Antibacterial activity in colostrum and milk associated with protection of piglets against enteric disease caused by K88-positive Escherichia coli.
Piglets suckled by dams that had been vaccinated with K88 antigen were significantly more resistant to deaths caused by neonatal diarrhea after challenge with a large dose of a K88-positive enteropathogenic strain of Escherichia coli than piglets suckled by control dams. The factors most likely to be involved in protection of the piglets were investigated by comparing the antibacterial activities of serum and mammary secretions from the two groups of dams. Vaccination stimulated the production of K88 antibodies, which were associated with anti-adhesive activity directed against the adhesive properties of the K88 antigen, and of O8 antibodies; the latter antibodies were attributed to traces of O8 antigen in the vaccine. Neutralizing activity against heat-labile enterotoxin was present in several dams before vaccination but was not stimulated by bacteriostatic activities were similar in serum and mammary secretions from both groups of dams and appeared to play no significant role in the protective after parturition were atrributed to exposure of the dams to the challenge strain excreted by the piglets. It was concluded that neutralization of the adhesive properties of K88 antigen by K88 antibodies in colostrum and in milk contributed significantly to the protection of piglets from vaccinated dams. However, the contribution of antibacterial activities associated with the greater levels of O8 antibodies in colstrum from the vaccinated group cannot be entirely excluded.


Facing uncertainty - Pilot testing of a palliative prognostic index training with hospital aged care assessment teams.
Prognostic avoidance can delay discussions about older hospital patients' life expectancy. This pilot study examined the effects of a prognostic training program on hospital clinicians' knowledge and confidence in identifying older patients at risk of dying. Fifty-seven clinicians from aged care assessment teams at two Australian hospitals were introduced to the Palliative Prognostic Index, a 5-item checklist indicating prognoses between 3 and 6 weeks. Mixed-methods training evaluation included pre-post-training surveys and semi-structured interviews, conducted three months post-training. Clinicians used a combination of experience, knowledge, and intuition as strategies to generate prognoses. Allied health staff relied on intuition more often than medical and nursing staff. Prognostic tools were rarely used. Pre-post-training comparisons showed significant improvements in clinicians' knowledge and confidence in identifying signs of dying, particularly amongst allied health. Follow-up interviews highlighted advantages and challenges of using prognostic tools. Recommendations are made for addressing these.


Maternal prepregnancy body mass index and child psychosocial development at 6 years of age.
Both obesity and developmental disabilities have increased in recent decades. Limited studies suggest associations between maternal prepregnancy obesity and child neurodevelopment. The Infant Feeding Practices Study II, a US nationally distributed longitudinal study of maternal health and infant health and feeding practices, was conducted from 2005 to 2007. In 2012, mothers were recontacted for information on their children's health and development. We examined associations between maternal prepregnancy BMI and child psychosocial development in 1311 mother-child pairs included in this follow-up study. Children's development was assessed by maternal report of child psychosocial difficulties from the Strengths and Difficulties Questionnaire, past developmental diagnoses, and receipt of special needs services. Adjusting for sociodemographic factors, children of obese class II/III mothers (BMI >35.0) had increased odds of emotional symptoms (adjusted odds ratio [aOR] 2.24; 95% confidence interval [CI], 1.27-3.98), peer problems (aOR 2.07; 95% CI, 1.26-3.40), total psychosocial difficulties (aOR 2.17; 95% CI, 1.24-3.77), attention-deficit/hyperactivity disorder diagnosis (aOR 4.55; 95% CI, 1.80-11.46), autism or developmental delay diagnosis (aOR 3.13; 95% CI, 1.10-8.94), receipt of speech language therapy (aOR 1.93; 95% CI, 1.18-3.15), receipt of psychological services (aOR 2.27; 95% CI, 1.09-4.73), and receipt of any special needs service (aOR 1.99; 95% CI, 1.33-2.97) compared with children of normal weight mothers (BMI 18.5-24.9). Adjustment for potential causal pathway factors including pregnancy weight gain, gestational diabetes, breastfeeding duration, postpartum depression, and child's birth weight did not substantially affect most estimates. Children whose mothers were severely obese before pregnancy had increased risk for adverse developmental outcomes.


VP5 of infectious bursal disease virus is not essential for viral replication in cell culture.
Infectious bursal disease virus (IBDV), a member of the Birnaviridae family, encodes in its bisegmented double-stranded RNA genome four structural virion proteins, VP1, VP2, VP3, and VP4, as well as a nonstructural protein, VP5. Recently, the establishment of an infectious cRNA system for IBDV has been described (E. Mundt and V. N. Vakharia, Proc. Natl. Acad. Sci. USA 93:11131-11136, 1996). Here, we report the isolation of a VP5- IBDV mutant constructed by site-directed mutagenesis of the methionine start codon of VP5, followed by cRNA transfection. The resulting virus mutant was replication competent in cell culture, which indicates that VP5 is not required for productive replication of IBDV. Absence of VP5 expression was verified by lack of reactivity with newly established anti-VP5 monoclonal antibodies and polyclonal sera. VP5- IBDV exhibited a delay in replication in chicken embryo cells compared to the VP5+ parental virus. However, final yields were similar. Our results thus show that VP5 is nonessential for IBDV replication, which makes it a prime candidate for the construction of deleted, marked vaccines.


[Carotid artery stenosis and cerebral circulatory disorders (clinico-angiographic correlation)].
Data on the clinical and angiographic examinations of 192 patients with stenoses of the extracranial part of the carotid artery are compared. The state of the intracranial branches of the median cerebral artery was evaluated with the use of Ring-Waddington's grid. Seven neurological syndromes resulting from the pathology of the intracranial branches of the carotid artery system are specified. In 70% of the cases structural changes of the intracranial vessels were revealed, these changes being the most likely due to thromboembolism from the stenotic carotid artery. The anterior parietal branch was involved less frequently, and the posterior branches of the median cerebral and the orbitofrontal arteries were affected extremely rarely.


[Venous thromboembolic disease : diagnostic pathways and follow-up].
Venous thromboembolism (VTE) is one of the leading causes of mortality and morbidity worldwide, and its diagnosis and risk stratification remain a challenge. Therapy and follow-up are also essential in the management of this pathology. The aim of this article is to summarize the most recent recommendations in the diagnostic pathway, risk stratification and follow-up of the more severe and frequent forms of VTE, pulmonary embolism and deep vein thrombosis of the lower limbs.


Cartilage formation by cultured chondrocytes in a new scaffold made of poly(L-lactide-epsilon-caprolactone) sponge.
This study investigated the ability of chondrocytes grown in culture and inoculated into a newly developed biodegradable sponge to form ectopic cartilage tissue. Chondrocytes obtained from costochondral cartilage dissected from Lewis rats were cultured to allow proliferation and then were inoculated into a sponge consisting of a biodegradable polymer, poly (L-lactide-epsilon-caprolactone). The composites of chondrocytes and sponge were transplanted subcutaneously into Nude mice and removed after 4 weeks for histologic and Northern blot analysis. Staining with hematoxylin and eosin showed the formation of a cartilage-like structure in the sponge. Northern blot analysis of the total RNA in the composites showed the presence of aggrecan transcripts of about 9 kb. The poly (L-lactide-epsilon-caprolactone) sponge system, is suitable as a matrix for tissue-engineered cartilage.


Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer's disease: many pathways to neurodegeneration.
Recently, the oxidoreductase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), has become a subject of interest as more and more studies reveal a surfeit of diverse GAPDH functions, extending beyond traditional aerobic metabolism of glucose. As a result of multiple isoforms and cellular locales, GAPDH is able to come in contact with a variety of small molecules, proteins, membranes, etc., that play important roles in normal and pathologic cell function. Specifically, GAPDH has been shown to interact with neurodegenerative disease-associated proteins, including the amyloid-beta protein precursor (AbetaPP). Studies from our laboratory have shown significant inhibition of GAPDH dehydrogenase activity in Alzheimer's disease (AD) brain due to oxidative modification. Although oxidative stress and damage is a common phenomenon in the AD brain, it would seem that inhibition of glycolytic enzyme activity is merely one avenue in which AD pathology affects neuronal cell development and survival, as oxidative modification can also impart a toxic gain-of-function to many proteins, including GAPDH. In this review, we examine the many functions of GAPDH with respect to AD brain; in particular, the apparent role(s) of GAPDH in AD-related apoptotic cell death is emphasized.


Persistent Autoimmune Activation and Proinflammatory State in Post-Coronavirus Disease 2019 Syndrome.
The immunopathological pathways enabling post-coronavirus disease 2019 (COVID-19) syndrome (PCS) development are not entirely known. We underwent a longitudinal analysis of patients with COVID-19 who developed PCS aiming to evaluate the autoimmune and immunological status associated with this condition. Thirty-three patients were included for longitudinal clinical and autoantibody analyses, 12 of whom were assessed for cytokines and lymphocyte populations. Patients were followed for 7-11 months after acute COVID-19. Autoimmune profile and immunological statuses were evaluated mainly by enzyme-linked-immunosorbent assays and flow cytometry. Latent autoimmunity and overt autoimmunity persisted over time. A proinflammatory state was observed in patients with PCS characterized by up-regulated interferon-α, tumor necrosis factor-α, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-17A, IL-6, IL-1β, and IL-13, whereas interferon-γ-induced protein 10 (IP-10) was decreased. In addition, PCS was characterized by increased levels of Th9, CD8+ effector T cells, naive B cells, and CD4+ effector memory T cells. Total levels of immunoglobulin G S1-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies remained elevated over time. The clinical manifestations of PCS are associated with the persistence of a proinflammatory and effector phenotype induced by SARS-CoV-2 infection. This long-term persistent immune activation may contribute to the development of latent and overt autoimmunity. Results suggest the need to evaluate the role of immunomodulation in the treatment of PCS.


