 4 streamings that required a restart of the transmission. Resolution was sufficient to diagnose even tiny anatomic structures inside the temporomandibular joint, but orientation was hardly recognizable. In many applications telecommunication technology can contribute to a quality improvement in cranio- and maxillofacial surgery because of the global availability of specialized knowledge. The required technical expenditure for teleconsultation crucially depends on the infrastructure that is already available at the clinic and the remote site. UMTS is a promising technology with the potential to be valuable in numerous craniomaxillofacial applications.


Gestational age at birth and hospitalisations for infections among individuals aged 0-50 years in Norway: a longitudinal, register-based, cohort study.
Preterm birth is associated with increased risk of childhood infections. Whether this risk persists into adulthood is unknown and limited information is available on risk patterns across the full range of gestational ages. In this longitudinal, register-based, cohort study, we linked individual-level data on all individuals born in Norway (January 01, 1967-December 31, 2016) to nationwide hospital data (January 01, 2008-December 31, 2017). Gestational age was categorised as 23-27, 28-31, 32-33, 34-36, 37-38, 39-41, and 42-44 completed weeks. The analyses were stratified by age at follow-up: 0-11 months and 1-5, 6-14, 15-29, and 30-50 years. The primary outcome was hospitalisation due to any infectious disease, with major infectious disease groups as secondary outcomes. Adjusted hospitalisation rate ratios (RRs) for any infection and infectious disease groups were estimated using negative binomial regression. Models were adjusted for year of birth, maternal age at birth, parity, and sex, and included an offset parameter adjusted for person-time at risk. Among 2,695,830 individuals with 313,940 hospitalisations for infections, we found a pattern of higher hospitalisation risk in lower gestational age groups, which was the strongest in childhood but still evident in adulthood. Comparing those born very preterm (28-31) and late preterm (34-36) to full-term (39-41 weeks), RRs (95% confidence interval) for hospitalisation for any infectious disease at ages 1-5 were 3.3 (3.0-3.7) and 1.7 (1.6-1.8), respectively. At 30-50 years, the corresponding estimates were 1.4 (1.2-1.7) and 1.2 (1.1-1.3). The patterns were similar for the infectious disease groups, including bacterial and viral infections, respiratory tract infections (RTIs), and infections not attributable to RTIs. Increasing risk of hospitalisations for infections in lower gestational age groups was most prominent in children but still evident in adolescents and adults. Possible mechanisms and groups that could benefit from vaccinations and other prevention strategies should be investigated. St. Olav's University Hospital and Norwegian University of Science and Technology, Norwegian Research Council, Liaison Committee for education, research and innovation in Central Norway, European Commission, Academy of Finland, Sigrid Jusélius Foundation, Foundation for Pediatric Research, and Signe and Ane Gyllenberg Foundation.


Transmission of Mobile Colistin Resistance (mcr-1) by Duodenoscope.
Clinicians increasingly utilize polymyxins for treatment of serious infections caused by multidrug-resistant gram-negative bacteria. Emergence of plasmid-mediated, mobile colistin resistance genes creates potential for rapid spread of polymyxin resistance. We investigated the possible transmission of Klebsiella pneumoniae carrying mcr-1 via duodenoscope and report the first documented healthcare transmission of mcr-1-harboring bacteria in the United States. A field investigation, including screening targeted high-risk groups, evaluation of the duodenoscope, and genome sequencing of isolated organisms, was conducted. The study site included a tertiary care academic health center in Boston, Massachusetts, and extended to community locations in New England. Two patients had highly related mcr-1-positive K. pneumoniae isolated from clinical cultures; a duodenoscope was the only identified epidemiological link. Screening tests for mcr-1 in 20 healthcare contacts and 2 household contacts were negative. Klebsiella pneumoniae and Escherichia coli were recovered from the duodenoscope; neither carried mcr-1. Evaluation of the duodenoscope identified intrusion of biomaterial under the sealed distal cap; devices were recalled to repair this defect. We identified transmission of mcr-1 in a United States acute care hospital that likely occurred via duodenoscope despite no identifiable breaches in reprocessing or infection control practices. Duodenoscope design flaws leading to transmission of multidrug-resistant organsisms persist despite recent initiatives to improve device safety. Reliable detection of colistin resistance is currently challenging for clinical laboratories, particularly given the absence of a US Food and Drug Administration-cleared test; improved clinical laboratory capacity for colistin susceptibility testing is needed to prevent the spread of mcr-carrying bacteria in healthcare settings.


