Circannual morphometric investigations of the rat suprachiasmatic nucleus after pinealectomy, ganglionectomy and thyroidectomy.
We karyometrically investigated the nucleus suprachiasmaticus (SCN) which had been manipulated in several ways in order to analyze the functional importance of the pineal gland on the primary pacemaker of mammals in the course of the year. The manipulation modes were (i) pinealectomy (PX), and (ii) sympathetic denervation of the pineal by bilateral extirpation of the upper cervical ganglia (ganglionectomy, GX). Additionally, the influence of the inactivated pineal, obtained through hypothyroidism which was realized by (iii) subtotal thyroidectomy (TX), was also investigated. With respect to annual oscillations the results of our investigations were able to illustrate the following. (1) The SCN consists of at least two parts (ventrolateral and dorsomedial) each with different functions and relationships. The nuclei of the ventrolateral cells are bigger and there are many indications both in our own research and from literature that the neurons of this part are involved in the generation of rhythms. (2) The size of the cell nuclei of the ventrolateral part shows annual patterns. In the course of the year the maxima of the nuclear volume were registered in March and September (bimodal pattern, equinox, L:D = 12:12). PX, GX or TX only negligibly changed the bimodal annual pattern. However, in comparison the smallest cell nuclei were registered in the winter (short day). The much smaller cell nuclei of the dorsomedial part likewise show bimodal patterns but only in the experimental groups. The control group of this part shows an unimodal annual curve with a minimum at long-day conditions (June, L:D = 16:8). (3) All manipulations which inactivated the pineal or reduced the content of melatonin (PX, GX, and TX) were followed by an increase (activation) of cell nuclei of the SCN. In contrast to these effects, an increase of thyroxine (by exposure to cold), has an opposite effect (not documented here). In conclusion these results indicate, without a doubt, that a negative correlation exists, functionally, between the SCN and the pineal (in the same annual experiment the nuclear size of the pinealocytes was increased, under short-day conditions in December, and decreased under long-day circumstances in June). Additionally, it could be shown that the degree of negative correlation between the pineal and the SCN was seasonally dependent. The lowest effects of PX, GX and TX were registered at short-day conditions (December, L:D = 8:16).


Why the long face? The mechanics of mandibular symphysis proportions in crocodiles.
Crocodilians exhibit a spectrum of rostral shape from long snouted (longirostrine), through to short snouted (brevirostrine) morphologies. The proportional length of the mandibular symphysis correlates consistently with rostral shape, forming as much as 50% of the mandible's length in longirostrine forms, but 10% in brevirostrine crocodilians. Here we analyse the structural consequences of an elongate mandibular symphysis in relation to feeding behaviours. Simple beam and high resolution Finite Element (FE) models of seven species of crocodile were analysed under loads simulating biting, shaking and twisting. Using beam theory, we statistically compared multiple hypotheses of which morphological variables should control the biomechanical response. Brevi- and mesorostrine morphologies were found to consistently outperform longirostrine types when subject to equivalent biting, shaking and twisting loads. The best predictors of performance for biting and twisting loads in FE models were overall length and symphyseal length respectively; for shaking loads symphyseal length and a multivariate measurement of shape (PC1- which is strongly but not exclusively correlated with symphyseal length) were equally good predictors. Linear measurements were better predictors than multivariate measurements of shape in biting and twisting loads. For both biting and shaking loads but not for twisting, simple beam models agree with best performance predictors in FE models. Combining beam and FE modelling allows a priori hypotheses about the importance of morphological traits on biomechanics to be statistically tested. Short mandibular symphyses perform well under loads used for feeding upon large prey, but elongate symphyses incur high strains under equivalent loads, underlining the structural constraints to prey size in the longirostrine morphotype. The biomechanics of the crocodilian mandible are largely consistent with beam theory and can be predicted from simple morphological measurements, suggesting that crocodilians are a useful model for investigating the palaeobiomechanics of other aquatic tetrapods.


Statin and non-steroidal anti-inflammatory drug use in relation to clinical outcome among patients with Rai stage 0 chronic lymphocytic leukemia.
Statins and non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications. In vitro studies suggest that statins and NSAIDs may have potential as anticancer therapies in low-grade non-Hodgkin lymphomas including chronic lymphocytic leukemia (CLL), and a recent observational study found statin use was associated with improved event free survival in patients with follicular lymphoma. Other studies have suggested that statins reduce the efficacy of rituximab by inhibiting binding to CD20. We therefore conducted an observational cohort study of 686 patients with newly diagnosed Rai stage 0 CLL to evaluate whether statin or NSAID use was related to their clinical outcome or influenced the efficacy of rituximab therapy. At diagnosis, 136 (20%) patients took statins and 230 (34%) scheduled daily aspirin, ibuprofen, or naproxen. No difference in time to treatment was observed based on statin or NSAID use. Among patients receiving a rituximab-containing first-line therapy, no difference in time to salvage treatment was observed based on statin use. Although previous studies suggested statins may improve event free survival among patients with follicular lymphoma, we find no impact of statins on time to initial therapy in this large study of patients with Rai stage 0 CLL. The in vitro observation that statins reduce rituximab efficacy does not appear to have clinical significance in CLL care.


Sonic Hedgehog-signalling patterns the developing chicken comb as revealed by exploration of the pea-comb mutation.
The genetic basis and mechanisms behind the morphological variation observed throughout the animal kingdom is still relatively unknown. In the present work we have focused on the establishment of the chicken comb-morphology by exploring the Pea-comb mutant. The wild-type single-comb is reduced in size and distorted in the Pea-comb mutant. Pea-comb is formed by a lateral expansion of the central comb anlage into three ridges and is caused by a mutation in SOX5, which induces ectopic expression of the SOX5 transcription factor in mesenchyme under the developing comb. Analysis of differential gene expression identified decreased Sonic hedgehog (SHH) receptor expression in Pea-comb mesenchyme. By experimentally blocking SHH with cyclopamine, the wild-type single-comb was transformed into a Pea-comb-like phenotype. The results show that the patterning of the chicken comb is under the control of SHH and suggest that ectopic SOX5 expression in the Pea-comb change the response of mesenchyme to SHH signalling with altered comb morphogenesis as a result. A role for the mesenchyme during comb morphogenesis is further supported by the recent finding that another comb-mutant (Rose-comb), is caused by ectopic expression of a transcription factor in comb mesenchyme. The present study does not only give knowledge about how the chicken comb is formed, it also adds to our understanding how mutations or genetic polymorphisms may contribute to inherited variations in the human face.


Synthesis and in vitro study of novel borneol derivatives as potent inhibitors of the influenza A virus.
Herein, we present the design and synthesis of a series of novel heterocyclic derivatives of (-)-borneol and (-)-isoborneol as potent inhibitors of the influenza A virus. All compounds were tested for their toxicity against MDCK cells and for virus-inhibiting activity against the influenza virus A/Puerto Rico/8/34 (H1N1). Compounds 7, 16 and 26 containing a morpholine fragment exhibited the highest efficiency as agents inhibiting the replication of the influenza virus A(H1N1) with selectivity indices of 82, 45 and 65, correspondingly. Derivatives 9 (SI = 23) and 18 (SI = 25) containing a 1-methylpiperazine motif showed moderate antiviral activity. Structure-activity analysis of this new series of borneol derivatives revealed that a 1,7,7-trimethylbicyclo[2.2.1]heptan scaffold is required for the antiviral activity.


Primary care patients with mental health problems: outcome of a randomised clinical trial.
The prevalence of patients with mental health problems in general practice is high, and at least one-third of these problems last for 6 months or longer. Patients with these problems take up more time during a consultation and attend more frequently. This study investigated the effectiveness of problem-solving treatment for primary care patients with mental health problems. The hypothesis was that patients receiving problem-solving treatment from a nurse would have fewer symptoms after 3 months, or a lower attendance rate, compared with patients receiving the usual care from the GP. Randomised clinical trial. Twelve general practices in Amsterdam and 12 nurses from a mental healthcare institution. A sample of patients aged >or=18 years were screened for mental health problems with the general health questionnaire (GHQ-12) in the waiting room of the general practices, and were randomised. Patients receiving the problem-solving treatment were required to complete four to six treatment sessions, while patients in the control group were treated as usual by the GP. No significant difference was found between the groups in terms of improved psychopathology or a decrease in attendance rate. Post-hoc analyses showed a sub-group of patients with more severe pathology who may benefit from problem-solving treatment. The main results show that problem-solving treatment provided by a nurse adds little to the usual care from the GP for frequent attenders with mental health problems. Post-hoc analyses show that there may be a sub-group of more severely depressed patients who could benefit from problem-solving treatment.


The promise of slow down ageing may come from curcumin.
No genes exist that have been selected to promote aging. The evolutionary theory of aging tells us that there is a trade-off between body maintenance and investment in reproduction. It is commonly acceptable that the ageing process is driven by the lifelong accumulation of molecular damages mainly due to reactive oxygen species (ROS) produced by mitochondria as well as random errors in DNA replication. Although ageing itself is not a disease, numerous diseases are age-related, such as cancer, Alzheimer's disease, atherosclerosis, metabolic disorders and others, likely caused by low grade inflammation driven by oxygen stress and manifested by increased level of pro-inflammatory cytokines such as IL-1, IL-6 and TNF-alpha, encoded by genes activated by the transcription factor NF-kappaB. It is believed that ageing is plastic and can be slowed down by caloric restriction as well as by some nutraceuticals. As the low grade inflammatory process is believed substantially to contribute to ageing, slowing ageing and postponing the onset of age-related diseases may be achieved by blocking the NF-kappaB-dependent inflammation. In this review we consider the possibility of the natural spice curcumin, a powerful antioxidant, anti-inflammatory agent and efficient inhibitor of NF-kappaB and the mTOR signaling pathway which overlaps that of NF-kappaB, to slow down ageing.