Neural Activity and Information Processing Capacity of Neuronal Culture.
Whether artificial or living, neural networks perform tremendously diverse kinds of information processing, such as visual feature extraction, speech recognition, motor control, and so on. Some studies have evaluated the computational ability of living neural networks based on the performances of specific tasks, yet could not comprehensively grasp the versatile ability. In this study, we investigated dissociated culture of neurons as a physical reservoir, which generates diverse outputs through linear regression, or readout, of the dynamical states. Based on the theory of reservoir computing, the potential computational capabilities of neuronal culture were evaluated by the information processing capacity (IPC), which indicates how a target function can be achieved from the given dynamics. As a result, we found that the neuronal culture exhibited significant IPC and that IPC varied with the inter-step interval (ISI), the time step of reservoir computing. The cultures exhibited a memory capacity of 10 time steps for computation, and this memory capacity decayed at an ISI of 5 ms or shorter. In addition, the IPC had a significant positive correlation with the intensity of the evoked response relative to spontaneous activity. The multiple regression model with evoked response and ISI showed the positive effect of evoked response and 30 ms as the best ISI for IPC. These results suggest that the distinct evoked response and the optimal time step to interact with the neuronal culture are key factors to uncover computational resources from the neuronal system.


The effect of the ketogenic diet on leptin, chemerin and resistin levels in children with epilepsy.
Recently, inflammation have been proposed as one of the mechanisms underlying the patology of drug-resistant epilepsy (DRE). Ketogenic diet (KD) is one of the therapeutic methods used in DRE. There are some data that adipokines may modulate inflammatory processes and their concentrations are influenced by KD. Therefore, the aim of this study was to evaluate the influence of KD on serum leptin, chemerin and resistin in children with DRE. A cross-sectional observational study performed on 72 subjects aged 3-9 years, divided into 3 groups: 24 children with DRE treated with KD, 26 treated with valproic acid (VPA), and a control group of 22 children. Anthropometric measurements (weight, heigth, BMI, waist to hip circumerences ratio) were performed in all participants. Biochemical tests included serum fasting glucose, insulin, beta-hydroxybutyric acid, lipid profile, alanine aminotransferase and aspartate aminotransferase activities and blood gasometry. Serum levels of leptin, chemerin and resistin were assayed using commercially available ELISA tests. Serum levels of leptin and chemerin in the KD group were significantly lower and resistin - higher in comparison to patients receiving VPA and the control group. In children treated with the KD, leptin concentrations correlate with insulin levels and HOMA-IR scores. Chemerin levels in this group, in contrast, show negative correlation with body mass and height expressed as standard deviation scores from the mean for age and sex. Modification of pro-inflammatory adipocytokine levels is potentially one of the mechanisms of anticonvulsant effects of KD in children with refractory epilepsy.


Complex formation between junctin, triadin, calsequestrin, and the ryanodine receptor. Proteins of the cardiac junctional sarcoplasmic reticulum membrane.
Several key proteins have been localized to junctional sarcoplasmic reticulum which are important for Ca2+ release. These include the ryanodine receptor, triadin, and calsequestrin, which may associate into a stable complex at the junctional membrane. We recently purified and cloned a fourth component of this complex, junctin, which exhibits homology with triadin and is the major 125I-calsequestrin-binding protein detected in cardiac sarcoplasmic reticulum vesicles (Jones, L. R., Zhang, L., Sanborn, K., Jorgensen, A. O., and Kelley, J. (1995) J. Biol. Chem. 270, 30787-30796). In the present study, we have examined the binding interactions between the cardiac forms of these four proteins with emphasis placed on the role of junctin. By a combination of approaches including calsequestrin-affinity chromatography, filter overlay, immunoprecipitation assays, and fusion protein binding analyses, we find that junctin binds directly to calsequestrin, triadin, and the ryanodine receptor. This binding interaction is localized to the lumenal domain of junctin, which is highly enriched in charged amino acids organized into "KEKE" motifs. KEKE repeats are also found in the common lumenal domain of triadin, which likewise is capable of binding to calsequestrin and the ryanodine receptor (Guo, W., and Campbell, K. P. (1995) J. Biol. Chem. 270, 9027-9030). It appears that junctin and triadin interact directly in the junctional sarcoplasmic reticulum membrane and stabilize a complex that anchors calsequestrin to the ryanodine receptor. Taken together, these results suggest that junctin, calsequestrin, triadin, and the ryanodine receptor form a quaternary complex that may be required for normal operation of Ca2+ release.


Live attenuated influenza vaccine provides superior protection from heterologous infection in pigs with maternal antibodies without inducing vaccine-associated enhanced respiratory disease.
Control of swine influenza A virus (IAV) in the United States is hindered because inactivated vaccines do not provide robust cross-protection against the multiple antigenic variants cocirculating in the field. Vaccine efficacy can be limited further for vaccines administered to young pigs that possess maternally derived immunity. We previously demonstrated that a recombinant A/sw/Texas/4199-2/1998 (TX98) (H3N2) virus expressing a truncated NS1 protein is attenuated in swine and has potential for use as an intranasal live attenuated influenza virus (LAIV) vaccine. In the present study, we compared 1 dose of intranasal LAIV with 2 intramuscular doses of TX98 whole inactivated virus (WIV) with adjuvant in weanling pigs with and without TX98-specific maternally derived antibodies (MDA). Pigs were subsequently challenged with wild-type homologous TX98 H3N2 virus or with an antigenic variant, A/sw/Colorado/23619/1999 (CO99) (H3N2). In the absence of MDA, both vaccines protected against homologous TX98 and heterologous CO99 shedding, although the LAIV elicited lower hemagglutination inhibition (HI) antibody titers in serum. The efficacy of both vaccines was reduced by the presence of MDA; however, WIV vaccination of MDA-positive pigs led to dramatically enhanced pneumonia following heterologous challenge, a phenomenon known as vaccine-associated enhanced respiratory disease (VAERD). A single dose of LAIV administered to MDA-positive pigs still provided partial protection from CO99 and may be a safer vaccine for young pigs under field conditions, where dams are routinely vaccinated and diverse IAV strains are in circulation. These results have implications not only for pigs but also for other influenza virus host species.


The effects of clinical pathways on professional practice, patient outcomes, length of stay, and hospital costs: Cochrane systematic review and meta-analysis.
This paper is a summary version of the previously published Cochrane review. It may increase the reach of the topic to health researchers and practitioners and encourage further discussion. The systematic review aims to summarize the evidence and assess the effect of clinical pathways on professional practice, patient outcomes, length of hospital stay, and hospital costs. The authors searched the Database of Abstracts of Reviews of Effectiveness, the Effective Practice and Organisation of Care Register, the Cochrane Central Register of Controlled Trials and bibliographic databases including MEDLINE, EMBASE, CINAHL, NHS EED, and Global Health. Twenty-seven studies considering a total of 11,398 participants were included for analysis. The main results were a reduction in in-hospital complications (odds ratio 0.58: 95% CI [0.36, 0.94] and improved documentation (odds ratio 11.95: 95% CI [4.72, 30.30]) associated with clinical pathways. Considerable variation in study design and settings prevented statistical pooling of results for length of stay (LOS) and hospital costs. The authors concluded that clinical pathways are associated with reduced in-hospital complications and improved documentation.


Numerical simulations of heating patterns and tissue temperature response due to high-intensity focused ultrasound.
The results of this paper show-for an existing high intensity, focused ultrasound (HIFU) transducer-the importance of nonlinear effects on the space/time properties of wave propagation and heat generation in perfused liver models when a blood vessel also might be present. These simulations are based on the nonlinear parabolic equation for sound propagation and the bio-heat equation for temperature generation. The use of high initial pressure in HIFU transducers in combination with the physical characteristics of biological tissue induces shock formation during the propagation of a therapeutic ultrasound wave. The induced shock directly affects the rate at which heat is absorbed by tissue at the focus without significant influence on the magnitude and spatial distribution of the energy being delivered. When shocks form close to the focus, nonlinear enhancement of heating is confined in a small region around the focus and generates a higher localized thermal impact on the tissue than that predicted by linear theory. The presence of a blood vessel changes the spatial distribution of both the heating rate and temperature.


Sleep Problems as Predictors in Attention-Deficit Hyperactivity Disorder: Causal Mechanisms, Consequences and Treatment.
Attention-deficit hyperactivity disorder (ADHD) is notorious for its debilitating consequences and early age of onset. The need for early diagnosis and intervention has frequently been underscored. Previous studies have attempted to clarify the bidirectional relationship between ADHD and sleep problems, proposing a potential role for sleep problems as early predictors of ADHD. Sleep deprivation, sleep-disordered breathing, and circadian rhythm disturbances have been extensively studied, yielding evidence with regard to their induction of ADHD-like symptoms. Genetic-phenotypic differences across individuals regarding the aforementioned sleep problems have been elucidated along with the possible use of these characteristics for early prediction of ADHD. The long-term consequences of sleep problems in individuals with ADHD include obesity, poor academic performance, and disrupted parent-child interactions. Early intervention has been proposed as an approach to preventing these debilitating outcomes of ADHD, with novel treatment approaches ranging from melatonin and light therapy to myofunctional therapy and adjustments of the time point at which school starts.


Comparison of social circumstances, substance use and substance-related harm in soon-to-be-released prisoners with and without intellectual disability.
The transition out of prison is likely to be a challenging time for prisoners with intellectual disability (ID). However, little evidence exists to inform interventions for people with ID making this transition. In this study we aimed to describe social circumstances, patterns of substance use and substance-related harm in soon-to-be-released prisoners with ID. We compare this group with those without ID, to better understand how the health-related needs of this group compare with the 'mainstream' prison population. Data came from face-to-face, confidential interviews with 1325 adult prisoners in seven adult prisons in Queensland, Australia. Prisoners with ID were identified using the Hayes Ability Screening Index (HASI). We used cross-sectional data to examine (i) demographics and criminographics; (ii) social circumstances; and (iii) substance use and substance use related harm. We compared characteristics of those with and without ID using univariable logistic regression. Prisoners with ID (n = 115) were more likely than their peers without ID to be male, to identify as Indigenous Australian, and to report low educational attainment (<10 years) and pre-incarceration unemployment. Those with ID reported a high prevalence of poly-drug use (28.0%), unsafe tattooing (51.1%), unsafe sex (91.0%) and HCV infection (55.6%), although differences with their peers were non-significant. The health and social needs of prisoners with ID transitioning into the community are a significant concern for researchers, policy makers and practitioners. Our findings highlight the need for proactive, appropriate and targeted service responses from disability, health and justice sectors.


