The Effectiveness of a Computer Game-Based Rehabilitation Platform for Children With Cerebral Palsy: Protocol for a Randomized Clinical Trial.
It is difficult to engage young children with cerebral palsy (CP) in repetitive, tedious therapy. As such, there is a need for innovative approaches and tools to motivate these children. We developed the low-cost, computer game-based rehabilitation platform CGR that combines fine manipulation and gross movement exercises with attention and planning game activities appropriate for young children with CP. The objective of this study is to provide evidence of the therapeutic value of CGR to improve upper extremity (UE) motor function for children with CP. This randomized controlled, single-blind, clinical trial with an active control arm will be conducted at 4 sites. Children diagnosed with CP between the ages of 4 and 10 years old with moderate UE impairments and fine motor control abnormalities will be recruited. We will test the difference between experimental and control groups using the Quality of Upper Extremity Skills Test (QUEST) and Peabody Developmental Motor Scales, Second Edition (PDMS-2) outcome measures. The parents of the children and the therapist experiences with the interventions and tools will be explored using semi-structured interviews using the qualitative description approach. This research protocol, if effective, will provide evidence for the therapeutic value and feasibility of CGR in the pediatric rehabilitation of UE function. Clinicaltrials.gov NCT02728375; http:https://clinicaltrials.gov/ct2/show/NCT02728375 (Archived by WebCite at http://www.webcitation.org/6qDjvszvh).


Particle-based modeling of heterogeneous chemical kinetics including mass transfer.
Connecting the macroscopic world of continuous fields to the microscopic world of discrete molecular events is important for understanding several phenomena occurring at physical boundaries of systems. An important example is heterogeneous catalysis, where reactions take place at active surfaces, but the effective reaction rates are determined by transport limitations in the bulk fluid and reaction limitations on the catalyst surface. In this work we study the macro-micro connection in a model heterogeneous catalytic reactor by means of stochastic rotation dynamics. The model is able to resolve the convective and diffusive interplay between participating species, while including adsorption, desorption, and reaction processes on the catalytic surface. Here we apply the simulation methodology to a simple straight microchannel with a catalytic strip. Dimensionless Damkohler numbers are used to comment on the spatial concentration profiles of reactants and products near the catalyst strip and in the bulk. We end the discussion with an outlook on more complicated geometries and increasingly complex reactions.


β-Nd(2)Mo(4)O(15).
The title compound, dineodymium(III) tetra-molybdate(VI), has been prepared by a flux technique and is the second polymorph of composition Nd(2)Mo(4)O(15). The crystal structure is isotypic with those of Ce(2)Mo(4)O(15) and Pr(2)Mo(4)O(15). It features a three-dimensional network composed of distorted edge- and corner-sharing NdO(7) polyhedra, NdO(8) polyhedra, MoO(4) tetra-hedra and MoO(6) octa-hedra.


White matter alterations at pubertal onset.
Recent neurodevelopmental research supports the contribution of pubertal stage to local and global grey and white matter remodelling. Little is known, however, about white matter microstructural alterations at pubertal onset. This study investigated differences in white matter properties between pre-pubertal and pubertal children using whole brain fixel-based analysis (FBA) of the microscopic density and macroscopic cross-section of fibre bundles. Diffusion-weighted imaging data were acquired for 74 typically developing children (M=10.4, SD=.43 years, 31 female) at 3.0T (60 diffusion gradient directions, b-value=2800s/mm2). Group comparisons of fibre density (FD) and fibre cross-section (FC) were made between age-matched pre-pubertal and pubertal groups, and post-hoc analyses were performed on regions of interest (ROIs) defined in the splenium, body and genu of the corpus callosum. Significant fixel-wise differences in FD were observed between the pubertal groups, where the pubertal group had significantly higher FD compared with age-matched pre-pubertal children, localised to the posterior corpus callosum. Post-hoc analyses on mean FD in the corpus callosum ROIs revealed group differences between the pubertal groups in the splenium, but not body or genu. The observed higher apparent fibre density in the splenium suggests that pubertal onset coincides with white matter differences explained by increasing axon diameter. This may be an important effect to account for over pubertal development, particularly for group studies where age-matched clinical and typical populations may be at various stages of puberty.


Self reported hearing difficulties following excision of vestibular schwannoma.
A new questionnaire, developed to investigate self-reported hearing difficulties in unilateral deafness, was completed by 221 post-surgical vestibular schwannoma patients. Results were compared to a group of 51 normal hearers and 12 patients with severe unilateral deafness from other causes. The vestibular schwannoma patients rated their post surgical hearing as profoundly deaf in the operated ear, and worse than pre-surgical in the other. Factor analysis of the results revealed a general hearing factor and five factors, indirect listening, direct listening, face-to-face listening, noise and distance, and localization, representing performance in specific listening situations. Two factors, direct listening and face-to-face listening have not been commented upon previously in the literature. No differences were found between the hearing-impaired groups on any of the factors. Both groups gave ratings significantly worse than the normal hearers on all factors, and rated themselves worst on indirect listening, in which speech comes from the impaired side. It was concluded that severe unilateral deafness is a significant disability, requiring more attention in clinical practice, particularly with pre-surgical vestibular schwannoma patients.


Molecular pathogenesis of T lymphocyte-induced liver injury in alcoholic hepatitis.
The development of alcohol-induced liver injury is, in part, a consequence of the immunological/inflammatory response that alcohol stimulates. The abnormalities of immune function in heavy drinkers have been documented well. Cytokines, especially TNF alpha, produced from macrophages/Kupffer cells, play a role in the induction of liver cell necrosis and apoptosis. TNF alpha can cause liver cell apoptosis through the TNF alpha receptor or Fas/CD95 which is expressed by liver cells. Furthermore, chronic ethanol consumption may damage the liver by inhibiting the hepatotrophic and hepatoprotective actions of TNF alpha and other cytokines. There exists an intrinsic lymphocyte population in the normal liver. Intrahepatic T lymphocytes consist of a heterogeneous population of cells that has many and varied functional characteristics in addition to classical T cell activity. The population of intrahepatic T lymphocytes may arise via a thymus-independent pathway. Our recent work has demonstrated the role of liver-associated T lymphocytes in the pathogenesis of alcohol related liver injury initiated by a variety of stimuli such as endotoxin (lipopolysaccharide, LPS) or concanavalin A (Con A). Our studies have, for the first time, suggested that alcohol consumption alone does not lead to the development of marked liver necrosis (at least in the rat), but rather that a second insult is required for this to occur. Liver-associated T lymphocytes in rats spontaneously secrete interleukin-1 alpha, interleukin-6 and TNF alpha in vitro culture. There is a significant decline in the amounts of interleukin-1 alpha and TNF alpha secreted in ethanol-consuming rats compared with non-ethanol consuming rats. The numbers of T cells, NK cells and Kupffer cells in liver perfusates remains stable over a prolonged period of ethanol consumption. However, following Con A injection, there was an inappropriate increase in the amounts of interleukin-6 and TNF alpha secreted in in vitro culture of liver-associated T lymphocytes and a significant increase in the percentage of CD4+ T cells and CD25+ T cells in liver perfusates compared with non-ethanol consuming rats. It suggested that liver-associated T lymphocytes are involved in the inflammatory process associated with alcohol related liver injury through increased cytokine secretion (TNF alpha).


[Population analysis of the immune status of immigrants in Far North].
In this article normative parameters of immune status of Nadym population of Yamalo-Nenets Autonomous Okrug are given. Type of immune status with moderate activation of cell part of immunity, humoral suppression and activation of non-specific resistance was determined.


[Effects of glycyrrihizic acid and prednisone on pathological and ultrastructural changes of kidney in rats with chronic aristolochic acid nephropathy].
To investigate the effects of glycyrrihizic acid (GA) and prednisone on renal injury in chronic aristolochic acid nephropathy (AAN) rat model. Ninety-eight male Wistar rats of SPF grade were randomly divided into 4 groups, the normal control group (n = 20), the GA group, the model group, and the prednisone group, 26 rats in each group. Rats in the latter 3 groups were made into AAN model by administration of aristolochic acid (AA, contained in extract of Caulis Aristolochiae Manshuriensis) 20 mg/(kg x d) by gastric gavage, and equal volume of drinking water was given to rats in the control group. Medication was started 2 h later, the GA group was treated with GA 25 mg/(kg x d), the prednisone group with prednisone 3.15 mg/(kg x d), and to the other two groups equal volume of drinking water was given. Body weight was measured weekly, renal function related indices and morphology of the renal tissue were examined at the 4th, 8th and 12th weekend. Along with the feeding time, body weight in the control group increased steadily, while that in the treated groups increased slowly. The ratio of serum creatinine/body weight increased markedly in the model group, while it significantly lowered in the treated groups. Morphological examination showed that the structural injury in the treated groups was milder than that in the model group, and its degree of fibrosis was milder also (15% - 20% vs 30%). Electronmicroscopy showed that AA induced, injury degeneration and necrosis of renal tubular epithelial cells, and markedly injured the cell organs, such as mitochondria, and induced nuclear variation, while in the treated groups, it was mainly limited in renal tubule, with normal cell organs, few nucleolus variation and less interstitial collagen fibers. GA and prednisone could reduce the serum creatinine level, improve renal function, relieve the renal morphological changes, and decrease the inter stitial fibrosis, showing a definite preventing effect on chronic AAN in rats.


Erythroid cells generated in the absence of specific β1-integrin heterodimers accumulate reactive oxygen species at homeostasis and are unable to mount effective antioxidant defenses.
We have previously reported that β1(Δ/Δ) mice have a markedly impaired response to hemolytic stress, but the mechanisms of this were unclear. In the present study we explored in detail quantitative, phenotypic and functional aspects of erythropoiesis at homeostasis in a large number of animals for each of 3 murine models with specific β1 heterodimer integrin deficiencies. We found that, at homeostasis, β1-deficient mice have a modest uncompensated anemia with ineffective erythropoiesis and decreased red blood cell survival. Mice lacking only α4 integrins (α4β1/α4β7) do not share this phenotype. There is an increased tendency for reactive oxygen species accumulation in β1(Δ/Δ) erythroid cells with decreased anti-oxidant defenses at homeostasis which are exaggerated after stress. Furthermore, expansion of erythroid cells in spleen post-stress is dependent on α5β1, likely through mechanisms activating focal adhesion kinase complexes that are distinct from α4β1-mediated responses. In vivo inhibition of focal adhesion kinase activation partially recapitulates the β1(Δ/Δ) stress response. Mice lacking all α4 and β1 integrins (double knockouts) had, at homeostasis, the most severe phenotype with selective impairment of erythroid responses. The fact that integrins participate in mitigating stress in erythroid cells through redox activation of distinct signaling pathways by specific integrin heterodimers is a link that has not been appreciated until now.