Propolis Modifies Collagen Types I and III Accumulation in the Matrix of Burnt Tissue.
Wound healing represents an interactive process which requires highly organized activity of various cells, synthesizing cytokines, growth factors, and collagen. Collagen types I and III, serving as structural and regulatory molecules, play pivotal roles during wound healing. The aim of this study was to compare the propolis and silver sulfadiazine therapeutic efficacy throughout the quantitative and qualitative assessment of collagen types I and III accumulation in the matrix of burnt tissues. Burn wounds were inflicted on pigs, chosen for the evaluation of wound repair because of many similarities between pig and human skin. Isolated collagen types I and III were estimated by the surface plasmon resonance method with a subsequent collagenous quantification using electrophoretic and densitometric analyses. Propolis burn treatment led to enhanced collagens and its components expression, especially during the initial stage of the study. Less expressed changes were observed after silver sulfadiazine (AgSD) application. AgSD and, with a smaller intensity, propolis stimulated accumulation of collagenous degradation products. The assessed propolis therapeutic efficacy, throughout quantitatively and qualitatively analyses of collagen types I and III expression and degradation in wounds matrix, may indicate that apitherapeutic agent can generate favorable biochemical environment supporting reepithelization.


Determinants of Health-Related Quality of Life and Physical Performance-Based Components of Frailty in Patients Undergoing Hemodialysis.
Health-related quality of life (HRQoL) measures capture the patient's experience of the burden of chronic disease and are strongly associated with adverse health-related outcomes across multiple populations. The SF-36 score is the most widely used HRQoL measure among patients with end-stage renal disease. Current understanding of determinants of the physical component summary (PCS) and the mental component summary (MCS) and their association with objectively measured physical performance and activity is limited. As an index of HRQoL, we prospectively examined the association of SF-36 and its component scores with physical function among 155 incident dialysis patients from the Hemodialysis Center. We investigated associations of HRQoL with the physical performance-based components of the frailty using multivariate linear and logistic regression after adjustment for confounders. Impaired physical performance was defined as having either slow usual gait speed or weak handgrip strength based on standardized and validated criteria derived from a large cohort study of older adults. The patients had a mean age of 65 ± 11 years, and 52.3% were male. After adjusting confounders, lower PCS was independently associated with decreased physical performance and reduced physical activity, but MCS was not associated. Among the PCS subscales, only physical functioning 10 (PF-10) was consistently associated with outcomes, and every 1 point increase in PF-10 score was associated with 4% lower odds of impaired physical performance (95% confidence interval 2-7, P = .01) after adjustment. SF-36, especially PF-10, is a valid surrogate that discriminates low physical performance and physical inactivity in the absence of formal physical function testing in patients on hemodialysis. The routine implementation of the PF-10 in clinical care has important clinical implications for medical management and therapeutic decision-making in patients undergoing hemodialysis.


Monocyte dependent regulation of autoimmune inflammation.
In chronic inflammation, across a number of quite different pathological conditions, monocytes accumulate. In autoimmune disease, these cells are widely recognised to play an inflammatory and tissue destructive role. But these cells also inhibit T cell proliferation by a range of different mechanisms that are accompanied by the depletion of specific amino acids in the local microenvironment and the downregulation of the T cell receptor zeta chain. This occurs within the pro-inflammatory environment and in the presence of Th1 (IFNgamma) and Th17 (IL-17) cytokines. In tumours, related cells are part of a population called myeloid-derived suppressor cells (MDSC) and they are associated with immunosuppression. Their depletion can lead to clinical improvement. In organ specific autoimmune disease, where such cells can be found in the spleen and in target organs, recent evidence indicates that they may play a role in limiting the T cell response to autoantigens in the target tissue. This occurs by a targeted disruption of T cell division. In this review we discuss evidence for the presence on MDSC in murine and human autoimmune disease and the mechanisms by which such cells inhibit T cell proliferation.


Absence of gamma interferon and interleukin 2 production during active visceral leishmaniasis.
The lymphocytes from eight patients with active visceral leishmaniasis (VL), a disease associated with marked immunologic dysfunction, were examined for ability to produce interleukin 2 (IL-2) and gamma interferon during in vitro cultivation. It was found that both IL-2 and gamma interferon production, in response to leishmania antigen, was absent during the active disease, but was restored after successful chemotherapy. Untreated VL patients produced IL-2 and gamma interferon when stimulated with phytohemagglutinin (PHA). Six patients with either active cutaneous or mucosal leishmaniasis, a disease not associated with immunosuppression, showed high levels of gamma interferon in response to leishmania antigen and PHA. Since IL-2 and gamma interferon have been shown to have important roles in the immune response and in the killing of leishmania, their absence may represent a key defect in the immune response in VL.


[Prevalence of common mental disorders in a population covered by the Family Health Program (QUALIS) in São Paulo, Brazil].
The prevalence of common mental disorders has increased in many countries. Cases are often not identified and adequately treated because traditional health care services are rarely prepared to deal with this problem. The Family Health Program (FHP) has been implemented in Brazil since 1995-1996 and provides a new primary health care model with the potential for better care for these patients. This study investigates common mental disorders prevalence according to FHP coverage and associated socio-demographic factors. A large health and health care survey was conducted from January to March 2001 in areas partly covered by the FHP in a peripheral area of the city of Sao Paulo and included common mental disorders screening in 2,337 individuals > 15 years of age. There was no significant difference in common mental disorders prevalence according to FHP. Common mental disorders prevalence was significantly higher among females (PR = 1.34), elderly (PR = 1.56), and individuals with lower income (PR = 2.64) or less schooling (PR = 2.83). Common mental disorders was associated with indicators of social disadvantage, implying the need to focus on specific health problems and risk groups to improve the impact of care.


Association of radiographic hand osteoarthritis with radiographic knee osteoarthritis after meniscectomy.
To evaluate the association between radiographic hand osteoarthritis (OA), a disease with marked heredity, and radiographic knee OA in patients treated with meniscectomy. We retrospectively identified 170 patients (mean age 54 years [range 33-87 years], 23% women) who had undergone isolated meniscectomy an average of 20 years earlier (range 17-22 years). Patients with cruciate ligament injury were excluded. All subjects were examined by standardized knee and hand radiography. Individual joints were considered to have OA when displaying radiographic features corresponding to a Kellgren/Lawrence (K/L) grade > or =2. Hand OA was considered present if at least 1 of the following criteria was fulfilled: the presence of radiographic OA (K/L grade > or =2) in at least 1 interphalangeal joint in each hand symmetrically, or in at least 2 distal or proximal interphalangeal joints in the same hand in a pattern consistent with primary OA (in the same row or ray), or in the first carpometacarpal joint bilaterally. The association between radiographic hand OA and radiographic knee OA was evaluated using logistic regression. Radiographic hand OA was present in 57 patients (34%) and radiographic knee OA was identified in 105 patients (62%), within 94 index knees (55%) and 47 contralateral knees (28%). In a multivariate model, radiographic hand OA was associated with an increased likelihood of radiographic OA in the index knee (odds ratio [OR] 3.0, 95% confidence interval [95% CI] 1.2-7.5) and in the nonoperated contralateral knee (OR 3.5, 95% CI 1.0-12.2). The presence of radiographic hand OA is associated with an increased frequency of radiographic knee OA after meniscectomy. This finding confirms and extends that of a single previous study showing an interaction between hereditary and environmental risk factors for OA, a common and genetically complex disease. Accordingly, the development of OA following a meniscal tear and the resulting meniscal surgery should not be regarded to be of secondary origin only.


Complementary roles of a noninvasive test battery and DSA in evaluating carotid artery disease.
Initial comparisons of the results of digital subtraction angiography (DSA) and a battery of tests for noninvasive diagnosis of carotid artery disease indicate the two techniques are complementary, rather than competitive. DSA provides important morphologic information at the carotid bifurcation and siphon, but the images are sometimes difficult to interpret with precision. Noninvasive testing gives discrete physiologic information related to hemodynamics, but the findings are less specific for the level of the lesion in the carotid/ophthalmic system. Noninvasive tests may be more useful than DSA for determining if a lesion is hemodynamically significant and whether advanced disease shows evidence of progression on sequential studies. The noninvasive tests are not definitive procedures, but are useful in selecting patients for a contrast study. They are the initial procedure of choice for the patient with asymptomatic bruit. Depending on the clinical situation and quality of the study, DSA can sometimes be a definitive procedure, but in some situations correlative noninvasive test results are necessary to assess whether the patient is a candidate for arteriography and/or surgery.


Assessing doping strategies for monolayer MoS2 towards non-enzymatic detection of cortisol: a first-principles study.
In this work, we investigate by means of atomistic density functional theory simulations the interaction between cortisol (the target molecule) and monolayer MoS2 (the substrate). The aim is to assess viable strategies for the non-enzymatic chemical sensing of cortisol. Metal doping of the sensing material could offer a way to improve the device response upon analyte adsorption, and could also enable novel and alternative detection mechanisms. For such reasons, we explore metal doping of MoS2 with Ni, Pd, and Pt, as these are metal elements commonly used in experiments. Then, we study the material response from the structural, electronic, and charge-transfer points of view. Based on our results, we propose two possible sensing mechanisms and device architectures: (i) a field-effect transistor, and (ii) an electrochemical sensor. In the former, Ni-doped MoS2 would act as the FET channel, and the sensing mechanism involves the variation of the surface electrostatic charge upon the adsorption of cortisol. In the latter, MoS2 decorated with Pt nanoparticles could act as the working electrode, and the sensing mechanism would involve the reduction of cortisol. In addition, our findings may suggest the suitability of both doped and metal-doped MoS2 as sensing layers in an optical sensor.


Determinants of Treatment Modification in Hypercholesterolemic Patients.
There is a lack of knowledge of those contemporary factors associated with modifying subtherapeutic treatments in hypercholesterolemic patients. The aim of this study was to assess determinants of treatment modification in patients not attaining their low-density lipoprotein cholesterol goals. The CEntralized Pan-Asian survey on tHE Under-treatment of hypercholeSterolemia enrolled patients taking stable lipid-lowering medications. The study physicians then determined existing patient treatments, which were to be continued or modified when treatments failed. The patient questionnaire surveying patient attitudes and perceptions toward their hypercholesterolemia management was prospectively collected. The odds ratios (ORs) (95% confidence intervals) were calculated. Among the 420 patients included for analysis, 35.7% were designated for planned treatment modification. Those patients assigned to treatment modification were more likely to have a family history of premature coronary heart disease (40% vs. 19%), an indication for secondary prevention (76% vs. 61%), elevated triglyceride (60% vs. 48%) and fasting sugar (84% vs. 67%), and were less adherent to their medications (29% vs. 12%) than patients assigned to treatment continuation. Patient recognition of treatment failure [OR, 1.82 (1.13-2.94)], the lower frequency of cholesterol checkup [OR, 2.40 (1.41-4.08)], patient satisfaction with provided cholesterol information [OR, 2.30 (1.21-4.39)], and their feelings toward cholesterol management [OR, 0.25 (0.10-0.62) and 3.80 (2.28-6.32)] for confusion and no strong feeling, respectively were determinants of the treatment modification assignment. There was a large gap between evidence-based goals and modification of subtherapeutic treatments, particularly among patients with lower treatment satisfaction and better compliance. Our findings have emphasized the need to further reduce inertia in implementing hypercholesterolemia management.