New Insights into IDO Biology in Bacterial and Viral Infections.
Initially, indoleamine-2,3-dioxygenase (IDO) has been introduced as a bactericidal effector mechanism and has been linked to T-cell immunosuppression and tolerance. In recent years, evidence has been accumulated that IDO also plays an important role during viral infections including HIV, influenza, and hepatitis B and C. Moreover, novel aspects about the role of IDO in bacterial infections and sepsis have been revealed. Here, we review these recent findings highlighting the central role of IDO and tryptophan metabolism in many major human infections. Moreover, we also shed light on issues concerning human-specific and mouse-specific host-pathogen interactions that need to be considered when studying the biology of IDO in the context of infections.


Laser patterning of transparent polymers assisted by plasmon excitation.
Plasmon-assisted lithography of thin transparent polymer films, based on polymer mass-redistribution under plasmon excitation, is presented. The plasmon-supported structures were prepared by thermal annealing of thin Ag films sputtered on glass or glass/graphene substrates. Thin films of polymethylmethacrylate, polystyrene and polylactic acid were then spin-coated on the created plasmon-supported structures. Subsequent laser beam writing, at the wavelength corresponding to the position of plasmon absorption, leads to mass redistribution and patterning of the thin polymer films. The prepared structures were characterized using UV-Vis spectroscopy and confocal and AFM microscopy. The shape of the prepared structures was found to be strongly dependent on the substrate type. The mechanism leading to polymer patterning was examined and attributed to the plasmon-heating. The proposed method makes it possible to create different patterns in polymer films without the need for wet technological stages, powerful light sources or a change in the polymer optical properties.


Contraceptive Knowledge and Practice among Married Immigrant Women.
The purpose of this study was to investigate the contraceptive knowledge and practice among married immigrant women. A cross-sectional survey design with a convenient sampling was used. 170 married immigrant women were recruited in Daejeon city and Chungcheong area. A structured questionnaire was self-administered from November 1, 2011 to January 13, 2012. 48.2% of subjects have used contraceptive practice. The widely used contraception methods were IUD, condom, oral pill and withdrawal. 73.2% of subjects got information about contraception from family and friends, and 18.3% of subjects had no source of information. The subjects' employment state (p = .006), duration of marriage (p = .019), number of baby (p = .021), family type (p = .046) have a significant influence on their contraceptive practice. The subjects' mean score of contraceptive knowledge was very low (5.72 points out of 15 points). There were significant differences in subjects' contraceptive knowledge depending on their education level (p = .002), employment state (p < .001), country of origin (p = .010), and family type (p = .003). To improve contraceptive knowledge and practice for married immigrant women, it is necessary to develop a proper contraceptive education program to enhance contraceptive knowledge and practice. Adjusted education program by this results will contribute to increase sexual health for married immigrant women.


Acoustic properties of the normal chest.
Laënnec invented the stethoscope in 1816 and published a treatise on auscultation in 1819. We then had to wait until the 1950s to observe development of modern devices and methods of recording and signal-processing, which allowed objective studies of lung sounds in time and frequency fields. Tracheobronchial sounds generated by ventilation originate in the upper airways, the frequency content of these sounds has led to extensive research. Consolidated lungs act as more efficient sound conductors to the chest wall (bronchial breathing murmur). Tracheobronchial sounds contain higher frequency components compared to vesicular lung sounds. The origin of vesicular lung sounds has been becoming progressively clear for about 10 yrs. It is at least partly produced locally, deep, and probably intralobular. Clearly, further studies need to be performed in order to elucidate the true mechanisms involved in generating vesicular lung sounds, the redistribution of intrapulmonary gas or vibrations caused by the stretching of lung tissue. The devices developed are already useful for monitoring the state of patients in intensive care. Sooner or later, real time analysis and automated diagnosis will become available.


Spray Drying of Blueberry Juice-Maltodextrin Mixtures: Evaluation of Processing Conditions on Content of Resveratrol.
Resveratrol is an antioxidant abundant in red fruits, and one of the most powerful inhibiting reactive oxygen species (ROS) and oxidative stress (OS) produced by human metabolism. The effect of the spray drying processing conditions of blueberry juice (BJ) and maltodextrin (MX) mixtures was studied on content and retention of resveratrol. Quantitatively, analysis of variance (ANOVA) showed that concentration of MX was the main variable influencing content of resveratrol. Response surface plots (RSP) confirmed the application limits of maltodextrins based on their molecular weight, where low molecular weight MXs showed a better performance as carrying agents. After qualitatively comparing results for resveratrol against those reported for a larger antioxidant molecule (quercetin 3-D-galactoside), it was observed a higher influence of the number of active sites available for the chemical interactions, instead of stearic hindrance effects.


Potent inhibition of aldehyde dehydrogenase-2 by diphenyleneiodonium: focus on nitroglycerin bioactivation.
Aldehyde dehydrogenase-2 (ALDH2) catalyzes vascular bioactivation of the antianginal drug nitroglycerin (GTN) to yield nitric oxide (NO) or a related species that activates soluble guanylate cyclase (sGC), resulting in cGMP-mediated vasodilation. Accordingly, established ALDH2 inhibitors attenuate GTN-induced vasorelaxation in vitro and in vivo. However, the ALDH2 hypothesis has not been reconciled with early studies demonstrating potent inhibition of the GTN response by diphenyleneiodonium (DPI), a widely used inhibitor of flavoproteins, in particular NADPH oxidases. We addressed this issue and investigated the effects of DPI on GTN-induced relaxation of rat aortic rings and the function of purified ALDH2. DPI (0.3 µM) inhibited the high affinity component of aortic relaxation to GTN without affecting the response to NO, indicating that the drug interfered with GTN bioactivation. Denitration and bioactivation of 1-2 µM GTN, assayed as 1,2-glycerol dinitrate formation and activation of purified sGC, respectively, were inhibited by DPI with a half-maximally active concentration of about 0.2 µM in a GTN-competitive manner. Molecular modeling indicated that DPI binds to the catalytic site of ALDH2, and this was confirmed by experiments showing substrate-competitive inhibition of the dehydrogenase and esterase activities of the enzyme. Our data identify ALDH2 as highly sensitive target of DPI and explain inhibition of GTN-induced relaxation by this drug observed previously. In addition, the data provide new evidence for the essential role of ALDH2 in GTN bioactivation and may have implications to other fields of ALDH2 research, such as hepatic ethanol metabolism and cardiac ischemia/reperfusion injury.


The investigation of galectin-3 in diseases of the thyroid gland.
Malignant tumors of the thyroid gland exhibit a variety of histopathologies and clinical behavior. Immune markers are gaining more and more importance in diagnostic pathology, especially in the differential diagnostics and in the grading of thyroid gland tumors. The Authors investigated the immunohistochemical reaction of galectin-3 (gal3) in patients with various thyroid gland diseases. They tested the diagnostic value of gal3 in determining the benign or malignant nature of various lesions, especially in lesions of follicular origin, because previous results have indicated nearly 100% specificity and sensitivity in this regard. Gal3 immunoperoxidase reaction was carried out on 91 sections of thyroid gland samples fixed in formalin and embedded in paraffin. While gal3 expressed itself strongly and diffusely in papillary carcinomas (19 of 20 cases), in other malignant lesions it showed weaker, focal or variable positivity. Focal positivity was found in four of 19 follicular adenomas, and negativity was found in three of 10 follicular carcinomas. In all cases of inflammation a focal positivity was observed (eight of eight cases). All nodular goiter and normal thyroid tIssue were negative (25 of 25 cases). Based on our results, the gal3 immunohistochemical reaction seems to be reliable in the diagnosis of papillary carcinomas. However, in the case of solitary thyroid nodules and follicular lesions, although it is still a useful supplementary marker, it is not of absolute value (as stated in previous studies) in determining whether a tumor is benign or malignant.


Cloning of a tobacco apoplasmic invertase inhibitor. Proof of function of the recombinant protein and expression analysis during plant development.
Higher plants express several isoforms of vacuolar and cell wall invertases (CWI), some of which are inactivated by inhibitory proteins at certain stages of plant development. We have purified an apoplasmic inhibitor (INH) of tobacco (Nicotiana tabacum) CWI to homogeneity. Based on sequences from tryptic fragments, we have isolated a full-length INH-encoding cDNA clone (Nt-inh1) via a reverse transcriptase-polymerase chain reaction. Southern-blot analysis revealed that INH is encoded by a single- or low-copy gene. Comparison with expressed sequence tag clones from Arabidopsis thaliana and Citrus unshiu indicated the presence of Nt-inh1-related proteins in other plants. The recombinant Nt-inh1-encoded protein inhibits CWI from tobacco and Chenopodium rubrum suspension-cultured cells and vacuolar invertase from tomato (Lycopersicon esculentum) fruit, whereas yeast invertase is not affected. However, only in the homologous system is the inhibition modulated by the concentration of Suc as previously shown for INH isolated from tobacco cells. Highly specific binding of INH to CWI could be shown by affinity chromatography of a total cell wall protein fraction on immobilized recombinant Nt-inh1 protein. RNA-blot analysis of relative transcript ratios for Nt-inh1 and CWI in different parts of adult tobacco plants revealed that the expression of both proteins is not always coordinate.


The herpes simplex virus type 1 (HSV-1) regulatory protein ICP0 interacts with and Ubiquitinates p53.
Herpes simplex virus type 1 regulatory protein ICP0 contains a zinc-binding RING finger and has been shown to induce the proteasome-dependent degradation of a number of cellular proteins in a RING finger-dependent manner during infection. This domain of ICP0 is also required to induce the formation of unanchored polyubiquitin chains in vitro in the presence of ubiquitin-conjugating enzymes UbcH5a and UbcH6. These data indicate that ICP0 has the potential to act as a RING finger ubiquitin ubiquitin-protein isopeptide ligase (E3) and to induce the degradation of certain cellular proteins through ubiquitination and proteasome-mediated degradation. Here we demonstrate that ICP0 is a genuine RING finger ubiquitin E3 ligase that can interact with and mediate the ubiquitination of the major oncoprotein p53 both in vitro and in vivo. Ubiquitination of p53 requires ICP0 to have an intact RING finger domain and occurs independently of its ability to bind to the ubiquitin-specific protease USP7.