Audiological tests for evaluation of central auditory disorders.
Three audiological tests (Competing Sentences, Rapidly Alternating Speech, Staggered Spondaic Words) currently being used to evaluate central auditory dysfunction are discussed. Audiological and neurological findings on three patients with central auditory lesions are presented, with special reference to their performance on these central auditory tests. Results suggest the tests are of value in identifying and/or corroborating central lesions, and in providing a more complete explanation of patient communicative difficulties.


Action at a distance for negative control of transcription of the glpD gene encoding sn-glycerol 3-phosphate dehydrogenase of Escherichia coli K-12.
Aerobic sn-glycerol 3-phosphate dehydrogenase is a cytoplasmic membrane-associated respiratory enzyme encoded by the glpD gene of Escherichia coli. The glpD operon is tightly controlled by cooperative binding of the glp repressor to tandem operators (O(D)1 and O(D)2) that cover the -10 promoter element and 30 bp downstream of the transcription start site. In this work, two additional operators were identified within the glpD structural gene at positions 568 to 587 (0(D)3) and 609 to 628 (0(D)4). The two internal operators bound the glp repressor in the presence or absence of the tandem operators (O(D)1 and O(D)2) in vitro, as shown by DNase I footprinting. To assess a potential regulatory role for the two internal operators in vivo, a glpD-lacZ transcriptional fusion containing all four operators was constructed. The response of this fusion to the glp repressor was compared with those of fusion constructs in which O(D)3 and O(D)4 were inactivated by either deletion or site-directed mutagenesis. It was found that the repression conferred by binding of the glp repressor to O(D)1 and O(D)2 was increased five- to sevenfold upon introduction of the internal operators. A regulatory role for HU was suggested when it was found that repressor-mediated control of glpD transcription was increased fourfold in strains containing HU compared with that of strains deficient in HU. The effect of HU was apparent only in the presence of all four glpD operators. The results suggest that glpD is controlled by formation of a repression loop between the tandem and internal operators. HU may assist repression by bending the DNA to facilitate loop formation.


Cavitation-Induced Synthesis of Biogenic Molecules on Primordial Earth.
Despite decades of research, how life began on Earth remains one of the most challenging scientific conundrums facing modern science. It is agreed that the first step was synthesis of organic compounds essential to obtain amino acids and their polymers. Several possible scenarios that could accomplish this step, using simple inorganic molecules, have been suggested and studied over the years. The present study examines, using atomistic reactive molecular dynamics simulations, the long-standing suggestion that natural cavitation in primordial oceans was a dominant mechanism of organic molecule synthesis. The simulations allow, for the first time, direct observation of the rich and complex sonochemistry occurring inside a collapsing bubble filled with water and dissolved gases of the early atmosphere. The simulation results suggest that dissolved CH4 is the most efficient carbon source to produce amino acids, while CO and CO2 lead to amino acid synthesis with lower yields. The efficiency of amino acid synthesis also depends on the nitrogen source used (i.e., N2, NH3) and on the presence of HCN. Moreover, cavitation may have contributed to the increase in concentration of NH3 in primordial oceans and to the production and liberation of molecular O2 into the early atmosphere. Overall, the picture that emerges from the simulations indicates that collapsing bubbles may have served as natural bioreactors in primordial oceans, producing the basic chemical ingredients required for the beginning of life.


Intestinal ferritin H is required for an accurate control of iron absorption.
To maintain appropriate body iron levels, iron absorption by the proximal duodenum is thought to be controlled by hepcidin, a polypeptide secreted by hepatocytes in response to high serum iron. Hepcidin limits basolateral iron efflux from the duodenal epithelium by binding and downregulating the intestinal iron exporter ferroportin. Here, we found that mice with an intestinal ferritin H gene deletion show increased body iron stores and transferrin saturation. As expected for iron-loaded animals, the ferritin H-deleted mice showed induced liver hepcidin mRNA levels and reduced duodenal expression of DMT1 and DcytB mRNA. In spite of these feedback controls, intestinal ferroportin protein and (59)Fe absorption were increased more than 2-fold in the deleted mice. Our results demonstrate that hepcidin-mediated regulation alone is insufficient to restrict iron absorption and that intestinal ferritin H is also required to limit iron efflux from intestinal cells.


Bibliometric analysis of global research on the rehabilitation of spinal cord injury in the past two decades.
We aimed to build a model to qualitatively and quantitatively evaluate publications of research of spinal cord injury rehabilitation from 1997 to 2016. Data were obtained from the Web of Science Core Collection on October 6, 2017. We conducted a qualitative and quantitative analysis of publication outputs, journals, authors, institutions, countries, cited references, keywords, and terms by bibliometric methods and bibliometric software packages. We identified 5,607 publications on rehabilitation of spinal cord injury from 1997 to 2016, and found that the annual publication rate increased with time. The Archives of Physical Medicine and Rehabilitation published the largest number of literature, the most active country was USA, the most active institution was University of Washington, and Post MWM was the leading author. Keyword analysis indicated that life satisfaction, muscle strength, wheelchair training, walking, gait, and others were the hot spots of these research studies, whereas classification, exoskeleton, plasticity, and old adult were research frontiers. This bibliometric study revealed that research on rehabilitation of spinal cord injury is a well-developed and promising research field. Global scientific research cooperation is close. However, higher quality research is needed. Our findings provide valuable information for researchers to identify better perspectives and develop the future research direction.


New anti-SARS-CoV-2 aminoadamantane compounds as antiviral candidates for the treatment of COVID-19.
Here, the antiviral activity of aminoadamantane derivatives were evaluated against SARS-CoV-2. The compounds exhibited low cytotoxicity to Vero, HEK293 and CALU-3 cells up to a concentration of 1,000 µM. The inhibitory concentration (IC50) of aminoadamantane was 39.71 µM in Vero CCL-81 cells and the derivatives showed significantly lower IC50 values, especially for compounds 3F4 (0.32 µM), 3F5 (0.44 µM) and 3E10 (1.28 µM). Additionally, derivatives 3F5 and 3E10 statistically reduced the fluorescence intensity of SARS-CoV-2 protein S from Vero cells at 10 µM. Transmission microscopy confirmed the antiviral activity of the compounds, which reduced cytopathic effects induced by the virus, such as vacuolization, cytoplasmic projections, and the presence of myelin figures derived from cellular activation in the face of infection. Additionally, it was possible to observe a reduction of viral particles adhered to the cell membrane and inside several viral factories, especially after treatment with 3F4. Moreover, although docking analysis showed favorable interactions in the catalytic site of Cathepsin L, the enzymatic activity of this enzyme was not inhibited significantly in vitro. The new derivatives displayed lower predicted toxicities than aminoadamantane, which was observed for either rat or mouse models. Lastly, in vivo antiviral assays of aminoadamantane derivatives in BALB/cJ mice after challenge with the mouse-adapted strain of SARS-CoV-2, corroborated the robust antiviral activity of 3F4 derivative, which was higher than aminoadamantane and its other derivatives. Therefore, aminoadamantane derivatives show potential broad-spectrum antiviral activity, which may contribute to COVID-19 treatment in the face of emerging and re-emerging SARS-CoV-2 variants of concern.


Injury-related spinal cord astrocytes are immunoglobulin-positive (IgM and/or IgG) at different time periods in the regenerative process.
IgG-positive astrocytes have been reported in scrapie-induced and Alzheimer's cortical plaques, multiple sclerosis, and CNS tissue around abscesses, metastatic tumors and primary tumors of glial origin. The present experiments ascertain if this immunoglobulin positivity is specific for these cases or a function of astrocytes around any site of injury in the CNS. The spinal cords of 30, 300-g Sprague-Dawley male rats were lesioned by passing a 26 gauge needle through the cord at T6. After periods as long as 9 months, the spinal cords were processed for paraffin immunohistochemistry with antisera to IgM, IgG or double labeled for these immunoglobulins and GFAP (glial fibrillary acidic protein) a specific cytoplasmic marker for astrocytes. From 1 through 7 days after lesioning double labeled astrocytes in and around the site of injury are both IgM- and IgG-positive. From 14 days through 9 months postlesion, double labeled astrocytes surrounding the lesion are only positive for IgG. These data indicate a relationship between immunoglobulin availability, continued blood-brain barrier perturbation to immunoglobulins and the ability of reactive astrocytes to sequestor immunoglobulins. IgM is an early determinant for reactive astrocytes and IgG positivity is determinant for reactive astrocytes at any time period.


Differences in rural and urban driver-injury severities in accidents involving large-trucks: an exploratory analysis.
This study explores the differences between urban and rural driver injuries (both passenger-vehicle and large-truck driver injuries) in accidents that involve large trucks (in excess of 10,000 pounds). Using 4 years of California accident data, and considering four driver-injury severity categories (no injury, complaint of pain, visible injury, and severe/fatal injury), a multinomial logit analysis of the data was conducted. Significant differences with respect to various risk factors including driver, vehicle, environmental, road geometry and traffic characteristics were found to exist between urban and rural models. For example, in rural accidents involving tractor-trailer combinations, the probability of drivers' injuries being severe/fatal increased about 26% relative to accidents involving single-unit trucks. In urban areas, this same probability increased nearly 700%. In accidents where alcohol or drug use was identified as being the primary cause of the accident, the probability of severe/fatal injury increased roughly 250% percent in rural areas and nearly 800% in urban areas. While many of the same variables were found to be significant in both rural and urban models (although often with quite different impact), there were 13 variables that significantly influenced driver-injury severity in rural but not urban areas, and 17 variables that significantly influenced driver-injury severity in urban but not rural areas. We speculate that the significant differences between rural and urban injury severities may be at least partially attributable to the different perceptual, cognitive and response demands placed on drivers in rural versus urban areas.


