Dietary interventions for multiple sclerosis.
Clinical and experimental data suggest that certain dietary regimens, particularly those including polyunsaturated fatty acids (PUFAs) and vitamins, might improve outcomes in people with multiple sclerosis (MS). Diets and dietary supplements are much used by people with MS in the belief that they might improve disease outcomes and overcome the effectiveness limits of conventional treatments.This is an update of the Cochrane review "Dietary intervention for multiple sclerosis" (first published on The Cochrane Library 2007, Issue 1). To answer MS patients' questions regarding the efficacy and safety of dietary regimens for MS. Can changes in dietary habits be an effective intervention for MS patients? Are the potential side effects of these interventions known, and have they been measured? Are potential interactions between dietary interventions and other curative or symptomatic treatments known and have they been studied? We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (November 2011), CENTRAL (The Cochrane Library 2011, Issue 4), MEDLINE (PubMed) (1966 to November 2011), EMBASE (embase.com) (1974 to November 2011) and reference lists of papers found. All controlled trials (randomised controlled trials (RCTs) and controlled clinical trials (CCTs)) on a specific dietary intervention, diet plan or dietary supplementation, except for vitamin D supplementation, compared to no dietary modification or placebo were eligible. Two review authors independently selected articles, assessed trial quality and extracted data. Data were entered and analysed in RevMan.Dichotomous data were summarised as relative risks (RR) with 95% confidence intervals (95% CI) using a random-effects model in the presence of heterogeneity (I² > 60%). Continuous data were analysed using weighted mean differences, determined by the difference between the pre- and post-intervention changes in the treatment and control groups. Six RCTs that investigated PUFAs emerged from the search strategy, accounting for 794 randomised patients.PUFAs did not have a significant effect on disease progression at 24 months. Omega-6 fatty acids (11 to 23 g/day linoleic acid) didn't show any benefit in 144 MS patients (RR 1.04, 95% CI 0.66 to 1.63). Linoleic acid (2.9 to 3.4 g/day) had no benefit in 65 chronic progressive MS patients (RR 0.78, 95% CI 0.43 to 1.42). Omega-3 fatty acids had no benefit in 292 relapsing remitting MS patients (RR 0.82, 95% CI 0.65 to 1.03, P = 0.08).Slight potential benefits in relapse outcomes were associated with omega-6 fatty acids in some studies, however these findings were limited by the reduced validity of the endpoints. No judgements about safety or patient-reported outcomes were possible. In general, trial quality was poor.No studies on vitamin supplementation and allergen-free diets were analysed as none met the eligibility criteria, mainly due to lack of clinical outcomes. PUFAs seem to have no major effect on the main clinical outcome in MS (disease progression), but they may tend to reduce the frequency of relapses over two years. However, the data that are available are insufficient to assess a real benefit or harm from PUFA supplementation because of their uncertain quality.Evidence on the possible benefits and risks of vitamin supplementation and antioxidant supplements in MS is lacking. More research is required to assess the effectiveness of dietary interventions in MS.


Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis.
Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [(123)I]-IBZM (radiotracer for dopamine D2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [(123)I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.


Elder Abuse: Global Situation, Risk Factors, and Prevention Strategies.
Elder mistreatment is now recognized internationally as a pervasive and growing problem, urgently requiring the attention of health care systems, social welfare agencies, policymakers, and the general public. In this article, we provide an overview of global issues in the field of elder abuse, with a focus on prevention. This article provides a scoping review of key issues in the field from an international perspective. By drawing primarily on population-based studies, this scoping review provided a more valid and reliable synthesis of current knowledge about prevalence and risk factors than has been available. Despite the lack of scientifically rigorous intervention research on elder abuse, the review also identified 5 promising strategies for prevention. The findings highlight a growing consensus across studies regarding the extent and causes of elder mistreatment, as well as the urgent need for efforts to make elder mistreatment prevention programs more effective and evidence based.