Physiologically based indices of volumetric capnography in patients receiving mechanical ventilation.
Several indices of ventilatory heterogeneity can be identified from the expiratory CO2 partial pressure or CO2 elimination versus volume curves. The aims of this study were: 1) to analyse several computerizable indices of volumetric capnography in order to detect ventilatory disturbances; and 2) to establish the relationship between those indices and respiratory system mechanics in subjects with normal lungs and in patients with acute respiratory distress syndrome (ARDS), both receiving mechanical ventilation. We studied six normal subjects and five patients with early ARDS mechanically ventilated at three levels of tidal volume (VT). Respiratory system mechanics were assessed by end-expiratory and end-inspiratory occlusion methods, respectively. We determined Phase III slopes, Fletcher's efficiency index, Bohr's dead space (VD,Bohr/VT), and the ratio of alveolar ejection volume to tidal volume (VAE/VT) from expiratory capnograms, as a function of expired volume. Differences between normal subjects and ARDS patients were significant both for capnographic and mechanical parameters. Changes in VT significantly altered capnographic indices in normal subjects, but failed to change ventilatory mechanics and VAE/VT in ARDS patients. After adjusting for breathing pattern, VAE/VT exhibited the best correlation with the mechanical parameters. In conclusion, volumetric capnography, and, specifically, the ratio of alveolar ejection volume to tidal volume allows evaluation and monitoring of ventilatory disturbances in patients with adult respiratory distress syndrome.


Deficient serotonin neurotransmission and depression-like serotonin biomarker alterations in tryptophan hydroxylase 2 (Tph2) loss-of-function mice.
Probably the foremost hypothesis of depression is the 5-hydroxytryptamine (5-HT, serotonin) deficiency hypothesis. Accordingly, anomalies in putative 5-HT biomarkers have repeatedly been reported in depression patients. However, whether such anomalies in fact reflect deficient central 5-HT neurotransmission remains unresolved. We employed a naturalistic model of 5-HT deficiency, the tryptophan hydroxylase 2 (Tph2) R439H knockin mouse, to address this question. We report that Tph2 knockin mice have reduced basal and stimulated levels of extracellular 5-HT (5-HT(Ext)). Interestingly, cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and fenfluramine-induced plasma prolactin levels are markedly diminished in the Tph2 knockin mice. These data seemingly confirm that low CSF 5-HIAA and fenfluramine-induced plasma prolactin reflects chronic, endogenous central nervous system (CNS) 5-HT deficiency. Moreover, 5-HT(1A) receptor agonist-induced hypothermia is blunted and frontal cortex 5-HT(2A) receptors are increased in the Tph2 knockin mice. These data likewise parallel core findings in depression, but are usually attributed to anomalies in the respective receptors rather than resulting from CNS 5-HT deficiency. Further, 5-HT(2A) receptor function is enhanced in the Tph2 knockin mice. In contrast, 5-HT(1A) receptor levels and G-protein coupling is normal in Tph2 knockin mice, indicating that the blunted hypothermic response relates directly to the low 5-HT(Ext). Thus, we show that not only low CSF 5-HIAA and a blunted fenfluramine-induced prolactin response, but also blunted 5-HT(1A) agonist-induced hypothermia and increased 5-HT(2A) receptor levels are bona fide biomarkers of chronic, endogenous 5-HT deficiency. Potentially, some of these biomarkers could identify patients likely to have 5-HT deficiency. This could have clinical research utility or even guide pharmacotherapy.


Herbal medicines in Brazil: pharmacokinetic profile and potential herb-drug interactions.
A plethora of active compounds found in herbal medicines can serve as substrate for enzymes involved in the metabolism of xenobiotics. When a medicinal plant is co-administered with a conventional drug and little or no information is known about the pharmacokinetics of the plant metabolites, there is an increased risk of potential herb-drug interactions. Moreover, genetic polymorphisms in a population may act to predispose individuals to adverse reactions. The use of herbal medicines is rapidly increasing in many countries, particularly Brazil where the vast biodiversity is a potential source of new and more affordable treatments for numerous conditions. Accordingly, the Brazilian Unified Public Health System (SUS) produced a list of 71 plant species of interest, which could be made available to the population in the near future. Physicians at SUS prescribe a number of essential drugs and should herbal medicines be added to this system the chance of herb-drug interactions further increases. A review of the effects of these medicinal plants on Phase 1 and Phase 2 metabolic mechanisms and the transporter P-glycoprotein was conducted. The results have shown that approximately half of these medicinal plants lack any pharmacokinetic data. Moreover, most of the studies carried out are in vitro. Only a few reports on herb-drug interactions with essential drugs prescribed by SUS were found, suggesting that very little attention is being given to the safety of herbal medicines. Here we have taken this information to discuss the potential interactions between herbal medicines and essential drugs prescribed to Brazilian patients whilst taking into account the most common polymorphisms present in the Brazilian population. A number of theoretical interactions are pinpointed but more pharmacokinetic studies and pharmacovigilance data are needed to ascertain their clinical significance.


Increases in reflex excitability of monkey masseter motoneurons before a jaw-bite reaction-time response.
Reflex excitability of the motoneurons innervating the masseter muscle of monkeys was tested before a phasic voluntary activation of the jaw-closing muscles (a RT bite response). Single test shocks were delivered to the Mes V which supplies a monosynaptic excitatory input to the jaw-muscle motoneurons. Changes in reflex excitability were assessed by measuring the amplitude of the synchronous muscle potential evoked by the test shock. Amplitudes of the muscle potentials evoked by shocks which occurred just before the beginning of the voluntary EMG response, as judged by the onset of EMG activity of the masseter muscle contralateral to the test shock were many times larger than potentials evoked immediately following the visual RT stimulus. Curves relating the average amplitude of the evoked response to its time before the beginning of the voluntary response suggest that the reflex excitability of the motoneuron pool begins to increase 25-45 ms before the first detectable EMG activity occurs. These results suggest that inputs arrive at the motoneurons of agonist muscles used in rapid RT tasks substantially before changes in the EMG of the muscle are noted. These results, in part, would account for the time interval noted between the beginning of neural activity in suprasegmental structures which presumably excites spinal motoneurons, and the first EMG activity of muscles which are innervated by these motoneurons.


Ethnic differences in eating patterns and their associations with obesity among adults in West China.
Despite observed ethnic differences in eating patterns and obesity, evidence in China is limited. This study examined ethnic differences in eating patterns and their associations with weight outcomes among multi-ethnic adults in West China. A cross-sectional survey collected self-reported data on demographics, eating behaviours, weight and height in 2021. Principal component analysis and multivariate regression were conducted to identify eating patterns and examine their associations with weight outcomes. In total, 4407 subjects aged ≥ 18 years were recruited across seven provinces in West China. Four eating patterns were identified: 'meat-lover' - characterised by frequent consumption of meat and dairy products, 'indulgent' - by frequent intakes of added salt, sugar, alcohol and pickled food, 'diversified-eating' - by frequently consuming food with diversified cooking methods and eating out and 'nutri-health-concerned' - by good food hygiene behaviours and reading food labels. Ethnic differences in eating patterns were observed. Compared with Han, Hui were less likely to exhibit meat-lover or diversified-eating patterns; Tibetans were less likely to have meat-lover or nutri-health-concerned patterns; Mongolians were more likely to have indulgent pattern. BMI was positively associated with meat-lover pattern in both genders (exp(β): 1·029; 95 % CI: 1·001, 1·058 for men; 1·018; 1·000, 1·036 for women) and negatively associated with nutri-health-concerned pattern in women (0·983; 0·966, 1·000). Mongolians were two times more likely to be overweight/obese than Han (OR: 3·126; 1·688, 5·790). Considerable ethnic differences existed in eating patterns in West China. Mongolians were more likely to be overweight/obese, which was associated with their indulgent eating patterns. Ethnic-specific healthy eating intervention programs are needed.


MEN15658: a new promising anti-tumoral drug active on resistant tumor cells.
We describe the identification of MEN15658, a molecule characterized by a promising cytotoxic effect against human tumor cell lines, including platinum- and anthracycline-resistant ovarian carcinoma. MEN15658 induces p53 accumulation, and activation of gadd-45, p21, c-fos and bcl-2 family genes in human ovarian carcinoma A2780 cell line. The compound causes a block in S phase of the cell cycle, inducing apoptotic cell death, thus suggesting an involvement of DNA damage in the MEN15658 effect on tumor cells. The anti-tumoral activity observed against the human ovarian carcinoma A2780 cell line xenotransplanted in nude mice makes this compound a new promising anti-tumoral drug.


Role of endogenous beta-adrenergic mechanism in the pathogenesis of spontaneous myocardial fibrosis in rats.
The role of endogenous beta-adrenergic activation in the pathogenesis of spontaneous myocardial fibrosis was investigated in male and female Sprague-Dawley (SD) rats. For the purpose of blocking endogenous beta-adrenergic activities, atenolol, a beta-adrenergic blocking a agent, was given at 20, 80 and 320 mg/kg/day mixed in the diet for 12 months. The transverse sections of the ventricles including the vulnerable region for spontaneous myocardial fibrosis was stained by Azan-Mallory method for collagen fibers and examined morphometrically, while being compared with the histological findings from standard hematoxylin-eosin procedure. The fibrosis was graded into 4 classes and compared between nontreated groups and treated groups of both sexes. Fibrous foci developed principally in the subendocardial myocardium. Atenolol failed to produce significant systemic toxic effects not only on weight gains and daily intakes of food but also on death rates. Atenolol did not prevent development of myocardial lesions in both sexes, whereas it significantly promoted fibrosis in the medium and high dose groups of male rats but not at any dose levels in female animals. It is suggested that endogenous beta-adrenergic activation plays no major role in the onset or development of spontaneous myocardial lesions, whereas the adrenergic system may probably control collagen synthesis in myocardial fibrosis.


The association of dissociative symptoms with exposure to trauma.
The Khyber Pakhtunkhwa province of North-West Pakistan has endured increased levels of violence in recent years. The psychological sequelae of such trauma including the presence of dissociative symptoms has been minimally investigated to date. The study examines psychopathology experienced including the presence of dissociative symptoms, and ascertain what factors are potentially predictive of these symptoms. Third-level students (n=303) completed psychometric instruments relating to their experience of traumatic events and assessed depression, anxiety and dissociative symptoms. Symptoms suggestive of post-traumatic stress disorder were evident in 28% of individuals. Symptoms relating to intrusive experiences and alterations in reactivity predicted dissociative, depressive and anxiety symptoms (p<0.01). Trauma related to violence in this study was associated with significant pathology including dissociative symptoms. Identification and subsequent treatment of dissociative symptoms in individuals who have experienced trauma, may have a significant ameliorating effect on levels of functioning and thus should be included in clinical assessment.