Effects of Early Nutrition on the Infant Metabolome.
Breastfeeding induces a different metabolic and endocrine response than feeding conventional infant formula, and it has also been associated with slower weight gain and reduced disease risk in later life. The underlying programming mechanisms remain to be explored. Breastfeeding has been reported to induce lower levels of insulin, insulin-like growth factor-1 and some amino acids (AAs) than formula feeding. In the Childhood Obesity Project (CHOP), infants fed a conventional protein-rich formula had a higher BMI at 2 and 6 years than those fed a protein-reduced formula. At 6 months, higher protein intakes induced increased plasma concentrations of branched-chain AAs (BCAAs) and their oxidation products, short-chain acylcarnitines. With increasing BCAA levels, these short-chain acylcarnitines increased proportionally only until a break point was reached, after which BCAAs seemed to escape their degradation. The resulting marked elevation in BCAA levels with high-protein (HP) intakes appears to contribute to increased insulin levels and to affect β-oxidation of fatty acids. The ratios of long-chain acylcarnitines to free carnitine decreased in infants who received a HP formula, which indicates a reduced initiation of β-oxidation. We conclude that HP intakes inducing high BCAA plasma levels may inhibit fat oxidation and thereby enhance body fat deposition and adiposity.


[Mesenteric cryptococcal lymphadenitis: report of one case].
Cryptococcosis is an invasive mycotic infection caused by Cryptococcus neoformans, an encapsulated, yeast-like fungus. It is considered an opportunist infection, since it mainly affects immunocompromised subjects. However there are isolated reports of the infection in immunocompetent subjects. Cryptococcal infection of intra-abdominal organs or tissues is extremely rare. We report a 21-year-old HIV positive male that, during the treatment of a meningeal cryptococcosis, presented a clinical picture of an acute abdomen suggesting acute appendicitis. The patient was operated, finding enlarged mesenteric lymph nodes forming conglomerates and a macroscopically normal appendix. The conglomerated lymph nodes and the appendix were excised. The pathological study of the surgical piece revealed an intra abdominal cryptococcal lymphadenitis and a normal appendix.


Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of l-DOPA-induced dyskinesia.
Opioid receptor-binding autoradiography was used as a way to map sites of altered opioid transmission in a rat model of l-DOPA-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathways sustained a 3-week treatment with l-DOPA (6 mg/kg/day, combined with 12 mg/kg/day benserazide), causing about half of them to develop dyskinetic-like movements on the side of the body contralateral to the lesion. Autoradiographic analysis of mu-, delta-, and kappa-opioid binding sites was carried out in the caudate-putamen (CPu), the globus pallidus (GP), the substantia nigra (SN), the primary motor area, and the premotor-cingulate cortex. The dopamine-denervating lesion alone caused an ipsilateral reduction in opioid radioligand binding in the CPu, GP, and SN, but not in the cerebral cortex. Chronic l-DOPA treatment affected opioid receptor binding in both the basal ganglia and the cerebral cortex, producing changes that were both structure- and receptor-type specific, and closely related to the motor response elicited by the treatment. In the basal ganglia, the most clear-cut differences between dyskinetic and nondyskinetic rats pertained to kappa opioid sites. On the lesioned side, both striatal and nigral levels of kappa binding densities were significantly lower in the dyskinetic group, showing a negative correlation with the rats' dyskinesia scores on one hand and with the striatal expression of opioid precursor mRNAs on the other hand. In the cerebral cortex, levels of mu and delta binding site densities were bilaterally elevated in the dyskinetic group, whereas kappa radioligand binding was specifically increased in the nondyskinetic cases and showed a negative correlation with the rats' dyskinesia scores. These data demonstrate that bilateral changes in cortical opioid transmission are closely associated with l-DOPA-induced dyskinesia in the rat. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in opioid radioligand binding suggests that the motor response to l-DOPA is determined, at least in part, by compensatory adjustments of brain opioid receptors.


Sterols of Pneumocystis carinii hominis organisms isolated from human lungs.
The opportunistic pathogen Pneumocystis carinii causes pneumonia (P. carinii pneumonia, or PCP) in immunocompromised individuals such as AIDS patients. Rat-derived P. carinii carinii organisms have distinct sterols which are not synthesized by mammals and not found in other microbes infecting mammalian lungs. The dominant sterol present in the organism is cholesterol (which is believed to be scavenged from the host), but other sterols in P. carinii carinii have an alkyl group at C-24 of the sterol side chain (C(28) and C(29) 24-alkylsterols) and a double bond at C-7 of the nucleus. Recently, pneumocysterol (C(32)), which is essentially lanosterol with a C-24 ethylidene group, was detected in lipids extracted from a formalin-fixed human P. carinii-infected lung, and its structures were elucidated by gas-liquid chromatography, mass spectrometry, and nuclear magnetic resonance spectrometry in conjunction with analyses of chemically synthesized authentic standards. The sterol composition of isolated P. carinii hominis organisms has yet to be reported. If P. carinii from animal models is to be used for identifying potential drug targets and for developing chemotherapeutic approaches to clear human infections, it is important to determine whether the 24-alkylsterols of organisms found in rats are also present in organisms in humans. In the present study, sterol analyses of P. carinii hominis organisms isolated from cryopreserved human P. carinii-infected lungs and from bronchoalveolar lavage fluid were performed. Several of the same distinct sterols (e.g., fungisterol and methylcholest-7-ene-3beta-ol) previously identified in P. carinii carinii were also present in organisms isolated from human specimens. Pneumocysterol was detected in only some of the samples.


[Pregnancy following renal transplants (author's transl)].
Women with uremia are usually infertile. Following successful renal transplants ovarian function resumes and conception becomes possible. Two cases of pregnancy following renal transplants are reported. The first patient had a Caesarean section at 33 weeks gestation for maternal indications, the second patient had a Caesarean section at 36 weeks gestation because of premature spontaneous rupture of the membranes. Both mothers and infants are in satisfactory condition. The problems of pregnancies following renal transplants are discussed and the literature since 1963 is reviewed. Pregnancy following renal transplantation is a high risk pregnancy for both the mother and the fetus. These high risks are acceptable if close supervision of the pregnancy by the nephrologist, gynaecologist and paediatrician are possible and if co-operation of the mother is satisfactory.


Intensity-modulated Radiation Therapy for Anal Cancer: Results From a Multi-Institutional Retrospective Cohort Study.
To assess toxicity and efficacy of intensity-modulated radiation therapy (IMRT) for anal cancer. Records of 152 patients were reviewed retrospectively from multiple institutions. Data on disease control and toxicity were collected as well as patient and treatment characteristics. Acute (<6 mo) and late (≥6 mo) severe toxicity (grade ≥3) were graded. Four patients were excluded due to the presence of metastatic disease or stage TX. Late toxicity data were available for 120 patients. Median cumulative IMRT dose was 51.25 Gy (median, 28 fractions). All but 2 patients received chemotherapy. With median follow-up of 26.8 months, local control at 3 years was 87%, worse for patients with T3-T4 than T1-T2 disease on univariate analysis (79% vs. 90%; P=0.04). Regional control, distant control, and overall survival were 97%, 91%, and 87%, respectively, at 3 years. Nodal status was associated with regional control, distant control, and overall survival (P<0.01 for each). Most common severe acute toxicity was hematologic (41%), skin (20%), and gastrointestinal tract (11%). Two grade 5 toxicities occurred (hematologic and gastrointestinal tract). Severe late toxicity affected skin (1%) and gastrointestinal tract (3%). IMRT with chemotherapy resulted in excellent local control. Although T stage predicted worse local control, most T3-T4 disease was controlled with IMRT. Nodal status predicted regional and distant control and overall survival. Severe toxicity was acceptable.


Disappearance of PML/RAR alpha acute promyelocytic leukemia-associated transcript during consolidation chemotherapy.
Acute promyelocytic leukemia (APL) (M3 according to FAB classification) is a subtype of acute myelogenous leukemia characterized by a specific t(15;17) (q22;q12) chromosomal translocation. The majority of APL patients achieve morphologic remission after induction chemotherapy. They can be followed from this point by cytogenetic and molecular analysis of the persistence of the PML/RAR alpha transcript. In order to determine the influence of successive courses of consolidation chemotherapy on clinical and molecular outcome, APL patients treated with all-trans retinoic acid (ATRA) and chemotherapy (AIDA-GIMEMA-LAP0493 protocol) were investigated. Twenty-four APL patients (pts) (15 males; 9 females) were studied by RT-PCR and cytogenetic analysis at diagnosis, after induction chemotherapy, at each point after any of three consolidation courses, and every 3 months during the first years of maintenance therapy. The median follow-up was 24 months (mths) (range 7-40 mths). All pts achieved hematologic remission after induction chemotherapy. Our results demonstrate that the majority (87%) of APL patients were still molecularly positive for the APL associated transcript after induction chemotherapy, while the majority (80%) of APL patients became PCR-after the second consolidation chemotherapy. The role of the third consolidation chemotherapy course in converting patients with persistent molecular evidence of disease from PCR+ to PCR- was minimal. We confirm the validity of molecular follow-up after single courses of chemotherapy in monitoring the role of molecular remission.


Oral and dental health status in patients with primary antibody deficiencies.
Primary antibody deficiencies (PAD) are a group of immune system disorders, associated with decreased levels of secretory and protective immunoglobulins. Because of the important role of immunoglobulins in the protection of oral cavity, patients with PADs are more susceptible to dental caries or oral manifestations. This study was performed to investigate the oral and dental manifestations of PADs patients. In this study, 33 patients with PADs (21 common variable immunodeficiency, 8 X-linked agammaglobulinemia and 4 hyper IgM syndrome) and 66 controls were examined; the number of decayed, missed and filled teeth (DMFT) were investigated. Aphthous was the most frequent manifestation in PADs patients (38.7%), which was significantly 16.7% higher than the controls (p=0.03). The patients with PADs showed significantly higher presentation of other oral and dental manifestations, including herpes sores, candidiasis tonsillitis, gingivitis, calculus, enamel hypoplasia and other ulcerations. The mean DMFT scores were 6.15±3.6 and 1.93±0.4 in PADs patients and controls, respectively (p<0.001). Although the patients with common variable immunodeficiency had higher means of DMFT in comparison with other groups of PADs, this difference was not statistically significant. This study showed significantly higher frequency of oral and dental manifestations in the patients with PADs compared to controls. Therefore, regular examination of oral cavity could be suggested in this group of immunodeficient patients.


