[Protamine sulfate-induced resistance to the hypoglycemic effect of insulin].
Administration of protamine sulfate in a dose (0.9-1.1 mg/200 g) sufficient for binding reactive circulatory heparin provokes in rats the status of temporary resistance to the hypoglycemic action of both exogenous and endogenous insulin. This effect occurs after protamine sulfate administration 5-30 minutes prior to insulin in doses of 0.2-2.4 Units/200 g, respectively, or release of endogenous heparin stimulated by sugar load. As the time interval between administration of protamine sulfate and administration (release) of insulin is prolonged or shortened, the status of resistance does not develop. Protamine sulfate does not produce any effect on the blood concentration of immunoreactive insulin. Similarly to protamine sulfate, the resistance to the hypoglycemic action of insulin may be also provoked by the synthetic heparin antagonist, 2,5-ionene that binds heparin, forming a stable polyelectrolyte complex ionene-heparin. Administration of a sufficient heparin dose (10 Units/200 g) may interrupt the protamine sulfate-induced resistance, which manifests in the recurrence of the hypoglycemic action of insulin. There are reasons to assume that the presence of reactive heparin in the circulation is necessary for insulin reception by target tissues.


Nucleosome translational position, not histone acetylation, determines TFIIIA binding to nucleosomal Xenopus laevis 5S rRNA genes.
We sought to study the binding constraints placed on the nine-zinc-finger protein transcription factor IIIA (TFIIIA) by a histone octamer. To this end, five overlapping fragments of the Xenopus laevis oocyte and somatic 5S rRNA genes were reconstituted into nucleosomes, and it was subsequently shown that nucleosome translational positioning is a major determinant of the binding of TFIIIA to the 5S rRNA genes. Furthermore, it was found that histone acetylation cannot override the TFIIIA binding constraints imposed by unfavorable translational positions.


Sex-Specific Variations in the mRNA Levels of Candidate Genes in Peripheral Blood Mononuclear Cells from Patients with Diabetes: A Multistep Study.
Type 2 diabetes (T2D) is one of the most prevalent diseases that also show sexual dimorphism in many different aspects. This study aimed to distinguish the mRNA expression of genes in peripheral blood mononuclear cells (PBMCs) in men or women with T2D using a multistep analysis. A total of 95 patients with T2D were compared based on their sex in terms of clinical variables and mRNA expression in their PBMCs. Men with T2D had lower LDLC, HDLC, and HbA1c values in their blood, but greater creatinine levels. In men with T2D, TLR4, CCR2, NOX2, and p67phox mRNA expression was greater, but IL6 and NF-κB mRNA expression was lesser in PBMCs. There was a link between fasting plasma glucose (FPG), triglycerides, and hs-CRP, as well as COX1 mRNA in men with T2D. In women with T2D, FPG was associated with the mRNA expression of THBS1 and p67phox, as well as triglycerides and HDLC levels. We found the exclusive effect of FPG on HDLC, HbA1c, as well as p67phox mRNA in PBMCs of women with T2D. Analysis revealed the exclusive effect of FPG on hs-CRP and PAFR mRNA in PBMCs of men with T2D. FPG was shown to be associated with body mass index, hs-CRP, triglycerides, and COX1 mRNA in men with T2D, and with serum triglycerides, THSB1, and p67phox mRNA in women with T2D, according to network analysis. HbA1c was linked with NF-κB mRNA in women with T2D. Using a multistep analysis, it was shown that network analysis outperformed traditional analytic techniques in identifying sex-specific alterations in mRNA gene expression in PBMCs of T2D patients. The development of sex-specific therapeutic approaches may result from an understanding of these disparities.


Continuous Erroneous Feedback Processing during Deviation from the Road within a 2D Steering Task.
Recent research of our group indicated that erroneous feedback processing can not only be detected via established correlates in the electroencephalogram (EEG) for discrete stimuli, but also arises as modulations of the brain signals when faced with a continuous and periodic error signal. However, limitations in our previous paradigm prevented a definitive statement on the error signal as the exclusive source of the modulations, as well as on the connection between the observed error-related negativity (ERN)-like and error positivity (Pe)-like continuous correlates. Within a new paradigm involving EEG recordings of 10 participants, we disentangled modulation sources, substantiating our hypothesis that the observed periodicity arises primarily due to feedback processing. Further, we provide evidence that the continuous ERN- and Pe-like potentials are locked to separate phases in the error signal, rather than time-locked to a shared event, indicating that both potentials arise independently of one another.


"Reversine" and its 2-substituted adenine derivatives as potent and selective A3 adenosine receptor antagonists.
The dedifferentiation agent "reversine" [2-(4-morpholinoanilino)-N(6)-cyclohexyladenine 2] was found to be a moderately potent antagonist for the human A(3) adenosine receptor (AR) with a K(i) value of 0.66 microM. This result prompted an exploration of the structure-activity relationship of related derivatives, synthesized via sequential substitution of 6-chloro-2-fluoropurine with selected nucleophiles. Optimization of substituents at these two positions identified 2-(phenylamino)-N(6)-cyclohexyladenine (12), 2-(phenylamino)-N(6)-cycloheptyladenine (19), and 2-phenylamino-N(6)-endo-norbornyladenine (21) as potent A(3) AR ligands with K(i) values of 51, 42, and 37 nM, respectively, with 30-200-fold selectivity in comparison to A(1) and A(2A) ARs. The most selective A(3) AR antagonist (>200-fold) was 2-(phenyloxy)-N(6)-cyclohexyladenine (22). 9-Methylation of 12, but not 19, was well-tolerated in A(3) AR binding. Extension of the 2-phenylamino group to 2-benzyl- and 2-(2-phenylethylamino) reduced affinity. In the series of 2-(phenylamino), 2-(phenyloxy), and 2-(phenylthio) substitutions, the order of affinity at the A(3) AR was oxy > or = amino > thio. Selected derivatives, including reversine (K(B) value of 466 nM via Schild analysis), competitively antagonized the functional effects of a selective A(3) AR agonist, i.e., inhibition of forskolin-stimulated cAMP production in stably transfected Chinese hamster ovary (CHO) cells. These results are in agreement with other studies suggesting the presence of a lipophilic pocket in the AR binding site that is filled by moderately sized cycloalkyl rings at the N(6) position of both adenine and adenosine derivatives. Thus, the compound series reported herein comprise an important new series of selective A(3) AR antagonists. We were unable to reproduce the dedifferentiation effect of reversine, previously reported, or to demonstrate any connection between A(3) AR antagonist effects and dedifferentiation.


Cytocompatibility of titanium and poly(etheretherketone) surfaces after O2 non-thermal plasma sterilization.
The sterilization of medical devices is paramount to achieve an acceptable level of sterility assurance and to prevent hospital-acquired infections. However, some medical devices cannot be sterilized by usual processes such as autoclave (AC) and gamma-ray irradiation (GI). A new non-thermal plasma (NTP) process using sealed bag that preserves the sterile state of the devices could be used as an alternative sterilization method. The aim of the study was to assess the cytocompatibility of titanium and poly(etheretherketone) (PEEK) surfaces after O2-NTP sterilization compared to GI and AC. MG-63 osteoblast-like cells were seeded on titanium (TA6V) and PEEK disks sterilized by AC, GI and O2-NTP. The cells' viability and proliferation, determined by WST-1 and DNA quantification respectively, were enhanced whatever the material types from 3 to 10 days. When seeded on titanium, MG-63 cells showed a higher viability and proliferation after GI and O2-NTP treatment compared to AC treatment. When cultured on PEEK, MG-63 cells showed a higher viability after O2-NTP treatment. No difference of proliferation was observed whatever the sterilization processes. The cell colonization of the materials' surface was confirmed by scanning electron microscopy. Lactate dehydrogenase (LDH) assay revealed no cytotoxicity. Thus, O2-NTP led to similar cell responses to AC and GI and could be a cost-effective alternative process to the usual sterilization methods for fragile medical devices.


Extracellular HSP27 mediates angiogenesis through Toll-like receptor 3.
The heat-shock protein 27 (HSP27) is up-regulated in tumor cells and released in their microenvironment. Here, we show that extracellular HSP27 has a proangiogenic effect evidenced on chick chorioallantoic membrane. To explore this effect, we test the recombinant human protein (rhHSP27) at physiopathological doses (0.1-10 μg/ml) onto human microvascular endothelial cells (HMECs) grown as monolayers or spheroids. When added onto HMECs, rhHSP27 dose-dependently accelerates cell migration (with a peak at 5 μg/ml) and favors spheroid sprouting within 12-24 h. rhHSP27 increases VEGF gene transcription and promotes secretion of VEGF-activating VEGF receptor type 2. Increased VEGF transcription is related to NF-κB activation in 30 min. All of these effects are initiated by rhHSP27 interaction with Toll-like receptor 3 (TLR3). Such an interaction can be detected by immunoprecipitation but does not seem to be direct, as we failed to detect an interaction between rhHSP27 and monomeric TLR3 by SPR analysis. rhHSP27 is rapidly internalized with a pool of TLR3 to the endosomal compartment (within 15-30 min), which is required for NF-κB activation in a cytosolic Ca(2+)-dependent manner. The HSP27/TLR3 interaction induces NF-κB activation, leading to VEGF-mediated cell migration and angiogenesis. Such a pathway provides alternative targets for antiangiogenic cancer therapy.


Glucagonoma and the glucagonoma syndrome - cumulative experience with an elusive endocrine tumour.
Glucagonoma is a pancreatic neuroendocrine tumour that arises from alpha cells in the pancreas and is often accompanied by a characteristic clinical syndrome. In this report, we present the cumulative experience and clinical characteristics of six patients diagnosed with glucagonoma and the glucagonoma syndrome and treated at our centre during the past 25 years. Although the course of the disease was variable, some features were similar. The median age at diagnosis was 53·5 years; the median time from onset of symptoms to diagnosis was 39 months. Presenting symptoms were as follows: weight loss 5/6 (83%), necrotizing migratory erythema (NME) 5/6 (83%), diabetes mellitus 4/6 (66%) and diarrhoea, weakness and thrombosis 2/6 (33%). Plasma glucagon was elevated in all patients upon diagnosis (range 200-10,000 pm; N < 50). Skin biopsy was diagnostic only in 1/6 specimens obtained, even after revision. Metastatic disease developed in all patients; 4/6 initially presented with hepatic metastasis. All patient symptoms responded to somatostatin analogue therapy. In 4/6, the NME responded to amino acid solutions. Other modes of therapy were as follows: surgery in 3/6 patients, peptide receptor radioligand therapy with (90) Y-DOTATOC (PRRT) in 3/6 patients (two responses) and chemotherapy in three patients (two responded). Four out of six patients died of the disease, and median survival time was 6·25 years (range 2-11) from diagnosis and 8 years (range 8-16) from initial symptoms. Five-year survival was 66%. Our data indicate that somatostatin analogues and an aggressive surgical approach offer symptom relief and tumour control. Among other available treatment modalities, PRRT seems to hold the most promise.