Surface hardness properties of resin-modified glass ionomer cements and polyacid-modified composite resins.
In this study the top and bottom surface hardness of two polyacid-modified composite resins (PMCRs), one resin-modified glass ionomer cement (RMGIC), and one composite resin were evaluated. The affect of water storage on their hardness was also investigated. The study was conducted using four different groups, each having five specimens obtained from fiberglass die molds with a diameter of 5 mm and a height of 2 mm. Measurements were made on the top and bottom surface of each specimen and recorded after 24 hours and again at 60 days. All tested materials showed different hardness values, and the values of top surfaces of the specimens were found to be higher than the bottom surface in all test groups. There was no statistical difference in the Vickers hardness (HV) values when the test specimens were kept in water storage. In conclusion Hytac displayed microhardness values higher than Vitremer and Dyract. We found the order of HV values to be Surfil > Hytac > Dyract > Vitremer, respectively. Vitremer presented the lowest microhardness level and Surfil the highest.


Economic analyses of phase III cooperative cancer group clinical trials: are they feasible?
Both economic and clinical evaluations of new pharmaceutical agents are important to physicians who practice in the current health care environment. While cooperative cancer groups carry out large-scale phase III clinical evaluations of these agents, few cooperative group studies incorporate economic analyses because of concerns over overburdening of data management, investigators, and statistical center personnel. In this study, we describe the results and operational considerations of one of the first completed economic analyses of a phase III cooperative group trial of the Eastern Cooperative Oncology Group (ECOG). We developed an economic model estimating economic benefits of yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjunct therapy for adult patients (56-70 years) with acute myelogenous leukemia. Clinical data were based on prospectively collected information from a recently reported double-blind phase III multi-institutional study carried out by ECOG. Retrospective economic data were obtained from financial information systems at our hospital, one of the study sites. The cost-minimization analyses were based on the perspective of a third-party payer. Indirect costs related to loss of earnings by patients and caregivers as well as quality-of-life adjustments were not incorporated into the model. Clinical trial results indicated that patients treated with GM-CSF had shorter times to recovery of absolute neutrophil count of 500 cells/mm3 and 1000 cells/mm3 and fewer serious infections than patients who received placebo following induction chemotherapy, while no significant differences were noted in red blood cell and platelet transfusion dependency, toxicities, and duration of hospitalization. The economic model estimated that the group treated with GM-CSF was estimated to have lower costs of care, associated with lower frequencies of serious infections and lower overall infection-related costs. Sensitivity analyses indicated that these results held true over a wide range of estimates of costs and infection rates. Prospective economic analyses of phase III cooperative cancer group clinical trials have not been completed to date. Strategies that are not likely to overburden data managers and statistical center personnel are possible to devise. However, these studies require careful planning and coordination between clinical trialists, economists, and health services researchers.


Phase retrieval with fast convergence employing parallel alternative projections and phase reset for coherent communications.
Phase-retrieval (PR) receivers can reconstruct complex-valued signals using only direct detection without the use of any optical carriers. We propose and demonstrate two PR receiver solutions with faster and better convergence. First, we demonstrate a PR receiver based on parallel alternative projections that are produced by propagating the signal through an array of dispersive elements of increasing length followed by direct detection. Fast convergence and high retrieved phase accuracy are achieved using a modified Gerchberg-Saxton (GS) algorithm that uses each projection as an intensity constraint. Second, we achieve similar performances employing an enhanced single projection GS algorithm with selective phase reset using symbol-wise GS errors. We experimentally reconstruct a 30 Gbaud QPSK signal after 55 km single-mode fiber transmission using the proposed solutions with a reduced number of iterations.


Radiology of carcinoid tumours of the small intestine.
Carcinoid tumors of the small intestine are particularly known in the literature for their hormonal activity and for the carcinoid syndrome caused by the serotonin they produce. The radiological symptoms are based, not only on changes caused by the tumour itself but also on changes induced by hormonal products in the intestinal wall and mesentery. The classical excentric intramural defect in the contrast column is therefore often accompanied by swollen mucosal folds, swelling of the intestinal wall and evidence of mesenteric retraction.


Prostate cancer immunotherapy: where are we and where are we going?
In this review, we present the progress and current landscape for prostate cancer immunotherapy and overview recent scientific findings that shed novel insights into immunoresistance and discuss potential therapeutic strategies. Prostate cancer immunogenicity is hampered by a highly immunosuppressive microenvironment and low mutation burden. Complex interactions between resident immunosuppressive cells such regulatory T cells, macrophages, myeloid-derived suppressor cells, and cancer cells cooperate to suppress antitumor immune responses and promote disease progression. A biphasic approach that boosts tumor immunogenicity and blockade of immunosuppressive pathways will most likely be required in order to produce meaningful therapeutic responses. Significant advances have shed new light on prostate cancer immunology. These findings should enhance the development of immunotherapeutic strategies, especially when used in combination with other cancer treatments.


Accuracy of maximum likelihood and least-squares estimates in the lidar slope method with noisy data.
The maximum likelihood estimator (MLE) is derived for retrieving the extinction coefficient and zero-range intercept in the lidar slope method in the presence of random and independent Gaussian noise. Least-squares fitting, weighted by the inverse of the noise variance, is equivalent to the MLE. Monte Carlo simulations demonstrate that two traditional least-squares fitting schemes, which use different weights, are less accurate. Alternative fitting schemes that have some positive attributes are introduced and evaluated. The principal factors governing accuracy of all these schemes are elucidated. Applying these schemes to data with Poisson rather than Gaussian noise alters accuracy little, even when the signal-to-noise ratio is low. Methods to estimate optimum weighting factors in actual data are presented. Even when the weighting estimates are coarse, retrieval accuracy declines only modestly. Mathematical tools are described for predicting retrieval accuracy. Least-squares fitting with inverse variance weighting has optimum accuracy for retrieval of parameters from single-wavelength lidar measurements when noise, errors, and uncertainties are Gaussian distributed, or close to optimum when only approximately Gaussian.


Anaemia and related nutrient deficiencies after Roux-en-Y gastric bypass surgery: a systematic review and meta-analysis.
To obtain a pooled risk estimate on the long-term impact of anaemia and related nutritional deficiencies in patients receiving Roux-en-Y gastric bypass (RYGB) surgery. Systematic review and meta-analysis. MEDLINE, EMBASE and Cochrane databases were searched to identify English reports published before 16 May 2014. Articles with case numbers >100, follow-up period >12 months, and complete data from both before and after surgery were selected. Outcomes of interest were changes in baseline measurements of proportion of patients with anaemia, by haemoglobin, haematocrit, ferritin, iron, vitamin B12 and folate levels. Two reviewers independently reviewed data and selected six prospective and nine retrospective studies with a total of 5909 patients. A random effect model with inverse variance weighting was used to calculate summary estimates of outcomes at 6, 12, 24 and 36 months postoperatively. Proportion of patients with anaemia was 12.2% at baseline, which, respectively, increased to 20.9% and 25.9% at 12 and 24 months follow-up, consistent with decreases in haemoglobin and haematocrit levels. Although the serum iron level did not change substantially after surgery, the frequency of patients with ferritin deficiency increased from 7.9% at baseline to 13.4% and 23.0% at 12 and 24 months, respectively, postoperation. Vitamin B12 deficiency increased from 2.3% at baseline to 6.5% at 12 months after surgery in those subjects receiving RYGB. There was no obvious increase in folate deficiency. RYGB surgery is associated with an increased risk of anaemia and deficiencies of iron and vitamin B12, but not folate. Ferritin is more sensitive when serum iron level is within normal range.


Effects of 1,25-dihydroxyvitamin D3 on colonic calcium transport in vitamin D-deficient and normal rats.
To determine whether prior vitamin D intake influences the intestinal calcium absorptive action of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], we measured in vitro the two unidirectional transepithelial fluxes of calcium across descending colon segments from rats fed either a vitamin D-deficient or normal diet and injected with either 10, 25, or 75 ng of 1,25(OH)2D3 or vehicle alone. Vitamin D deficiency abolished net calcium absorption [J net, -2 +/- 2 vs. 12 +/- 2 (SE) nmol X cm-2 X h-1, P less than 0.001], and 10 ng of 1,25(OH)2D3 raised J net to levels found in normal rats. Larger doses (25 and 75 ng) increased J net above levels in normal rats given the same dose. In normal rats only 75 ng of 1,25(OH)2D3 increased calcium J net above vehicle control values (12 +/- 2 vs. 38 +/- 4 nmol X cm-2 X h-1, P less than 0.001). Circulating 1,25(OH)2D3 measured by radioreceptor assay was well correlated with calcium transport. For each dose of 1,25(OH)2D3 higher serum 1,25(OH)2D3 levels were reached in vitamin D-deficient rats. Only the 75-ng dose increased circulating 1,25(OH)2D3 and colonic calcium transport in normal rats. Intravenous [3H]-1,25(OH)2D3 disappeared more rapidly from the circulation of normal rats, suggesting that accelerated metabolic degradative processes for 1,25(OH)2D3 may be present in normal but not in vitamin D-deficient rats and may account for the lack of a biological response to 1,25(OH)2D3 in normal animals.


Consensus on criteria for potential areas for wolf reintroduction in Mexico.
Given the conflict with human interests that in many cases results in the extirpation of large carnivores, acceptance of their reintroduction is a considerable challenge. By the 1980s Mexican wolves (Canis lupus) were extinct in the wild. In 1998 a population was reintroduced in the Blue Range Mountains of New Mexico (U.S.A.). Efforts to reintroduce the species in Mexico have been ongoing since the late 1980s. Four teams working independently identified 6 areas in northern Mexico in the historic range of Mexican wolves, where reintroductions could potentially be successful. Each team used different methods and criteria to identify the areas, which makes it difficult to prioritize among these areas. Therefore, members of the different teams worked together to devise criteria for use in identifying priority areas. They identified areas with high, intermediate, and low potential levels of conflict between wolves and humans. Areas with low potential conflict had larger buffers (i.e., distance from human settlement to areas suitable for wolves) around human settlements than high- and intermediate-conflict areas and thus were thought most appropriate for the first reintroduction. High-conflict areas contained habitat associated with wolf presence, but were closer to human activity. The first reintroduction of Mexican wolves to Mexico occurred in October 2011 in one of the identified low-conflict areas. The identification of suitable areas for reintroduction represents a crucial step in the process toward the restoration of large carnivores. Choice of the first reintroduction area can determine whether the reintroduction is successful or fails. A failure may preclude future reintroduction efforts in a region or country.