[Suppurative-necrotic pancreatitis and its surgical treatment].
Purulent-necrotic processes in the pancreas may arise against the background of different forms of acute pancreatitis. Biological tamponade of the pancreas with the greater omentum and hermical closure of the abdomen result in a reduced number of cases of the gland suppuration. The treatment of purulent pancreatitis should be complex, comprising an early surgical intervention with subsequent rational conservative therapy.


Envelope glycoprotein determinants of neutralization resistance in a simian-human immunodeficiency virus (SHIV-HXBc2P 3.2) derived by passage in monkeys.
The simian-human immunodeficiency virus SHIV-HXBc2 contains the envelope glycoproteins of a laboratory-adapted, neutralization-sensitive human immunodeficiency virus type 1 variant, HXBc2. Serial in vivo passage of the nonpathogenic SHIV-HXBc2 generated SHIV KU-1, which causes rapid CD4(+) T-cell depletion and an AIDS-like illness in monkeys. A molecularly cloned pathogenic SHIV, SHIV-HXBc2P 3.2, was derived from the SHIV KU-1 isolate and differs from the parental SHIV-HXBc2 by only 12 envelope glycoprotein amino acid residues. Relative to SHIV-HXBc2, SHIV-HXBc2P 3.2 was resistant to neutralization by all of the antibodies tested with the exception of the 2G12 antibody. The sequence changes responsible for neutralization resistance were located in variable regions of the gp120 exterior envelope glycoprotein and in the gp41 transmembrane envelope glycoprotein. The 2G12 antibody, which neutralized SHIV-HXBc2 and SHIV-HXBc2P 3.2 equally, bound the HXBc2 and HXBc2P 3.2 envelope glycoproteins on the cell surface comparably. The ability of the other tested antibodies to achieve saturation was less for the HXBc2P 3.2 envelope glycoproteins than for the HXBc2 envelope glycoproteins, even though the affinity of the antibodies for the two envelope glycoproteins was similar. Thus, a highly neutralization-sensitive SHIV, by modifying both gp120 and gp41 glycoproteins, apparently achieves a neutralization-resistant state by decreasing the saturability of its envelope glycoproteins by antibodies.


Development of a Generic Physiologically Based Kinetic Model to Predict In Vivo Uterotrophic Responses Induced by Estrogenic Chemicals in Rats Based on In Vitro Bioassays.
The present study assessed the potential of a generic physiologically based kinetic (PBK) model to convert in vitro data for estrogenicity to predict the in vivo uterotrophic response in rats for diethylstibestrol (DES), ethinylestradiol (EE2), genistein (GEN), coumestrol (COU), and methoxychlor (MXC). PBK models were developed using a generic approach and in vitro concentration-response data from the MCF-7 proliferation assay and the yeast estrogen screening assay were translated into in vivo dose-response data. Benchmark dose analysis was performed on the predicted data and available in vivo uterotrophic data to evaluate the model predictions. The results reveal that the developed generic PBK model adequate defines the in vivo kinetics of the estrogens. The predicted dose-response data of DES, EE2, GEN, COU, and MXC matched the reported in vivo uterus weight response in a qualitative way, whereas the quantitative comparison was somewhat hampered by the variability in both in vitro and in vivo data. From a safety perspective, the predictions based on the MCF-7 proliferation assay would best guarantee a safe point of departure for further risk assessment although it may be conservative. The current study indicates the feasibility of using a combination of in vitro toxicity data and a generic PBK model to predict the relative in vivo uterotrophic response for estrogenic chemicals.


Patient-reported outcomes and quality of life in PMM2-CDG.
Patient-reported outcomes (PROs) measure important aspects of disease burden, however they have received limited attention in the care of patients with Congenital Disorders of Glycosylation (CDG). We evaluated the PROs and correlation between clinical disease severity scoring and reported quality of life (QoL) in a PMM2-CDG patient cohort. Twenty-five patients with diagnosis of PMM2-CDG were enrolled as part of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study. Patient- Reported Outcomes Measurement Information System (PROMIS) was completed by caregivers to assess health-related QoL. Clinical disease severity was scored by medical providers using the Nijmegen Progression CDG Rating Scale (NPCRS). The domains such as physical activity, strength impact, upper extremity, physical mobility, and a satisfaction in social roles (peer relationships) were found to be the most affected in the PMM2-CDG population compared to US general population. We found a strong correlation between NPCRS 1 (current functional ability) and three out of ten PROMIS subscales. NPCRS 2 (laboratory and organ function) and NPCRS 3 (neurological involvement) did not correlate with PROMIS. Mental health domains, such as anxiety, were positively correlated with depressive symptoms (r = 0.76, p = 0.004), fatigue (r = 0.67, p = 0.04). Surprisingly, patients with severely affected physical mobility showed low anxiety scores according to PROMIS (inverse correlation, r = -0.74, p = 0.005). Additionally, there was a positive correlation between upper extremity and physical mobility (r = 0.75, p = 002). Here, we found that PROMIS is an informative additional tool to measure CDG disease burden, which could be used as clinical trial outcome measures. The addition of PROMIS to clinical follow-up could help improve the quality of care for PMM2-CDG by facilitating a holistic approach for clinical decision-making. SYNOPSIS: We recommend PROMIS as an informative tool to measure disease burden in PMM2-CDG in addition to traditional CDG disease severity scores.


[Vertebrobasilar abnormalities in patients with hemifacial spasm: MR-angiography findings].
Hemifacial spasm (HFS) is a disorder characterized by a complex of symptoms with hyperactive motor dysfunction of the facial nerve. It is indicated that HFS in the majority of cases can be caused by a blood vessel compressing the nerve adjacent to the brainstem. We studied and treated 44 patients with HFS. Magnetic resonance imaging (MR) and MR-angiography of the brain were performed in patients with HFS to asses the presence of an artery of the vertebrobasilar system compressing the root of the facial nerve. We evaluate the response to treatment with Botulinum toxin in these cases. 14 patients were excluded (6 patients presented HFS due to other lesions and in 8 patients the MR was not performed). The remaining 30 patients with idiopathic HFS underwent MR/MRA (3D-FISP) and it was also performed in 14 patients with synkineses after facial palsy to be used as controls. The MRA documented an abnormal position of the arteries surrounding the facial nerve (ipsilaterally to HFS) in 22 patients. The compressing artery was the PICA in 3 patients (10%), the AICA in 3 patients, the vertebral artery in 7 patients and the basilar artery in 8 patients, one patient showed a combined compression by AICA and PICA. The remaining 8 patients had a normal MRI. At the control group only one patient presented an abnormal AICA and the other had a normal MRI-MRA. Patients were followed-up for 22.4 months and after Botulinum toxin treatment patients kept 4.81 months free of symptoms. We recommend to perform MR studies in all HFS patients to rule out a secondary cause of the disease and MRA to evaluate the underlying vertebrobasilar abnormalities if surgery is planned. Botulinum toxin is a useful treatment in these patients and only after its failure, microvascular decompression will be considered.


Feedback Regulation of DYT1 by Interactions with Downstream bHLH Factors Promotes DYT1 Nuclear Localization and Anther Development.
Transcriptional regulation is one of the most important mechanisms controlling development and cellular functions in plants and animals. The Arabidopsis thaliana bHLH transcription factor (TF) DYSFUNCTIONL TAPETUM1 (DYT1) is required for normal male fertility and anther development and activates the expression of the bHLH010/bHLH089/bHLH091 genes. Here, we showed that DYT1 is localized to both the cytoplasm and nucleus at anther stage 5 but specifically to the nucleus at anther stage 6 and onward. The bHLH010/bHLH089/bHLH091 proteins have strong nuclear localization signals, interact with DYT1, and facilitate the nuclear localization of DYT1. We further found that the conserved C-terminal BIF domain of DYT1 is required for its dimerization, nuclear localization, transcriptional activation activity, and function in anther development. Interestingly, when the BIF domain of DYT1 was replaced with that of bHLH010, the DYT1(N)-bHLH010(BIF) chimeric protein shows nuclear-preferential localization at anther stage 5 but could not fully rescue the dyt1-3 phenotype, suggesting that the normal spatio-temporal subcellular localization of DYT1 is important for DYT1 function and/or that the BIF domains from different bHLH members might be functionally distinct. Our results support an important positive feedback regulatory mechanism whereby downstream TFs increase the function of an upstream TF by enhancing its nucleus localization through the BIF domain.


Bioactive dammarane triterpenes from the mangrove plant Bruguiera gymnorrhiza.
Three new dammarane triterpenes, bruguierins A-C (1-3), were isolated from a petroleum ether extract of the flowers of Bruguiera gymnorrhiza. Their structures were determined on the basis of physical and spectroscopic data interpretation. With stably transfected HepG2 cells, the three isolates activated antioxidant response element (ARE luciferase activation) with EC(50) values of 7.8, 9.4, and 15.7 microM, respectively. Bruguierin A (1) also inhibited phorbol ester-induced NFkappaB (nuclear factor-kappaB) luciferase activation with an IC(50) value of 1.4 microM and selectively inhibited cyclooxygenase-2 (COX-2) activity with an IC(50) value of 0.37 microM. Compounds 2 and 3 were not active in these bioassays.