Dual functionality nanobioconjugates targeting intracellular bacteria in cancer cells with enhanced antimicrobial activity.
Bacterial drug resistance has emerged as a serious global threat mandating the development of novel methodologies that allow facile modulation of antimicrobial action in a controlled fashion. Conjugating antibiotics to nanoparticles helps to meet this goal by increasing the drug's overall avidity, bioavailability and easier internalisation into mammalian cells, targeting bacteria that otherwise escape antibacterial action by host cell-localisation. We used polymyxin B sulfate (PMB) and sushi peptide as model drugs against Gram-negative bacteria and established their enhanced antimicrobial activity on Escherichia coli (E. coli) cells after conjugation to gold nanoparticles (AuNPs). The efficacy of the bioconjugates was also tested on Salmonella typhi (S. typhi) bacteria infected into cervical cancer cells (HeLa) and further improved through specific targeting via folate receptors. Our results demonstrate significantly lower inhibitory concentration values for sushi-NP assemblies as compared to free drug, especially at optimal drug loading levels. No major cytotoxicity was observed in mammalian cells alone.


High-risk multimorbidity patterns on the road to cardiovascular mortality.
Multimorbidity, the co-occurrence of two or more diseases in one patient, is a frequent phenomenon. Understanding how different diseases condition each other over the lifetime of a patient could significantly contribute to personalised prevention efforts. However, most of our current knowledge on the long-term development of the health of patients (their disease trajectories) is either confined to narrow time spans or specific (sets of) diseases. Here, we aim to identify decisive events that potentially determine the future disease progression of patients. Health states of patients are described by algorithmically identified multimorbidity patterns (groups of included or excluded diseases) in a population-wide analysis of 9,000,000 patient histories of hospital diagnoses observed over 17 years. Over time, patients might acquire new diagnoses that change their health state; they describe a disease trajectory. We measure the age- and sex-specific risks for patients that they will acquire certain sets of diseases in the future depending on their current health state. In the present analysis, the population is described by a set of 132 different multimorbidity patterns. For elderly patients, we find 3 groups of multimorbidity patterns associated with low (yearly in-hospital mortality of 0.2-0.3%), medium (0.3-1%) and high in-hospital mortality (2-11%). We identify combinations of diseases that significantly increase the risk to reach the high-mortality health states in later life. For instance, in men (women) aged 50-59 diagnosed with diabetes and hypertension, the risk for moving into the high-mortality region within 1 year is increased by the factor of 1.96 ± 0.11 (2.60 ± 0.18) compared with all patients of the same age and sex, respectively, and by the factor of 2.09 ± 0.12 (3.04 ± 0.18) if additionally diagnosed with metabolic disorders. Our approach can be used both to forecast future disease burdens, as well as to identify the critical events in the careers of patients which strongly determine their disease progression, therefore constituting targets for efficient prevention measures. We show that the risk for cardiovascular diseases increases significantly more in females than in males when diagnosed with diabetes, hypertension and metabolic disorders.


[Treatment by Bach flowers: magical potion or factual medicine? A review of the literature].
In 1930, Dr Edward Bach developed flower essences known as Bach flowers. Today, over 70 years later, they are becoming more and more popular and are used by many practitioners, despite a total lack of scientific support for their use. A review of the literature on the controversial use of this alternative treatment is discussed.


[Use of plasma scalpel and one-layer suture in resection of the stomach].
110 cases of resection of the stomach with transection of the stomach and the duodenum by plasmic scalpel and suturing of curvatura minor of the stump and anastomosis with the use of original one-layer sero-muscular-submucosal suture have been analysed. Changes in gastric wound at the site of plasma transection were evaluated microscopically. It was established that plasma transection of the stomach is aseptic, hemostatic, thermal trauma is minimal and does not exceed the level of 3-4 mm from transection line. Favourable conditions for applications of one-layer suture contribute much to a decrease of the number of stitch puncture, to rejection of catgut, to reduction of tissue mass involved and deformation of intestinal wall. In the early postoperative period wound and anastomoses healing occurred without substantial inflammatory changes. 109 patients were operated by Billroth-1 and 1 patient--by Billroth-II. One patient died (lethality 0.9%). Early postoperative complications occurred in 7.2% of operated patients.