Assessment of Birmingham medical students.
At Birmingham University since 1966 the major medical examinations began to be replaced by a process of continuous assessment. This is based on fairly frequent tests, usually at the end of each course, including short essay questions, multiple-choice questions, and tests of ability in wards and laboratory. At the end of the first final-year course 96 students underwent assessment. Of these 77 passed; 19 were referred for re-examination, of whom a further 12 passed subsequently. The scheme was found suitable by both teachers and external examiners.


Walking, cycling and transport safety: an analysis of child road deaths.
To examine trends in road death rates for child pedestrians, cyclists and car occupants. Analysis of road traffic injury death rates per 100 000 children and death rates per 10 million passenger miles travelled. England and Wales between 1985 and 2003. Children aged 0-14 years. None. Death rates per 100,000 children and per 10 million child passenger miles for pedestrians, cyclists and car occupants. Death rates per head of population have declined for child pedestrians, cyclists and car occupants but pedestrian death rates remain higher (0.55 deaths/100,000 children; 95% confidence interval [CI] 0.42 to 0.72 deaths) than those for car occupants (0.34 deaths; 95% CI 0.23 to 0.48 deaths) and cyclists (0.16 deaths; 95% CI 0.09 to 0.27 deaths). Since 1985, the average distance children travelled as a car occupant has increased by 70%; the average distance walked has declined by 19%; and the average distance cycled has declined by 58%. Taking into account distance travelled, there are about 50 times more child cyclist deaths (0.55 deaths/10 million passenger miles; 0.32 to 0.89) and nearly 30 times more child pedestrian deaths (0.27 deaths; 0.20 to 0.35) than there are deaths to child car occupants (0.01 deaths; 0.007 to 0.014). In 2003, children from families without access to a vehicle walked twice the distance walked by children in families with access to two or more vehicles. More needs to be done to reduce the traffic injury death rates for child pedestrians and cyclists. This might encourage more walking and cycling and also has the potential to reduce social class gradients in injury mortality.


The Infernal Alternatives of Corporate Pharmaceutical Research: Abandoning Psychiatry.
What happens when health research is measured by market size? How does this change the dynamics of medical research, and how is its growth envisioned and managed? In this article, I build on my arguments in Drugs for Life: How Pharmaceutical Companies Define our Health, which focused primarily on the development and marketing of mass medications for heart disease and I examine the market dynamics that are used to drive research into and out of psychiatric and other neuromedicines, such as the closing of mental health research at most major pharmaceutical companies. Industry compares entire sectors of medical research to evaluate their relative chances of profits and growth; it is willing to sacrifice a whole region of effective and profitable medicine if it can grow profits more in other regions. Baudrillard, Pignarre, and Stengers are used to consider whether this situation can best be described as one of infernal alternatives, and how to analyze the responses of psychiatric leaders.


Stability and function of secondary Th1 memory cells are dependent on the nature of the secondary stimulus.
Following acute infection in some mouse models, CD4+ memory T cells steadily decline over time. Conversely, in humans, CD4+ memory T cells can be maintained for many years at levels similar to CD8+ T cells. Because we previously observed that the longevity of Th1 memory cell survival corresponded to their functional avidity, we hypothesized that secondary challenge, which enriches for high functional avidity Th1 responders, would result in more stable Th1 memory populations. We found that following a heterologous secondary challenge, Th1 memory cells were maintained at stable levels compared with primary Th1 memory cells, showing little to no decline after day 75 postinfection. The improved stability of secondary Th1 memory T cells corresponded to enhanced homeostatic turnover; enhanced trafficking of effector memory Th1 cells to tissue sites of infection, such as the liver; and acquisition or maintenance of high functional avidity following secondary challenge. Conversely, a weaker homologous rechallenge failed to induce a stable secondary Th1 memory population. Additionally, homologous secondary challenge resulted in a transient loss of functional avidity by Th1 memory cells recruited into the secondary response. Our findings suggest that the longevity of Th1 memory T cells is dependent, at least in part, on the combined effects of primary and secondary Ag-driven differentiation. Furthermore, they demonstrate that the quality of the secondary challenge can have profound effects on the longevity and function of the ensuing secondary Th1 memory population.


Effects of sound energy on proteins and their complexes.
Mechanical energy in the form of ultrasound and protein complexes intuitively have been considered as two distinct unrelated topics. However, in the past few years, increasingly more attention has been paid to the ability of ultrasound to induce chemical modifications on protein molecules that further change protein-protein interaction and protein self-assembling behavior. Despite efforts to decipher the exact structure and the behavior-modifying effects of ultrasound on proteins, our current understanding of these aspects remains limited. The limitation arises from the complexity of both phenomena. Ultrasound produces multiple chemical, mechanical, and thermal effects in aqueous media. Proteins are dynamic molecules with diverse complexation mechanisms. This review provides an exhaustive analysis of the progress made in better understanding the role of ultrasound in protein complexation. It describes in detail how ultrasound affects an aqueous environment and the impact of each effect separately and when combined with the protein structure and fold, the protein-protein interaction, and finally the protein self-assembly. It specifically focuses on modifying role of ultrasound in amyloid self-assembly, where the latter is associated with multiple neurodegenerative disorders.


Hypoxia/reoxygenation cardiac injury and regeneration in zebrafish adult heart.
the adult zebrafish heart regenerates spontaneously after injury and has been used to study the mechanisms of cardiac repair. However, no zebrafish model is available that mimics ischemic injury in mammalian heart. We developed and characterized zebrafish cardiac injury induced by hypoxia/reoxygenation (H/R) and the regeneration that followed it. adult zebrafish were kept either in hypoxic (H) or normoxic control (C) water for 15 min; thereafter fishes were returned to C water. Within 2-6 hours (h) after reoxygenation there was evidence of cardiac oxidative stress by dihydroethidium fluorescence and protein nitrosylation, as well as of inflammation. We used Tg(cmlc2:nucDsRed) transgenic zebrafish to identify myocardial cell nuclei. Cardiomyocyte apoptosis and necrosis were evidenced by TUNEL and Acridine Orange (AO) staining, respectively; 18 h after H/R, 9.9±2.6% of myocardial cell nuclei were TUNEL(+) and 15.0±2.5% were AO(+). At the 30-day (d) time point myocardial cell death was back to baseline (n = 3 at each time point). We evaluated cardiomyocyte proliferation by Phospho Histone H3 (pHH3) or Proliferating Cell Nuclear Antigen (PCNA) expression. Cardiomyocyte proliferation was apparent 18-24 h after H/R, it achieved its peak 3-7d later, and was back to baseline at 30d. 7d after H/R 17.4±2.3% of all cardiomyocytes were pHH3(+) and 7.4±0.6% were PCNA(+) (n = 3 at each time point). Cardiac function was assessed by 2D-echocardiography and Ventricular Diastolic and Systolic Areas were used to compute Fractional Area Change (FAC). FAC decreased from 29.3±2.0% in normoxia to 16.4±1.8% at 18 h after H/R; one month later ventricular function was back to baseline (n = 12 at each time point). zebrafish exposed to H/R exhibit evidence of cardiac oxidative stress and inflammation, myocardial cell death and proliferation. The initial decrease in ventricular function is followed by full recovery. This model more closely mimics reperfusion injury in mammals than other cardiac injury models.


Weight change and its correlates among breast cancer survivors.
We assessed weight change from diagnosis to approximately 18 mo after cancer diagnosis and evaluated its correlates in a large, population-based, cohort study of women diagnosed with stage 0-IV breast cancer. A total of 4,561 cases with weight information 1 yr prior to diagnosis, at diagnosis, and at the 18-mo postdiagnosis interview were included in the study. Multinomial logistic regression models were conducted to examine the association of weight change from diagnosis to 18 mo after diagnosis with sociodemographic, clinical, and lifestyle factors. The mean weight change from diagnosis to 18 mo after diagnosis was a gain of 1.7 kg (median: 2.0). Overall, 61% of women gained weight, 27% gained 2-5 kg, and 24% gained ≥5 kg, while approximately 14% lost >2 kg during the 18-mo postdiagnosis period. Greater weight gain was significantly related to younger age, premenopausal status, mixed receptor status, more advanced disease stage, prediagnosis weight loss, higher dietary intake, and cigarette smoking. Women with obesity and serious comorbidity were more likely to lose weight. Moderate exercise was not significantly related to weight change. Weight gain is common among breast cancer survivors. Sociodemographic, clinical, and lifestyle factors are related to weight change. Appropriate intervention strategies should be developed.


[Do obstetric complications increase the risk of schizophrenia?].
Schizophrenia is a serious mental disease of unknown aetiology. Genetic liability is the most important risk factor. Several studies have demonstrated that pre and perinatal complications/traumas are associated with an increased risk of developing schizophrenia in adult age. The purpose of this article is to provide an overview of research on obstetric complications as risk factors for schizophrenia. The article is based on literature identified through non-systematic searches in the databases PubMed and Embase. The putative association between obstetric complications and schizophrenia has been investigated for almost 80 years. Numerous controlled studies have found that maternal infection (influenza, rubella, toxoplasmosis), prenatal malnutrition and birth-associated complications (such as low birth weight and asphyxia) are associated with an increased risk of developing schizophrenia. Experiments in animal models suggest that foetal hypoxia and maternal inflammatory responses may affect neuronal development. However, underlying pathophysiological mechanisms and modes of interaction with schizophrenia susceptibility genes are unknown. An association between obstetric complications and an increased risk of schizophrenia is strongly supported by scientific evidence.


Quantitative imaging biomarkers: a review of statistical methods for technical performance assessment.
Technological developments and greater rigor in the quantitative measurement of biological features in medical images have given rise to an increased interest in using quantitative imaging biomarkers to measure changes in these features. Critical to the performance of a quantitative imaging biomarker in preclinical or clinical settings are three primary metrology areas of interest: measurement linearity and bias, repeatability, and the ability to consistently reproduce equivalent results when conditions change, as would be expected in any clinical trial. Unfortunately, performance studies to date differ greatly in designs, analysis method, and metrics used to assess a quantitative imaging biomarker for clinical use. It is therefore difficult or not possible to integrate results from different studies or to use reported results to design studies. The Radiological Society of North America and the Quantitative Imaging Biomarker Alliance with technical, radiological, and statistical experts developed a set of technical performance analysis methods, metrics, and study designs that provide terminology, metrics, and methods consistent with widely accepted metrological standards. This document provides a consistent framework for the conduct and evaluation of quantitative imaging biomarker performance studies so that results from multiple studies can be compared, contrasted, or combined.