Differences in hippocampal CREB phosphorylation in trace fear conditioning of two inbred mouse strains.
The effects of genetic background on fear trace conditioning were evaluated in relation to phosphorylated levels of cAMP response element-binding protein (CREB) in the hippocampus using two different inbred strains of mice, C57BL/6 and DBA/2. The male mice received a trace fear conditioning protocol and unpaired control groups were included to assess nonassociative effects on test performance. Both C57BL/6 and DBA/2 mice with paired training displayed higher freezing responses during testing than those with unpaired training, respectively. The C57BL/6 mice with paired training also displayed higher freezing responses to the tone-CS during testing than the DBA/2 mice with paired training. Because much evidence implicates the hippocampus as an important neural substrate for trace fear conditioning, the engagement of the hippocampus was examined after testing by measuring levels of CREB and phosphorylated CREB (pCREB). The results revealed that hippocampal CREB levels in both strains of mice were not significantly altered according to the type of training (unpaired vs. paired). However, the hippocampal pCREB levels were significantly higher in the paired training group than the unpaired control group in C57BL/6 mice, but not in DBA/2 mice. These findings indicate that hippocampal pCREB is closely tied to this form of associative conditioning only in C57BL/6 mice and that different neural substrates may support trace conditioning in C57BL/6 and DBA/2 strains.


Cognitive evoked potentials in narcolepsy: a review of the literature.
Subtle cognitive deficits have been described in narcolepsy. They have been hypothesised to be related to changes in the hypocretin system. Event-related potential (ERP) paradigms are known to be useful tools in the investigation of information processing and seem to be sensitive to subtle neuropsychological changes. We review empirical articles on ERPs in narcolepsy in order to contribute to clarify the pattern of cognitive deficits that are specific to this disease and, possibly, to identify specific cognitive domains that improve with treatment. Fourteen peer-reviewed articles were selected for this review. These studies were conducted with passive and active oddball paradigms and support the existence of changes in cognitive attentive processing in narcolepsy, possibly in association with altered functioning of the prefrontal cortex. ERP low-resolution electromagnetic tomography revealed that modafinil improved information processing speed and increased energetic resources in prefrontal cortical areas. These findings suggest that it is worthwhile to further evaluate the usefulness of ERPs in the detection of cognitive dysfunction in this disorder before and after treatment.


Repression of Escherichia coli PhoP-PhoQ signaling by acetate reveals a regulatory role for acetyl coenzyme A.
The PhoP-PhoQ two-component system regulates the transcription of numerous genes in response to changes in extracellular divalent cation concentration and pH. Here we demonstrate that the Escherichia coli PhoP-PhoQ two-component system also responds to acetate. Signaling by the E. coli PhoP-PhoQ system was repressed during growth in acetate (> or = 25 mM) in a PhoQ-dependent manner. The periplasmic sensor domain of PhoQ was not required for acetate to repress signaling. Acetate-mediated repression of the PhoP-PhoQ system was not related to changes in the intracellular concentration of acetate metabolites such as acetyl-phosphate or acetyladenylate. Genetic analysis of acetate metabolism pathways suggested that a perturbation of acetyl coenzyme A turnover was the cause of decreased PhoP-PhoQ signaling during growth in acetate. Consistent with this hypothesis, intracellular acetyl coenzyme A levels rose during growth in the presence of exogenous acetate. Acetyl coenzyme A inhibited the autokinase activity of PhoQ in vitro, suggesting that the in vivo repressing effect may be due to a direct inhibition mechanism.


[The method of surgical correction of the endoprosthesis ptosis after performance of subglandular enlarging mammoplasty].
The method of reendoprosthesis of mammary glands after performance of subglandular enlarging mammoplasty for the glands form correction, the implants ptosis occurrence in postoperative period prophylaxis, reduction of possibility of the capsular contracture occurrence, as well as reduction of the implants "visualization" and palpation rate, especially in patients-women lacking covering tissues volume, was adduced. In 2005-2010 yrs in the Centre there were performed 18 operations of the mammary glands reendoprosthesis after subglandular enlarging mammoplasty using the method proposed. Maximal duration of follow-up have constituted five years. In 17 patients-women the result was estimated as an excellent and in 1--as good. Application of this method guarantees the foreseeable and stable late results achievement, as well as satisfaction of patients and surgeons. The perspective of further development of scientific investigation assumes studying of late results concerning application of the method proposed.


A needs assessment of pediatric epilepsy surgery in Haiti.
Epilepsy disproportionately affects low- and/or middle-income countries (LMICs). Surgical treatments for epilepsy are potentially curative and cost-effective and may improve quality of life and reduce social stigmas. In the current study, the authors estimate the potential need for a surgical epilepsy program in Haiti by applying contemporary epilepsy surgery referral guidelines to a population of children assessed at the Clinique d'Épilepsie de Port-au-Prince (CLIDEP). The authors reviewed 812 pediatric patient records from the CLIDEP, the only pediatric epilepsy referral center in Haiti. Clinical covariates and seizure outcomes were extracted from digitized charts. Electroencephalography (EEG) and neuroimaging reports were further analyzed to determine the prevalence of focal epilepsy or surgically amenable syndromes and to assess the lesional causes of epilepsy in Haiti. Lastly, the toolsforepilepsy instrument was applied to determine the proportion of patients who met the criteria for epilepsy surgery referral. Two-thirds of the patients at CLIDEP (543/812) were determined to have epilepsy based on clinical and diagnostic evaluations. Most of them (82%, 444/543) had been evaluated with interictal EEG, 88% of whom (391/444) had abnormal findings. The most common finding was a unilateral focal abnormality (32%, 125/391). Neuroimaging, a prerequisite for applying the epilepsy surgery referral criteria, had been performed in only 58 patients in the entire CLIDEP cohort, 39 of whom were eventually diagnosed with epilepsy. Two-thirds (26/39) of those patients had abnormal findings on neuroimaging. Most patients (55%, 18/33) assessed with the toolsforepilepsy application met the criteria for epilepsy surgery referral. The authors' findings suggest that many children with epilepsy in Haiti could benefit from being evaluated at a center with the capacity to perform basic brain imaging and neurosurgical treatments.


Accidental Peccei-Quinn Symmetry Protected to Arbitrary Order.
A SU(N)_{L}×SU(N)_{R} gauge theory for a scalar multiplet Y transforming in the bifundamental representation (N,N[over ¯]) preserves, for N>4, an accidental U(1) symmetry first broken at operator dimension N. A vacuum expectation value for Y can break the symmetry to H_{s}=SU(N)_{L+R} or to H_{h}=SU(N-1)_{L}×SU(N-1)_{R}×U(1)_{L+R}. In the first case the accidental U(1) gets also broken, yielding a pseudo-Nambu-Goldstone boson with mass suppression controlled by N. In the second case a global U(1) remains unbroken. The strong CP problem is solved by coupling Y to new fermions carrying color. The first case allows for a Peccei-Quinn solution with U(1)_{PQ} protected by the gauge symmetry up to order N. In the second case U(1) can get broken by condensates of the new strong dynamics, resulting in a composite axion. By coupling Y to fermions carrying only weak isospin, models for axionlike particles can be constructed.


CT-Derived Pulmonary Artery Diameters to Preselect for Echocardiography in COPD Patients Eligible for Bronchoscopic Treatments.
Currently, patients with COPD who are evaluated for bronchoscopic treatments are routinely screened for pulmonary hypertension (PH) and systolic left ventricle dysfunction by echocardiography. We evaluated the prevalence of PH and systolic left ventricle dysfunction in this patient group and investigated if the previously proposed CT-derived pulmonary artery to aorta (PA:A) ratio >1 and PA diameter measurements can be used as alternative screening tools for PH. Two hundred fifty-five patients were included in this retrospective analysis (FEV1 25%pred, RV 237%pred). All patients received transthoracic echocardiography and chest CT scans on which diameters of the aorta and pulmonary artery were measured at the bifurcation and proximal to the bifurcation. Following echocardiography, 3 patients (1.2%) had PH and 1 (0.4%) had systolic left ventricle dysfunction. Using a PA:A ratio >1, only 10.3% of the patients with a right ventricular systolic pressure (RVSP) ≥35 mm Hg were detected and none of the patients with an RVSP >50 mm Hg were detected. Patients with an RVSP ≥35 mm Hg had significantly higher PA diameters (29.5 vs. 27.5 mm; p = 0.02) but no significantly different PA:A ratios. All patients with an RVSP >50 mm Hg had PA diameters >30 mm. The prevalence of PH and systolic left ventricle dysfunction is low in this preselected cohort of patients with severe COPD. In this population, a PA:A ratio >1 is not a useful cardiac screening tool for PH. A PA diameter >30 mm could substitute for routinely performed echocardiography in the screening for PH in this patient group.


Modeling magnetic interactions in high-valent trinuclear [Mn3(IV)O4]4+ complexes through highly compressed multi-configurational wave functions.
In this work we apply a quantum chemical framework, recently designed in our laboratories, to rationalize the low-energy electronic spectrum and the magnetic properties of an homo-valent trinuclear [Mn3(IV)O4]4+ model of the oxygen-evolving center in photosystem II. The method is based on chemically motivated molecular orbital unitary transformations, and the optimization of spin-adapted many-body wave functions, both for ground- and excited-states, in the transformed MO basis. In this basis, the configuration interaction Hamiltonian matrix of exchange-coupled multi-center clusters is extremely sparse and characterized by a unique block diagonal structure. This property leads to highly compressed wave functions (oligo- or single-reference) and crucially enables state-specific optimizations. This work is the first showing that compression and selective targeting of ground- and excited-states wave functions is possible for systems with three magnetic centers that are not exactly half-filled, and that potentially exhibit frustrated spin interactions. The reduced multi-reference character of the wave function greatly simplifies the interpretation of the ground- and excited-state electronic structures, and provides a route for the direct rationalization of magnetic interactions in these compounds, often considered a challenge in polynuclear transition-metal chemistry. In this study, strong electron correlation effects have explicitly been described by conventional and stochastic multiconfigurational methodologies, while dynamic correlation effects have been accounted for by multiconfigurational second order perturbation theory, CASPT2. Ab initio results for the [Mn3(IV)O4]4+ system have been mapped to a three-site Heisenberg model with two magnetic coupling constants. The magnetic coupling constants and the temperature dependence of the effective magnetic moment predicted by the ab initio calculations are in good agreement with the available experimental data, and confirm the antiferromagnetic interaction among the three magnetic centers, while providing a simple and rigorous description of the noncollinearity of the local spins, that characterize most of the low-energy states for this system.