Morphological effects of oestradiol-17beta, and selective oestrogen receptor alpha and beta agonists on luteinising hormone-secreting cells in tamoxifen-treated ovariectomised rats.
To investigate the role played by the different rat gonadotroph oestrogen receptor (ER) pools in the effects of oestradiol-17beta (E2) on gonadectomy cells, two-week ovariectomised (OVX) rats were used. The basic experimental group of rats was injected with 3 mg of the selective ER modulator tamoxifen (TX) on days 15-20 after OVX. Groups of TX-treated OVX rats were additionally injected on days 18-20 after OVX with 10 microg oestradiol benzoate (EB), 1 mg of the selective ERalpha agonist propylpyrazole triol (PPT), or 1 mg of the selective ERbeta diarylpropionitrile (DPN). Negative and positive control groups were OVX rats injected over six days after OVX with 0.2 ml oil and EB, respectively. On day 21 after OVX, anterior pituitary glands were dissected out and divided into halves. One hemipituitary was processed for light microscopy and immunocytochemistry for betaLH subunit and progesterone receptor (PR), and the other hemipituitary for ultrastructural evaluation. Results showed that: gonadotrophs were the only pituitary cell type expressing PR; treatment with TX alone shrunk gonadectomy cells and induced both reorganization of membrane-enclosed intracellular organelles and PR expression, and treatment with DPN or EB, but not PPT, reduced the agonistic morphological effects of TX. Considering that TX activates nuclear ERalpha, the results indicate that activation of nuclear ERalpha is determinant for the reversal effects of E2 on gonadotrope morphology and PR expression, and the simultaneous activation of ERbeta modulates the action of ERalpha in an inhibitory fashion.


Gene expression profiling of neu-induced mammary tumors from transgenic mice reveals genetic and morphological similarities to ErbB2-expressing human breast cancers.
Numerous studies have shown that the overexpression and amplification of ErbB2/Neu are observed in 20-30% of patients afflicted with breast cancer. Furthermore, it has also been observed that the elevated expression of ErbB2/Neu also correlates with poor prognosis and clinical outcome. Given the prevalence of this disease, we sought to create mouse models that mimic the human condition. In this study, we compared two mouse models expressing activated neu under the control of the endogenous and mouse mammary tumor virus promoters. Although histologically similar, the latency and metastatic potential of these tumors are remarkably different. Gene expression profiling of tumor RNA from the two Neu mouse models revealed distinctive and nonoverlapping patterns of gene expression. Consistent with noninvasive nature of the mammary tumors induced by expression of neu under the endogenous promoter, these tumors expressed a number of markers characteristic of a highly differentiated state. In addition to these differences, these analyses revealed that in contrast to the mouse mammary tumor virus-based Neu model, the endogenous promoter tumors expressed elevated levels of two genes (Grb7 and Cab1) that are closely linked to ErbB2 and often coamplified in noninvasive ductal carcinoma in situ. Furthermore, this analysis has revealed several transcription factors that may be involved in ErbB2-mediated tumorigenesis. Taken together, these results illustrate the similarity of the endogenously regulated Neu tumor model to the human disease.


Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions.
Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.


Investigation of zinc and copper levels in methimazole-induced hypothyroidism: relation with the oxidant-antioxidant status.
Thyroid hormones are associated with the oxidative and antioxidative status of the organism. Depression of metabolism by hypothyroidism has been reported to decrease oxidant production and thus protect tissues against oxidant damage. The purpose of the present study was to investigate Zn and Cu levels in MMI-induced hypothyroidism and to show whether there is a connection between these trace elements and the oxidant-antioxidant status in experimental hypothyroidism. 3-Nitrotyrosine was measured as a marker of nitro-oxidative stress. In order to examine the antioxidant status of MMI-induced hypothyroidism in rats, GSH and SOD levels were determined as well. Significantly decreased 3-nitrotyrosine, Cu and Zn levels were observed in our experimental model when compared with the controls. On the other hand, GSH and SOD levels remained constant. It may be suggested that Cu and Zn serve as antioxidant molecules and exert their effects in an indirect manner to reduce oxidative stress in experimental hypothyroidism.