Imaging detection of endolymphatic sac tumor-associated hydrops.
To determine if physiologically based MRI sequences can be used to detect endolymphatic sac tumor (ELST)-associated hydrops, the authors performed contrast-enhanced delayed FLAIR imaging in consecutive ELST patients with clinical findings consistent with hydrops. Consecutive patients with von Hippel-Lindau (VHL) disease and clinical findings of endolymphatic hydrops and ELSTs underwent contrast-enhanced delayed FLAIR MRI. Clinical, audiological, operative, and imaging findings were analyzed. Three patients (2 male, 1 female) with 4 ELSTs (1 patient had bilateral ELSTs) were identified who had clinical findings consistent with endolymphatic hydrops. Computed tomography and MRI evidence of an ELST was found in all patients. Their mean age at initial evaluation was 39.7 years (range 28-51 years). All patients demonstrated progressive sensorineural hearing loss that was associated with episodic vertigo and tinnitus. Contrast-enhanced delayed FLAIR MRI clearly demonstrated dilation of the membranous labyrinth consistent with hydrops in the affected ears but not the unaffected ears. Two patients underwent resection of the associated ELST that resulted in stabilization of progressive hearing loss, as well as amelioration of tinnitus and vertigo. Contrast-enhanced delayed FLAIR MRI can be used to detect ELST-associated hydrops. Noninvasive MRI detection of hydrops can permit earlier detection of ELSTs in patients with VHL disease and provides direct insight into a mechanism that underlies ELST-associated audiovestibular morbidity.


Categorizing Susceptibility of Clinical Isolates of Candida auris to Amphotericin B, Caspofungin, and Fluconazole by Use of the CLSI M44-A2 Disk Diffusion Method.
We evaluated the CLSI M44ed3E disk diffusion method compared with the CLSI M27ed4 broth microdilution method for caspofungin and fluconazole and the Etest method for amphotericin B to categorize susceptibility of 347 clinical isolates of Candida auris Utilizing the zone diameter cutoffs established here, we observed overall categorical agreement between the two methods. For caspofungin, concordant results were observed for 98% of isolates, with <1% very major and 1% major errors. For fluconazole, concordant results were observed for 91% of isolates, with 1% very major and 8% major errors. For amphotericin B, concordant results were observed for 74% of isolates, with <1% very major errors and 25% major errors. The disk diffusion approach provides an accurate method for determining the susceptibility of C. auris for caspofungin and fluconazole and for identification of at least 75% of amphotericin B-susceptible isolates.


[Fatty acid complex "bien" incorporation into liposomes multilayered].
The conditions of fatty acid complex "bien" incorporation into multilayered liposomes prepared by mechanical dispersion techniques (vortexing) have been investigated. Drug incorporation depends on the lipid composition used to prepare the vesicles, overall lipid and "bien" concentrations and the presence of an antioxidant. Vortexing and incubation regimes for the homogeneous liposomal suspension were determined. The effects of contents of DL-alpha-tocopherol and cholesterol on lipid peroxidation were evaluated.


Nonlinear actuation of micromechanical Casimir oscillators with topological insulator materials toward chaotic motion: Sensitivity on magnetization and dielectric properties.
We have investigated the dynamical actuation of micro-electromechanical systems under the influence of attractive and repulsive Casimir forces between topological insulator plates as a function of their dielectric function and coating magnetization. The analysis of the Casimir force in the limit of strong and weak magnetization shows that the attractive force, which is produced for plate magnetizations in the same direction, is greater than the repulsive force that is produced for opposite magnetizations. However, both forces remain comparable for intermediate magnetizations. Moreover, for weak magnetization, the attractive force becomes stronger for an increasing dielectric function, while the opposite occurs for the repulsive force. On the other hand, increasing magnetization decreases the influence of the dielectric function on both the repulsive and attractive forces. Furthermore, for conservative systems, bifurcation and phase portrait analysis revealed that increasing magnetization decreases the regime of stable operation for devices with attractive forces, while their operation remains always stable under the presence of repulsive forces. Finally, for non-conservative periodically driven systems, the Melnikov function and Poincaré portrait analysis show that for magnetizations in the same direction leading to strong attractive Casimir forces, chaotic motion toward stiction is highly likely to occur preventing the long-term prediction of actuating dynamics. A remedy for this situation is obtained by the application of any magnetization in opposite directions between the interacting surfaces since the repulsive force makes it possible to prevent stiction.


Hypervariations of a protease-encoding gene, PD0218 (pspB), in Xylella fastidiosa strains causing almond leaf scorch and Pierce's disease in California.
Xylella fastidiosa is a gram-negative plant pathogenic bacterium that causes almond leaf scorch disease (ALSD) and Pierce's disease (PD) of grape in many regions of North America and Mexico. Of the two 16S rRNA gene genotypes described in California, A genotype strains cause ALSD only and G genotype strains cause both PD and ALSD. While G genotype strains cause two different diseases, little is known about their genetic variation. In this study, we identified a putative protease locus, PD0218 (pspB), in the genome of X. fastidiosa and evaluated the variation at this locus in X. fastidiosa populations. PD0218 contains tandem repeats of ACDCCA, translated to threonine and proline (TP), upstream of the putative protease conserved domain. Among 116 X. fastidiosa ALSD and PD strains isolated from seven locations in California, tandem repeat numbers (TRNs) varied from 9 to 47, with a total of 30 TRN genotypes, indicating that X. fastidiosa possesses an active mechanism for contracting and expanding tandem repeats at this locus. Significant TRN variation was found among PD strains (mean = 29.9), which could be further divided into two TRN groups: PD-G(small) (mean = 17.3) and PD-G(large) (mean = 44.3). Less variation was found in ALSD strains (mean = 21.7). The variation was even smaller after ALSD strains were subdivided into the A and G genotypes (mean = 13.3, for the G genotype; mean = 27.1, for the A genotype). Genetic variation at the PD0218 locus is potentially useful for sensitive discrimination of X. fastidiosa strains. However, TRN stability, variation range, and correlation to phenotypes should be evaluated in epidemiological applications such as pathotype identification and delineation of pathogen origin.


Nitric oxide binds to the proximal heme coordination site of the ferrocytochrome c/cardiolipin complex: formation mechanism and dynamics.
Mammalian mitochondrial cytochrome c interacts with cardiolipin to form a complex (cyt. c/CL) important in apoptosis. Here we show that this interaction leads to structural changes in ferrocytochrome c that leads to an open coordinate site on the central iron, resulting from the dissociation of the intrinsic methionine residue, where NO can rapidly bind (k = 1.2 x 10(7) m(-1) s(-1)). Accompanying NO binding, the proximal histidine dissociates leaving the heme pentacoordinate, in contrast to the hexacoordinate nitrosyl adducts of native ferrocytochrome c or of the protein in which the coordinating methionine is removed by chemical modification or mutation. We present the results of stopped-flow and photolysis experiments that show that following initial NO binding to the heme, there ensues an unusually complex set of kinetic steps. The spectral changes associated with these kinetic transitions, together with their dependence on NO concentration, have been determined and lead us to conclude that NO binding to cyt. c/CL takes place via an overall scheme comparable to that described for cytochrome c' and guanylate cyclase, the final product being one in which NO resides on the proximal side of the heme. In addition, novel features not observed before in other heme proteins forming pentacoordinate nitrosyl species, include a high yield of NO escape after dissociation, rapid (<1 ms) dissociation of proximal histidine upon NO binding and its very fast binding (60 ps) after NO dissociation, and the formation of a hexacoordinate intermediate. These features all point at a remarkable mobility of the proximal heme environment induced by cardiolipin.


Adolescent girls in context: Not all patterns may be created equal.
Much research exists on the importance of risk factors within individual contexts of parenting, neighborhood, school, and peers for adolescent development. However little exists on whether risks in certain contexts may be more or less likely for risk accumulation across contexts - referred to as the Weighted Risk Phenomenon (WRP). One way to study WRP is to study adolescent patterns of co-existing risk characteristics across domains and over time. The present study focuses on studying information about parenting, neighborhood, school, and peers in order to understand how risk can have different patterns over time. Participants were all girls recruited from junior high schools in rural and metropolitan areas of Sweden. The results illustrate that there are stable structural and individual pathways across four contexts of adolescent girls which may represent risk over time. Structurally, patterns which emerged at grade 7 reappeared again a year later and again a year after that in grade 9. In general, the same individuals seem to re-emerge in the same or similar patterns over time. Those who showed risk accumulation patterns tended to report prior risk factors in the parenting context. Such trends are supported in the literature and give support to the postulation that parenting is one of the strongest risk factors for adolescents. The findings indicate possible underpinnings of WRP.


Factors influencing acquired upper airway obstruction in newborn infants receiving assisted ventilation because of respiratory failure: an overview.
A critical review of published English literature was undertaken to identify the risk factors for the development of upper airway obstruction in the neonate after intubation for ventilatory support. An English-language computerized search (MEDLINE database from 1966 forward) was done to identify relevant studies; in addition, the reference list of retrieved articles was reviewed to ensure completeness of the search. Papers that presented original data on the risk factors for the development of postintubation upper airway obstruction were included. The inconsistency in defining the population being studied and the lack of a standard definition and method for reporting severity of subglottic stenosis make it difficult to interpret the risk factors associated with subglottic stenosis, and its incidence among various institutions cannot be compared. Prematurity was the only risk factor that was identified in the published literature that one could reliably and consistently associate with the development of subglottic stenosis.