Enhancement of Na(+) uptake currents, time-dependent inward-rectifying K(+) channel currents, and K(+) channel transcripts by K(+) starvation in wheat root cells.
Excessive low-affinity Na(+) uptake is toxic to the growth of glycophytic plants. Recently, several reports have suggested that the interaction between K(+) and Na(+) uptake might represent a key factor in determining the Na(+) tolerance of plants. We investigated the effects of K(+) starvation on Na(+) and K(+) uptake mechanisms in the plasma membrane of wheat (Triticum aestivum L.) root cortex cells using the patch-clamp technique. Unexpectedly, K(+) starvation of wheat seedlings was found to enhance the magnitude and frequency of occurrence of time-dependent inward-rectifying K(+) channel currents (I(K)(+)(in)). We examined whether the transcription of a wheat root K(+)(in) channel gene is induced by K(+) starvation. A cDNA coding for a wheat root K(+) channel homolog, TaAKT1 (accession no. AF207745), was isolated. TaAKT1 mRNA levels were up-regulated in roots in response to withdrawal of K(+) from the growth medium. Furthermore, K(+) starvation caused an enhancement of instantaneous Na(+) currents (I(Na)(+)). Electrophysiological analyses suggested that I(K)(+)(in) and I(Na)(+) are not mediated by the same transport protein based on: (a) different activation curves, (b) different time dependencies, (c) different sensitivities to external Ca(2+), and (d) different cation selectivities. These data implicate a role for I(Na)(+) in Na(+) uptake and stress during K(+) starvation, and indicate that K(+)(in) channels may contribute to K(+)-starvation-induced K(+) uptake in wheat roots.


Acute and recurrent viral meningitis.
Acute viral meningitis is the most common infection of the central nervous system. Most cases occur in children and young adults and are due to enteroviruses. Although the common causes of acute viral meningitis still lack treatment with an effective antiviral agent, management of patients is changing because of better and more rapid diagnostic tests to determine the exact viral etiology. These tests reduce the cost of workups and shorten hospitalizations. Recurrent meningitis is less common, with most cases caused by herpes simplex virus 2 in young adults. Early administration of antiviral drugs such as acyclovir, valaciclovir, or famciclovir can shorten the duration of an episode of aseptic meningitis. Daily prophylactic administration of any of these medicines also reduces the frequency of future episodes.


Potential energy surface of triplet O4.
We present a global ground-state potential energy surface (PES) for the triplet spin state of O4 that is suitable for treating high-energy vibrational-rotational energy transfer and collision-induced dissociation in electronically adiabatic spin-conserving O2-O2 collisions. The surface is based on MS-CASPT2/maug-cc-pVTZ electronic structure calculations with scaled external correlation; the active space has 16 electrons in 12 orbitals. The global ground-state potential energy surface was fitted by a many-body approach with an accurate O-O pairwise interaction and a fit of the many-body interaction potential to 10 180 electronic structure data points. The many-body fit is based on permutationally invariant polynomials in terms of bond-order functions of the six interatomic distances; the bond-order functions are mixed exponential-Gaussian functions. The geometries calculated and used for the fit include geometry scans corresponding to dissociative and vibrationally excited diatom-diatom collisions of O2, scans corresponding to O3 interacting with O, additional geometries identified by running trajectories, and geometries along linear synchronous transit paths connecting randomly selected points. The global O4 PES includes subsurfaces describing the interaction of diatomic molecules with other diatomic molecules or interactions of triatomic molecules and an atom. The interaction of ozone with a ground-state oxygen atom occurs on the triplet O4 surface, and our surface includes high-energy points with O3-O geometries as well as O2-O2 geometries and O2-O-O geometries.


A Case Report of Cushing's Disease Presenting as Hair Loss.
Cushing's syndrome is a rare endocrine disorder that comprises a large group of signs and symptoms resulting from chronic exposure to excess corticosteroids. Most cases of Cushing's syndrome are due to increased adrenocorticotropic hormone production from a pituitary adenoma, which is referred to as Cushing's disease. Most of the signs and symptoms are nonspecific and common in the general population, making a diagnosis often challenging. However, several dermatological manifestations, such as fragile skin, easy bruising, and reddish purple striae, are more discriminatory. Because uncontrolled Cushing's syndrome of any etiology is associated with substantial morbidity, including increased cardiovascular disease and mortality, it is important to make an early diagnosis. Unfortunately, median delays of 2 years to diagnosis have been reported. We report a case of a woman who had multiple dermatological findings, including facial plethora, easy bruising, violaceous striae, hirsutism, and acne, the latter 2 signs reflecting androgen excess. Of interest, our patient presented with a chief complaint of hair loss, a common complaint in the general population that occurs with a greater frequency in patients with Cushing's disease and is attributed to androgenetic alopecia, but it is rarely the presenting symptom.


Full-length huntingtin levels modulate body weight by influencing insulin-like growth factor 1 expression.
Levels of full-length huntingtin (FL htt) influence organ and body weight, independent of polyglutamine length. The growth hormone-insulin like growth factor-1 (GH-IGF-1) axis is well established as a regulator of organ growth and body weight. In this study, we investigate the involvement of the IGF-1 pathway in mediating the effect of htt on body weight. IGF-1 expression was examined in transgenic mouse lines expressing different levels of FL wild-type (WT) htt (YAC18 mice), FL mutant htt (YAC128 and BACHD mice) and truncated mutant htt (shortstop mice). We demonstrate that htt influences body weight by modulating the IGF-1 pathway. Plasma IGF-1 levels correlate with body weight and htt levels in the transgenic YAC mice expressing human htt. The effect of htt on IGF-1 expression is independent of CAG size. No effect on body weight is observed in transgenic YAC mice expressing a truncated N-terminal htt fragment (shortstop), indicating that FL htt is required for the modulation of IGF-1 expression. Treatment with 17beta-estradiol (17beta-ED) lowers the levels of circulating IGF-1 in mammals. Treatment of YAC128 with 17beta-ED, but not placebo, reduces plasma IGF-1 levels and decreases the body weight of YAC128 animals to WT levels. Furthermore, given the ubiquitous expression of IGF-1 within the central nervous system, we also examined the impact of FL htt levels on IGF-1 expression in different regions of the brain, including the striatum, cerebellum of YAC18, YAC128 and littermate WT mice. We demonstrate that the levels of FL htt influence IGF-1 expression in striatal tissues. Our data identify a novel function for FL htt in influencing IGF-1 expression.


High-throughput detection of prostate cancer in histological sections using probabilistic pairwise Markov models.
In this paper we present a high-throughput system for detecting regions of carcinoma of the prostate (CaP) in HSs from radical prostatectomies (RPs) using probabilistic pairwise Markov models (PPMMs), a novel type of Markov random field (MRF). At diagnostic resolution a digitized HS can contain 80Kx70K pixels - far too many for current automated Gleason grading algorithms to process. However, grading can be separated into two distinct steps: (1) detecting cancerous regions and (2) then grading these regions. The detection step does not require diagnostic resolution and can be performed much more quickly. Thus, we introduce a CaP detection system capable of analyzing an entire digitized whole-mount HS (2x1.75cm(2)) in under three minutes (on a desktop computer) while achieving a CaP detection sensitivity and specificity of 0.87 and 0.90, respectively. We obtain this high-throughput by tailoring the system to analyze the HSs at low resolution (8microm per pixel). This motivates the following algorithm: (Step 1) glands are segmented, (Step 2) the segmented glands are classified as malignant or benign, and (Step 3) the malignant glands are consolidated into continuous regions. The classification of individual glands leverages two features: gland size and the tendency for proximate glands to share the same class. The latter feature describes a spatial dependency which we model using a Markov prior. Typically, Markov priors are expressed as the product of potential functions. Unfortunately, potential functions are mathematical abstractions, and constructing priors through their selection becomes an ad hoc procedure, resulting in simplistic models such as the Potts. Addressing this problem, we introduce PPMMs which formulate priors in terms of probability density functions, allowing the creation of more sophisticated models. To demonstrate the efficacy of our CaP detection system and assess the advantages of using a PPMM prior instead of the Potts, we alternately incorporate both priors into our algorithm and rigorously evaluate system performance, extracting statistics from over 6000 simulations run across 40 RP specimens. Perhaps the most indicative result is as follows: at a CaP sensitivity of 0.87 the accompanying false positive rates of the system when alternately employing the PPMM and Potts priors are 0.10 and 0.20, respectively.


A National Process to Enhance the Validity of Entrustment Decisions for Dutch Pediatric Residents.
Postgraduate medical education (PGME) has become increasingly individualized, and entrustable professional activities (EPAs) have been adopted to operationalize this. At the same time, the process and content to determine residents' progress using high-stakes summative entrustment decisions by clinical competency committees (CCCs) is not yet well established. We evaluated the experiences with a structured process for assessment of EPAs to attain uniform summative entrustment decisions for a national sample of pediatric residents. An EPA-based national PGME program for pediatric residents was introduced in the Netherlands, including a process of uniform summative entrustment decisions, termed the Evaluation and Assessment of Residents by Supervisors (EARS) procedure. To evaluate the program, we assessed survey data and information from invitational conferences. Beginning in January 2017, 125 pediatric residents in all 8 Dutch residency regions started training in the EARS program. The program enabled robust summative entrustment decisions. Preliminary data suggested that faculty, despite increased preparation time, appreciated the comprehensive appraisal of resident qualifications. The EPA-based program was well accepted by residents. Fifty-one percent (57 of 112) had at least 2 EARS procedures per year, and for 75% (84 of 112) the level of supervision was often or always adjusted to their level of training. A national EPA-based program provided a structured process for summative entrustment decisions by CCCs and enabled individualized stepwise progression of residents toward unsupervised practice. Broader application of these concepts may require adaptations to accommodate different health care systems and specialties.