Outcomes of Patients With Sickle Cell Disease and Trait After Congenital Heart Disease Surgery.
Sickle cell disease (SCD) is a hemoglobinopathy that can cause multiorgan dysfunction. This study assessed the perioperative outcomes of patients undergoing operations for congenital heart disease who had SCD or sickle cell trait (SCT). We performed a retrospective review of patients with SCD or SCT who had records in The Society of Thoracic Surgeons Congenital Heart Surgery Database between 2014 and 2019. The primary outcome was operative mortality. Secondary outcomes included postoperative complications. One-to-one propensity score matching was performed between the SCD and SCT groups and the control group for further analysis. Our study population consisted of 73, 411, and 36 501 patients in the SCD, SCT, and control groups, respectively. Median (25%-75% interquartile range) age at surgery was 2.8 (0.4-9.7), 0.60 (0.2-3.1), and 0.70 (0.2-6.4) years in the SCD, SCT, and control cohorts, respectively. Operative mortality, surgery duration, cardiopulmonary bypass time, and cross-clamp time were not significantly different among the 3 groups. The SCD group had a higher rate of postsurgical cardiac arrest than its propensity score-matched control group (5.5% vs 0%, P < .05); otherwise, there were no statistically significant differences in the outcomes between the SCD and SCT groups and their respective matched control groups. Operative mortality after cardiothoracic procedures in patients with SCD or SCT appeared similar to our control patients. While these patients may require unique perioperative management, they can undergo cardiac surgery without an observed increase in mortality.


Chronic asymptomatic ischemic optic neuropathy. A report of two cases in adults with diabetes mellitus.
Two adult diabetic patients with chronic asymptomatic optic neuropathy attributed to an ischemic etiology are reported. In one case the typical syndrome of ischemic optic neuropathy occurred in one eye, while the fellow eye had asymptomatic hyperemic optic disc edema that persisted for 6 months without optic atrophy. A minor visual field defect initially detected in that eye resolved spontaneously in 1 month. In the second case, a recent onset, middle-aged diabetic developed bilateral optic neuropathy and optic disc edema that persisted for 12 months, with minimal signs of visual dysfunction. Axoplasmic transport blockage from low-grade ischemia to the optic nerve may cause acute or chronic optic disc edema with minimal or no visual symptoms.


Characterizing variability in warfarin dose requirements in children using modelling and simulation.
Although genetic, clinical and demographic factors have been shown to explain approximately half of the inter-individual variability in warfarin dose requirement in adults, less is known about causes of dose variability in children. This study aimed to identify and quantify major genetic, clinical and demographic sources of warfarin dose variability in children using modelling and simulation. Clinical, demographic and genetic data from 163 children with a median age of 6.3 years (range 0.06-18.9 years), covering over 183 years of warfarin therapy and 6445 INR observations were used to update and optimize a published adult pharmacometric warfarin model for use in children. Genotype effects in children were found to be comparable with what has been reported for adults, with CYP2C9 explaining up to a four-fold difference in dose (CYP2C9 *1/*1 vs. *3/*3) and VKORC1 explaining up to a two-fold difference in dose (VKORC1 G/G vs. A/A), respectively. The relationship between bodyweight and warfarin dose was non-linear, with a three-fold difference in dose for a four-fold difference in bodyweight. In addition, age, baseline and target INR, and time since initiation of therapy, but not CYP4F2 genotype, had a significant impact on typical warfarin dose requirements in children. The updated model provides quantitative estimates of major clinical, demographic and genetic factors impacting on warfarin dose variability in children. With this new knowledge more individualized dosing regimens can be developed and prospectively evaluated in the pursuit of improving both efficacy and safety of warfarin therapy in children.


Surgery for pancreas divisum.
We present our experience of open surgical treatment in 5 patients with symptomatic pancreas divisum (PD). Choice of therapy was based on allocation of patients to one of five clinical presentation groups: (i) with minor symptoms (no operation); (ii) with recurrent acute pancreatitis or upper abdominal pain (RAP/RUAP)--3 patients; (iii) with radiological evidence of chronic pancreatitis (CP)--1 patient; (iv) chronic pancreatic pain without radiological evidence of chronic pancreatitis (CPP); and (v) other pancreatic complications--1 patient. This classification helps to decide management and predict possible outcome. Various types of operation were performed as indicated (open surgical accessory sphincteroplasty [2 also had distal pancreatectomy], n = 3; Puestow's operation, n = 1; or Beger's pancreatectomy, n = 1). All patients improved significantly and are now leading normal personal, professional, and social lives. We conclude that, with careful selection of patients and appropriate therapy, the response to surgical treatment is good.


Effect of water-aging on the antimicrobial activities of an ORMOSIL-containing orthodontic acrylic resin.
Quaternary ammonium methacryloxy silicate (QAMS), an organically modified silicate (ORMOSIL) functionalized with polymerizable methacrylate groups and an antimicrobial agent with a long lipophilic alkyl chain quaternary ammonium group, was synthesized through a silane-based sol-gel route. By dissolving QAMS in methyl methacrylate monomer, this ORMOSIL molecule was incorporated into an auto-polymerizing, powder/liquid orthodontic acrylic resin system, yielding QAMS-containing poly(methyl methacrylate). The QAMS-containing acrylic resin showed a predominant contact-killing effect on Streptococcus mutans (ATCC 35668) and Actinomyces naeslundii (ATCC 12104) biofilms, while inhibiting adhesion of Candida albicans (ATCC 90028) on the acrylic surface. The antimicrobial activities of QAMS-containing acrylic resin were maintained after a 3month water-aging period. Bromophenol blue assay showed minimal leaching of quaternary ammonium species when an appropriate amount of QAMS (<4wt.%) was incorporated into the acrylic resin. The results suggest that QAMS is predominantly co-polymerized with the poly(methyl methacrylate) network, and only a minuscule amount of free QAMS molecules is present within the polymer network after water-aging. Acrylic resin with persistent antimicrobial activities represents a promising method for preventing bacteria- and fungus-induced stomatitis, an infectious disease commonly associated with the wearing of removable orthodontic appliances.


Research Trends and Recommendations for Physical Activity Interventions Among Children and Youth With Disabilities: A Review of Reviews.
This scoping review synthesized reviews of physical activity (PA) interventions for children and youth with disabilities to highlight promising elements of effective interventions, research methodological limitations, and research priorities. Twenty studies were eligible and underwent three rounds of review by an expert panel. Rich and diverse PA programs derived potential short-term benefits toward health, function, and PA. Strategies to increase sample sizes included embedding programs in the community and using information communication technology to deliver exercise programs. Methodological limitations of interventions included a lack of generalizability, transferability, and scientific rigor. Three research priorities were identified: develop and report precision-based intervention strategies, identify strategies that promote both long-term and sustainable PA participation and outcomes, and develop scalable interventions and recruitment strategies. If addressed, these areas could enhance the impact of PA interventions for children and youth with disabilities.


Molecular biology. Mothers setting boundaries.
Certain genes are only expressed at one allele, a phenomenon called imprinting. Although it is well established that one allele of certain imprinted genes is silenced through methylation, this does not appear to be the case for all imprinted genes. In a thoughtful Perspective, Thorvaldsen and Bartolomei discuss new findings showing that insertion of insulator elements (boundary regions) between the promoter of a gene and its enhancer (a sequence that boosts gene expression) may be another way in which genes are silenced during imprinting.


One year of ethanol feeding increases circulating thyroid hormones in the dog.
Nine greyhound dogs were fed ethanol for 1 year to examine the effects of long-term ethanol feeding on circulating thyroid hormones. The dose of ethanol consumed per day was 2 gm/kg for the first month, 3 gm/kg for the second month, and 4 gm/kg for the rest of the study. Plasma triiodothyronine (T3), thyroxine (T4), and reverse triiodothyronine (rT3) were measured by radioimmunoassay. Plasma T3 and T4 concentrations increased significantly during the period of ethanol administration compared with control values (ANOVA, P less than 0.005). Levels of rT3 showed a trend to increase, although this was not significant. Resin T3 uptake decreased significantly (ANOVA, P less than 0.005) and the calculated free T4 index and free T3 index showed significant elevations (ANOVA, P less than 0.005) during ethanol administration. The results of this study indicate that long-term ethanol feeding to dogs induces an increase in circulating thyroid hormones.


[Human papillomavirus testing in cervical cancer screening at a public health service of Santiago, Chile].
Molecular techniques for human papillomavirus (HPV) detection have a good performance as screening tests and could be included in cervical cancer early detection programs. We conducted a population-based trial comparing HPV detection and Papanicolaou as primary screening tests, in a public health service in Santiago, Chile. To describe the experience of implementing this new molecular test and present the main results of the study. Women aged 25 to 64 enrolled in three public health centers were invited to participate. In all women, samples were collected for Papanicolaou and HPV DNA testing, and naked-eye visual inspection of the cervix with acetic acid was performed. Women with any positive screening test were referred to the local area hospital for diagnostic confirmation with colposcopy and biopsy of suspicious lesions. Screening results were obtained for 8265 women, of whom 931 (11.3%) were positive to any test. The prevalence of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) was 1.1%; nine women had invasive cervical cancer. Sensitivities for the detection of CIN2+ were 22.1% (95% confidence interval (CI) 16.4-29.2) for Papanicolaou and 92.7% (95% CI 84.4-96.8) for HPV testing; specificities were 98.9% (95% CI 98.7-99.0) and 92.0% (95% CI 91.4-92.6) respectively. This experience showed that the implementation of a molecular test for cervical cancer screening is not a major challenge in Chile: it was well accepted by both the health team and the participants, and it may improve the effectiveness of the screening program.


A generalizable, tunable microfluidic platform for delivering fast temporally varying chemical signals to probe single-cell response dynamics.
Understanding how biological systems transduce dynamic, soluble chemical cues into physiological processes requires robust experimental tools for generating diverse temporal chemical patterns. The advent of microfluidics has seen the development of platforms for rapid fluid exchange allowing ease of changes in the cellular microenvironment and precise cell handling. Rapid exchange is important for exposing systems to temporally varying signals. However, direct coupling of macroscale fluid flow with microstructures is potentially problematic due to the high shear stresses that inevitably add confounding mechanical perturbation effects to the biological system of interest. Here, we have devised a method of translating fast and precise macroscale flows to microscale flows using a monolithically integrated perforated membrane. We integrated a high-density cell trap array for nonadherent cells that are challenging to handle under flow conditions with a soluble chemical signal generator module. The platform enables fast and repeatable switching of stimulus and buffer at low shear stresses for quantitative live, single-cell fluorescent studies. This modular design allows facile integration of any cell-handling chip design with any chemical delivery module. We demonstrate the utility of this device by characterizing heterogeneity of oscillatory response for cells exposed to alternating Ca(2+) waveforms at various periodicities. This platform enables the analysis of cell responses to chemical perturbations at a single-cell resolution that is necessary in understanding signal transduction pathways.