Alternative solutions to the concrete fully-slatted floor for the housing of finishing beef cattle: effects on growth performance, health of the locomotor system and behaviour.
The aim of this study was to assess the effect of two potential alternative solutions to the concrete fully-slatted floor (FS), namely, a perforated floor (PF) and a perforated floor coated with a rubber mattress (RM), on growth, locomotor system health, and behaviour of intensively finished young bulls. Forty-eight male beef-crosses (Charolais × Aubrac) were allotted to six pens of eight animals (two pens/floor type) for a finishing period of 175 ± 7 days. Growth was recorded and two health checks and two 8-h behavioural observations were carried out by trained assessors 1 month after the beginning of the trial (Initial) and 2 weeks before slaughter (Final). Feed intake was not affected by floor type, but average daily gain of RM bulls was higher than that of FS (1.37 vs. 1.19 kg, P=0.01), with PF being intermediate (1.27 kg). Behavioural observations showed that FS bulls had a higher number of slipping events (6.5) than PF (2.1; P=0.01) and RM bulls (0.9; P<0.01). Bulls on FS showed more lying down attempts (2.2 vs. 0.1; P=0.001), a lower number of lying/standing transitions (4.5 vs. 7.3; P<0.001) and a longer lying duration (5.9 vs. 4.7s; P<0.01) than RM bulls. Signs of lameness were observed in five FS bulls at the final assessment. RM floor proved to be a good alternative to FS but it increased the likelihood of overgrown claws due to insufficient hoof wear.


Daily regulation of hormone profiles.
The highly coordinated output of the hypothalamic biological clock does not only govern the daily rhythm in sleep/wake (or feeding/fasting) behaviour but also has direct control over many aspects of hormone release. In fact, a significant proportion of our current understanding of the circadian clock has its roots in the study of the intimate connections between the hypothalamic clock and multiple endocrine axes. This chapter will focus on the anatomical connections used by the mammalian biological clock to enforce its endogenous rhythmicity on the rest of the body, using a number of different hormone systems as a representative example. Experimental studies have revealed a highly specialised organisation of the connections between the mammalian circadian clock neurons and neuroendocrine as well as pre-autonomic neurons in the hypothalamus. These complex connections ensure a logical coordination between behavioural, endocrine and metabolic functions that will help the organism adjust to the time of day most efficiently. For example, activation of the orexin system by the hypothalamic biological clock at the start of the active phase not only ensures that we wake up on time but also that our glucose metabolism and cardiovascular system are prepared for this increased activity. Nevertheless, it is very likely that the circadian clock present within the endocrine glands plays a significant role as well, for instance, by altering these glands' sensitivity to specific stimuli throughout the day. In this way the net result of the activity of the hypothalamic and peripheral clocks ensures an optimal endocrine adaptation of the metabolism of the organism to its time-structured environment.


Suppression of YAP safeguards human naïve pluripotency.
Propagation of human naïve pluripotent stem cells (nPSCs) relies on the inhibition of MEK/ERK signalling. However, MEK/ERK inhibition also promotes differentiation into trophectoderm (TE). Therefore, robust self-renewal requires suppression of TE fate. Tankyrase inhibition using XAV939 has been shown to stabilise human nPSCs and is implicated in TE suppression. Here, we dissect the mechanism of this effect. Tankyrase inhibition is known to block canonical Wnt/β-catenin signalling. However, we show that nPSCs depleted of β-catenin remain dependent on XAV939. Rather than inhibiting Wnt, we found that XAV939 prevents TE induction by reducing activation of YAP, a co-factor of TE-inducing TEAD transcription factors. Tankyrase inhibition stabilises angiomotin, which limits nuclear accumulation of YAP. Upon deletion of angiomotin-family members AMOT and AMOTL2, nuclear YAP increases and XAV939 fails to prevent TE induction. Expression of constitutively active YAP similarly precipitates TE differentiation. Conversely, nPSCs lacking YAP1 or its paralog TAZ (WWTR1) resist TE differentiation and self-renewal efficiently without XAV939. These findings explain the distinct requirement for tankyrase inhibition in human but not in mouse nPSCs and highlight the pivotal role of YAP activity in human naïve pluripotency and TE differentiation. This article has an associated 'The people behind the papers' interview.