The potential role of cotinine in the cognitive and neuroprotective actions of nicotine.
Cotinine is a primary metabolite of nicotine that has been suggested in many studies in animals and in humans to exert measurable effects on aspects of on-going behavior or on cognitive function. Much of the interest in cotinine derives from its long pharmacological half-life (15-19 hours) relative to nicotine (2-3 hours). Despite decades of study focusing on nicotine as the predominant behaviorally active component of tobacco, there continue to be aspects of the pharmacology of the drug that have yet to be explained. For example, nicotine can evoke a protracted behavioral response, i.e., in great excess of the presence of the drug in the plasma. Also, there is often a striking differential between the potency for nicotine-induced behavioral responses in humans and animals, and its potency as a cholinergic agonist, neurochemically. One possibility that may explain one or more of these properties of nicotine is the presence of a long-lived bioactive metabolite or breakdown product of nicotine such as cotinine. Preliminary data in support of this hypothesis are consistent with the ability of cotinine to improve performance accuracy on delayed matching task by macaque monkeys, and in reversing apomorphine-induced deficits in prepulse inhibition of acoustic startle in rats. The drug also was shown to be as potent as nicotine in the ability to act as a cytoprotective agent in cells that express a neuronal cholinergic phenotype. This new appreciation for the role of cotinine in nicotine's actions, and as a pharmacological agent in its own right, particularly in aspects of cognitive function and for neuroprotection, ultimately may be applied towards the treatment of Alzheimer's disease and related disorders, and for various psychiatric syndromes.


Pharmacokinetic pitfalls of present antiepileptic medications.
Some patients fail to respond to antiepileptic drugs (AEDs) or their response varies over time. Unexpected fluctuations in AED concentrations can cause loss of seizure control or side effects. Recent advances in AED clinical pharmacology have characterized a number of factors that alter AED concentrations. Storage of carbamazepine (CBZ) and phenytoin (PHT) formulations in hot, humid conditions alters the dosage form and reduces bioavailability up to 50%. Diurnal changes in gastrointestinal physiology affect disintegration of valproate (VPA) enteric-coated tablets, reducing nighttime drug concentrations 30 to 40% compared with daytime values. Drug-drug interactions or pathophysiologic conditions (e.g., hypoalbuminemia) may displace AEDs from protein-binding sites reducing total but not unbound drug concentrations decrease. VPA not only displaces PHT from protein-binding sites but inhibits its metabolism, causing a decrease in total concentration and an increase in the unbound concentration, occasionally necessitating a reduction in PHT dosage. Alterations in drug metabolism can cause fluctuations in the concentrations of AEDs and active metabolites. Enzyme inhibitors such as cimetidine or VPA can increase concentrations of both CBZ and CBZ epoxide (CBZE). Enzyme inducers such as ethanol, PHT, CBZ, and phenobarbital accelerate the metabolism of other AEDs. Some forms of physiologic stress increase binding to alpha 1-acid glycoprotein (AAG), which is stimulated within hours of a myocardial infarction or major surgery. Total CBZ and CBZE, both of which bind to AAG, increase over the same period. Stress may also activate hepatic drug metabolism. Unbound PHT clearance increases 7 to 21 days following head trauma, necessitating larger maintenance doses. Age greater than 65 years is associated with decreases in protein binding and drug clearance and longer elimination half-lives. In elderly patients, AED dosage may need to be reduced and the dosing interval extended. Knowledge of these factors permits prospective assessment of risk and the design of treatment plans that minimize fluctuations in response.