Accuracy of field methods in assessing body fat in collegiate baseball players.
When assessing the fitness levels of athletes, body composition is usually estimated, as it may play a role in athletic performance. Therefore, the purpose of this study was to determine the validity of bioelectrical impedance analysis (BIA) and skinfold (SKF) methods compared with dual-energy X-ray absorptiometry (DXA) for estimating percent body fat (%BF) in Division 1 collegiate baseball players (n = 35). The results of this study indicate that the field methods investigated were not valid compared with DXA for estimating %BF. In conclusion, this study does not support the use of the TBF-350, HBF-306, HBF-500, or SKF thickness for estimating %BF in collegiate baseball players. The reliability of these BIA devices remains unknown; therefore, it is currently uncertain if they may be used to track changes over time.


Cytomegalovirus-based cancer vaccines expressing TRP2 induce rejection of melanoma in mice.
Cytomegalovirus (CMV) induces strong and long-lasting immune responses, which make it an attractive candidate for a cancer vaccine vector. In this study, we tested whether a tumor antigen expressed in CMV can induce a strong anti-tumor effect. We expressed an unmodified melanoma antigen, mouse tyrosinase-related protein 2 (TRP2), in mouse cytomegalovirus (MCMV). Prophylactic vaccination of the mice with a single dose of MCMV-TRP2 induced rejection of B16 melanoma challenge; therapeutic vaccination with MCMV-TRP2 prolonged the survival of the mice challenged with B16 cells. Additionally, vaccination with MCMV-TRP2 five months before tumor challenge still induced tumor rejection, which indicated that the vaccine induced long-term protection. Furthermore, MCMV-TRP2 protected mice against B16 melanoma challenge regardless of the pre-existing CMV infection. We found that vaccination with MCMV-TRP2 induced long-lasting TRP2 specific antibodies but not CD8 T cells. In addition, depletion of CD4 and CD8 T cells did not compromise the antitumor effect by MCMV-TRP2; while in B cell deficient (μMT) mice, the vaccine lost its antitumor effect. These results indicate that antibodies, not T cells, are important in mediating the antitumor effect during the effector phase by the vaccine. We also made a spread deficient MCMV-TRP2 lacking the essential glycoprotein gL, which showed a similar antitumor effect. In conclusion, our study indicates that tumor antigen (TRP2) expressed in MCMV induces a strong and long-lasting anti-melanoma effect through an antibody-dependent mechanism. Our findings demonstrate that CMV might be a promising vector for the development of cancer vaccines.


ABCC2 is associated with Bacillus thuringiensis Cry1Ac toxin oligomerization and membrane insertion in diamondback moth.
Cry1A insecticidal toxins bind sequentially to different larval gut proteins facilitating oligomerization, membrane insertion and pore formation. Cry1Ac interaction with cadherin triggers oligomerization. However, a mutation in an ABC transporter gene (ABCC2) is linked to Cry1Ac resistance in Plutella xylostella. Cry1AcMod, engineered to lack helix α-1, was able to form oligomers without cadherinbinding and effectively countered Cry1Ac resistance linked to ABCC2. Here we analyzed Cry1Ac and Cry1AcMod binding and oligomerization by western blots using brush border membrane vesicles (BBMV) from a strain of P. xylostella susceptible to Cry1Ac (Geneva 88) and a strain with resistance to Cry1Ac (NO-QAGE) linked to an ABCC2 mutation. Resistance correlated with lack of specific binding and reduced oligomerization of Cry1Ac in BBMV from NO-QAGE. In contrast, Cry1AcMod bound specifically and still formed oligomers in BBMV from both strains. We compared association of pre-formed Cry1Ac oligomer, obtained by incubating Cry1Ac toxin with a Manduca sexta cadherin fragment, with BBMV from both strains. Our results show that pre-formed oligomers associate more efficiently with BBMV from Geneva 88 than with BBMV from NO-QAGE, indicating that the ABCC2 mutation also affects the association of Cry1Ac oligomer with the membrane. These data indicate, for the first time, that ABCC2 facilitates Cry1Ac oligomerization and oligomer membrane insertion in P. xylostella.


Tobacco cessation center in a dental college: An 8 year institution-based study.
Oral cancer is a major health concern in the Indian subcontinent, where it ranks among the top three types of cancer in the country. Tobacco and its products have been implicated as a major etiologic factor behind cancers. It is believed that tobacco is an epidemic in itself taking the death toll to 7 million globally. In India alone, mortality because of tobacco is more than 1.3 million. Dentists are the first to notice any change in the oral cavity or come across any suspicious looking oral lesion and therefore are instrumental in primary prevention and care. The present study data are of the patients enrolled in a Tobacco Cessation Center(TCC) at a Dental College in Meerut in Meerut from May 2012 (since its inception) to March 2020. The following methods of counseling were carried out: group counseling, interactive sessions, audio-visual aids, and individual counseling sessions. Self-training for oral cavity examination was also given after every group counseling session. Behavioral counseling and pharmacological intervention were given as per Fagerström Test for Nicotine Dependence (FTND) score. At the end of 1 year, patients who quit were graded into 0, 1, and 2, with 0 for those who failed to quit, 1 for those who did completely quit, and 2 for those who reduced their habit by more than 50%. The quit rate achieved was 57.6% (complete responders -43.2% and partial responders 14.4%). The relapse reported was 1.8%. A Tobacco cessation Center set up in a Dental College could be of great help in the primary prevention of oral cancer and can bring a drastic increase in quit rates. Proper counseling skills once nurtured in young under-graduates can boost the tobacco-free India campaign.


Host age and time of exposure in Trypanosoma brucei gambiense Human African Trypanosomiasis.
Human African Trypanosomiasis is related to behavioural risk factors but complex interactions exist between (i) environmental and behavioural risk factors, (ii) vector and (iii) human host. Our aim was to investigate the interrelationships between previously analysed risk factors and the roles of age and time of exposure according to ethnic group and migration status. However, this descriptive and retrospective study is based on cases only (no controls) and our results must therefore be regarded as hypothesis-generating. Individuals originating from areas where sleeping sickness is absent and who settle in an endemic area seem to develop the disease after a shorter time of exposure than native subjects from endemic areas. Our results emphasise the complexity of vector-transmitted disease epidemiology, involving behavioural and/or environmental risk factors on the one hand, and more individual ones such as ageing, immunity and genetic background on the other hand.


The risk and added values of the atherosclerotic cardiovascular risk enhancers on prediction of cardiovascular events: Tehran lipid and glucose study.
In 2013 American College of Cardiology and the American Heart Association released a guideline on the management of atherosclerotic cardiovascular disease (ASCVD) including a composite of death from CVD, non-fatal myocardial infarction, or non-fatal stroke (hard CVD). This guideline recommended a risk score that was calculated using pooled cohort equations (ASCVD-PCE). The guideline was updated in 2018/2019 and further risk discussion was suggested for deciding whether to continue or initiate statin therapy among non-diabetic individuals with ASCVD-PCE score ranged 5-20%. They recommended a risk discussion with considering risk enhancing factors (ASCVD-REFs) including family history of premature CVD, chronic kidney disease, triglycerides ≥ 175 mg/dl, low-density lipoprotein cholesterol (LDL-C) ≥ 160 mg/dl, metabolic syndrome (Mets), and for women premature menopause, and hypertensive disorders of pregnancy (HDP). In the current study, we aimed to examine the predictability of recommended ASCVD-REFs on incident hard CVD in non-diabetic individuals with LDL-C 70-189 mg/dl, with ASCVD-PCE risk 5-20% during 10 and 15-year follow-up. Among a total of 3546 non-diabetic individuals aged 40-75 years, after excluding those with ASCVD-PCE score < 5% and ≥ 20% (n = 2342), 1204 individuals (women = 332) were included. The univariable and multivariable (further adjusted for ASCVD-PCE) Cox regression analysis were used to evaluate the association of each potential ASCVD-REFs with hard CVD. Additionnaly, the role of different components of Mets and a history of gestational diabetes (GDM)/macrosomia was also examined. The predictive ability of each significant ASCVD-REFs, then was evaluated by the discrimination accuracy and risk reclassification index. During the 10-year follow-up, 73 hard CVD events occurred. Although in univariable analysis, high blood pressure (BP) component of Mets, GDM/macrosomia, and HDP remained as significant ASCVD-REFs, in the multivariable analysis, only the history of HDP (5.35 (1.22-23.38)) and GDM/macrosomia (3.18 (1.05-9.65)) showed independent risks. During the 15-year follow-up, Mets (1.47 (1.05-2.06)) and its components of high waist circumference (1.40 (1.0-1.95)) and high BP (1.52 (1.07-2.15)) significantly increased the risk. These ASCVD-REFs did not improve discrimination or predictive ability. In a decade follow-up, only conditions specific for women and in longer follow-up, the presence of Mets perse, and its components of high WC and high BP were shown as significant ASCVD-REFs.


Networks as a novel tool for studying team ball sports as complex social systems.
This paper describes and evaluates the novel utility of network methods for understanding human interpersonal interactions within social neurobiological systems such as sports teams. We show how collective system networks are supported by the sum of interpersonal interactions that emerge from the activity of system agents (such as players in a sports team). To test this idea we trialled the methodology in analyses of intra-team collective behaviours in the team sport of water polo. We observed that the number of interactions between team members resulted in varied intra-team coordination patterns of play, differentiating between successful and unsuccessful performance outcomes. Future research on small-world networks methodologies needs to formalize measures of node connections in analyses of collective behaviours in sports teams, to verify whether a high frequency of interactions is needed between players in order to achieve competitive performance outcomes.


[The impact of urbanization on malaria infection rate and parasite density in children in the municipality of Yopougon, Abidjan (Côte d'Ivoire)].
From September 23-30, 2005, we conducted a cross-sectional study in six townships of Yopougon, a municipality of Abidjan. These townships were grouped in three levels of urbanization (village, precarious township, and residential township). The main objective of this survey was to determine the impact of urbanization on the malaria infection (parasite) rate and parasite density, and their consequences on the heterogeneity of malaria transmission in urban Abidjan. Specifically we compared these rates in all three urbanization levels, selecting two townships for each level to take environmental specificities observed from previous data into account. The study included 400 households per township. All children younger than 5 years in these households were included. Thick and thin blood smears were taken for each child on slides, and each slide was examined by microscope after staining. The malaria infection rate was 21.8%, indicating mesoendemic malaria. Its distribution varied significantly between the three urbanization levels. Malaria parasite densities also varied significantly between them. These results confirm the involvement of urbanization in the heterogeneity of malaria transmission in the city of Abidjan.