Implementing and evaluating online advance care planning training in UK nursing homes during COVID-19: findings from the Necessary Discussions multi-site case study project.
Advance care planning in nursing homes is important to ensure the wishes and preferences of residents are recorded, especially during the COVID-19 pandemic. However, care staff and family members frequently report feeling unprepared for these conversations. More resources are needed to support them with these necessary discussions. This research aimed to develop, implement and evaluate a website intervention for care staff and family members to provide training and information about advance care planning during COVID-19. The research was a primarily qualitative case study design, comprising multiple UK nursing home cases. Data collection included semi-structured interviews with care staff and family members which were coded and analysed thematically. A narrative synthesis was produced for each case, culminating in a thematic cross-case analysis of the total findings. Theoretical propositions were refined throughout the research. Eight nursing homes took part in the study, involving 35 care staff and 19 family members. Findings were reported according to the RE-AIM framework which identified the reach, effectiveness, adoption, implementation and maintenance of the intervention. Themes included: website content that was well received; suggestions for improvement; implementation barriers and facilitators; examples of organisational and personal impact. Four theoretical propositions relating to advance care planning in nursing homes are presented, relating to: training and information needs, accessibility, context, and encouraging conversations. Implications for practice and training include an awareness of diverse learning styles, re-enforcing the right to be involved in advance care planning and encouraging opportunities for facilitated discussion. ISRCTN registry (ID 18003630 ) on 19.05.21.


Probe drug T-1032 N-oxygenation mediated by cytochrome P450 3A5 in human hepatocytes in vitro and in humanized-liver mice in vivo.
Polymorphic cytochrome P450 3A5 (CYP3A5) expression contributes to individual differences in the pharmacokinetics of probe drugs. The identification of suitable in vivo CYP3A5 probes would benefit drug metabolism and drug interaction studies using chimeric mice with humanized liver. In this study, we investigated the pharmacokinetic profiles of T-1032, which is known as an in vitro CYP3A5 probe substrate, using humanized-liver mice. Substantial N-oxygenation of T-1032 was observed in hepatocytes from humans and from humanized-liver mice. Hepatocytes from the human donor genotyped as CYP3A5∗3/∗3 (poor expressers) showed significantly lower T-1032 N-oxidation rates than those from donors harboring CYP3A5∗1. After a single oral dose of T-1032 (1.0 mg/kg) in humanized-liver mice, the plasma levels of T-1032 N-oxide were higher in five mice with CYP3A5∗1/∗7 hepatocytes than in four mice with CYP3A5∗3/∗3 hepatocytes. The maximum concentrations of T-1032 N-oxide after oral administration of T-1032 in humanized-liver mice with CYP3A5∗1/∗7 hepatocytes were twice (a significant difference) those from humanized-liver mice with CYP3A5∗3/∗3 hepatocytes. These results suggest that polymorphic CYP3A5-dependent T-1032 N-oxidation was observed in humanized liver mice in vitro and in vivo. However, the contribution of CYP3A5 genotypes may have little or only limited effects on the overall pharmacokinetic profiles of T-1032 in vivo.


Otogenic intracranial abscess: concurrent craniotomy and mastoidectomy--changing trends in a developing country.
To evaluate (1) the clinical profile, treatment, and outcome of adult and pediatric patients presenting with intracranial abscess of otogenic origin and (2) the advantages of concurrent craniotomy and mastoidectomy. A prospective case series. An academic tertiary referral center in India. Thirty-six patients clinically diagnosed as having intracranial abscess that was secondary to suppurative otitis media and confirmed by computed tomographic scanning. Concurrent craniotomy and mastoidectomy. Children were more commonly affected than adults, and there was a male preponderance. All patients had cholesteatoma at surgery, although one third of the children had only granulation tissue on otoscopy. More than two thirds of the patients in both the groups presented with more than one intracranial complication and definitive surgical intervention was done later than 24 hours. Meningitis was the most frequent intracranial complication, followed by cerebellar abscess. There was no significant intraoperative or postoperative morbidity, mortality, recurrence of intracranial complications, or residual neurological deficits. Three children (14%) showed evidence of recidivism cholesteatoma requiring revision surgery. In suppurative otitis media with intracranial complications, it is accepted practice to treat the neurosurgical complication first, followed by mastoidectomy at a later date after the patient has been stabilized. Craniotomy with concurrent mastoidectomy is not only safe, but it also removes the source of infection at the same time the complications are being treated, thus avoiding reinfection while the patient is awaiting the ear surgery. In addition, the treatment is completed with a single, shorter hospital stay, which is more economical for the patient.