Human cytomegalovirus UL130 protein promotes endothelial cell infection through a producer cell modification of the virion.
Human cytomegalovirus (HCMV) growth in endothelial cells (EC) requires the expression of the UL131A-128 locus proteins. In this study, the UL130 protein (pUL130), the product of the largest gene of the locus, is shown to be a luminal glycoprotein that is inefficiently secreted from infected cells but is incorporated into the virion envelope as a Golgi-matured form. To investigate the mechanism of the UL130-mediated promotion of viral growth in EC, we performed a complementation analysis of a UL130 mutant strain. To provide UL130 in trans to viral infections, we constructed human embryonic lung fibroblast (HELF) and human umbilical vein endothelial cell (HUVEC) derivative cell lines that express UL130 via a retroviral vector. When the UL130-negative virus was grown in UL130-complementing HELF, the infectivity of progeny virions for HUVEC was restored to the wild-type level. In contrast, the infectivity of the UL130-negative virus for UL130-complementing HUVEC was low and similar to that of the same virus infecting control noncomplementing HUVEC. The UL130-negative virus, regardless of whether or not it had been complemented in the prior cycle, could form plaques only on UL130-complementing HUVEC, not control HUVEC. Because (i) both wild-type and UL130-transcomplemented virions maintained their infectivity for HUVEC after purification, (ii) UL130 failed to complement in trans the UL130-negative virus when it was synthesized in a cell separate from the one that produced the virions, and (iii) pUL130 is a virion protein, models are favored in which pUL130 acquisition in the producer cell renders HCMV virions competent for a subsequent infection of EC.


[Reactivation of the scar of BCG vaccination in Kawasaki's disease: clinical case and literature review].
Kawasaki disease is an acute febrile multisystemic vasculitis affecting children that can affect the coronary arteries. Routine BCG vaccination in Mexico leads to a 99% coverage in infants younger than 1 year. We present a case of Kawasaki disease with skin lesions at the site of BCG. Clinicians should be aware of this clinical manifestation that could help diagnose atypical or incomplete cases of the disease.


Self-management of injection-related wounds among injecting drug users.
Injection-related wounds are an important complication of injection drug use. This study describes behaviors related to self-management of injection-related wounds and identifies factors associated with behaviors that may increase the potential for harm. We conducted interviews with 101 injecting drug users in Washington, DC. A total of 82 (81.2%) injecting drug users reported ever having an injection-related wound, and of these 93.9% reported self-management of their wounds. The most commonly reported behaviors were cleaning and applying ointment to wounds; however, several participants engaged in behaviors determined to be more potentially harmful, including acquiring antibiotics without prescriptions and manipulating their wounds. In multivariate analysis, injecting drug users who had ever injected amphetamines were more likely to engage in potentially harmful self-management behaviors (adjusted odds ratio = 4.38; 95% confidence interval = 1.15-16.64). Self-management of injection-related wounds is common and certain behaviors may increase the potential for harm. Further research is needed to best focus efforts to improve wound care for injecting drug users.


Possibilities for critical social theory and Foucault's work: a toolbox approach.
The benefits and constraints of philosophical frameworks using the work of Michel Foucault and critical social theorists, such as Fay, Giroux and McLaren, are examined in the light of their traditions. The reasons nurse researchers adopt these frameworks are explored, as are the tensions between the respective theories. A complementary 'toolbox' approach to the research process addresses some of the theoretical and methodological challenges presented by each framework. Such an approach provides distinctive insights into nursing practice that the other has ignored or missed. It is argued that by converging the two frameworks into a toolbox approach, it is possible to examine or deconstruct existing practices, whilst also providing an avenue for nurses to reconstruct or change such practices.


Human genetics and malaria resistance.
Malaria has been the pre-eminent cause of early mortality in many parts of the world throughout much of the last five thousand years and, as a result, it is the strongest force for selective pressure on the human genome yet described. Around one third of the variability in the risk of severe and complicated malaria is now explained by additive host genetic effects. Many individual variants have been identified that are associated with malaria protection, but the most important all relate to the structure or function of red blood cells. They include the classical polymorphisms that cause sickle cell trait, α-thalassaemia, G6PD deficiency, and the major red cell blood group variants. More recently however, with improving technology and experimental design, others have been identified that include the Dantu blood group variant, polymorphisms in the red cell membrane protein ATP2B4, and several variants related to the immune response. Characterising how these genes confer their effects could eventually inform novel therapeutic approaches to combat malaria. Nevertheless, all together, only a small proportion of the heritable component of malaria resistance can be explained by the variants described so far, underscoring its complex genetic architecture and the need for continued research.


Dysregulation of miR-181c expression influences recurrence of endometrial endometrioid adenocarcinoma by modulating NOTCH2 expression: An NRG Oncology/Gynecologic Oncology Group study.
Endometrial cancer can be diagnosed early and cured, yet cases that recur portend a very poor prognosis with over 10,000 women succumbing to the disease every year. In this study we addressed the question of how to recognize cases likely to recur early in the course of therapy using dysregulation of tumor microRNAs (miRNAs) as predictors. Using the tissue collection from Gynecologic Oncology Group Study-210, we selected and analyzed expression of miRNAs in 54 recurrent and non-recurrent cases. The three most common histologic types, endometrioid adenocarcinoma (EEA), serous adenocarcinoma (ESA) and carcinosarcoma (UCS), were analyzed as three independent sets and their miRNA expression profiles compared. Only one miRNA was statistically different between recurrent and non-recurrent cases, and in only one histologic type: significant down-regulation of miR-181c was observed in EEA recurrence. Using several well-known databases to assess miR-181c targets, one target of particular relevance to cancer, NOTCH2, was well supported. Using The Cancer Genome Atlas and our validation tumor panel from the GOG-210 cohort, we confirmed that NOTCH2 is significantly over-expressed in EEA. In the most relevant endometrial adenocarcinoma cell model, Ishikawa H, altering miR-181c expression produces significant changes in NOTCH2 expression, consistent with direct targeting. Our findings suggest that increased NOTCH2 via loss of miR-181c is a significant component of EEA recurrence. This presents an opportunity to develop miR-181c and NOTCH2 as markers for early identification of high risk cases and the use of NOTCH inhibitors in the prevention or treatment of recurrent disease.


Complications of indwelling chemotherapy catheters.
Fifty consecutive chemotherapeutic infusions for cancer via precutaneously introduced arterial catheters were reviewed to determine the frequency of angiographic and clinical complications related to the indwelling catheter. Fibrin cloaking along the catheter was found in 20 patients studied by pull-out arteriography and was unassociated with clinical symptoms. Major thrombus formation occurred around the catheter tip in 28% of the infused vessels, all within the hepatic artery. Clinical symptoms developed in only three patients where thrombosis of the hepatic artery had propagated into the celiac axis. Systemic heparinization did not reduce the incidence of thrombus formation but did increase the incidence of mild gastrointestinal bleeding. Several factors may reduce the incidence of complications, such as puncture of a large artery, use of soft, pliable, and small diameter catheters, proper free position of the catheter in the infused vessel, regular angiographic checkups for catheters position, and early evidence of thrombus formation.


An inexact fuzzy-chance-constrained air quality management model.
Regional air pollution is a major concern for almost every country because it not only directly relates to economic development, but also poses significant threats to environment and public health. In this study, an inexact fuzzy-chance-constrained air quality management model (IFAMM) was developed for regional air quality management under uncertainty. IFAMM was formulated through integrating interval linear programming (ILP) within a fuzzy-chance-constrained programming (FCCP) framework and could deal with uncertainties expressed as not only possibilistic distributions but also discrete intervals in air quality management systems. Moreover, the constraints with fuzzy variables could be satisfied at different confidence levels such that various solutions with different risk and cost considerations could be obtained. The developed model was applied to a hypothetical case of regional air quality management. Six abatement technologies and sulfur dioxide (SO2) emission trading under uncertainty were taken into consideration. The results demonstrated that IFAMM could help decision-makers generate cost-effective air quality management patterns, gain in-depth insights into effects of the uncertainties, and analyze tradeoffs between system economy and reliability. The results also implied that the trading scheme could achieve lower total abatement cost than a nontrading one.


Inferring microbial interaction networks from metagenomic data using SgLV-EKF algorithm.
Inferring the microbial interaction networks (MINs) and modeling their dynamics are critical in understanding the mechanisms of the bacterial ecosystem and designing antibiotic and/or probiotic therapies. Recently, several approaches were proposed to infer MINs using the generalized Lotka-Volterra (gLV) model. Main drawbacks of these models include the fact that these models only consider the measurement noise without taking into consideration the uncertainties in the underlying dynamics. Furthermore, inferring the MIN is characterized by the limited number of observations and nonlinearity in the regulatory mechanisms. Therefore, novel estimation techniques are needed to address these challenges. This work proposes SgLV-EKF: a stochastic gLV model that adopts the extended Kalman filter (EKF) algorithm to model the MIN dynamics. In particular, SgLV-EKF employs a stochastic modeling of the MIN by adding a noise term to the dynamical model to compensate for modeling uncertainties. This stochastic modeling is more realistic than the conventional gLV model which assumes that the MIN dynamics are perfectly governed by the gLV equations. After specifying the stochastic model structure, we propose the EKF to estimate the MIN. SgLV-EKF was compared with two similarity-based algorithms, one algorithm from the integral-based family and two regression-based algorithms, in terms of the achieved performance on two synthetic data-sets and two real data-sets. The first data-set models the randomness in measurement data, whereas, the second data-set incorporates uncertainties in the underlying dynamics. The real data-sets are provided by a recent study pertaining to an antibiotic-mediated Clostridium difficile infection. The experimental results demonstrate that SgLV-EKF outperforms the alternative methods in terms of robustness to measurement noise, modeling errors, and tracking the dynamics of the MIN. Performance analysis demonstrates that the proposed SgLV-EKF algorithm represents a powerful and reliable tool to infer MINs and track their dynamics.