Human MxA protein inhibits the replication of Crimean-Congo hemorrhagic fever virus.
Crimean-Congo hemorrhagic fever virus (CCHFV) belongs to the genus Nairovirus within the family Bunyaviridae and is the causative agent of severe hemorrhagic fever. Despite increasing knowledge about hemorrhagic fever viruses, the factors determining their pathogenicity are still poorly understood. The interferon-induced MxA protein has been shown to have an inhibitory effect on several members of the Bunyaviridae family, but the effect of MxA against CCHFV has not previously been studied. Here, we report that human MxA has antiviral activity against CCHFV. The yield of progeny virus in cells constitutively expressing MxA was reduced up to 1,000-fold compared with control cells, and accumulation of viral genomes was blocked. Confocal microscopy revealed that MxA colocalizes with the nucleocapsid protein (NP) of CCHFV in the perinuclear regions of infected cells. Furthermore, we found that MxA interacted with NP by using a coimmunoprecipitation assay. We also found that an amino acid substitution (E645R) within the C-terminal domain of MxA resulted in a loss of MxA antiviral activity and, concomitantly, in the capacity to interact with CCHFV NP. These results suggest that MxA, by interacting with a component of the nucleocapsid, prevents replication of CCHFV viral RNA and thereby inhibits the production of new infectious virus particles.


Effect of immunomodulators on bleomycin-induced lung injury.
The role of lymphocytes and their subpopulations in lung fibrosis is as yet unclear. To define the role of immunomodulation in bleomycin-induced inflammatory fibrotic lung injury, by testing the effect of two known Th1 inhibitors: linomide and pentoxifylline. C57BL/6 mice were treated by a single intratracheal instillation of 0.06 mg bleomycin in 0.01 ml saline or saline alone. Treatment groups included: (1) intratracheal bleomycin and daily treatment with linomide or pentoxifylline; (2) intratracheal bleomycin and daily water; (3) intratracheal saline and daily linomide or pentoxifylline; (4) intratracheal saline and daily water. Linomide and pentoxifylline were available per os in the drinking water from 1 day prior to intratracheal instillation. Animals were studied 14 days after intratracheal instillation. Lung injury was evaluated by total and differential cell count in bronchoalveolar lavage fluid, by a semiquantitative morphological index of lung injury and a quantitative image analysis of cellularity, fibrosis fraction and alveolar wall area fraction, and by biochemical analysis of lung hydroxyproline content. Linomide or pentoxifylline did not cause any lung injury in saline-treated control mice. Overt signs of lung injury were apparent in bleomycin-treated mice. These changes were not affected by daily treatment with linomide or pentoxifylline, which were given in the highest tolerable dose. This study does not support the use of linomide or pentoxifylline to prevent or ameliorate lung fibrosis and may suggest that drug-induced differentiation of T lymphocytes into Th1/th2 subpopulations does not affect the evolution of bleomycin-induced lung injury.


The Associations of Vitamin D Status with Athletic Performance and Blood-borne Markers in Adolescent Athletes: A Cross-Sectional Study.
The purpose of this study was to examine the associations of vitamin D status with athletic performance and blood-borne markers in adolescent athletes. This cross-sectional study included forty-seven Taekwondo athletes, aged 15-18 years old. Athletic performance was assessed using maximal oxygen consumption (VO2max), Wingate anaerobic power test, vertical jump, agility T-test, lower limb muscle strength, and fatigue resistance. Blood samples were collected to assess serum 25-hydroxyvitamin D [25(OH)D], free-testosterone, cortisol, creatine kinase, and urea. One-way ANOVAs were applied using Bonferroni adjusted alpha levels, which was 0.02 (i.e., 0.05/3). Multiple linear regressions analyses as well as Pearson and partial correlation analyses were used to examine the relationship among 25(OH)D concentration, athletic performance, and blood-borne markers. The participants 25(OH)D concentration were ranged from 16 to 73.25 nmol/L, indicating that 74.5% of the adolescent athletes have vitamin D insufficiency or deficiency. The vitamin D status did not show any significant effects on the performance factors or blood-borne markers. Serum 25(OH)D concentration was positively correlated with mean power output (r = 0.359, p < 0.05) and relative mean power output (r = 0.325, p < 0.05) after adjusting for bone age, height, weight, training experience, lean body mass, and fat mass. However, 25(OH)D concentration was not associated with other performance-related factors and blood-borne markers. In addition, multiple linear regressions analyses revealed that serum 25(OH)D concentration were not significant predictors of athletic performance in adolescent athletes. In conclusion, vitamin D status is weakly correlated with anaerobic capacity; moreover, the underlying mechanisms of how vitamin D influence anaerobic performance is unclear in the present study. Nevertheless, the importance of vitamin D on health benefits should not be underestimated, especially during growth periods.


Differential expression of H-2K and H-2D in the central nervous system of mice infected with Theiler's virus.
A model of demyelination induced by Theiler's murine encephalomyelitis virus (TMEV) was used to study differential regulation of class I MHC gene products in the brain and spinal cord of resistant (B10) and susceptible (B10.Q and B10.RBQ) mice. Allelic polymorphisms in the H-2D region, but not the H-2K region, play a primary role in determining susceptibility to late demyelinating disease. However, even though significant structural diversity distinguishes class I alleles, there are no discernible K or D-specific patterns of structural diversity within the peptide binding domains of these glycoproteins. Our hypothesis was that D region association of susceptibility to demyelination was related to differences in the expression of the K and D Ag in the central nervous system (CNS) after TMEV infection. Using allele-specific mAb and an immunoperoxidase technique, we demonstrated transient but equivalent increases in K and D Ag expression in the brain and spinal cord of resistant mice beginning 7 days after TMEV infection, which returned to baseline by 90 days. However, when genetically susceptible animals were examined, a significantly greater increase in D expression relative to K expression was seen in the brain and spinal cord at all post-infection observation periods. Immunosuppression of genetically resistant animals before TMEV infection, which results in viral persistence, was accompanied by equivalent increases in both the K and D Ag. Depletion of CD8+ T cells, but not CD4+ T cells, in susceptible mice ablated class I expression in the CNS in response to TMEV infection, implying that CD8+ cells contribute to the differential regulation of K and D Ag in the CNS. These findings are consistent with the hypothesis that differences in gene regulation may account for different roles of the K and D loci play in determining resistance and susceptibility to TMEV-induced demyelinating disease.


Jumping Stand Apparatus Reveals Rapidly Specific Age-Related Cognitive Impairments in Mouse Lemur Primates.
The mouse lemur (Microcebus murinus) is a promising primate model for investigating normal and pathological cerebral aging. The locomotor behavior of this arboreal primate is characterized by jumps to and from trunks and branches. Many reports indicate insufficient adaptation of the mouse lemur to experimental devices used to evaluate its cognition, which is an impediment to the efficient use of this animal in research. In order to develop cognitive testing methods appropriate to the behavioral and biological traits of this species, we adapted the Lashley jumping stand apparatus, initially designed for rats, to the mouse lemur. We used this jumping stand apparatus to compare performances of young (n = 12) and aged (n = 8) adults in acquisition and long-term retention of visual discriminations. All mouse lemurs completed the tasks and only 25 trials, on average, were needed to master the first discrimination problem with no age-related differences. A month later, all mouse lemurs made progress for acquiring the second discrimination problem but only the young group reached immediately the criterion in the retention test of the first discrimination problem. This study shows that the jumping stand apparatus allows rapid and efficient evaluation of cognition in mouse lemurs and demonstrates that about half of the old mouse lemurs display a specific deficit in long-term retention but not in acquisition of visual discrimination.


Bactericidal effect of colistin on planktonic Pseudomonas aeruginosa is independent of hydroxyl radical formation.
The bactericidal effect of several major types of antibiotics has recently been demonstrated to be dependent on the formation of toxic amounts of hydroxyl radicals (OH·) resulting from oxidative stress in metabolically active cells. Since killing by the antimicrobial peptide colistin does not require bacterial metabolic activity, we tested whether the bactericidal effect of colistin depends on the formation of OH·. In Pseudomonas aeruginosa cultures, OH-mediated killing by ciprofloxacin was demonstrated by decreased bacterial survival and induction of 3'-(p-hydroxyphenyl) fluorescein (HPF) fluorescence. OH·-mediated killing by ciprofloxacin was further confirmed by rescue of cells and reduction of HPF fluorescence due to prevention of OH· accumulation by scavenging with thiourea, by chelating with dipyridyl, by decreasing metabolism as well as by anoxic growth. In contrast, no formation of OH· was seen in P. aeruginosa during killing by colistin, and prevention of OH· accumulation could not rescue P. aeruginosa from killing by colistin. These results therefore demonstrate that the bactericidal activity of colistin on P. aeruginosa is not dependent on oxidative stress. In conclusion, antimicrobial peptides that do not rely on OH· formation should be considered for treatment of Gram-negative bacteria growing at low oxygen tension such as in endobronchial mucus and paranasal sinuses in cystic fibrosis patients, in abscesses and in infectious biofilm.


Binding of the pathogen receptor HSP90AA1 to avibirnavirus VP2 induces autophagy by inactivating the AKT-MTOR pathway.
Autophagy is an essential component of host innate and adaptive immunity. Viruses have developed diverse strategies for evading or utilizing autophagy for survival. The response of the autophagy pathways to virus invasion is poorly documented. Here, we report on the induction of autophagy initiated by the pathogen receptor HSP90AA1 (heat shock protein 90 kDa α [cytosolic], class A member 1) via the AKT-MTOR (mechanistic target of rapamycin)-dependent pathway. Transmission electron microscopy and confocal microscopy revealed that intracellular autolysosomes packaged avibirnavirus particles. Autophagy detection showed that early avibirnavirus infection not only increased the amount of light chain 3 (LC3)-II, but also upregulated AKT-MTOR dephosphorylation. HSP90AA1-AKT-MTOR knockdown by RNA interference resulted in inhibition of autophagy during avibirnavirus infection. Virus titer assays further verified that autophagy inhibition, but not induction, enhanced avibirnavirus replication. Subsequently, we found that HSP90AA1 binding to the viral protein VP2 resulted in induction of autophagy and AKT-MTOR pathway inactivation. Collectively, our findings suggest that the cell surface protein HSP90AA1, an avibirnavirus-binding receptor, induces autophagy through the HSP90AA1-AKT-MTOR pathway in early infection. We reveal that upon viral recognition, a direct connection between HSP90AA1 and the AKT-MTOR pathway trigger autophagy, a critical step for controlling infection.