Facilitatory/inhibitory intracortical imbalance in REM sleep behavior disorder: early electrophysiological marker of neurodegeneration?
Previous studies found an early impairment of the short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) to transcranial magnetic stimulation (TMS) in Parkinson's disease. However, very little is known on the TMS correlates of rapid eye movement (REM) sleep behavior disorder (RBD), which can precede the onset of a α-synucleinopathy. The following TMS measures were obtained from 14 de novo patients with isolated RBD and 14 age-matched healthy controls: resting motor threshold, cortical silent period, latency and amplitude of the motor evoked potentials, SICI, and ICF. A cognitive screening and a quantification of subjective sleepiness (Epworth Sleepiness Scale [ESS]) and depressive symptoms were also performed. Neurological examination, global cognitive functioning, and mood status were normal in all participants. ESS score was higher in patients, although not suggestive of diurnal sleepiness. Compared to controls, patients exhibited a significant decrease of ICF (median 0.8, range 0.5-1.4 vs. 1.9, range 1.4-2.3; p < 0.01) and a clear trend, though not significant, towards a reduction of SICI (median 0.55, range 0.1-1.4 vs. 0.25, range 0.1-0.3), with a large effect size (Cohen's d: -0.848). REM Sleep Atonia Index significantly correlated with SICI. In still asymptomatic patients for a parkinsonian syndrome or neurodegenerative disorder, changes of ICF and, to a lesser extent, SICI (which are largely mediated by glutamatergic and GABAergic transmission, respectively) might precede the onset of a future neurodegeneration. SICI was correlated with the muscle tone alteration, possibly supporting the proposed RBD model of retrograde influence on the cortex from the brainstem.


Major urinary metabolites in hamsters and rats treated with N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine.
Rats and hamsters were administered a single dose of N-[1-14C]nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP), and their urinary metabolites were examined at various time intervals. In both species, urinary excretion of radiolabeled metabolites reached a plateau at 6 h following injection. At this time, 35 and 28% of the total dose was found in the urine of rats and hamsters, respectively. Separation by liquid chromatography and subsequent characterization by nuclear magnetic resonance, gas chromatography-mass spectroscopy, and infrared showed that the major metabolites in rat urine were HPOP, N-nitrosobis(2-hydroxypropyl)amine (BHP), and their glucuronic acid conjugates. The conjugates accounted for 30 and 9%, while free HPOP and BHP accounted for 42 and 16% of the total metabolites, respectively. Hamster urine, on the other hand, contained free HPOP, BHP, their glucuronic acid conjugates, and a sulfate ester of HPOP not found in rat urine. Six h following administration of HPOP, hamster urine contained BHP, BHP glucuronide, HPOP, HPOP glucuronide, and HPOP sulfate ester at levels of 35, 9, 16, 9, and 14%, respectively. These data suggest that hamsters reduce HPOP to BHP more efficiently than rats, while rats are more effective in forming their glucuronic acid conjugates. Hamsters differ significantly from rats in their capacity to form and excrete the sulfate ester of HPOP.


Apparent total tract digestibility of dietary calcium and phosphorus and their efficiency in bone mineral retention are affected by body mineral status in growing pigs.
Improving dietary P utilization without modifying pig performance is crucial for production sustainability. A feeding program comprising three 28-d phases (20 to 40, 40 to 70, and 70 to 100 kg) was used to feed 72 pigs with an initial BW of 20 kg. The ability of the pigs to modify the digestive and metabolic utilization of P when fed either a control (CON) diet or a low-P (LOW) diet providing 40% less digestible P with a constant Ca:digestible P was studied using different sequences of dietary P and Ca restriction (i.e., depletion [LOW]) and recovery (i.e., repletion [CON]), namely CON-CON-CON, CON-CON-LOW, CON-LOW-LOW, LOW-CON-CON, LOW-LOW-CON, and LOW-LOW-LOW. Bone mineral content (BMC) was measured in the lumbar region (L2-L4) by dual-energy X-ray absorptiometry at the beginning and end of each feeding phase. Total feces and urine were collected during phases 2 and 3. At the end of phase 1, BMC was lower in the LOW pigs than in the C pigs (29%; P < 0.001). During phase 2, the BMC gain was greater in the LOW-CON pigs than in the CON-CON pigs (16%; P < 0.001). During phase 3, the LOW-LOW-CON pigs absorbed 26% more Ca (P < 0.001) and retained 56% more BMC (P < 0.001) than the CON-CON-CON pigs did. Digestive and metabolic adaptations allowed the LOW-LOW-CON and LOW-CON-CON pigs to reach BMC similar to that of the CON-CON-CON pigs. These metabolic adaptations are promising, but practical applications of these results requires a better understanding of the underlying mechanisms to fine-tune the degree of depletion, pig age, and the duration of P and Ca depletion and repletion periods.


Acute myeloid leukemia developing in patients with autoimmune diseases.
Therapy-related acute myeloid leukemia is an unfortunate complication of cancer treatment, particularly for patients with highly curable primary malignancies and favorable life expectancy. The risk of developing therapy-related acute myeloid leukemia also applies to patients with non-malignant conditions, such as autoimmune diseases treated with cytotoxic and/or immunosuppressive agents. There is considerable evidence to suggest that there is an increased occurrence of hematologic malignancies in patients with autoimmune diseases compared to the general population, with a further increase in risk after exposure to cytotoxic therapies. Unfortunately, studies have failed to reveal a clear correlation between leukemia development and exposure to individual agents used for the treatment of autoimmune diseases. Given the dismal outcome of secondary acute myeloid leukemia and the wide range of available agents for treatment of autoimmune diseases, an increased awareness of this risk and further investigation into the pathogenetic mechanisms of acute leukemia in autoimmune disease patients are warranted. This article will review the data available on the development of acute myeloid leukemia in patients with autoimmune diseases. Possible leukemogeneic mechanisms in these patients, as well as evidence supporting the association of their primary immunosuppressive status and their exposure to specific therapies, will also be reviewed. This review also supports the idea that it may be misleading to label leukemias that develop in patients with autoimmune diseases who are exposed to cytotoxic agents as 'therapy-related leukemias'. A better understanding of the molecular defects in autoimmune disease patients who develop acute leukemia will lead to a better understanding of the association between these two diseases entities.


Magnetic collimation system for improving ion trap loading efficiency.
This work considers a solenoid-based magnetic collimation system for improving the efficiency of ion trap loading with ions created by laser ablation. We discuss a physical model of ion beam collimation in such a system, provide qualitative analytical estimates of its collimation characteristics, develop a numerical model of ion collimation based on a test-particle approach, and describe a real experimental setup where the proposed approach is effectively employed to collimate 232Th3+ and 88Sr1+ ions. The experimental results are compared with the results of the performed numerical modeling. The observed inconsistencies between the two are discussed, and their possible explanations are suggested.


Validating Reference Equations for Impulse Oscillometry in Healthy Mexican Children.
The impulse oscillometry system (IOS) measures the impedance (Z) of the respiratory system, but proper interpretation of its results requires adequate reference values. The objectives of this work were: (1) to validate the reference equations for the IOS published previously by our group and (2) to compare the adjustment of new available reference equations for the IOS from different countries in a sample of healthy children. Subjects were healthy 4-15-y-old children from the metropolitan area of Mexico City, who performed an IOS test. The functional IOS parameters obtained were compared with the predicted values from 12 reference equations determined in studies of different ethnic groups. The validation methods applied were: analysis of the differences between measured and predicted values for each reference equation; correlation and concordance coefficients; adjustment by Z-score values; percentage of predicted value; and the percentage of patients below the lower limit of normality or above the upper limit of normality. Of the 224 participants, 117 (52.3%) were girls, and the mean age was 8.6 ± 2.3 y. The equations that showed the best adjustment for the different parameters were those from the studies by Nowowiejska et al (2008) and Gochicoa et al (2015). The equations proposed by Frei et al (2005), Hellinckx et al (1998), Kalhoff et al (2011), Klug and Bisgaard (1998), de Assumpção et al (2016), and Dencker et al (2006) overestimated the airway resistance of the children in our sample, whereas the equation of Amra et al (2008) underestimated it. In the analysis of the lower and upper limits of normality, Gochicoa et al equation was the closest, since 5% of subjects were below or above percentiles 5 and 95, respectively. The study found that, in general, all of the equations showed greater error at the extremes of the age distribution. Because of the robust adjustment of the present study reference equations for the IOS, it can be recommended for both clinical and research purposes in our population. The differential adjustment of other equations underlines the need to obtain local reference values.


Prevalence and significance of potential drug-drug interactions among cancer patients receiving chemotherapy.
Cancer patients often receive multiple drugs to maximize their therapeutic benefit, treat co-morbidities and counter the adverse effects of chemotherapy. Concomitant administration of multiple drugs increases the risk of drug interactions leading to compromised therapeutic efficacy or safety of therapy. The purpose of this study was to identify the prevalence, levels and predictors of potential drug-drug interactions (pDDIs) among cancer patients. Six hundred and 78 patients receiving chemotherapy from two tertiary care hospitals were included in this cross-sectional study. Patient medication profiles were screened for pDDIs using the Micromedex® database. Logistic regression analysis was performed to identify the predictors of pDDIs. The overall prevalence of pDDIs was 78%, majority of patients had 1-2 pDDIs (39.2%). A total of 1843 pDDIs were detected. Major-pDDIs were most frequent (67.3%) whereas, a significant association of pDDIs was found between > 7 all prescribed drugs (p < 0.001) and ≥ 3 anti-cancer drugs (p < 0.001). Potential adverse outcomes of these interactions include reduced therapeutic effectiveness, QT interval prolongation, tendon rupture, bone marrow suppression and neurotoxicity. Major finding of this study is the high prevalence of pDDIs signifying the need of strict patient monitoring for pDDIs among cancer patients. Patients at higher risk to pDDIs include those prescribed with > 7 any types of drugs or ≥ 3 anticancer drugs. Moreover, list of most frequently identified major and moderate interactions will aid health care professional in timely identification and prevention of pDDIs.