[Age-specific characteristics of functional disorders of the cardiovascular system and respiration in experimental atherosclerosis].
Results of investigations into age-specific peculiarities inherent in the contractile function of the cardiac ventricular myocardium, hemodynamics of the lesser circulation, oxygen supply of the organism in young (6--12 months old) and old (3 1/2--4 1/2 year old) rabbits in normalcy and with experimental atherosclerosis are reported. The contractility of the left ventricle myocardium in old animals was down as compared to the normal in young ones. Induction of atherosclerosis impairs this important function of the myocardium to a still greater degree. In old animals hemodynamics of the lesser circulation is characterized by a rising systolic pressure in the right ventricle and of the tension-time index (TTI) as contrasted against the young one in normalcy and with atherosclerosis. Against this background an additional action on the organism is attended by more pronounced pathological manifestations, i.e. in reactions of the cardiovascular system (including the lesser circulation). The initial manifestations of hypoxia recorded in older animals, as compared to the younger ones in normality, become more intensive in cases of induced atherosclerosis. There is reduced consumption of oxygen, oxygen saturation of arterial and, especially, mixed venous blood, as well as oxygen tension in the arterial blood. The recorded changes are of significance in clarifying the caused and conditions conducive to the development of atherosclerosis and to the intensification of its manifestations in an old organism.


Risk models for predicting chemotherapy-induced neutropenia.
Neutropenia and its complications, including febrile neutropenia, are major dose-limiting toxicities of systemic cancer chemotherapy. A number of studies have attempted to identify risk factors for neutropenia and its consequences to develop predictive models capable of identifying patients at greater risk for such complications and to guide more effective and cost-effective applications of the colony-stimulating factors. A systematic review of the literature showed that age, performance status, nutritional status, chemotherapy dose intensity, and low baseline blood cell counts were associated with the risk of severe and febrile neutropenia or reduced chemotherapy dose intensity in multivariate analysis in two or more studies. Similarly, age, diagnosis of leukemia or lymphoma, high temperature or low blood pressure at admission, and i.v. site infection along with low blood cell counts and organ dysfunction were associated with serious medical complications of febrile neutropenia, including bacteremia and death. The available risk model studies, however, had several limitations, including retrospective analyses of small study populations lacking independent validation, frequent missing values, and differences in the predictive factors considered. To overcome the limitations of previous studies, efforts are under way to develop and validate risk models based on large prospective studies in representative populations of patients receiving systemic chemotherapy.


Highly stretchable ionically crosslinked acrylate elastomers inspired by polyelectrolyte complexes.
Dynamic bonds are a powerful approach to tailor the mechanical properties of elastomers and introduce shape-memory, self-healing, and recyclability. Among the library of dynamic crosslinks, electrostatic interactions among oppositely charged ions have been shown to enable tough and resilient elastomers and hydrogels. In this work, we investigate the mechanical properties of ionically crosslinked ethyl acrylate-based elastomers assembled from oppositely charged copolymers. Using both infrared and Raman spectroscopy, we confirm that ionic interactions are established among polymer chains. We find that the glass transition temperature of the complex is in between the two individual copolymers, while the complex demonstrates higher stiffness and more recovery, indicating that ionic bonds can strengthen and enhance recovery of these elastomers. We compare cycles to increasing strain levels at different strain rates, and hypothesize that at fast strain rates ionic bonds dynamically break and reform while entanglements do not have time to slip, and at slow strain rates ionic interactions are disrupted and these entanglements slip significantly. Further, we show that a higher ionic to neutral monomer ratio can increase the stiffness, but its effect on recovery is minimal. Finally, taking advantage of the versatility of acrylates, ethyl acrylate is replaced with the more hydrophilic 2-hydroxyethyl acrylate, and the latter is shown to exhibit better recovery and self-healing at a cost of stiffness and strength. The design principles uncovered for these easy-to-manufacture polyelectrolyte complex-inspired bulk materials can be broadly applied to tailor elastomer stiffness, strength, inelastic recovery, and self-healing for various applications.