Congenital brain tumors: diagnostic pitfalls and therapeutic interventions.
Congenital brain tumors are rare, accounting for 0.5% to 4% of all pediatric brain tumors. A 10-year retrospective study based on autopsy and neurosurgical clinical reports with a diagnosis of congenital/fetal/neonatal brain tumor identified 6 cases. Four cases were diagnosed antenatally by neuroradiology. Clinical outcomes in 5 cases resulted in death; 1 patient with choroid plexus papilloma underwent successful resection of the tumor and is still alive. Tumor pathologies consisted of 2 teratomas, 2 choroid plexus papillomas, 1 gemistocytic astrocytoma, and 1 glioblastoma multiforme. A literature review of all fetal cases specific to the pathologies presented in this series was also performed. Relative to the literature, this series contains a rare case of congenital gemistocytic astrocytoma. This series further sheds light on the diagnostic, histological, prognostic, and therapeutic differences between congenital brain tumors and tumors of the same pathology in older pediatric and adult populations.


The proportion of core species in a community varies with spatial scale and environmental heterogeneity.
Ecological communities are composed of a combination of core species that maintain local viable populations and transient species that occur infrequently due to dispersal from surrounding regions. Preliminary work indicates that while core and transient species are both commonly observed in community surveys of a wide range of taxonomic groups, their relative prevalence varies substantially from one community to another depending upon the spatial scale at which the community was characterized and its environmental context. We used a geographically extensive dataset of 968 bird community time series to quantitatively describe how the proportion of core species in a community varies with spatial scale and environmental heterogeneity. We found that the proportion of core species in an assemblage increased with spatial scale in a positive decelerating fashion with a concomitant decrease in the proportion of transient species. Variation in the shape of this scaling relationship between sites was related to regional environmental heterogeneity, with lower proportions of core species at a given scale associated with high environmental heterogeneity. Understanding this influence of scale and environmental heterogeneity on the proportion of core species may help resolve discrepancies between studies of biotic interactions, resource availability, and mass effects conducted at different scales, because the importance of these and other ecological processes are expected to differ substantially between core and transient species.


A tide of change in the management of an old fracture?
Colles' fractures are manipulated under a variety of anaesthetic techniques. An increasing awareness of cost and time within the National Health Service contributes to a marked change in the anaesthetic management of Colles' fractures. This paper presents the results of a survey of the anaesthetic techniques used in the larger accident and emergency (A&E) departments of the UK, and demonstrates the increasing popularity of the haematoma block compared with 5 years ago (7% in 1989 vs. 33% in 1994), at the expense of the general anesthetic (44% in 1989 vs 24% in 1994). The popularity of the Bier's block has remained unchanged (33% in 1989 and 1994). Local and regional anaesthetic techniques can be safely performed by A&E doctors, with appropriate monitoring, and this has beneficial resource implications for the anaesthetic department and the hospital.


Intentional and unintentional non-adherence to social distancing measures during COVID-19: A mixed-methods analysis.
Social distancing measures implemented by governments worldwide during the COVID-19 pandemic have proven an effective intervention to control the transmission of SARS-CoV-2. There is a growing literature on predictors of adherence behaviours to social distancing measures, however, there are no comprehensive insights into the nature and types of non-adherence behaviours. To address this gap in the literature, we studied non-adherence in terms of counts of infringements and people's accounts on their behaviours in a sample of North London residents. We focused on the following social distancing rules: keeping 2 mts. distancing, meeting family and friends, and going out for non-essential reasons. A mixed-methods explanatory sequential design was used comprising an online survey (May 1-31, 2020) followed by semi-structured in-depth interviews held with a purposive sample of survey respondents (August 5 -September 21, 2020). A negative binomial regression model (quantitative) and Framework Analysis (qualitative) were undertaken.681 individuals completed the survey, and 30 individuals were interviewed. We integrated survey and interview findings following three levels of the Social Ecological model: individual, interpersonal and community levels. We identified non-adherence behaviours as unintentional (barriers beyond individual's control) and intentional (deliberate decision). Unintentional adherence was reported by interviewees as, lack of controllability in keeping 2 mts. distancing, environmental constraints, social responsibility towards the community and feeling low risk. Intentional non-adherence was statistically associated with and reported as lack of trust in Government, support from friends, and lack of knowledge about rules. In addition, interviewees reported individual risk assessment and decision making on the extent to following the rules, and perceived lack of adherence in the local area. Our findings indicate that unintentional and intentional non-adherence should be improved by Government partnerships with local communities to build trust in social distancing measures; tailored messaging to young adults emphasising the need of protecting others whilst clarifying the risk of transmission; and ensuring COVID-secured environments by working with environmental health officers.


Zoledronic Acid Improves Muscle Function in Healthy Mice Treated with Chemotherapy.
Carboplatin is a chemotherapy drug used to treat solid tumors but also causes bone loss and muscle atrophy and weakness. Bone loss contributes to muscle weakness through bone-muscle crosstalk, which is prevented with the bisphosphonate zoledronic acid (ZA). We treated mice with carboplatin in the presence or absence of ZA to assess the impact of bone resorption on muscle. Carboplatin caused loss of body weight, muscle mass, and bone mass, and also led to muscle weakness as early as 7 days after treatment. Mice treated with carboplatin and ZA lost body weight and muscle mass but did not lose bone mass. In addition, muscle function in mice treated with ZA was similar to control animals. We also used the anti-TGFβ antibody (1D11) to prevent carboplatin-induced bone loss and showed similar results to ZA-treated mice. We found that atrogin-1 mRNA expression was increased in muscle from mice treated with carboplatin, which explained muscle atrophy. In mice treated with carboplatin for 1 or 3 days, we did not observe any bone or muscle loss, or muscle weakness. In addition, reduced caloric intake in the carboplatin treated mice did not cause loss of bone or muscle mass, or muscle weakness. Our results show that blocking carboplatin-induced bone resorption is sufficient to prevent skeletal muscle weakness and suggests another benefit to bone therapy beyond bone in patients receiving chemotherapy. © 2019 American Society for Bone and Mineral Research.


[Solubilization of brain thromboplastin. Effect of different detergents].
The effect of 3 different detergents (Triton X-100, Lubrol WX and Nonidet) on brain thromboplastin was examined and compared with the solubilisation due to deoxycholate. The effect of deoxycholate is superior over that of the other examined detergents. Deoxycholate extracts thromboplastic activity from brain tissue to a large extent. Furthermore it has no interfering absorbance at 280 nm. The aminopeptidase of brain tissue may be separated from thromboplastin. It does not have any coagulation activity.


Trypanosomosis in The Gambia: prevalence in working horses and donkeys detected by whole genome amplification and PCR, and evidence for interactions between trypanosome species.
The Gambia has an increasing population of equidae largely used for agriculture and transportation. A review of cases at The Gambian Horse and Donkey Trust (GHDT) indicated that a common reason for presentation is a poorly defined medical condition often attributed to trypanosomosis. There are few reports describing the prevalence or the range of clinical signs associated with infection with different species of trypanosomes in horses and donkeys, but given the importance of these animals, the role of trypanosomosis requires investigation. In total 241 animals from the Central River Division in The Gambia (183 horses and 58 donkeys) were screened using Whole Genome Amplification (WGA) followed by trypanosome species identification using polymerase chain reaction (PCR). The results indicated overall trypanosome prevalence of 91%; with an infection rate of 31% for Trypanosoma congolense Savannah, 87% for Trypanosoma vivax and 18% for Trypanosoma brucei sp. Multiple species were present in 43% of infections. Microscopy had a good specificity (100%) and positive predictive value (100%) for trypanosome detection, but the sensitivity (20%) and negative predictive value (10.5%) were low relative to PCR-based diagnosis. Infection with T congolense showed the greatest negative effect on packed cell volume (PCV), while infection with T. brucei sp also had a significant, although lesser, negative effect on PCV. In addition, cases positive by microscopy were associated with significantly lower PCV. However, concurrent infection with T. vivax appeared to cause less effect on PCV, compared to animals infected with T. congolense alone. The prevalence of Trypanosomosis was high in both horses and donkeys. Infection with T. congolense appeared to have the greatest clinical significance, while T. vivax infection may be of limited clinical significance in this population. Indeed, there is evidence of T. vivax co-infection ameliorating the pathology caused by T. congolense. WGA and PCR allowed a more comprehensive analysis of field infections with the detection of infections below the threshold of microscopy, and provided indications of interactions between parasite species that would otherwise remain undetected. The study raises important questions about the epidemiology of trypanosome infection in relation to disease that require a full scale longitudinal analysis.


hv1 is an evolutionarily conserved H2A variant that is preferentially associated with active genes.
Polyclonal antibodies to the Tetrahymena macronuclear-specific histone variant hv1 cross-react with histone-like molecules from yeast, wheat, and mouse. A novel purification scheme has allowed isolation of sufficient hv1 to enable determination of the sequence of 61 amino-terminal residues as well as 27 additional internal residues. These data clearly demonstrate that hv1 shares a number of conserved sequence elements with the H2A family of histones. Comparison of hv1 with H2A.F (= H2A.Z = M1), another evolutionarily conserved H2A variant whose sequence is known, reveals that they share an unblocked amino-terminal alanine (instead of acetylserine) and a distinctive structure in a "variant box" region that distinguishes them from major H2As. In addition, 10 residues have been identified which are identical (or highly similar) in hv1 and H2A.F, but are different from residues conserved in the major H2As. Therefore, in many ways hv1 resembles chick H2A.F more than the major Tetrahymena H2A. The sites of acetylation of hv1 also differ from those of the major Tetrahymena H2As. In spite of their similarities, hv1 and H2A.Z differ significantly in their amino termini, and antibodies against hv1 do not react with H2A.Z. Interestingly, the nucleolar staining pattern reported with anti-hv1 serum is similar to that reported for an antiserum to another H2A variant, mouse testes-enriched H2A.X. Since both H2A.Z and hv1 appear to be enriched in transcriptionally active chromatin, these results suggest that there may be a number of different, functionally distinct, nonallelic variants in the H2A family of histones and that hv1 is a hybrid H2A variant with properties of both vertebrate H2A.Z and H2A.X.