Antibiotic-responsive histiocytic ulcerative colitis in 9 dogs.
Canine histiocytic ulcerative colitis (HUC) is characterized by colonic inflammation with predominantly periodic acid-Schiff (PAS)-positive macrophages. The inflammation results in colonic thickening, ulcerations, and distortion of normal glandular architecture. Resultant clinical signs consist of chronic large bowel diarrhea, tenesmus, and marked weight loss, and the disease frequently results in euthanasia. Conventional therapy consists of some combination of prednisone, azathioprine, sulfasalazine, and metronidazole. Nine dogs (8 Boxers and 1 English Bulldog) with histologic confirmation of HUC were treated with antibiotic therapy (either with enrofloxacin alone or in combination with metronidazole and amoxicillin). Clinical signs, physical examination findings, laboratory abnormalities, and the histologic severity of the disease were evaluated. Four of the 9 dogs had been treated previously with conventional therapy and had failed to respond favorably; then, these dogs were placed on antibiotic therapy (enrofloxacin, n = 1; enrofloxacin, metronidazole, and amoxicillin, n = 3) and had resolution of clinical signs within 3-12 days. Five dogs were treated solely with antibiotic therapy (enrofloxacin, n = 1; enrofloxacin and metronidazole, n = 1; enrofloxacin, metronidazole, and amoxicillin, n = 3), and clinical signs resolved in 2-7 days. Repeated biopsy specimens were obtained from 5 dogs after treatment, and all showed marked histologic improvement. The increase in body weight after treatment was statistically significant (P = .01). Three dogs currently are not on any treatment and have had resolution of clinical signs for up to 14 months. These observations suggest that an infectious agent responsive to antibiotics plays an integral role in the clinical manifestation of canine HUC, and they support the use of antibiotics in its treatment.


Import of mitochondrial carriers mediated by essential proteins of the intermembrane space.
In order to reach the inner membrane of the mitochondrion, multispanning carrier proteins must cross the aqueous intermembrane space. Two essential proteins of that space, Tim10p and Tim12p, were shown to mediate import of multispanning carriers into the inner membrane. Both proteins formed a complex with the inner membrane protein Tim22p. Tim10p readily dissociated from the complex and was required to transport carrier precursors across the outer membrane; Tim12p was firmly bound to Tim22p and mediated the insertion of carriers into the inner membrane. Neither protein was required for protein import into the other mitochondrial compartments. Both proteins may function as intermembrane space chaperones for the highly insoluble carrier proteins.


Efficient Imaging: Examining the Value of Ultrasound in the Diagnosis of Traumatic Adult Brachial Plexus Injuries, A Systematic Review.
Traumatic brachial plexus injury (BPI) can result in debilitating sequelae of the upper extremity. Presently, therapeutic decisions are based on the mechanism of injury, serial physical examination, electromyography, nerve conduction, and imaging studies. While magnetic resonance imaging is the current imaging modality of choice for BPI, ultrasound is a promising newcomer that is inexpensive, accessible, and available at point of care. To evaluate ultrasound as a diagnostic tool in the assessment of traumatic adult BPI through a systematic review. An electronic literature search was completed in MEDLINE, EMBASE, CINAHL, and Cochrane databases up to July 2016. Two independent reviewers completed the screening and data extraction. Methodological quality of studies was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Statistical analysis was used to estimate pooled sensitivities and study heterogeneity. Seven studies were included. Four studies compared the detection of pre- and postganglionic lesions at different levels (C5-T1) to surgical exploration as the reference standard. Sensitivity of lesion detection was greater in the upper and middle spinal nerves: C5 (93%, confidence interval [CI] = 78%-100%), C6 (94%, CI = 82%-100%), and C7 (95%, CI = 86%-100%) than in the lower: C8 (71%, CI = 36%-95%) and T1 (56%, CI = 29%-81%). Individual studies demonstrate ultrasound as an effective diagnostic tool for traumatic adult BPI. Sensitivity of lesion detection was noted to be greater in the upper and middle (C5-C7) than in the lower spinal nerves (C8, T1). Further standardized studies should be performed to confirm the utility of ultrasound in the diagnosis of traumatic adult BPI.


New testing and calculation method for determination viscoelasticity of optical glass.
Viscoelastic properties of glass within molding temperatures, such as shear relaxation modulus and bulk relaxation modulus, are key factors to build successful numerical model, predict forming process, and determine optimal process parameters for precision glass molding. However, traditional uniaxial compression creep tests with large strains are very limited in obtaining high-accuracy viscoelastic data of glass, due to the declining compressive stress caused by the increasing cross-sectional area of specimen in testing process. Besides, existing calculation method has limitation in transforming creep data to viscoelasticity data, especially when Poisson's ratio is unknown at molding temperature, which further induces a block to characterize viscoelastic parameter. This study proposes a systematic acquisition method for high-precision viscoelastic data, including creep testing, viscoelasticity calculation, and finite element verification. A minimal uniaxial creep testing (MUCT) method based on thermo-mechanical analysis (TMA) instrument is first built to obtain ideal and accurate creep data, by keeping compressive stress as a constant. A new calculation method on viscoelasticity determination is then proposed to derive shear relaxation modulus without the need of knowing bulk modulus or Poisson's ratio, which, compared with traditional method, extends the application range of viscoelasticity calculation. After determination, the obtained viscoelastic data are further incorporated into a numerical simulation model of MUCT to verify the accuracy of the determined viscoelasticity. Base on the great consistence between simulated and measured results (uniaxial creep displacement), the proposed systematic acquisition method can be used as a high accuracy viscoelasticity determination method.


The anti-apoptotic effect of IGF-1 on tissue resident stem cells is mediated via PI3-kinase dependent secreted frizzled related protein 2 (Sfrp2) release.
Previous studies suggest that IGF-1 may be used as an adjuvant to stem cell transfer in order to improve cell engraftment in ischemic tissue. In the current study, we investigated the effect of IGF-1 on serum deprivation and hypoxia induced stem cell apoptosis and the possible mechanisms involved. Exposure of adipose tissue derived stem cells (ASCs) to serum deprivation and hypoxia resulted in significant apoptosis in ASC which is partially prevented by IGF-1. IGF-1's anti-apoptotic effect was abolished in ASCs transfected with Sfrp2 siRNA but not by the control siRNA. Using Western blot analysis, we demonstrated that serum deprivation and hypoxia reduced the expression of nuclear beta-catenin, which is reversed by IGF-1. IGF-1's effect on beta-catenin expression was abolished by the presence of PI3-kinase inhibitor LY294002 or in ASCs transfected with Sfrp2 siRNA. These results suggest that IGF-1, through the release of the Sfrp2, contributes to cell survival by stabilizing beta-catenin.


Endoscopic carpal tunnel release using the subligamentous two-portal technique.
The surgical treatment for entrapment neuropathy of the median nerve in the carpal tunnel is varied. Recent publications have demonstrated a closed, endoscopic method for release of the carpal tunnel using a two-portal technique. In this report, a surgical technique for performing a subligamentous modification of this two-portal procedure is discussed, and the special tools used in this approach are demonstrated. In the early portion of this series of 75 symptomatic hands in 65 patients, 8% (6/75 hands) developed transient postoperative ulnar nerve neuropraxia. One patient experienced an iatrogenic laceration of the median nerve. Following the institution of the subligamentous approach, no postoperative nerve complications occurred. The majority of the patients experienced a significant decrease in their median nerve symptoms. This procedure has been found to be safe and is equally as effective as open surgical treatment of patients with carpal tunnel syndrome.


[Psychological approach in pediatric oncology (author's transl)].
An attempt to describe the procedures with fatally ill children, from a psychotherapeutic point of view is made. Special attention is paid to selecting nursing staff assigned to those children, requiring highly human and professional qualifications. Children with mild or severe psychopathological reactions, and/or their parents, are referred to Psychiatric Services for individual and/or family therapy. At the same time, group therapy is carried with parents. Finally, parents are followed in order to prevent unwanted psychopathological reactions after death of the child.


Normative Data for Critical Speed and D' for High-Level Male Rugby Players.
Kramer, M, Clark, IE, Jamnick, N, Strom, C, and Pettitt, RW. Normative data for critical speed and D' for high-level male rugby players. J Strength Cond Res 32(3): 783-789, 2018-The critical speed (CS) concept helps characterize the aerobic and anaerobic fitness of an athlete. Rugby players should, hypothetically, have modest CS values but extremely high curvature constant (D') values, yet, normative data are currently unavailable. To develop normative data of CS and D' for high-level male rugby players, a total of 30 male rugby players were recruited from the Eastern Cape of South Africa. All subjects performed the running 3-minute all-out exercise test (3 MT) using global positioning system (GPS) technology to determine CS and D'. The GPS data were used to determine the total distance and velocities performed, and to examine for pacing effects. Summary statistics of mean ± SD are provided. High total running speeds for the initial 150 seconds (S150s = 5.79 ± 0.59 m·s), and total distance (3 MT distance = 871.5 ± 71.9 m) were observed. A total of 13 of 30 subjects surpassed the 300 m D' value (mean D' = 288.2 ± 49.1 m). The CS of the total group was 3.87 ± 0.55 m·s. All 3 MT-derived data were categorized using standard nine (stanine) tables that allowed for the generation of normative data with which future performances, performances across similar sporting domains, and more accurate contrasts across the literature can be compared. Skewing of CS and D' was observed between forwards and backs, therefore, between-group differences in neither CS nor D' were observed (p > 0.05). Comparisons with previous literature indicate that male rugby players have higher CS values than female rugby players. When compared with Olympic distance runners, male rugby players have markedly higher D' values and markedly lower CS values. The 3 MT provides a useful procedure for assessing and prescribing high-intensity interval training for rugby athletes.