High-power and high-gain organic dye-doped polymer optical fiber amplifiers: novel techniques for preparation and spectral investigation.
Rhodamine B (RB), Rhodamine 6G (R6G), Oxazine 4 perchlorate (O4PC), and 4-Dicyanomethylene-2-methyl-6-(p-dimethylaminostyryl-4H-pyran)-doped graded-index (GI) polymer optical fiber amplifiers (POFA's) were successfully prepared by novel techniques to prevent degradation of organic dyes and to enhance solubility of the dyes in methyl methacrylate and in poly(methyl methacrylate) (PMMA). High-power (620 W) and high-gain (33-dB, 2070 times) amplification was achieved for RB-doped GI POFA's based on the spectral investigation of dyes in PMMA bulk. It should be noted that amplification in the low-loss region of polymer optical fibers was achieved in the R6G- and O4PC-doped GI POFA.


Does disinfection of environmental surfaces influence nosocomial infection rates? A systematic review.
To review the evidence on the effects of disinfection of environmental surfaces in hospitals (as compared with cleaning without use of disinfectants) on the occurrence of nosocomial infections. Systematic review of experimental and nonexperimental intervention studies dealing with environmental disinfection or cleaning in different health care settings. A total of 236 scientific articles were identified. None described a meta-analysis, systematic review, or randomized controlled trial. Only 4 articles described completed cohort studies matching the inclusion criteria. None of these studies showed lower infection rates associated with routine disinfection of surfaces (mainly floors) versus cleaning with detergent only. Disinfectants may pose a danger to staff, patients, and the environment and require special safety precautions. However, targeted disinfection of certain environmental surfaces is in certain instances an established component of hospital infection control. Given the complex, multifactorial nature of nosocomial infections, well-designed studies that systematically investigate the role of surface disinfection are required.


Seeing how we smell.
PET allows noninvasive imaging of a variety of events in the body, including the activity of neuronal circuits in the brain that are involved in cognition and behaviors, by using radiotracers that detect relevant biological reactions. A major impediment to expanding PET applications to study the brain has been the lack of radiotracers that can identify and measure specific types of neurons or glial cells. In this issue of the JCI, Van de Bittner and colleagues describe a promising step toward solving this problem by identifying and describing a radiotracer, [11C]GV1-57, that appears to specifically label olfactory sensory neurons (OSNs), which are essential for olfaction (Figure 1). This tracer, if its specificity is confirmed, has the potential to become a prototype for future radiotracers that can identify other neuronal cell types and would allow visualization and in-depth characterization of these neurons and their genesis.


[High life expectancy of Muscovites at old ages: reality or statistical artifact?]
Since the mid-2000s, after a few decades of negative trends and fluctuations, Russia has experienced the longest and most stable period of life expectancy increasing for the entire period of observation which was determined not only by a decrease in mortality at the middle ages, but also at the old ages. This period has been marked by a very fast increase in life expectancy of Muscovites. The paper shows that the mortality at old ages in Moscow systematically deviates from the patterns observed in economically developed countries with reliable mortality statistics. We assume that experience of these countries is applicable to regions of Russia. Based on this assumption the adjusted estimates of life expectancy at old ages in Moscow and Russia were calculated, as well as effect of the underestimation of mortality over age 80 on life expectancy at birth and at the age of retirement.


Phosphorus-mediated alleviation of aluminum toxicity revealed by the iTRAQ technique in Citrus grandis roots.
Citrus grandis seedlings were irrigated with nutrient solutions with four Al-P combinations [two Al levels (0 mM and 1.2 mM AlCl3·6H2O) × two P levels (0 μM and 200 μM KH2PO4)] for 18 weeks. Al dramatically inhibited the growth of C. grandis seedlings, as revealed by a decreased dry weight of roots and shoots. Elevating P level could ameliorate the Al-induced growth inhibition and organic acid (malate and citrate) secretion in C. grandis. Using a comparative proteomic approach revealed by the isobaric tags for relative and absolute quantification (iTRAQ) technique, 318 differentially abundant proteins (DAPs) were successfully identified and quantified in this study. The possible mechanisms underlying P-induced alleviation of Al toxicity in C. grandis were proposed. Furthermore, some DAPs, such as GLN phosphoribosyl pyrophosphate amidotransferase 2, ATP-dependent caseinolytic (Clp) protease/crotonase family protein, methionine-S-oxide reductase B2, ABC transporter I family member 17 and pyridoxal phosphate phosphatase, were reported for the first time to respond to Al stress in Citrus plants. Our study provides some proteomic details about the alleviative effects of P on Al toxicity in C. grandis, however, the exact function of the DAPs identified herein in response to Al tolerance in plants must be further investigated.


PD-L1 Expression in Monocytes Correlates with Bacterial Burden and Treatment Outcomes in Active Pulmonary Tuberculosis.
The PD-1/PD-L1 pathway is critical in T cell biology; however, the role of the PD-1/PD-L1 pathway in clinical characteristics and treatment outcomes in pulmonary tuberculosis (PTB) patients is unclear. We prospectively enrolled PTB, latent TB infection (LTBI), and non-TB, non-LTBI subjects. The expression of PD-1/PD-L1 on peripheral blood mononuclear cells (PBMCs) was measured and correlated with clinical characteristics and treatment outcomes in PTB patients. Immunohistochemistry and immunofluorescence were used to visualize PD-1/PD-L1-expressing cells in lung tissues from PTB patients and from murine with heat-killed MTB (HK-MTB) treatment. A total of 76 PTB, 40 LTBI, and 28 non-TB, non-LTBI subjects were enrolled. The expression of PD-1 on CD4+ T cells and PD-L1 on CD14+ monocytes was significantly higher in PTB cases than non-TB subjects. PTB patients with sputum smear/culture unconversion displayed higher PD-L1 expression on monocytes. PD-L1-expressing macrophages were identified in lung tissue from PTB patients, and co-localized with macrophages in murine lung tissues. Mycobacterium tuberculosis (MTB) whole cell lysate/EsxA stimulation of human and mouse macrophages demonstrated increased PD-L1 expression. In conclusion, increased expression of PD-L1 on monocytes in PTB patients correlated with higher bacterial burden and worse treatment outcomes. The findings suggest the involvement of the PD-1/PD-L1 pathway in MTB-related immune responses.


Evolutionary relations of Hexanchiformes deep-sea sharks elucidated by whole mitochondrial genome sequences.
Hexanchiformes is regarded as a monophyletic taxon, but the morphological and genetic relationships between the five extant species within the order are still uncertain. In this study, we determined the whole mitochondrial DNA (mtDNA) sequences of seven sharks including representatives of the five Hexanchiformes, one squaliform, and one carcharhiniform and inferred the phylogenetic relationships among those species and 12 other Chondrichthyes (cartilaginous fishes) species for which the complete mitogenome is available. The monophyly of Hexanchiformes and its close relation with all other Squaliformes sharks were strongly supported by likelihood and Bayesian phylogenetic analysis of 13,749 aligned nucleotides of 13 protein coding genes and two rRNA genes that were derived from the whole mDNA sequences of the 19 species. The phylogeny suggested that Hexanchiformes is in the superorder Squalomorphi, Chlamydoselachus anguineus (frilled shark) is the sister species to all other Hexanchiformes, and the relations within Hexanchiformes are well resolved as Chlamydoselachus, (Notorynchus, (Heptranchias, (Hexanchus griseus, H. nakamurai))). Based on our phylogeny, we discussed evolutionary scenarios of the jaw suspension mechanism and gill slit numbers that are significant features in the sharks.


CD44 is a direct target of miR-199a-3p and contributes to aggressive progression in osteosarcoma.
Osteosarcoma is the most common primary bone malignancy in children and adolescents. Herein, we investigated the role of cluster of differentiation 44 (CD44), a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion, and migration in osteosarcoma. We constructed a human osteosarcoma tissue microarray with 114 patient tumor specimens, including tumor tissues from primary, metastatic, and recurrent stages, and determined the expression of CD44 by immunohistochemistry. Results showed that CD44 was overexpressed in metastatic and recurrent osteosarcoma as compared with primary tumors. Higher expression of CD44 was found in both patients with shorter survival and patients who exhibited unfavorable response to chemotherapy before surgical resection. Additionally, the 3'-untranslated region of CD44 mRNA was the direct target of microRNA-199a-3p (miR-199a-3p). Overexpression of miR-199a-3p significantly inhibited CD44 expression in osteosarcoma cells. miR-199a-3p is one of the most dramatically decreased miRs in osteosarcoma cells and tumor tissues as compared with normal osteoblast cells. Transfection of miR-199a-3p significantly increased the drug sensitivity through down-regulation of CD44 in osteosarcoma cells. Taken together, these results suggest that the CD44-miR-199a-3p axis plays an important role in the development of metastasis, recurrence, and drug resistance of osteosarcoma. Developing strategies to target CD44 may improve the clinical outcome of osteosarcoma.


Involvement of oxidative stress, NF-IL-6, and RANTES expression in dengue-2-virus-infected human liver cells.
The liver has been suspected to be one of the major targets of dengue virus infection. Here, we detected increasing secretion of the chemokine RANTES (regulated upon activation, normal T cell expressed and secreted), which functions to recruit the immune cells, in dengue-virus-infected liver cells and patients. Three luciferase reporter genes with various deletions at the 5'-end of the RANTES promoter were constructed to explore the RANTES activation mechanism in human liver cells. The reporter gene was optimally activated by dengue-2 virus when the RANTES promoter contains the region from the transcription starting site (+1) to the nucleotide at the -181 position. NF-IL-6 and an undefined factor forming DNA-protein complexes in the RANTES promoter E and A/B regions in the infected cells were demonstrated by electrophoretic mobility shift assay. Further analysis showed that oxidative stress was an upstream inducer of NF-IL-6 and RANTES signaling in dengue-virus-infected liver cells. This finding was demonstrated by three antioxidants (N-acetyl-l-cysteine, nitro-l-arginine methyl ester, and pyrrolidine dithiocarbamate) used to suppress the activation. In contrast, the DNA binding activity of the undefined factor was not affected by the antioxidant treatment, indicating the existence of an oxidant-independent pathway. We hypothesize that dengue virus infection of the liver cells may trigger both an oxidant-dependent and an oxidant-independent pathway to up-regulate RANTES mRNA expression through activating NF-IL-6 and an undefined factor, respectively. In conclusion, the present study suggests a new direction for the study of liver pathogenesis involving RANTES in host immune responses during dengue virus infection.