Exploring the spiritual/religious dimension of patients: a timely opportunity for personal and professional reflection for graduating medical students.
Teaching about spirituality in medical school training is lacking. Spirituality is a dimension of humanity that can put experiences of health and illness into a meaningful context. Medical students might benefit from understanding how spirituality is an important element in learning to care for patients. Spirituality also provides a context for medical students to explore their own motivations for doctoring. This article describes a longitudinal senior elective course at the end of their medical school training to delve into matters of religion/spirituality surrounding patient care. The authors pose their own perspectives on what both students and faculty gained from the experience.


Risk factors for irinotecan-induced liver injury: a retrospective multicentre cross-sectional study in China.
The hepatotoxicity of irinotecan has been widely implicated in the treatment of multiple solid tumours. However, there are few studies on the influencing factors of irinotecan-induced hepatotoxicity. Herein, we investigated the risk factors for irinotecan-induced liver injury among 421 patients receiving irinotecan-based regimens (IBRs). Retrospective multi-centre cross-sectional study. This study surveyed four hospitals in China. After excluding participants with missing variables, we retrospectively collected the demographic, clinical and therapeutic data of 421 patients who received IBRs in four hospitals between January 2020 and December 2021 and divided the patients into two groups: those without liver injury and those with liver injury. The 421 enrolled patients were grouped (liver injury group: n=92; control group: n=329) according to their hepatic biochemical monitoring parameters. In our study, the multivariate logistic regression results showed that three to four cycles of chemotherapy (OR (95% CI): 2.179 (1.272 to 3.733); p=0.005) and liver metastasis (OR (95% CI): 1.748 (1.079 to 2.833); p=0.023) were independent risk factors for irinotecan-induced liver injury. The Cox proportional hazards model demonstrated that alcohol consumption history (OR (95% CI): 2.032 (1.183 to 3.491); p=0.010) and a cumulative dose of irinotecan ≥1000 mg (OR (95% CI): 0.362 (0.165 to 0.792); p=0.011) were significantly correlated with the onset time of irinotecan-induced liver injury. These findings suggest that patients with liver metastasis or who received three to four cycles of chemotherapy should undergo rigorous liver function monitoring to prevent or reduce the incidence of irinotecan-induced liver injury. Moreover, patients with a history of alcohol consumption should also be closely monitored.


Implication of NGF and endocannabinoid signaling in the mechanism of action of sesamol: a multi-target natural compound with therapeutic potential.
Sesamol, a natural compound with anti-inflammatory, antioxidant and neuroprotective properties, has shown promising antidepressant-like effects. However, its molecular target(s) have not been well defined, which merits further investigation. Based on the interaction between the neurotrophin and endocannabinoid (eCB) systems and their contribution to emotional reactivity and antidepressant action, we aimed to investigate the involvement of nerve growth factor (NGF) and eCB signalling in the mechanism of action of sesamol. Following acute and 4-week intraperitoneal (i.p.) administration of sesamol (40, 80 and 100 mg/kg), the classical antidepressant amitriptyline (2.5, 5 and 10 mg/kg) or the benzodiazepine flurazepam (5, 10 and 20 mg/kg), brain regional levels of NGF and eCB contents were quantified in rats by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. In the case of any significant change, the cannabinoid CB1 and CB2 receptor antagonists (AM251 and SR144528) were administered i.p. 30 min prior to the injection of sesamol, amitriptyline or flurazepam. Following the chronic treatment, sesamol, similar to amitriptyline, resulted in the sustained elevation of NGF and eCB contents in dose-dependent and brain region-specific fashion. Neither acute nor chronic treatment with flurazepam altered brain NGF or eCB contents. Pretreatment with 3 mg/kg AM251, but not SR144528, prevented the elevation of NGF protein levels. AM251 exerted no effect by itself. Sesamol, similar to amitriptyline, is able to affect brain NGF and eCB signalling under the regulatory drive of the CB1 receptors.