Effectiveness of Dry Needling and Ischemic Trigger Point Compression in the Gluteus Medius in Patients with Non-Specific Low Back Pain: A Randomized Short-Term Clinical Trial.
The presence of latent myofascial trigger points (MTrPs) in the gluteus medius is one of the possible causes of non-specific low back pain. Dry needling (DN) and ischemic compression (IC) techniques may be useful for the treatment of these MTrPs. For this study, 80 participants were randomly divided into two groups: the dry needling group, who received a single session of DN to the gluteus medius muscle plus hyperalgesia (n = 40), and the IC group, who received a single session of IC to the gluteus medius muscle plus hyperalgesia (n = 40). Pain intensity, the pressure pain threshold (PPT), range of motion (ROM), and quality of life were assessed at baseline, immediately after treatment, after 48 h, and one week after treatment. Statistically significant differences were shown between the two groups immediately after the intervention, showing a decrease in PPT (p < 0.05) in the DN group and an increase in PPT in the IC group. These values increased more and were better maintained at 48 h and after one week of treatment in the DN group than in the IC group. Quality of life improved in both groups, with greater improvement in the DN group than in the IC group. IC could be more advisable than DN with respect to UDP and pain intensity in the most hyperalgesic latent MTrPs of the gluteus medius muscle in subjects with non-specific low back pain, immediately after treatment. DN may be more effective than IC in terms of PPT, pain intensity, and quality of life in treating latent plus hyperalgesic gluteus medius muscle MTrPs in subjects with non-specific low back pain after 48 h and after one week of treatment.


The cocktail party effect in infants revisited: listening to one's name in noise.
This study examined infants' abilities to separate speech from different talkers and to recognize a familiar word (the infant's own name) in the context of noise. In 4 experiments, infants heard repetitions of either their names or unfamiliar names in the presence of background babble. Five-month-old infants listened longer to their names when the target voice was 10 dB, but not 5 dB, more intense than the background. Nine-month-olds likewise failed to identify their names at a 5-dB signal-to-noise ratio, but 13-month-olds succeeded. Thus, by 5 months, infants possess some capacity to selectively attend to an interesting voice in the context of competing distractor voices. However, this ability is quite limited and develops further when infants near 1 year of age.


Genomic evidence for an African expansion of anatomically modern humans by a Southern route.
There is general agreement among scientists about a recent (less than 200,000 yrs ago) African origin of anatomically modern humans, whereas there is still uncertainty about whether, and to what extent, they admixed with archaic populations, which thus may have contributed to the modern populations' gene pools. Data on cranial morphology have been interpreted as suggesting that, before the main expansion from Africa through the Near East, anatomically modern humans may also have taken a Southern route from the Horn of Africa through the Arabian peninsula to India, Melanesia and Australia, about 100,000 yrs ago. This view was recently supported by archaeological findings demonstrating human presence in Eastern Arabia >90,000 yrs ago. In this study we analyzed genetic variation at 111,197 nuclear SNPs in nine populations (Kurumba, Chenchu, Kamsali, Madiga, Mala, Irula, Dalit, Chinese, Japanese), chosen because their genealogical relationships are expected to differ under the alternative models of expansion (single vs. multiple dispersals). We calculated correlations between genomic distances, and geographic distances estimated under the alternative assumptions of a single dispersal, or multiple dispersals, and found a significantly stronger association for the multiple dispersal model. If confirmed, this result would cast doubts on the possibility that some non-African populations (i.e., those whose ancestors expanded through the Southern route) may have had any contacts with Neandertals.


Professional e-mail communication among health care providers: proposing evidence-based guidelines.
E-mail is now a primary method of correspondence in health care, and proficiency with professional e-mail use is a vital skill for physicians. Fundamentals of e-mail courtesy can be derived from lay literature, but there is a dearth of scientific literature that addresses the use of e-mail between physicians. E-mail communication between providers is generally more familiar and casual than other professional interactions, which can promote unprofessional behavior or misunderstanding. Not only e-mail content but also wording, format, and tone may influence clinical recommendations and perceptions of the e-mail sender. In addition, there are serious legal and ethical implications when unprofessional or unsecured e-mails related to patient-identifying information are exchanged or included within an electronic medical record. The authors believe that the appropriate use of e-mail is a vital skill for physicians, with serious legal and ethical ramifications and the potential to affect professional development and patient care. In this article, the authors analyze a comprehensive literature search, explore several facets of e-mail use between physicians, and offer specific recommendations for professional e-mail use.


Formation mechanism of (001) oriented perovskite SrTiO3 microplatelets synthesized by topochemical microcrystal conversion.
To develop a better understanding of the mechanism responsible for topochemical microcrystal conversion (TMC) from Aurivillius SrBi4Ti4O15 precursors to perovskite SrTiO3 microplatelets, compositional/structural evolutions, morphological development, and reaction interface evolution of the (001) oriented SrBi4Ti4O15 microplatelets were investigated during the conversion process. The results show that multiple topotactic nucleation events of SrTiO3 occurred directly on the surfaces of SrBi4Ti4O15 above 700 °C, while reacting zones of intermediate phase(s) with less Bi(3+) contents were observed to form in the interior of SrBi4Ti4O15. Extensive exfoliation of the precursors occurred generally parallel to the (001) surfaces above 775 °C. At 950 °C, the original single-crystal SrBi4Ti4O15 platelet was replaced by a polycrystalline aggregate consisting of (001) aligned SrTiO3 crystallites and poorly crystallized intermediate phase(s). With further increasing the temperature or holding time, the SrTiO3 phase formed from related intermediate phase(s), and the aligned crystallites were sintered to form dense SrTiO3 with strong (001) orientation. The obtained SrTiO3 microplatelets preserved the shape of SrBi4Ti4O15 and show high chemical and phase purity. This TMC mechanism has general applicability to a variety of compounds and will be very useful for the design and synthesis of novel anisotropic perovskite crystals with high quality in the future.


The impact of two related prevention strategies on head injury reduction among nonfatally injured motorcycle riders, California, 1991-1993.
Although the traumatic injury death rate in the United States decreased during the last 20 years, the percent of all injury deaths attributable to brain injuries has remained steady. Head injuries are a leading cause of injury among motorcycle riders in crashes, and the helmet is an effective measure to reduce these injuries. To reduce the burden and cost of motorcycle injuries, many states have increased helmet use by introducing mandatory helmet legislation. This report presents evidence on the effects of the motorcycle helmet and helmet use legislation--two interrelated prevention strategies which decrease traumatic brain injury among motorcycle riders. Nonfatally injured motorcyclists were included if they crashed between January 1, 1991 and December 31, 1993 and were treated in one of 18 hospitals in 10 California counties. Medical records for all injured motorcyclists admitted to these 18 hospitals and those treated in the emergency department and released in eight of these hospitals were individually reviewed. Complete lists of injury diagnoses for each rider were coded according to the 1990 Abbreviated Injury Severity Scale by trained clinical staff. Before the universal helmet law was introduced (when only a third of injured riders wore helmets) 38.2% of riders sustained head injuries. When helmet use increased to over 85% of injured riders following the law, less than 25% of riders sustained head injuries. Both the severity and the number of head injuries per individual rider decreased after the mandatory helmet use law led to increased helmet use. Riders wearing helmets suffered fewer skull fractures, fewer intracranial injuries, had less frequent and shorter periods of loss of consciousness, more favorable GCS scores, and shorter hospital stays. Mandatory motorcycle helmet use laws are an effective mechanism to increase helmet use among riders and thus prevent head and brain injuries resulting from motorcycle crashes.


HFE gene mutations in susceptibility to childhood leukemia: HuGE review.
The hereditary hemochromatosis (HHC) gene, HFE on chromosome 6p21.3, encodes a protein involved in iron homeostasis. HFE mutations have low penetrance with a mild effect on serum iron levels. Animal, twin, and population studies have shown that carrier state for C282Y can increase iron levels. A proportion of heterozygotes show slightly elevated serum iron levels. Increased serum iron has been suggested to increase the risk for oxidative damage to DNA. Epidemiologic studies established a correlation between iron levels and cancer risk. Case-control studies have reported associations between HFE mutations C282Y/H63D and several cancers, some of which in interaction with the transferrin receptor gene TFRC or dietary iron intake. Increased cancer risk in C282Y carriers is likely due to higher iron levels in a multifactorial setting. In childhood acute lymphoblastic leukemia (ALL), there is an association of C282Y with a gender effect in two British populations. No association has been found in acute myeloblastic leukemia and Hodgkin disease in adults. The childhood leukemia association possibly results from elevated intracellular iron in lymphoid cells increasing the vulnerability to DNA damage at a critical time window during lymphoid cell development. Interactions of HFE with environmental and genetic factors, most of which are recognized, may play a role in modification of susceptibility to leukemia conferred by C282Y. Given the population frequency of C282Y and the connection between iron and cancer, clarification of the mechanism of HFE associations in leukemia and cancer will have strong implications in public health.


Influence of anesthetic regimen on the frequency of seizures after cervical myelography in the dog.
We examined the influence of various anesthetic drug combinations on the frequency of seizures in dogs after cervical myelography with metrizamide. Over a 12-month period, 78 dogs admitted to the teaching hospital for cervical myelography were assigned randomly to 1 of 6 anesthetic protocols. Myelography was performed, and the dogs were observed for signs of seizure activity after recovery from anesthesia. The person making the decision as to whether or not a dog had had a seizure was unaware of the anesthetic protocol that had been used. Preanesthetic treatment with pentobarbital (5.0 mg/kg) and maintenance of anesthesia with methoxyflurane significantly reduced the frequency of seizures (P less than 0.05). No reduction in seizure frequency was seen with any anesthetic protocol using halothane as the maintenance agent.


Contributions of Stepping Intensity and Variability to Mobility in Individuals Poststroke.
Background and Purpose- The amount of task-specific stepping practice provided during rehabilitation poststroke can influence locomotor recovery and reflects one aspect of exercise dose that can affect the efficacy of specific interventions. Emerging data suggest that markedly increasing the intensity and variability of stepping practice may also be critical, although such strategies are discouraged during traditional rehabilitation. The goal of this study was to determine the individual and combined contributions of intensity and variability of stepping practice to improving walking speed and distance in individuals poststroke. Methods- This phase 2, randomized, blinded assessor clinical trial was performed between May 2015 and November 2018. Individuals between 18 and 85 years old with hemiparesis poststroke of >6 months duration were recruited. Of the 152 individuals screened, 97 were randomly assigned to 1 of 3 training groups, with 90 completing >10 sessions. Interventions consisted of either high-intensity stepping (70%-80% heart rate reserve) of variable, difficult stepping tasks (high variable), high-intensity stepping performing only forward walking (high forward), and low-intensity stepping in variable contexts at 30% to 40% heart rate reserve (low variable). Participants received up to 30 sessions over 2 months, with testing at baseline, post-training, and a 3-month follow-up. Primary outcomes included walking speeds and timed distance, with secondary measures of dynamic balance, transfers, spatiotemporal kinematics, and metabolic measures. Results- All walking gains were significantly greater following either high-intensity group versus low-variable training (all P<0.001) with significant correlations with stepping amount and rate (r=0.48-60; P<0.01). Additional gains in spatiotemporal symmetry were observed with high-intensity training, and balance confidence increased only following high-variable training in individuals with severe impairments. Conclusions- High-intensity stepping training resulted in greater improvements in walking ability and gait symmetry than low-intensity training in individuals with chronic stroke, with potential greater improvements in balance confidence. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT02507466.