Apatinib treatment in extensive metastatic advanced thymic carcinoma.
Apatinib is a novel oral, anti-tumor, angiogenic-targeting drug that can selectively target vascular endothelial growth factor receptor-2 (VEGFR-2). In clinical trials, this new tyrosine kinase inhibitor (TKI) has been shown to be an effective and safe treatment for a variety of malignancies. Currently, there is a lack of studies of patients with thymic carcinoma; therefore, we present a case of advanced thymic carcinoma treated with apatinib after chemotherapy failure with multiple lung metastases. This patient has been taking a dose of 500 mg of apatinib per day, and his efficacy has achieved partial response (PR), according to the RECIST 1.1 standard, and progression-free survival (PFS) is 6.3 months at this point. Apatinib will continue as his maintenance treatment. During the treatment, drug-related toxicity and side effects were tolerable. Thus, apatinib may be a meaningful option for the treatment of advanced metastatic thymic carcinoma after chemotherapy failure.


Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients.
Postprandial hypertriglyceridemia and hyperglycemia are considered risk factors for cardiovascular disease. Evidence suggests that postprandial hypertriglyceridemia and hyperglycemia induce endothelial dysfunction and inflammation through oxidative stress. Statins and angiotensin type 1 receptor blockers have been shown to reduce oxidative stress and inflammation, improving endothelial function. Twenty type 2 diabetic patients ate 3 different test meals: a high-fat meal, 75 g glucose alone, and a high-fat meal plus glucose. Glycemia, triglyceridemia, endothelial function, nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6 were assayed during the tests. Subsequently, diabetics took atorvastatin 40 mg/d, irbesartan 300 mg/d, both, or placebo for 1 week. The 3 tests were performed again between 5 and 7 days after the start of each treatment. High-fat load and glucose alone produced a decrease in endothelial function and increases in nitrotyrosine, C-reactive protein, intercellular adhesion molecule-1, and interleukin-6. These effects were more pronounced when high-fat load and glucose were combined. Short-term atorvastatin and irbesartan treatments significantly counterbalanced these phenomena, and their combination was more effective than either therapy alone. This study confirms an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial function and inflammation, suggesting oxidative stress as a common mediator of such an effect. Short-term treatment with atorvastatin and irbesartan may counterbalance this phenomenon; the combination of the 2 compounds is most effective.


Regional grey matter atrophy in clinically isolated syndromes at presentation.
The presence and degree of neuronal degeneration already existing in patients at their initial presentation with a clinically isolated syndrome suggestive of multiple sclerosis (CIS) is unclear, and whole brain or whole normalised grey matter analyses have not demonstrated significant atrophy in CIS cohorts at clinical presentation. Voxel-based analyses allow detection of regional atrophy throughout the brain and, therefore, may be sensitive to regional atrophy in CIS patients, and these changes may correspond with clinical disability. This study used a modified voxel-based morphometry (VBM) method to correct for lesion effects to analyse regional atrophy and perform voxel-wise correlations between volume and clinical metrics in 41 untreated CIS patients at presentation compared with 49 healthy controls. The results confirmed that there was no significant difference in whole normalised grey matter volume between CIS and controls, whereas VBM showed significant areas of bilateral thalamic, hypothalamic, putamen and caudate atrophy. Voxel-wise correlations with clinical measures showed that cerebellar volumes correlated with clinical cerebellar function, nine-hole peg test scores and the Multiple Sclerosis Functional Composite (MSFC) score, and that the MSFC score was also correlated with putamen volume. Lastly, T1 lesion volumes were found to correlate with thalamic and hippocampal atrophy, suggesting a link between white matter lesions and grey matter degeneration at the earliest stages of multiple sclerosis. Atrophy is present in CIS patients at presentations, particularly in the thalamus, and other deep grey matter structures. Furthermore, the correlations with clinical metrics suggest the importance of this atrophy to clinical status and the correlation with T1 lesion load suggests a possible role of Wallerian degeneration.


[Uncovering the giardiasis-outbreak in Bergen 2004].
There was a large community outbreak of giardiasis in Bergen in the autumn of 2004 that was acknowledged about two months after the first patients became ill. The aim of this article is to describe the diagnostic approach of clinicians faced with an unexpected problem, and how they reacted when communicable disease was detected. A focus group interview was conducted with six of the 18 doctors who had requested stool examinations from patients in October 2004 with the aim of detecting parasites. This was after the first patients became ill, but before the outbreak was widely recognized. Discussions among doctors were instrumental, both in reaching the correct diagnosis, and in acknowledging a possible outbreak in the community. There was no uniform approach to reaching the diagnosis, but rather a common unravelling of a mutual problem. Doctors contacted or tried to make contact with public health authorities when at least one case was confirmed and this case was linked to other patients with diarrhoeal disease. Clinicians need meeting places where they can discuss problems that arise in everyday practice. Public health authorities and clinicians need better procedures for warning, reception and follow-up when outbreaks of communicable diseases are suspected.


[Iron-oxide-enhanced MR imaging of inflammatory atherosclerotic lesions: overview of experimental and initial clinical results].
Numerous pathologic studies in the 1990's have shown atherosclerosis to be a chronic inflammatory disorder. This new insight and the advent of new plaque-stabilizing drugs, in particular antilipemic agents (statins), have led to an increased clinical interest in the development of new imaging modalities. These are aimed at visualizing the inflammatory atherosclerotic wall lesion as reflecting the active progression of the disease process and at identifying so-called vulnerable or high-risk lesions that are associated with a higher rate of vascular complications. A diagnostic modality currently undergoing investigation in terms of its potential for the diagnostic assessment of atherosclerosis is contrast-enhanced magnetic resonance imaging (MRI) using certain blood pool contrast media such as ultrasmall superparamagnetic iron oxide (USPIO) particles. Endothelial dysfunction and macrophage infiltration are two crucial pathomechanisms of atherosclerosis and these mechanisms also underlie the accumulation of iron oxide particles in experimental and human atherosclerotic lesions. Experimental results furthermore suggest that there is selective uptake of iron oxide by thrombi. The following experimental MR imaging techniques have a potential for providing complementary diagnostic information in assessing atherosclerotic lesions: 1. Unenhanced MRI for visualizing vulnerable plaques (wall thickness, fibrous cap, lipid core). 2. Visualization of the vessel lumen and quantitative assessment of stenosis using iron-oxide-enhanced MR angiography. 3. Delayed MRI studies for the functional characterization of inflammatory lesions (T 2 -effects produced by iron oxide uptake in macrophages of inflammatory lesions) with a potential for identifying mural thrombus as a sign of plaque rupture (T 1 -effects produced by binding of iron oxide to the thrombus). This article presents the experimental and initial clinical results obtained with iron-oxide-enhanced MRI of atherosclerotic lesions.


A new transacting factor that modulates hypoxia-induced expression of the erythropoietin gene.
Hypoxia is a strong stimulus for the transcription of a set of genes, including erythropoietin and vascular endothelial growth factor. Here we report on the cloning, functional significance, and expression of a complementary DNA (cDNA) that is involved in hypoxia-mediated expression of these 2 genes. The full-length cDNA encodes a predicted protein of 806 amino acids that contains a leucine zipper motif. This protein, termed HAF for hypoxia-associated factor, binds to a 17-base pair (bp) region of the erythropoietin promoter, which was shown earlier to participate in hypoxia-induced expression of the erythropoietin gene. In Hep3B cells, clones modified to express HAF antisense RNA showed an attenuated response to hypoxia-mediated induction of both erythropoietin and vascular endothelial growth factor transcription. HAF showed sequence-specific interaction with a DNA element in the 5' untranslated region of VEGF gene. The HAF 2.6-kilobase (kb) messenger RNA (mRNA) is expressed in most adult tissues. The highest expression occurs in fetal liver and the least in adult liver. HAF is the murine homolog of Sart-1, a 125-kd human protein expressed in the nuclei of normal and malignant cells. (Blood. 2000;96:491-497)


[Work-related stress and mobbing: case series and gender differences].
The attention of international agencies and scientific community on mobbing (bullying) and work-related stress is increasing. However, research on gender differences and etiologic agents is still limited. This study describes the gender differences found in victims of mobbing and work-related stress in an Italian case series. Between 2001 and 2009, at the Occupational Medicine Unit of our Institution we examined 345 outpatients (197 women and 148 men) for suspected psychopathological work-related problems. After interdisciplinary diagnostic evaluation, the diagnosis of "mobbing syndrome" was formulated, according to international criteria (ICD-I0 and DSM-IV), in a minority of cases: 35 subjects. In the other workers, we found pre-existing psychiatric conditions (not related to work), or altered relationships dynamics with the colleagues. Significant gender differences emerged among people with "mobbing syndrome": there was a high prevalence of women (65%), with medium to high level of education; the most affected age group was between 34 and 45 years; several occupations were involved, with a clear preponderance of office workers. Women are mostly harassed for personal aspects related to emotional and relational factors; men for the content of their work. The knowledge of the phenomenon is an essential prerogative to contrast mobbing; this can be realized, at a preventive level, only through effective information and training for workers and employers, who have the legal obligation to preserve the integrity of the mental and physical status of their employees during the work.


Three-loop slope of the dirac form factor and the 1S lamb shift in hydrogen
The last unknown contribution to hydrogen energy levels at order malpha(7), due to the slope of the Dirac form factor at three loops, is evaluated in a closed analytical form. The resulting shift of the hydrogen nS energy level is found to be 3.016/n(3) kHz. Using the QED calculations of the 1S Lamb shift, we extract a precise value of the proton charge radius r(p) = 0.883+/-0.014 fm.


[Value of velocimetric studies in acrosyndromes of the upper extremities].
The velocimetric examination by Doppler effect of arteries and veins of the arm, forearm and hands, performed in an indifferent position, then during dynamic exercises, provides sometimes determining factors in the etiology of some vascular disorders of the upper extremities. Requiring learning, experience, time and patience, this examination is debatable, but, in our experience, absolutely necessary to the work-up of these disorders.