Mutation analysis by whole exome sequencing of endometrial hyperplasia and carcinoma in one patient: Abnormalities of polymerase epsilon and the phosphatidylinositol-3 kinase pathway.
In order to understand the role of gene mutations in endometrial carcinogenesis, whole exome sequencing via laser microdissection was performed in the normal endometrium, atypical endometrial hyperplasia and endometrial carcinoma in the same patient. A total of 4046 and 5746 mutations with amino acid substitution were detected in endometrial hyperplasia and endometrial carcinoma, respectively; 2252 were common in both tissues and might play crucial roles in early carcinogenesis. These common mutations included polymerase epsilon (POLE) and DNA mismatch repair (MMR) genes, indicating that an ultra-mutated phenotype, and also included PTEN and PIK3CA. The mutation-prone environment evoked by mutations in the POLE and MMR genes associated with the activated phosphatidylinositol-3 kinase pathway played a pivotal role in this case.


Procidentia: a reversible cause of hydronephrosis in an 80-year-old woman.
We describe an unusual presentation of hydronephrosis in an 80-year-old woman who was managed conservatively after transfer to a specialist unit. This case highlights the role of accurate history taking and a focused physical examination in elderly female patients presenting with renal failure and hydronephrosis.


Fluorescent chitosan-BODIPY macromolecular chemosensors for detection and removal of Hg2+ and Fe3+ ions.
The detection of heavy metals, such as Hg2+ and Fe3+, is of great significance. In this work, fluorescent small-molecule BODIPY (BY-3) bearing CC group was synthesized firstly. And then, the chitosan-based polymer sensor CY-1 was synthesized through the spontaneous NH2/C≡C click reaction. The synthesized CY-1 can effectively bind and recognize Hg2+/Hg+ by the -C=N groups formed in the click reaction. Moreover, the macromolecular sensors CS-1 and CS-2 were synthesized by incorporating another recognition sites to CY-1. These synthesized macromolecular sensors can not only recognize Hg2+/Hg+, but also effectively recognize Fe3+/Fe2+. All of them exhibited significant quenching effect, visible to the naked eye under UV irradiation. The detection limit of CY-1 for Hg2+ was 1.51 × 10-6 mol/L, and the detection limit of CS-2 for Fe3+ was 2.30 × 10-6 mol/L. The BODIPY-chitosan sensors synthesized in this work have the functions of removing heavy metal ions besides the identifying ability. The maximum adsorption capacity of 1 g chitosan to Hg2+ was 108 mg as the best one. This article provides a new method to prepare macromolecular sensors for the detection and removal of heavy metal ions. As a useful natural polymer, chitosan's application scope was enlarged.


Inflammatory bowel disease and thromboembolism. Is inflammation at the centre of the clot?
Thromboembolic events are well recognised in patients with inflammatory bowel disease (IBD). We present three cases which highlight the need for vigilance with respect to this complication. We also propose that consideration be given to re-evaluating disease activity in those patients who develop thromboembolic complications.


Pathogenesis of feline diabetes mellitus.
Cats are one of the few species that develop a form of diabetes mellitus that is clinically and histologically analogous to human type 2 diabetes mellitus. Figure 9 summarizes the etiologic factors thought to be involved in the development of feline and human type 2 diabetes. The main metabolic characteristics of type 2 diabetes mellitus are impaired insulin secretion and resistance to the action of insulin in its target tissues. Impaired beta cell function occurs before histologic changes become evident. The characteristic histologic finding in cats with type 2 diabetes is deposition of amyloid in pancreatic islets. Amyloid deposition occurs before the onset of clinical signs, but does not seem to be the primary defect. Pancreatic amyloid is derived form the recently discovered pancreatic hormone amylin. Amylin is synthesized in pancreatic beta cells, and is co-stored and co-secreted with insulin. Amylin has been postulated to be involved in the pathogenesis of feline diabetes mellitus both through its metabolic effects, which include inhibition of insulin secretion and induction of insulin resistance, and via progressive amyloid deposition and beta cell degeneration. Increased amylin concentration has been documented intracellularly in cats with impaired glucose tolerance and in the plasma of diabetic cats, and supports the hypothesis that amylin is involved in the pathogenesis of type 2 diabetes. Obesity is a common finding in diabetic felines and is a contributing factor to the insulin resistance present in type 2 diabetes. Clinical signs of diabetes develop once total insulin secretion decreases to 20% to 25% of normal levels. Many diabetic cats have been treated successfully with oral hypoglycemics, but 50% to 70% of diabetic cats are insulin dependent. Based on histologic evidence, this is the result of extensive amyloid deposition and subsequent beta cell degeneration, rather than autoimmune destruction of pancreatic beta cells associated with type 1 diabetes. Alternative ways of treating type 2 diabetes currently are being investigated. Amylin antagonists recently have been proposed as a novel treatment to reverse the deleterious effects of excessive amylin concentrations. The gastrointestinal hormone glucagon-like peptide-1 may also prove useful in treating diabetic cats, because of its stimulatory effect on insulin secretion and synthesis, and the absence of significant hypoglycemic effect.