[Nutritional knowledge and perception on dialysis: influence on adhesion and transgression; initial study].
The dialysis patients have problems in maintaining proper conduct and adherence to the diet prescribed in liquid nephrology consultation. Indicate the interdialytic weight gain, serum potassium and phosphorus along with self-report instruments, markers that have been used as indicators of non-adherence to the diet. Most of the time is not counted in dialysis units with dietitians-nutritionists. Nephrologists and nurses lack the time and / or sufficient to establish and monitor adherence to an individualized diet knowledge. The main objective is to determine adherence to dietary guidelines and hemodialysis fluids by DDFQ questionnaire and establish its relationship with the dietary habits of the patients, assessed by test dietary habits and cooking procedures. Secondary objectives are to measure adherence by DDFQ and relate the results to biochemical markers of intake and interdialytic weight gain (GID). Linking monitoring liquid diet and reported by the patient, biochemical markers of intake, interdialytic weight gain and the outcome of DDFQ. Determine membership based on sex, time on hemodialysis, have diabetes or have been transplanted once. And linking dietary habits reported by patients in the test of dietary habits and cooking procedures with patients' knowledge of the guidelines prescribed by nephrologists in consultation. Cross-sectional pilot study. Sociodemographic variables: age and sex. Clinical variables: diabetic transplant patient ever, time on dialysis, dry weight and GID. Biochemical markers: serum potassium and phosphorus. Variables adherence to diet questionnaire measures DDFQ. SPSS 20 Descriptive, Spearman correlation test, Student t test, Mann-Whitney U test and contingency table. 42 patients; 59.5% male, 40.5% female. Age 63.64 ± 16.17 years. Diabetics 11.9%. GID 1.96 ± 0.70 kg. Potassium 5.08 ± 0.86 meq / l phosphorus 4.71 ± 1.63 mg / dl. DDFQ Measured with 50% of patients not adhering to the diet in 2 days 14 days and 50% have no adherence to liquid in 1 day 14 days. There are correlations between adherence to diet and phosphorus (ρ= 0.304) and adherence to fluid and GID (ρ= 0.413). There is a lack of adherence to dietary guidelines in dialysis patients, in contrast to the accession referred by them. The review of dietary and fluid patterns is necessary in patients with CKD on dialysis. Hence the importance of training and support for nurses using simple tools to detect breaches and act with greater dietary education.


Superoxide dismutase is upregulated in Staphylococcus aureus following protoporphyrin-mediated photodynamic inactivation and does not directly influence the response to photodynamic treatment.
Staphylococcus aureus, a major human pathogen causes a wide range of disease syndromes. The most dangerous are methicillin-resistant S. aureus (MRSA) strains, resistant not only to all β-lactam antibiotics but also to other antimicrobials. An alarming increase in antibiotic resistance spreading among pathogenic bacteria inclines to search for alternative therapeutic options, for which resistance can not be developed easily. Among others, photodynamic inactivation (PDI) of S. aureus is a promising option. Photodynamic inactivation is based on a concept that a non toxic chemical, called a photosensitizer upon excitation with light of an appropriate wavelength is activated. As a consequence singlet oxygen and other reactive oxygen species (e.g. superoxide anion) are produced, which are responsible for the cytotoxic effect towards bacterial cells. As strain-dependence in photodynamic inactivation of S. aureus was observed, determination of the molecular marker(s) underlying the mechanism of the bacterial response to PDI treatment would be of great clinical importance. We examined the role of superoxide dismutases (Sod) in photodynamic inactivation of S. aureus as enzymes responsible for oxidative stress resistance. The effectiveness of photodynamic inactivation towards S. aureus and its Sod isogenic mutants deprived of either of the two superoxide dismutase activities, namely SodA or SodM or both of them showed similar results, regardless of the Sod status in TSB medium. On the contrary, in the CL medium (without Mn++ ions) the double SodAM mutant was highly susceptible to photodynamic inactivation. Among 8 clinical isolates of S. aureus analyzed (4 MRSA and 4 MSSA), strains highly resistant and strains highly vulnerable to photodynamic inactivation were noticed. We observed that Sod activity as well as sodA and sodM transcript level increases after protoporphyrin IX-based photodynamic treatment but only in PDI-sensitive strains. We confirmed that porphyrin-based photokilling efficacy is a strain-dependent phenomenon. We showed that oxidative stress sensitivity caused by the lack of both Sod enzymes can be relieved in the presence of Mn ions and partially in the presence of Fe ions. The fact that Sod activity increase is observed only in PDI-susceptible cells emphasizes that this is probably not a direct factor affecting S. aureus vulnerability to porphyrin-based PDI.


Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle.
Protein affinity reagents (PARs), frequently antibodies, are essential tools for basic research, diagnostics, separations and for clinical applications. However, there is growing concern about the reproducibility, quality and cost of recombinant and animal-derived antibodies. This has prompted the development of alternatives that could offer economic, and time-saving advantages without the use of living organisms. Synthetic copolymer nanoparticles (NPs), engineered with affinity for specific protein targets, are potential alternatives to PARs. Although there are now a number of examples of abiotic protein affinity reagents (APARs), most have been evaluated in vitro limiting a realistic assessment of their potential for more demanding, practical in vivo applications. We demonstrate for the first time that an abiotic copolymer hydrogel nanoparticle (NP1) engineered to bind a key signaling protein, vascular endothelial growth factor (VEGF165), functions in vivo to suppress tumor growth by regulating angiogenesis. Lightly cross-linked N-isopropylacrylamide based NPs that incorporate both sulfated N-acetylglucosamine and hydrophobic monomers were optimized by dynamic chemical evolution for VEGF165 affinity. NP1 efficacy in vivo was evaluated by systemic administration to tumor-bearing mice. The study found that NP1 suppresses tumor growth and reduces tumor vasculature density. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. NP1 treatment did not show off target anti-coagulant activity. In addition, >97% of injected NPs are rapidly excreted from the body following IV injection. These results establish the use of APARs as inhibitors of protein-protein interactions in vivo and may point the way to their broader use as abiotic, cost effective protein affinity reagents for the treatment of certain cancers and more broadly for regulating signal transduction.


A bayesian model of polychronicity.
A significant feature of spiking neural networks with varying connection delays, such as those in the brain, is the existence of strongly connected groups of neurons known as polychronous neural groups (PNGs). Polychronous groups are found in large numbers in these networks and are proposed by Izhikevich (2006a) to provide a neural basis for representation and memory. When exposed to a familiar stimulus, spiking neural networks produce consistencies in the spiking output data that are the hallmarks of PNG activation. Previous methods for studying the PNG activation response to stimuli have been limited by the template-based methods used to identify PNG activation. In this letter, we outline a new method that overcomes these difficulties by establishing for the first time a probabilistic interpretation of PNG activation. We then demonstrate the use of this method by investigating the claim that PNGs might provide the foundation of a representational system.


Localization of herpes simplex virus type 1 UL37 in the Golgi complex requires UL36 but not capsid structures.
The herpes simplex virus type 1 (HSV-1) UL37 gene encodes a 120-kDa polypeptide which resides in the tegument structure of the virion and is important for morphogenesis. The goal of this study was to use green fluorescent protein (GFP) to follow the fate of UL37 within cells during the normal course of virus replication. GFP was inserted in frame at the C terminus of UL37 to generate a fluorescent-protein-tagged UL37 polypeptide. A virus designated K37eGFP, which replicated normally on Vero cells, was isolated and was shown to express the fusion polypeptide. When cells infected with this virus were examined by confocal microscopy, the fluorescence was observed to be predominantly cytoplasmic. As the infection progressed, fluorescence began to accumulate in a juxtanuclear structure. Mannosidase II and giantin were observed to colocalize with UL37eGFP at these structures, as judged by immunofluorescence assays. Therefore, UL37 traffics to the Golgi complex during infection. A VP26mRFP marker (red fluorescent protein fused to VP26) was recombined into K37eGFP, and when cells infected with this "dual-color" virus were examined, colocalization of the red (capsid) and green (UL37) fluorescence in the Golgi structure was observed. Null mutations in VP5 (DeltaVP5), which abolished capsid assembly, and in UL36 (Delta36) were recombined into the K37eGFP virus genome. In cells infected with K37eGFP/DeltaVP5, localization of UL37eGFP to the Golgi complex was similar to that for the parental virus (K37eGFP), indicating that trafficking of UL37eGFP to the Golgi complex did not require capsid structures. Confocal analysis of cells infected with K37eGFP/Delta36 showed that, in the absence of UL36, accumulation of UL37eGFP at the Golgi complex was not evident. This indicates an interaction between these two proteins that is important for localization of UL37 in the Golgi complex and thus possibly for cytoplasmic envelopment of the capsid. This is the first demonstration of a functional role for UL36:UL37 interaction in HSV-1-infected cells.


Effects of family history of alcohol dependence on the subjective response to alcohol using the intravenous alcohol clamp.
Alcohol use disorders are well recognized to be common, debilitating, and the risk of developing them is influenced by family history (FH). The subjective response to alcohol may be determined familialy and related to the risk of developing alcoholism. The aim of this study was to evaluate differences between family history positive (FHP) and family history negative (FHN) individuals in their response to alcohol within the domains of subjective, coordination, and cognitive effects using an intravenous (IV) clamping method of alcohol administration. Two groups of healthy subjects, those with an FHP (n = 65) versus those who were FHN (n = 115), between the ages of 21 to 30, participated in 3 test days. Subjects were scheduled to receive placebo, low-dose ethanol (EtOH) (target breath alcohol clamping [BrAC] = 40 mg%), and high-dose EtOH (target BrAC = 100 mg%) on 3 separate test days at least 3 days apart in a randomized order under double-blind conditions. Outcome measures included subjective effects, measures of coordination, and cognitive function. Both low- and high-dose alcohol led to dose-related stimulant and sedative subjective effects as measured the Biphasic Alcohol Effects Scale and subjective measures of "high" and "drowsy" measured on a visual analog scale. However, there were no effects of FH. Similar dose-related effects were observed on cognitive and coordination-related outcomes, but were not moderated FH. Results from this study showed that healthy individuals responded to an IV alcohol challenge in a dose-related manner; however, there were no significant differences on subjective response, or on EtOH-induced impairment of coordination or cognition, between individuals with a positive FH for alcoholism and those with a negative FH. Results suggest that FH may not be a specific enough marker of risk, particularly in individuals who are beyond the age where alcohol use disorders often develop.


Efavirenz conceptions and regimen management in a prospective cohort of women on antiretroviral therapy.
Use of the antiretroviral drug efavirenz (EFV) is not recommended by the WHO or South African HIV treatment guidelines during the first trimester of pregnancy due to potential fetal teratogenicity; there is little evidence of how clinicians manage EFV-related fertility concerns. Women on antiretroviral therapy (ART) were enrolled into a prospective cohort in four public clinics in Johannesburg, South Africa. Fertility intentions, ART regimens, and pregnancy testing were routinely assessed during visits. Women reporting that they were trying to conceive while on EFV were referred for regimen changes. Kaplan-Meier estimators were used to assess incidence across ART regimens. From the 822 women with followup visits between August 2009-March 2011, 170 pregnancies were detected during study followup, including 56 EFV conceptions. Pregnancy incidence rates were comparable across EFV, nevirapine, and lopinavir/ritonavir person-years (95% 100/users (P=0.25)); incidence rates on EFV were 18.6 Confidence Interval: 14.2-24.2). Treatment substitution from EFV was made for 57 women, due to pregnancy intentions or actual pregnancy; however, regimen changes were not systematically applied across women. High rates of pregnancy on EFV and inconsistencies in treatment management suggest that clearer guidelines are needed regarding how to manage fertility-related issues in. women on EFV-based regimens.