Tailored therapy of adult acute leukaemia in Jehovah's Witnesses: unjustified reluctance to treat.
Treatment of acute leukaemia in adult Jehovah's Witnesses (JW) is challenging because of 'a priori' refusal of most physicians to apply diagnostic and therapeutic procedures to haematological abnormalities resembling acute leukaemia. Rejection of blood transfusions by individuals of this faith is usually blamed to justify this attitude, thus leading to severe personal, medical and psychological distress related to the lack of care. We therefore intended to verify whether a standard (tailored) chemotherapy, without the use of prophylactic blood product transfusions, could be applied during treatment of acute leukaemia under such circumstances. Eleven consecutive JW adult patients with acute leukaemia, all of whom had been denied care in other institutions, were treated at the European Institute of Oncology (EIO) in Milan, Italy. Five had acute lymphoblastic leukaemia (ALL) (one bcr/abl positive), six had acute myeloid leukaemia (AML) with immunophenotype and/or cytogenetic intermediate-high risk features, except one patient with acute promyelocytic leukaemia (APML). Standard induction chemotherapy [cytosine arabinoside (ARA-C) and daunorubicin (DNR) for AML, vincristine (VCR), DNR and prednisone (PDN) for ALL, all-trans retinoic acid (ATRA) and DNR for APML] with the antracycline dose of at least 30 mg/sqm were used. All patients experienced severe anaemia after induction chemotherapy despite erythropoietin. Median haemoglobin nadir for patients with ALL and AML was 4.5 g/dL (range 1.3-6.9) and 5.1 g/dL (range 2.6-6.8), respectively. Median platelet nadir counts for all patients was 14.5 x 10(9))/L (range 1-24). One patient died during induction probably due to haemorrhage. Four of five patients with ALL achieved a complete remission (CR) (including the bcr/abl case) while among patients with AML only the one with APML achieved CR. Three patients (APML = 1 and ALL = 2) are still alive and disease-free. This small series of adult patients with leukaemia illustrates difficulties in treating patients who are practising JW, yet nevertheless provides a significant argument against the prejudicial decision leading to evasion of treatment in these patients.


rMSI: an R package for MS imaging data handling and visualization.
R platform provides some packages that are useful to process mass spectrometry imaging (MSI) data; however, none of them provide an easy to use graphical user interface (GUI). Here, we introduce rMSI, an R package for MSI data analysis focused on providing an efficient way to manage MSI data together with a GUI integrated in R environment. MS data is loaded in rMSI custom format optimized to minimize the memory footprint yet maintaining a fast spectra access. The rMSI GUI is designed for simple and effective data exploration and visualization. Moreover, rMSI is designed to be integrated in the R environment through a library of functions that can be used to share MS data across others R packages. The release of rMSI for R environment establishes a novel and flexible platform for MSI data analysis, completely free and open-source. The code, the documentation, a tutorial and example data are available open-source at: github.com/prafols/rMSI. email@example.com. Supplementary data are available at Bioinformatics online.


Post-transplant recurrence of steroid resistant nephrotic syndrome in children: the Italian experience.
Steroid resistant nephrotic syndrome (SRNS) is a frequent cause of end stage renal disease in children and post-transplant disease recurrence is a major cause of graft loss. We identified all children with SRNS who underwent renal transplantation in Italy, between 2005 and 2017. Data were retrospectively collected for the presence of a causative gene mutation, sex, histology, duration of pre-transplant dialysis, age at onset and transplant, HLA matching, recurrence, therapy for recurrence, and graft survival. 101 patients underwent a first and 22 a second renal transplant. After a median follow-up of 58.5 months, the disease recurred on the first renal transplant in 53.3% of patients with a non-genetic and none with a genetic SRNS. Age at transplant > 9 years and the presence of at least one HLA-AB match were independent risk factors for recurrence. Duration of dialysis was longer in children with relapse, but did not reach statistical significance. Overall, 24% of patients lost the first graft, with recurrence representing the commonest cause. Among 22 patients who underwent a second transplant, 5 suffered of SRNS recurrence. SRNS relapsed in 5/9 (55%) patients with disease recurrence in their first transplant and 2 of them lost the second graft. Absence of a causative mutation represents the major risk factor for post-transplant recurrence in children with SRNS, while transplant can be curative in genetic SRNS. A prolonged time spent on dialysis before transplantation has no protective effect on the risk of relapse and should not be encouraged. Retransplantation represents a second chance after graft loss for recurrence.


APACHE-acute physiology and chronic health evaluation: a physiologically based classification system.
Investigations describing the utilization pattern and documenting the value of intensive care are limited by the lack of a reliable and valid classification system. In this paper, the authors describe the development and initial validation of acute physiology and chronic health evaluation (APACHE), a physiologically based classification system for measuring severity of illness in groups of critically ill patients. APACHE uses information available in the medical record. In studies on 582 admissions to a university hospital ICU and 223 admissions to a community hospital ICU, APACHE was reliable in classifying ICU admissions. In validation studies involving these 805 admissions, the acute physiology score of APACHE demonstrated consistent agreement with subsequent therapeutic effort and mortality. This was true for a broad range of patient groups using a variety of sensitivity analyses. After successful completion of multi-institutional validation studies, the APACHE classification system could be used to control for case mix, compare outcomes, evaluate new therapies, and study the utilization of ICUs.


Taping patients with clinical signs of subacromial impingement syndrome: the design of a randomized controlled trial.
Shoulder problems are a common complaint of the musculoskeletal system. Physical therapists treat these patients with different modalities such as exercise, massage, and shoulder taping. Although different techniques have been described, the effectiveness of taping has not yet been established. The aim of this study is to assess the effectiveness and cost-effectiveness of usual physical therapy care in combination with a particular tape technique for subacromial impingement syndrome of the shoulder compared to usual physical therapy care without this tape technique in a primary healthcare setting. An economic evaluation alongside a randomized controlled trial will be conducted. A sample of 140 patients between 18 and 65 years of age with a diagnosis of subacromial impingement syndrome (SAIS) as assessed by physical therapists will be recruited. Eligible patients will be randomized to either the intervention group (usual care in combination with the particular tape technique) or the control group (usual care without this tape technique). In both groups, usual care will consist of individualized physical therapy care. The primary outcomes will be shoulder-specific function (the Simple Shoulder Test) and pain severity (11-point numerical rating scale). The economic evaluation will be performed using a societal perspective. All relevant costs will be registered using cost diaries. Utilities (Quality Adjusted Life Years) will be measured using the EuroQol. The data will be collected at baseline, and 4, 12, and 26 weeks follow-up. This pragmatic study will provide information about the effectiveness and cost-effectiveness of taping in patients presenting with clinical signs of SAIS. NTR2575.


Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase.
Acetyl-coenzyme A carboxylases (ACCs) are required for the biosynthesis and oxidation of long-chain fatty acids. They are targets for therapeutics against obesity and diabetes, and several herbicides function by inhibiting their carboxyltransferase (CT) domain. We determined the crystal structure of the free enzyme and the coenzyme A complex of yeast CT at 2.7 angstrom resolution and found that it comprises two domains, both belonging to the crotonase/ClpP superfamily. The active site is at the interface of a dimer. Mutagenesis and kinetic studies reveal the functional roles of conserved residues here. The herbicides target the active site of CT, providing a lead for inhibitor development against human ACCs.


Suppressive Effects of Ginsenoside Rh1 on HMGB1-Mediated Septic Responses.
High mobility group box 1 (HMGB1) is considered as a late mediator of sepsis and the inhibition of HMGB1-mediated severe inflammatory responses, and restoration of endothelial integrity have emerged as attractive therapeutic strategies for the management of sepsis. Ginsenoside Rh1, a protopanaxatriol type ginsenoside, is one of the major bioactive components of Korean red ginseng, which has been increasingly used for enhancing cognition and physical health worldwide. Ginsenoside Rh1 exhibits potent biological activities such as antistress, anti-oxidant, anti-inflammatory and immunomodulatory effects. We examined the effects of ginsenoside Rh1 on HMGB1-mediated septic responses and survival rate in a mouse model of sepsis. Ginsenoside-Rh1 was administered after the HMGB1 challenge. The antiseptic activity of ginsenoside Rh1 was determined by measuring the permeability, leukocyte adhesion and migration, activation of pro-inflammatory proteins in HMGB1-activated human umbilical vein endothelial cells (HUVECs) and mice, and the survival rate in a sepsis mouse model. Ginsenoside Rh1 significantly reduced HMGB1 release in lipopolysaccharide (LPS)-activated HUVECs. Furthermore, ginsenoside Rh1 suppressed the production of tumor necrosis factor (TNF)- α , interleukin (IL)-6, activation of nuclear factor (NF)- κ B and extracellular signal-regulated kinase (ERK) 1/2 by HMGB1. Ginsenoside Rh1 also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with ginsenoside Rh1 reduced the cecal ligation and puncture (CLP)-induced release of HMGB1, sepsis-related mortality and tissue injury in vivo. Our results indicated that ginsenoside Rh1 might be useful in the treatment of sepsis by targeting HMGB1.


Rapid evolution of HIV-1 to functional CD8⁺ T cell responses in humanized BLT mice.
The development of mouse/human chimeras through the engraftment of human immune cells and tissues into immunodeficient mice, including the recently described humanized BLT (bone marrow, liver, thymus) mouse model, holds great promise to facilitate the in vivo study of human immune responses. However, little data exist regarding the extent to which cellular immune responses in humanized mice accurately reflect those seen in humans. We infected humanized BLT mice with HIV-1 as a model pathogen and characterized HIV-1-specific immune responses and viral evolution during the acute phase of infection. HIV-1-specific CD8(+) T cell responses in these mice were found to closely resemble those in humans in terms of their specificity, kinetics, and immunodominance. Viral sequence evolution also revealed rapid and highly reproducible escape from these responses, mirroring the adaptations to host immune pressures observed during natural HIV-1 infection. Moreover, mice expressing the protective HLA-B*57 allele exhibited enhanced control of viral replication and restricted the same CD8(+) T cell responses to conserved regions of HIV-1 Gag that are critical to its control of HIV-1 in humans. These data reveal that the humanized BLT mouse model appears to accurately recapitulate human pathogen-specific cellular immunity and the fundamental immunological mechanisms required to control a model human pathogen, aspects critical to the use of a small-animal model for human pathogens.