Eptifibatide: a pharmacoeconomic review of its use in percutaneous coronary intervention and acute coronary syndromes.
Eptifibatide (Integrilin) is a selective inhibitor of platelet glycoprotein (GP) IIb/IIIa receptors used as adjunctive therapy for patients undergoing percutaneous coronary intervention (PCI) and for patients with acute coronary syndromes (ACS), particularly those requiring PCI. Most economic analyses of eptifibatide have incorporated clinical and healthcare resource use data from either the ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) study in low- to moderate-risk patients undergoing selective PCI with stent implantation or the PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) trial in patients with ACS. Eptifibatide achieved statistically significant reductions in combined endpoints of death and ischaemic complications in both of these large multicentre clinical trials, in which patients were randomised to receive intravenous eptifibatide or placebo as adjunctive therapy to heparin and aspirin (plus a thienopyridine in ESPRIT). In US economic analyses using ESPRIT trial data, approximately 40% and 70% of the acquisition cost of eptifibatide was offset by reduced medical resource consumption during the initial hospitalisation period and over a 1-year period, respectively. Eptifibatide was associated with a favourable cost-effectiveness ratio of $US1407 (year 2000 costs) per life-year gained (LYG) in a retrospective US cost-effectiveness analysis that incorporated data from the ESPRIT trial and modelled life expectancy using a large cardiovascular database.Several cost-effectiveness analyses used prospectively collected data from the PURSUIT trial and modelled survival projections using similar methods. These analyses, conducted in the US, Canada and Western Europe, also showed favourable results ($US3761-$US18 774 per LYG; various years of costing). Cost-utility ratios reported in US analyses varied somewhat, but remained <$US20 000 per quality-adjusted life-year gained (1996 values) when clinical efficacy data were derived from the US cohort of PURSUIT. Significant clinical benefits have been demonstrated with eptifibatide as adjunctive therapy in patients undergoing selective PCI with stent implantation in the ESPRIT trial and in patients with ACS in the PURSUIT trial. Pharmacoeconomic analyses using data from either ESPRIT or PURSUIT have demonstrated favourable cost-effectiveness ratios for both indications in various countries. ESPRIT-based results from the limited number of available economic analyses are particularly favourable. The cost-effectiveness of eptifibatide in ACS (i.e. PURSUIT-based results) may be further improved by targeting the drug for patients in whom catheterisation and PCI are planned, although further analyses are required to confirm this.


Design, Synthesis, and Characterization of N-Oxide-Containing Heterocycles with in Vivo Sterilizing Antitubercular Activity.
Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), is the infectious disease responsible for the highest number of deaths worldwide. Herein, 22 new N-oxide-containing compounds were synthesized followed by in vitro and in vivo evaluation of their antitubercular potential against Mtb. Compound 8 was found to be the most promising compound, with MIC90 values of 1.10 and 6.62 μM against active and nonreplicating Mtb, respectively. Additionally, we carried out in vivo experiments to confirm the safety and efficacy of compound 8; the compound was found to be orally bioavailable and highly effective, leading to a reduction of Mtb to undetectable levels in a mouse model of infection. Microarray-based initial studies on the mechanism of action suggest that compound 8 blocks translation. Altogether, these results indicate that benzofuroxan derivative 8 is a promising lead compound for the development of a novel chemical class of antitubercular drugs.