Cytomegalovirus: biology, clinical features and methods for diagnosis.
Cytomegalovirus (CMV) infections remain a major obstacle to the successful outcome of bone marrow transplantation (BMT). The clinical manifestations of CMV-induced disease are many and varied and may mimic other disease processes commonly seen after BMT. The development of effective strategies for the prevention and treatment of such infections requires an understanding of the life cycle of the virus. In this review we discuss the molecular structure of CMV, the modes of replication and transmission, and the biology of the development of latency and reactivation. The recent availability of potentially effective anti-CMV drugs emphasizes the need for rapid diagnostic techniques which permit the initiation of treatment early in the disease. We review the diagnostic methods in common use and compare the newly developed rapid assays with the standard techniques of viral isolation and serological responses, with particular reference to their use in marrow transplant recipients.


Engineering osteoblastic metastases to delineate the adaptive response of androgen-deprived prostate cancer in the bone metastatic microenvironment.
While stromal interactions are essential in cancer adaptation to hormonal therapies, the effects of bone stroma and androgen deprivation on cancer progression in bone are poorly understood. Here, we tissue-engineered and validated an in vitro microtissue model of osteoblastic bone metastases, and used it to study the effects of androgen deprivation in this microenvironment. The model was established by culturing primary human osteoprogenitor cells on melt electrowritten polymer scaffolds, leading to a mineralized osteoblast-derived microtissue containing, in a 3D setting, viable osteoblastic cells, osteocytic cells, and appropriate expression of osteoblast/osteocyte-derived mRNA and proteins, and mineral content. Direct co-culture of androgen receptor-dependent/independent cell lines (LNCaP, C4-2B, and PC3) led cancer cells to display functional and molecular features as observed in vivo. Co-cultured cancer cells showed increased affinity to the microtissues, as a function of their bone metastatic potential. Co-cultures led to alkaline phosphatase and collagen-I upregulation and sclerostin downregulation, consistent with the clinical marker profile of osteoblastic bone metastases. LNCaP showed a significant adaptive response under androgen deprivation in the microtissues, with the notable appearance of neuroendocrine transdifferentiation features and increased expression of related markers (dopa decarboxylase, enolase 2). Androgen deprivation affected the biology of the metastatic microenvironment with stronger upregulation of androgen receptor, alkaline phosphatase, and dopa decarboxylase, as seen in the transition towards resistance. The unique microtissues engineered here represent a substantial asset to determine the involvement of the human bone microenvironment in prostate cancer progression and response to a therapeutic context in this microenvironment.


Moderate coffee or tea consumption decreased the risk of cognitive disorders: an updated dose-response meta-analysis.
Although several epidemiological studies have examined the association between coffee or tea intake and the risk of cognitive disorders, the results to date are inconsistent. An updated systematic review and dose-response meta-analysis was conducted to confirm the association between coffee, tea, and caffeine consumption and the risk of cognitive disorders. PubMed, Embase, and Web of Science were searched from inception to January 2022 for relevant studies, including dementia, Alzheimer disease (AD), and cognitive impairment or decline. Two reviewers independently performed data extraction and assessed the study quality. Restricted cubic splines were used to conduct the dose-response meta-analysis for coffee and tea intake. Twenty-two prospective studies and 11 case-control studies involving 389 505 participants were eligible for this meta-analysis. Coffee and tea consumption was linked to a lower risk of cognitive disorders, with an overall relative risk (RR) of 0.73 (95% CI: 0.60-0.86) and 0.68 (95% CI: 0.56-0.80), respectively. The subgroup analysis revealed that ethnicity, sex, and outcomes had significant effects on this association. Protection was stronger for men than that for women in both coffee and tea consumption. A nonlinear relationship was found between coffee consumption and AD risk, and the strength of protection peaked at approximately 2.5 cups/day (RR: 0.74; 95% CI: 0.59-0.93). A linear relationship was found between tea consumption and cognitive disorders, and the risk decreased by 11% for every 1-cup/day increment. This meta-analysis demonstrated that the consumption of 2.5 cups coffee/day minimizes the risk of AD, and 1 cup/day of tea intake leads to an 11% reduction in cognitive deficits. Effective interventions involving coffee and tea intake might prevent the occurrence of dementia.


"In situ cross-docking" to simultaneously address multiple targets.
In standard docking, every target structure requires separate docking calculations. To overcome this limitation, an approach is presented by which multiple proteins can be addressed simultaneously in a single docking run. This "in situ cross-docking" is built on a grid-based docking method and follows the idea that grids calculated for single binding sites may be joined to one common grid. Docking then allows for a direct selection of the optimal target by the ligand being docked. The approach is technically feasible and can lead to significant time savings over conventional cross-docking.


Early events in naphthalene-induced acute Clara cell toxicity. II. Comparison of glutathione depletion and histopathology by airway location.
One of the presumed roles of intracellular glutathione (GSH) is the protection of cells from injury by reactive intermediates produced by the metabolism of xenobiotics. To establish whether GSH depletion is a critical step in the initiation of events that lead to cytotoxicity by P450-activated cytotoxicants, naphthalene, a well-defined Clara cell cytotoxicant, was administered to mice (200 mg/kg) by intraperitoneal injection. Shortly after injection (1, 2, and 3 h), intracellular GSH content was assessed by high performance liquid chromatography or quantitative epifluorescent imaging microscopy and compared with the degree of cytotoxicity as assessed by high resolution histopathology. In highly susceptible airways (distal bronchioles), GSH decreased by 50% in 1 h. Cytoplasmic vacuolization was not visible until 2 h, when GSH had decreased by an additional 50%. By 3 h, cytoplasmic blebbing was extensive. In minimally susceptible airways (lobar and proximal bronchi), GSH depletion varied widely within the population; a small proportion of the cells lost greater than 50% of their GSH by 2 h and a significant percentage of the cells retained most of their GSH throughout the entire 3 h. Cytoplasmic vacuolization was apparent in some of the cells at 2 h but not visible in any cells at 3 h. We conclude that (1) loss of intracellular GSH is an early event that precedes initial signs of cellular damage in Clara cell cytotoxicity; (2) this pattern of loss in relation to early injury is found both in highly susceptible and minimally susceptible airway sites; (3) there is wide cell-to-cell heterogeneity in the response; (4) the heterogeneity in the response profile varies between populations in highly susceptible and minimally susceptible sites; and (5) once the intracellular GSH concentration within the entire cell population drops below a certain threshold, the initial phase of injury becomes irreversible.


Chimpanzee vertebrate consumption: Savanna and forest chimpanzees compared.
There is broad consensus among paleoanthropologists that meat-eating played a key role in the evolution of Homo, but the details of where, when, and why are hotly debated. It has been argued that increased faunivory was causally connected with hominin adaptation to open, savanna habitats. If savanna-dwelling chimpanzees eat meat more frequently than do forest chimpanzees, it would support the notion that open, dry, seasonal habitats promote hunting or scavenging by hominoids. Here we present observational and fecal analysis data on vertebrate consumption from several localities within the dry, open Ugalla region of Tanzania. Combining these with published fecal analyses, we summarize chimpanzee vertebrate consumption rates, showing quantitatively that savanna chimpanzee populations do not differ significantly from forest populations. Compared with forest populations, savanna chimpanzees consume smaller vertebrates that are less likely to be shared, and they do so more seasonally. Analyses of chimpanzee hunting that focus exclusively on capture of forest monkeys are thus difficult to apply to chimpanzee faunivory in open-country habitats and may be misleading when used to model early hominin behavior. These findings bear on discussions of why chimpanzees hunt and suggest that increases in hominin faunivory were related to differences between hominins and chimpanzees and/or differences between modern and Pliocene savanna woodland environments.


Bombesin/gastrin-releasing peptide receptor: a potential target for antibody-mediated therapy of small cell lung cancer.
Bombesin/gastrin releasing peptide (BN/GRP) is a growth factor for small cell lung cancer (SCLC). The receptor (R) for BN/GRP is overexpressed on SCLC cells and other solid tumors. BN/GRP and its receptor form an autocrine loop to promote tumor growth. We developed a novel immunotherapeutic approach targeting cell surface BN/GRP-R on SCLC cells and an immune trigger molecule on host immune effector cells to direct immune effector cells to SCLC cells and mediate targeted cancer cell destruction. Targeted immunotherapy combined with chemotherapy enhanced cell killing. We designed a synthetic BN/GRP antagonist (Antag 2) and constructed a bispecific molecule (BsMol), H22xAntag 2 (humanized monoclonal antibody) for FcgammaRI. We tested the binding of the BsMol to several SCLC cell lines, its ability to mediate cytotoxicity of SCLC by IFN-gamma-activated human monocytes with chemotherapy, and BsMol-mediated immunotherapy in an animal model of SCLC human xenograft. Common chemotherapy (cisplatin, etoposide, and paclitaxel) inhibited thymidine uptake into SCLC cells in a dose-dependent pattern. Antibody-dependent cellular cytotoxicity mediated by the BsMol inhibited thymidine uptake into SCLC cells and was largely dependent on E:T cell ratio. When SCLC cells were treated with antibody-dependent cellular cytotoxicity followed by exposure to chemotherapy agents an additional 25-40% inhibition of thymidine uptake into SCLC cells was observed consistently. With BsMol and IFN-gamma-activated human monocytes, tumor burdens were reduced significantly in immunodeficient mice bearing human SCLC xenografts. Combined chemotherapy and immunotherapy targeting BN/GRP-R with a BsMol significantly enhances targeted SCLC cell killing.