Synthesis and characterization of cationic glycidyl-based poly(aminoester)-folic acid targeting conjugates and study on gene delivery.
A new poly(aminoester) (EPAE-FA) containing folic acid and amino groups in the backbone and side chain was synthesized. EPAE-FA self-assembled readily with the plasmid DNA (pCMV-βgal) in HEPES buffer and was characterized by dynamic light scattering, zeta potential, fluorescence images, and XTT cell viability assays. To evaluate the transfection effect of graft ratio of FA on the EPAE system, EPAE-FA polymers with two different graft ratios (EPAE-FA12k and EPAE-FA14k) were also prepared. This study found that all EPAE-FA polymers were able to bind plasmid DNA and yielded positively charged complexes with nano-sized particles (< 200 nm). To assess the transfection efficiency mediated by EPAE and EPAE-FA polymers, we performed in vitro transfection activity assays using FR-negative (COS-7) and FR-positive (HeLa) cells. The EPAE-FA12k/DNA and EPAE-FA14k/DNA complexes were able to transfect HeLa cell in vitro with higher transfection efficiency than PEI25k/DNA at the similar weight ratio. These results demonstrated that the introduction of FA into EPAE system had a significant effect on transferring ability for FR-positive cells (HeLa). Examination of the cytotoxicity of PEI25k and EPAE-FA system revealed that EPAE-FA system had lower cytotoxicity. In this paper, EPAE-FA seemed to be a novel cationic poly(aminoester) for gene delivery and an interesting candidate for further study.


A population-based epidemiological study of human T-cell leukemia virus type I infection in Kin-Hu, Kinmen.
Kinmen is a group of small islands located between Taiwan and Fu-Kien Province of mainland China. The general population in Kinmen are descendants of immigrants from mainland China who began arriving around 317 A.D. Since it has been reported that 0.48% of adults in Taiwan have HTLV-I infection, the decision was made to conduct a community-based epidemiological study in Kinmen to understand the origin and dissemination of HTLV-I in north-east Asia. Over 68% of residents of Kin-Hu township in Kinmen over 30 years of age participated in this study. Eight of 1,425 males and 14 of 1,595 females had HTLV-I infection. Antibody reactivities were further tested by Western blot assays with HTLV-I or HTLV-II type-specific recombinant envelope glycoproteins, and it was determined that all of those infected had HTLV-I and none had HTLV-II. Logistic regression was used for multivariate analysis. The final model indicated that the significant factors associated with HTLV-I infection in Kinmen were age and coastal residency. Age was positively correlated with HTLV-I infection. The eastern coastal area had a rate of HTLV-I infection 3.1 times higher than other areas in Kin-Hu. Further genetic analysis in Kinmen is needed to elucidate a relationship with other HTLV-I isolates in the world.


Hysteroscopy in postmenopausal bleeding.
1) To study the etiology of postmenopausal bleeding (PMB). 2) To study the significance of hysteroscopy in evaluation of the etiopathogenic factors. 3) Correlating the diagnosis after transvaginal sonography (TVS), hysteroscopy and histopathologic diagnosis. 4) Feasibility of conservative management with hysteroscopy in PMB. Prospective study from January 2008 to June 2009. Department of Obstetrics and Gynecology of Ruby Hall Clinic, Pune. Sixty postmenopausal women with complaint of bleeding per vaginum. Clinical and sonographic evaluation, followed by diagnostic and/or therapeutic hysteroscopy and guided biopsy. Hysteroscopic images were analyzed and compared with histopathologic results. On hysteroscopy, endometrium was classified as suggestive of normal, atrophic, endometrial hyperplasia or endometrial carcinoma. Histopathologic diagnosis is taken as a gold standard to determine the efficacy of hysteroscopy in diagnosing endometrial pathologies. The sensitivity and specificity of hysteroscopy in diagnosing endometrial pathologies was assessed. In women with PMB, hysteroscopy is the basic tool that allows precise diagnosis of various endouterine pathologies. The average sensitivity of hysteroscopy was 97% in our study and the specificity was 98.66%. Hence, we can conclude that it is highly accurate for evaluating endometrial pathologies. For obvious benign lesions, it also provides treatment in the same sitting, therefore avoiding an extensive, morbid, and expensive procedure like hysterectomy.


Dynamical anomalies and intermittency in burgers turbulence
We analyze the field theory of fully developed Burgers turbulence. Its key elements are shock fields, which characterize the singularity statistics of the velocity field. The shock fields enter an operator product expansion describing intermittency. The latter is found to be constrained by dynamical anomalies expressing finite dissipation in the inviscid limit. The link between dynamical anomalies and intermittency is argued to be important in a wider context of turbulence.


[Changes in respiratory mechanics in post-tuberculosis emphysema and pneumosclerosis].
The mechanics of breathing was studied in 457 patients with pulmonary tuberculosis. The restrictive mechanism of lowering the ventilation reserves was essential in sclerotic changes in the lower lung. Obstructive changes increased with the extent of pneumosclerosis. X-ray emphysematous changes were confirmed by functional diagnostic findings. The elastic properties of the lung were of the greatest value. Functional diagnosis is important in making clear the clinical and X-ray symptoms of pneumosclerosis and emphysema.


Biotic and abiotic variables affecting internalization and fate of Escherichia coli O157:H7 isolates in leafy green roots.
Preharvest internalization of Escherichia coli O157:H7 into the roots of leafy greens is a food safety risk because the pathogen may be systemically transported to edible portions of the plant. In this study, both abiotic (degree of soil moisture) and biotic (E. coli O157:H7 exposure, presence of Shiga toxin genes, and type of leafy green) factors were examined to determine their potential effects on pathogen internalization into roots of leafy greens. Using field soil that should have an active indigenous microbial community, internalized populations in lettuce roots were 0.8 to 1.6 log CFU/g after exposure to soil containing E. coli O157:H7 at 5.6 to 6.1 log CFU/g. Internalization of E. coli O157:H7 into leafy green plant roots was higher when E. coli O157:H7 populations in soil were increased to 7 or 8 log CFU/g or when the soil was saturated with water. No differences were noted in the extent to which internalization of E. coli O157:H7 occurred in spinach, lettuce, or parsley roots; however, in saturated soil, maximum levels in parsley occurred later than did those in spinach or lettuce. Translocation of E. coli O157:H7 from roots to leaves was rare; therefore, decreases observed in root populations over time were likely the result of inactivation within the plant tissue. Shiga toxin-negative (nontoxigenic) E. coli O157:H7 isolates were more stable than were virulent isolates in soil, but the degree of internalization of E. coli O157:H7 into roots did not differ between isolate type. Therefore, these nontoxigenic isolates could be used as surrogates for virulent isolates in field trials involving internalization.


[Development of hypothalamic control over thyrotropin secretion during human prenatal life].
It was shown in the tissue culture experiments that the human hypophysis secreted autonomously the thyrotrophin during the last three fourths of the prenatal life. The intensity of secretion is the highest in the end of the first third of this period, then it decreases, but during the last third it increases reliably again. During the second half of development the level of thyrotrophin in female foetuses in reliably higher than in the male ones. In the beginning of the second third of prenatal life, the hypothalamic factors decrease the autonomous thyrotrophin secretion twice in foetuses of both the sexes. In the end of the second third, sexual differences appear in their effect; they decrease reliably the autonomous thyrotrophin secretion in the male foetuses, whereas no such effect is observed in the female ones. The stimulating effect of the hypothalamic thyrotrophin releasing hormone manifests itself during the last third of prenatal life in foetuses of both the sexes. During the second half of prenatal life, the thyrotrophin concentration in blood of female foetuses is also reliably higher than in male foetuses. There is a positive correlation in female foetuses between the thyrotrophin concentration in blood and the level of hypophysial secretion under the effect of hypothalamic factors. Thyrotrophin is found in the cranial fluid of foetuses. In some cases its concentration in the cranial fluid is higher than in the blood. No correlation was found between the levels of the hormone in fluid and blood in female foetuses; a positive correlation was found in male foteuses.


TRANSPORT PROPERTIES OF CARTILAGINOUS TISSUES.
Cartilaginous tissues, such as articular cartilage and intervertebral disc, are avascular tissues which rely on transport for cellular nutrition. Comprehensive knowledge of transport properties in such tissues is therefore necessary in the understanding of nutritional supply to cells. Furthermore, poor cellular nutrition in cartilaginous tissues is believed to be a primary source of tissue degeneration, which may result in osteoarthritis (OA) or disc degeneration. In this mini-review, we present an overview of the current status of the study of transport properties and behavior in cartilaginous tissues. The mechanisms of transport in these tissues, as well as experimental approaches to measuring transport properties and results obtained are discussed. The current status of bioreactors used in cartilage tissue engineering is also presented.