Physiological and Biochemical Changes in Lucerne (Medicago sativa) Plants Infected with 'Candidatus Phytoplasma australasia'-Related Strain (16SrII-D Subgroup).
Changes in physiological and biochemical patterns in lucerne plants caused by the presence of 'Candidatus Phytoplasma australasia', which is one of the significant pathogens causing yield losses in lucerne plants, were investigated. Significant differences were evident in total chlorophyll, chlorophyll a, chlorophyll b, and protein amounts between 'Ca. Phytoplasma australasia'-positive and negative lucerne plants. Stress-related metabolites such as phenol, malondialdehyde, and proline accumulations in 'Ca. Phytoplasma australasia'-positive plants were remarkably higher than those of phytoplasma-negative plants. As a response to disease attack, phytoplasma-positive plants exhibited higher antioxidant enzymes (peroxidase and catalase) and non-enzymatic metabolite responses such as jasmonic and salicylic acids. We state that partial disease responses were revealed for the first time to breed resistant lucerne lines infected by 'Ca. Phytoplasma australasia'.


The impact of medical errors on physician behavior: evidence from malpractice litigation.
How do medical errors affect physician behavior? Despite the importance of this question empirical evidence about it remains limited. This paper studies the impact of obstetricians' medical errors that resulted in malpractice litigation on their subsequent choice of whether to perform a C-section, a common procedure that is thought to be sensitive to physician incentives. The main result is that C-section rates jumped discontinuously by 4% after a medical error, establishing an association between medical errors and treatment patterns. C-section rates continued to increase afterwards, bringing the cumulative increase 2.5 years after a medical error to 8%.


Transporters in the intestine limiting drug and toxin absorption.
The pharmacokinetic behaviour of drugs strongly depends on transporters in intestine and liver. The extent of absorption in the intestine depends on diffusion across the mucosa as well as transporter-mediated uptake across the apical membrane of enterocytes. Efflux pumps in this membrane may strongly reduce the extent of net uptake. These efflux pumps are ATP-binding cassette (ABC) transporters which are also expressed in the apical membrane of the hepatocyte were they mediate excretion into bile. This combined activity strongly determines whether drugs have access to the systemic circulation.


Spontaneous and pokeweed mitogen induced in vitro immunoglobulin and IgM rheumatoid factor production by peripheral blood and synovial fluid mononuclear cells in rheumatoid arthritis.
Enzyme-linked immunosorbent assays (ELISA) were used to measure IgG, IgM and IgM rheumatoid factor (IgM RF) production in supernatants of pokeweed mitogen (PWM) stimulated peripheral blood mononuclear cells (PBMNC) of patients with rheumatoid arthritis (RA) and controls. Spontaneous and stimulated IgG and IgM production by RA and controls was comparable, but spontaneous production of IgM RF was only observed in RA and was related to their drug therapy. A significant difference was found between PWM induced IgM RF production in RA and controls and also between patients on "second-line" and on nonsteroidal anti-inflammatory drugs (NSAID). In addition, spontaneous IgM RF production by synovial fluid cells was significantly higher than the paired PBMNC.


Two-stage culture process for improved production of ganoderic acid by liquid fermentation of higher fungus Ganoderma lucidum.
Investigations on the impact of pellet size on the cellular oxygen uptake and accumulation of ganoderic acid (GA) suggested the favorable effect of oxygen limitation on GA formation by the higher fungus Ganoderma lucidum. A two-stage fermentation process was thus proposed for enhanced GA production by combining conventional shake-flask fermentation with static culture. A high cell density of 20.9 g of DW/L (DW = dry cell weight) was achieved through a 4-day shake-flask fermentation followed by a 12-day static culture. A change in the cell morphology and a decrease in the sugar consumption rate were observed during the static culture. The GA production in the new two-stage process was considerably enhanced with its content increased from 1.36 (control) to 3.19 mg/100 mg of DW, which was much higher than previously observed.


Presynaptic proteoglycans: sweet organizers of synapse development.
Synaptic adhesion molecules control neuronal synapse development. In this issue of Neuron, Siddiqui et al. (2013) and de Wit et al. (2013) demonstrate that LRRTM4, a postsynaptic adhesion molecule, trans-synaptically interacts with presynaptic heparan sulfate proteoglycans (HSPGs) to promote synapse development.