Investigation of Demyelination and Remyelination Processes of the Compressed Optic Chiasm: An Experimental Model.
To demonstrated demyelination and remyelination of the optic nerve histologically by electron microscopy in an experimental model similar to the compression of pituitary adenomas on the optic chiasm. The rats were fixed to a stereotaxic device under deep anesthesia, and a balloon catheter was placed under the optic chiasm through a burr hole which was in front of the bregma in accordance with the brain atlas of rats. The animals were divided into five groups (n=8): control, mild compression demyelination, severe compression demyelination, mild compression remyelination, severe compression remyelination. The fine structures of the tissues obtained were evaluated using electron microscopy. We found a significant difference in the severity of degeneration when comparing group 1 with group 5 (p < 0.001); there was no degeneration in group 1 rats and severe degeneration in all of the group 5 rats. Oligodendrocytes were found in all rats in group 1 and none of the rats in no group 2. The nuclei were preserved in the group 1 rats but damaged in all of the group 5 rats. There were no lymphocytes or erythrocytes in group 1 and all positives in group 5. This technique, which induced degeneration without causing damage to the optic nerve with toxic or chemical agents, revealed Wallerian degeneration similar to tumoral compression. After compression relief, the optic nerve remyelination process can be better understood, particularly for sellar lesions. In our opinion, this model may guide future experiments to identify protocols to induce and accelerate remyelination.


Fatal light aircraft accidents in Papua New Guinea.
The number of light aircraft (less than 5,700) in the developing world is small compared to those in the West, and little information on aviation accidents is readily available from developing countries. Papua New Guinea, enjoys a priviledged position, since aviation was introduced early and much of the country was opened through flying. During the period of Australian trusteeship until independence in 1975, the Australian Department of Transport applied its own rigorous standards to aviation in Papua New Guinea, a policy continued by the present Civil Aviation Agency. As a result of tight supervisory controls, accurate statistics on accidents are available, from which comparisons with other countries can be made. A study has been made of fatal light aircraft accidents in Papua New Guinea. Some of the Medical problems involved in accident prevention in a developing country are discussed.


Second dose thiopentone attenuates the haemodynamic response to laryngoscopy and intubation.
The study was undertaken to evaluate the effectiveness of large (divided) thiopentone dosage on the peripheral haemodynamic response to laryngoscopy and intubation. Seventy-six (76) patient aged 18 to 67 years were sequentially assigned to either the second dose thiopentone group (n = 36) or the control group (n = 40). The first group had 4 mg.kg-1 thiopentone for induction of anaesthesia, then 1.5 mg.kg-1 suxamethonium chloride for muscle relaxation and a second dose of thiropentone (4 mg.kg-1) just before laryngoscopy and intubation. The control group had thiopentone 4 mg.kg-1 for induction of anaesthesia, suxamethonium 1.5 mg.kg-1 for muscle relaxation and then laryngoscopy and intubation. The heart rate (HR), systolic arterial pressure (SAP), diastolic arterial pressure (DAP), mean arterial pressure (MAP), and rate pressure product (RPP) were measured before induction of anaesthesia and after laryngoscopy and intubation. The difference in the values represented the haemodynamic response to laryngoscopy and intubation. The second dose thiopentone technique compared with the control group, significantly attenuated the post-intubation rise in HR (19.7 vs. 30.9), SAP (18.0 vs. 37.5) and RPP (4795.4 vs. 8440.0). The post intubation rise in DAP (33.9 vs. 42.5) and MAP (31.9 vs. 42.0) didn't show significant difference between the two groups.


The efficacy and safety of sunitinib given on an individualised schedule as first-line therapy for metastatic renal cell carcinoma: A phase 2 clinical trial.
Sunitinib is administered on a rigid schedule that may not be optimal for all patients. We hypothesised that toxicity-driven dose and schedule changes would optimise drug exposure and outcome for each patient. In a phase 2 trial, 117 patients with metastatic clear cell renal cell cancer were started on sunitinib 50 mg/day with the aim to treat for 28 days. Treatment breaks were reduced to 7 days. Sunitinib dose and the number of days on therapy were individualised based on toxicity aiming for ≤ grade II toxicity with dose escalation in patients with minimal toxicity. The null hypothesis for the primary end-point was a progression-free survival (PFS) of 8.5 months based on a study with similar eligibility criteria. The null hypothesis was rejected (p < 0.001) with a median PFS of 12.5 months (95% confidence interval [CI]: 9.6-16.5). The median overall survival was 38.5 months (95% CI: 28.3-not reached). The objective response rate (46.1%) and stable disease rate (38.5%) translated into a clinical benefit for 84.6% of patients with no decline in quality of life scores during therapy. Fewer patients were dose reduced (26.5% vs. 50%) or discontinued due to toxicity (7.7 vs. 18-20%) compared to standard sunitinib dosing, and 20 (18.4%) patients were dose escalated to 62.5 mg (12) and 75 mg (8) with a wide individual variation in the optimal dose and treatment duration. Individualised sunitinib therapy is feasible, safe and an effective method to manage toxicity with one of the best efficacy seen for oral vascular endothelial growth factor inhibitors in metastatic renal cell carcinoma. CLINICALTRIALS. NCT01499121.


Turnip curly top virus, a highly divergent geminivirus infecting turnip in Iran.
From 2006 onwards turnip crops in Fars province, Iran, have been noted with unusual leaf curling and vein swelling symptoms which are characteristic of the leafhopper-transmitted viruses of the genus Curtovirus (family Geminiviridae). Rolling circle amplification was used to clone viruses from five turnip isolates exhibiting leaf curl symptoms. Analysis of the sequences showed them to have >93% sequence identity and to be distinct from all other geminiviruses previously characterised. Analysis of the sequence of this virus, for which we propose the name Turnip curly top virus (TCTV), showed it to have a genome arrangement in the complementary-sense similar to that of curtoviruses (consisting of four overlapping genes) but only two open reading frames in the virion-sense (the curtoviruses encode three). The complementary-sense genes are homologous to those of curtoviruses but show little sequence identity to their curtovirus homologs, with the exception of the product of the C4 open reading frame (ORF) which shows approximately 70.6% amino acid sequence identity to the C4 of the North American curtoviruses, Pepper curly top virus and Beet mild curly top virus. For curtoviruses the C4 protein is a symptom determinant, which likely explains the similarity of TCTV symptoms to those of curtoviruses. In the virion-sense the predicted product of the V2 ORF of TCTV shows no significant similarity with any proteins in the databases whereas the product of the V1 ORF (encoding the coat protein [CP] of geminiviruses) shows low levels of sequence identity to the CPs of curtoviruses. These findings show TCTV to be a highly divergent geminivirus with similarities to viruses of the genus curtovirus. The significance of these findings, particularly the taxonomic implications are discussed.


The Prevalence of Internet Addiction in Turkish Adolescents with Psychiatric Disorders.
The aim of this study is to determine the prevalence of Internet addiction (IA) in adolescents with psychiatric disorders. A total of 310 adolescents, aged from 12 to 18, participated in the study. The psychiatric sample group included 162 participants who had applied to the child psychiatry outpatients service. The psychiatric disorders among those in this group were assessed through clinical interviews based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Text Revision (DSM-IV-TR). The control group was chosen from adolescents of families who had never sought psychiatric help. The demographics of the participants and the features of their Internet usage habits were gathered through a questionnaire prepared by researchers. Young's Internet Addiction Test was used to assess internet addiction. The frequency of IA was found to be significantly higher in the psychiatric sample group than in the control group (24.1% vs. 8.8%, respectively). A total of 23.9% of the subjects had one, and 12.6% had two or more co-morbid psychiatric diagnoses. The frequencies of the diagnostic groups were as follows: attention deficit hyperactivity disorder 55.6%, anxiety disorder 29.0%, mood disorder 21.0%. IA was found to be significantly more common among adolescents in the child psychiatry outpatient department than among the adolescents who had no psychiatric history, even after confounding variables had been controlled. Further studies are needed to define IA more precisely and to improve prevention approaches.


[Laparoscopic Total Pelvic Exenteration of Locally Advanced Rectal Cancer Invading Urogenital Organs].
Application of laparoscopic surgery(Lap)for colorectal cancer has expanded, and laparoscopic total pelvic exenteration (TPE)of locally advanced rectal cancer(LARC)invading the urogenital organs has been introduced in some institutions. In our institute, we have performed Lap TPE and posterior-TPE(PPE)in a total of 6 LARC patients so far. Here, we report the surgical technique of Lap TPE, and the associated surgical and short-term outcomes. We performed Lap TPE and Lap PPE in 3 patients each. Operation time was approximately 562 min, and the blood loss was 310 mL on an average. No patient developed postoperative complications above Clavien-Dindo Grade Ⅲ. One patient exhibited recurrence in the liver and another in peritoneum in the Lap PPE group. No recurrence was observed in the Lap TPE group(median follow-up period: 24.5 months). Although Lap TPE and PPE are difficult to perform and time consuming, it is suggested that these procedures may help reduce the intraoperative bleeding volume and shorten the length of postoperative hospital stay compared to open TPE and PPE.


Marek's disease: effects of B histocompatibility alloalleles in resistant and susceptible chicken lines.
Lines of chickens selected from a common ancestral population for either resistance or susceptibility to Marek's disease developed contrasting frequencies of particular B alloalleles. Comparison of inoculated sibs in backcross-families revealed that the B alloalleles characterizing the two lines accounted for an eightfold difference in tumor incidence. This genetic difference in tumorigenesis associated with the alloalleles of the major histocompatibility complex is probably expressed through the cell-mediated immune system.


Corneal wound healing after 193-nm excimer laser keratectomy.
As part of a human trial of phototherapeutic keratectomy, we performed anterior keratectomy using excimer laser 193-nm ablation on patients with superficial corneal opacities. We examined the ultrastructural changes in the corneas of four patients who underwent penetrating keratoplasty 6 to 15 months after excimer laser ablation. The four cases included macular dystrophy, recurrent keratoconus in a graft, and corneal scarring (two eyes). Light microscopy showed epithelial thickening, absence of Bowman's layer, and superficial stromal scarring in the area of ablation. Ultrastructural study showed that the epithelial basement membrane had focal discontinuities. At the margin of the ablation superficial collagen bundles terminated abruptly in a steplike configuration. The anterior stroma was scarred, with loss of lamellar structure and an increase in number of fibrocytes. The laser-induced scar was 10 to 15 microns thick in the two eyes without a stromal scar before laser ablation. The stroma underlying the scarred areas and that in the untreated area appeared normal. Linear collagen-like fibers were present in the posterior aspect of Descemet's membrane. Laser-induced scarring may be an important factor in limiting visual improvement in patients undergoing phototherapeutic keratectomy.