Uptake and subcellular localization of tritiated dihydro-microcystin-LR in rat liver.
Microcystin-LR (MC-LR), a cyclic heptapeptide hepatotoxin (mol. wt = 994) produced by the blue-green alga (cyanobacterium), Microcystis aeruginosa, was reduced with tritium labeled sodium borohydride, converted to [3H]-dihydro-microcystin-LR ( [3H]-2HMC-LR), and purified to greater than 99% purity by C-18 reverse-phase high-performance liquid chromatography. The uptake and subcellular distribution of [3H]-2HMC-LR were determined in suspensions of hepatocytes at 0 degrees C and 37 degrees C, or following rifampicin pretreatment, and in perfused rat liver. The remaining cells were homogenized and subfractionated using sucrose gradient centrifugation. Suspensions of 7.5 x 10(6) hepatocytes also were incubated with 10 micrograms/ml of toxin, solubilized in Triton X-100, and ultracentrifuged to pellet the detergent insoluble fraction (containing actin). Isolated rat livers were perfused with media containing [3H]-2HMC-LR and the uptake of radiolabel was determined. Sequential biopsy samples were collected for histologic examination. The remaining liver was homogenized and subcellular fractions prepared. Uptake of radiolabel was rapid in both cell suspension at 37 degrees C and perfused liver; however, uptake in cell suspensions was reduced by about 50% at 0 degrees C and by rifampicin (50 micrograms/ml) pretreatment. Hepatocyte necrosis was observed in isolated perfused livers 45 min after initiation of perfusion with [3H]-2HMC-LR. In both hepatocyte suspensions and perfused livers 65 to 77% of the radiolabel was in the cytosolic fraction. In the hepatocyte suspensions, 13 to 18% of the radiolabel was present in the plasma membrane/nuclear fraction with lesser amounts in the other fractions. Trichloroacetic acid treatment of cytosolic fractions indicated that in hepatocyte suspensions, 50-60% of the radiolabel was bound to cytosolic protein. Studies using the perfused liver confirmed that the majority of the radiolabeled MCLR (78-88%) was bound to cytosolic protein. These data suggest that the uptake of [3H]-2HMC-LR occurs primarily by an energy-dependent transport process involving the rifampicin-sensitive hepatic bile acid carrier and that once inside the hepatocyte, the toxin binds to a cytosolic protein(s).


Pore size distribution analysis of selected hexagonal mesoporous silicas by grand canonical Monte Carlo simulations.
We combine here a regularization procedure with individual adsorption isotherms obtained from grand canonical Monte Carlo simulations in order to obtain reliable pore size distributions. The methodology is applied to two hexagonal high-ordered silica materials: SBA-15 and PHTS, synthesized in our laboratory. Feasible pore size distributions are calculated through an adaptable procedure of deconvolution over the adsorption integral equation, with two necessary inputs: the experimental adsorption data and individual adsorption isotherms, assuming the validity of the independent pore model. The application of the deconvolution procedure implies an adequate grid size evaluation (i.e., numbers of pores and relative pressures to be considered for the inversion, or kernel size), the fulfillment of the discret Picard condition, and the appropriate choice of the regularization parameter (L-curve criteria). Assuming cylindrical geometry for both porous materials, the same set of individual adsorption isotherms generated from molecular simulations can be used to construct the kernel to obtain the PSD of SBA-15 and PHTS. The PSD robustness is measured imposing random errors over the experimental data. Excellent agreement is found between the calculated and the experimental global adsorption isotherms for both materials. Molecular simulations provide new insights into the studied systems, pointing out the need of high-resolution isotherms to describe the presence of complementary microporosity in these materials.


HIF-1-dependent lipin1 induction prevents excessive lipid accumulation in choline-deficient diet-induced fatty liver.
Adaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1α gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1α-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARα/PGC-1α pathway, could be attributed to impaired peroxisomal β-oxidation in Hif-1α-deficient livers. The lipin1-mediated binding of PPARα to the acyl CoA oxidase promoter was markedly reduced in Hif-1α-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1α deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.


Giant contribution of the ligand states to the magnetic properties of the Cr2Ge2Te6 monolayer.
The magnetic properties of the Cr2Ge2Te6 monolayer - an important two-dimensional (2D) ferromagnetic (FM) material - are systematically investigated on the basis of ab initio electronic structure calculations within density functional theory (DFT). For these purposes we construct a minimal tight-binding model in the basis of maximally localized Wannier functions, which describes the behavior of the magnetic Cr 3d, Ge 4p, and Te 5p electrons. This model allows us to rationalize the results of conventional DFT calculations at the microscopic level. We explore the abilities of different techniques, including the Green's function perturbation theory and constraint calculations with an external magnetic field, for the analysis of magnetic interactions, that allow us to decompose these interactions in terms of partial contributions coming from different atomic sites. We argue that, although the magnetism of Cr2Ge2Te6 originates from the Hund's rule effects in the partially filled Cr 3d shell, the contributions of the ligand - and particularly Te 5p - states are crucially important and have a significant effect on the behavior of isotropic exchange interactions, magnetocrystalline anisotropy energy (MAE), and antisymmetric Dzyaloshinskii-Moriya (DM) interactions induced by an electric field. In particular, the Te 5p states increase dramatically the FM coupling and DM interactions between the Cr spins. They are also largely responsible for the behavior of MAE, manifesting themselves in non-Heisenberg type effects, which go beyond the scopes of the conventional Mermin-Wagner theorem for the analysis of 2D magnetism of Cr2Ge2Te6.


A monoclonal antibody against human Notch1 ligand-binding domain depletes subpopulation of putative breast cancer stem-like cells.
Overexpression of Notch receptors and ligands has been associated with various cancers and developmental disorders, making Notch a potential therapeutic target. Here, we report characterization of Notch1 monoclonal antibodies (mAb) with therapeutic potential. The mAbs generated against epidermal growth factor (EGF) repeats 11 to 15 inhibited binding of Jagged1 and Delta-like4 and consequently, signaling in a dose-dependent manner, the antibodies against EGF repeats 11 to 12 being more effective than those against repeats 13 to 15. These data emphasize the role of EGF repeats 11 to 12 in ligand binding. One of the mAbs, 602.101, which specifically recognizes Notch1, inhibited ligand-dependent expression of downstream target genes of Notch such as HES-1, HES-5, and HEY-L in the breast cancer cell line MDA-MB-231. The mAb also decreased cell proliferation and induced apoptotic cell death. Furthermore, exposure to this antibody reduced CD44(Hi)/CD24(Low) subpopulation in MDA-MB-231 cells, suggesting a decrease in the cancer stem-like cell subpopulation. This was confirmed by showing that exposure to the antibody decreased the primary, secondary, and tertiary mammosphere formation efficiency of the cells. Interestingly, effect of the antibody on the putative stem-like cells appeared to be irreversible, because the mammosphere-forming efficiency could not be salvaged even after antibody removal during the secondary sphere formation. The antibody also modulated expression of genes associated with stemness and epithelial-mesenchymal transition. Thus, targeting individual Notch receptors by specific mAbs is a potential therapeutic strategy to reduce the potential breast cancer stem-like cell subpopulation.


Is Gut Microbiota a Key Player in Epilepsy Onset? A Longitudinal Study in Drug-Naive Children.
Microbiota alterations have been recently investigated in individuals with epilepsy and in other neurological diseases as environmental factors that play a role, by acting through the gut-brain axis, in the pathological process. Most studies focus on the contribution of bacterial communities in refractory epilepsy and suggest a beneficial role of ketogenic diet in modulating the gut microbiota and seizure occurrence. However, they do not evaluate whether epilepsy itself alters the gut microbiota in these patients or if the gut microbial communities could contribute as a seizure trigger. In this pilot study, we performed 16S rRNA sequencing and investigated the gut microbial communities of eight children at their seizure onset and after anti-seizure was started (one year follow-up) and we compared microbial data with seven healthy children, age- and sex-matched. In drug-naive subjects, we observed a microbial signature that shared several features with those reported in refractory epilepsy, such as an increased abundance in Akkermansia spp. and Proteobacteria and a decreased relative abundance in Faecalibacterium spp.We suggest that a bacterial-mediated proinflammatory milieu could contribute to seizure occurrence in children with new onset of epilepsy, as already reported for individuals with drug-resistant epilepsy, and that it could vary during treatment in those who are drug-responsive.


Is Invasive Micropapillary Serous Carcinoma a Low-grade Carcinoma?
"Invasive micropapillary serous carcinoma" has been proposed as a synonym for low-grade serous carcinoma by some expert pathologists. In contrast, Singer and colleagues reported that some serous carcinomas with conspicuous invasive micropapillary pattern (SC-IMPs) can show high-grade nuclear atypia. However, the molecular features of such tumors have not been well documented. The aim of this study was to demonstrate and emphasize the fact that high-grade serous carcinoma confirmed by immunohistochemistry and molecular analysis can show conspicuous invasive micropapillary pattern. We selected 24 "SC-IMPs" and investigated: (1) their morphologic features; (2) the immunostaining pattern of p53 protein; and (3) KRAS/BRAF/TP53 gene mutations. The 24 SC-IMPs were subdivided into low-grade and high-grade tumors based primarily on the nuclear atypia, with the mitotic rate used as a secondary feature: low grade (n=5) and high grade (n=19). Low-grade SC-IMPs were characterized by low-mitotic activity, absence of abnormal mitosis, presence of serous borderline tumor, occasional BRAF mutation, and infrequent TP53 mutation. High-grade SC-IMPs were characterized by high-mitotic activity, presence of abnormal mitosis, conventional high-grade serous carcinoma, frequent TP53 mutation, and lack of KRAS/BRAF mutation. We demonstrated that high-grade serous carcinoma confirmed by aberrant p53 immunostaining and molecular analysis can show conspicuous invasive micropapillary pattern, validating Singer and colleague's report. Serous carcinoma with conspicuous invasive micropapillary pattern should not be readily regarded as low-grade serous carcinoma. Nuclear grade is the most important diagnostic feature in the SC-IMPs.


Evaluation of immunity status to routine vaccination in pediatric liver transplant candidates.
Generally, prevention of infections by vaccination is the least invasive and most cost-effective approach to reduce the incidence of infections and the morbidity and mortality in transplant recipients. Genetic diversity and different liver disease among patients contributes to variability in immune responses to vaccines and pathogens. The aim of this study was to evaluate immunity status to different vaccinated organisms in pediatric liver-transplant candidates. The vaccination charts of 90 patients who were referred to Organ Transplant Center of Shiraz University of Medical Sciences were reviewed and compare with National Immunization Program recommendation, after that 10 mL blood was drawn from these patients for serologic studies by ELISA. Eighty percent of the patients had protective antibody titers for poliomyelitis, 65.6% for rubella, 62.3% for diphtheria, 60% for tetanus, 57.7% for pertussis, 55.5% for measles, 42.2% for hepatitis B and 36.7% for mumps. Overall seroconversion rates were not satisfactory for many infections that may be due to lower rate of vaccination or even the underlying liver disease that interfere with optimal immunogenecity of vaccination. Therefore, vaccination charts should be periodically reviewed and updated, also repeated measurements of serum antibodies and appropriate revaccination if titers decline is recommended to prevent the vaccine-preventable disease in liver transplant candidates after transplant.