Cathepsin S Contributes to Lung Inflammation in Acute Respiratory Distress Syndrome.
Rationale: Although the cysteine protease cathepsin S has been implicated in the pathogenesis of several inflammatory lung diseases, its role has not been examined in the context of acute respiratory distress syndrome, a condition that still lacks specific and effective pharmacological treatments. Objectives: To characterize the status of cathepsin S in acute lung inflammation and examine the role of cathepsin S in disease pathogenesis. Methods: Human and mouse model BAL fluid samples were analyzed for the presence and activity of cathepsin S and its endogenous inhibitors. Recombinant cathepsin S was instilled directly into the lungs of mice. The effects of cathepsin S knockout and pharmacological inhibition were examined in two models of acute lung injury. Protease-activated receptor-1 antagonism was used to test a possible mechanism for cathepsin S-mediated inflammation. Measurements and Main Results: Pulmonary cathepsin S concentrations and activity were elevated in acute respiratory distress syndrome, a phenotype possibly exacerbated by the loss of the endogenous antiprotease cystatin SN. Direct cathepsin S instillation into the lungs induced key pathologies of acute respiratory distress syndrome, including neutrophilia and alveolar leakage. Conversely, in murine models of acute lung injury, genetic knockdown and prophylactic or therapeutic inhibition of cathepsin S reduced neutrophil recruitment and protein leakage. Cathepsin S may partly mediate its pathogenic effects via protease-activated receptor-1, because antagonism of this receptor abrogated cathepsin S-induced airway inflammation. Conclusions: Cathepsin S contributes to acute lung injury and may represent a novel therapeutic target for acute respiratory distress syndrome.


Treatment decision-making in the medical encounter: comparing the attitudes of French surgeons and their patients in breast cancer care.
To explore attitudes of French surgeons and their patients towards treatment decision-making (TDM) in the medical encounter. Surgeons involved in early stage breast cancer and their patients treated in a French cancer care network received a cross-sectional survey questionnaire containing examples of four different approaches to TDM: paternalistic, "some sharing", informed TDM and, shared TDM. Surgeons' interaction styles were clearly distributed among paternalistic, shared and mixed. The paternalistic approach seemed to be associated with private rather than public practice and with less professional experience. Patients reported a rather low level of participation in TDM, varying by socio-demographic characteristics. One third of patients were dissatisfied with the way their treatment decision had been made. Most surgeons reported adopting the "some sharing" approach. However, one patient out of three reported that they would have liked to participate more in the TDM process. Surgeons need to ask patients what their preferences for involvement in TDM are and then think about ways to accommodate both their own and patients' preferences regarding the TDM process to be used in each encounter. In addition, decision aids could be offered to surgeons to help them discuss treatment options with their patients.


Phobic postural vertigo treated with autogenic training: a case report.
Patients suffering from dizziness due to vertigo are commonly encountered in the department of otolaryngology. If various clinical examinations do not reveal any objective findings, then the patients are referred to the department of internal medicine or psychiatry. In many cases, the diagnosis is psychological dizziness. Phobic postural vertigo, which was first reported by Brandt T et al in 1994, is supposed to be a type of psychological dizziness. The diagnosis is based on 6 characteristics proposed by Brandt et al. Patients are usually treated with conventional medical therapy, but some cases may be refractory to such a therapy. Psychotherapy is recommended in some cases; however, psychotherapy including autogenic training, which can be used for general relaxation, is not widely accepted. This paper describes the successful administration of autogenic training in a patient suffering from phobic postural vertigo. We present a case of a patient who suffered from phobic postural vertigo. A 37-year-old female complained of dizziness. She had started experiencing dizziness almost 3 years She was intractable to many sort of conventional therapy. In the end, her symptom disappeared after introduction of autogenic training. Autogenic training can be a viable and acceptable treatment option for phobic postural vertigo patients who fail to respond to other therapies. This case emphasizes the importance of autogenic training as a method to control symptom of phobic postural vertigo.


The spermidine transport system is regulated by ligand inactivation, endocytosis, and by the Npr1p Ser/Thr protein kinase in Saccharomyces cerevisiae.
We have characterized the regulation of spermidine transport in yeast and identified some of the genes involved in its control. Disruption of the SPE2 gene encoding S-adenosylmethionine decarboxylase, which catalyzes an essential step in polyamine biosynthesis, upregulated the initial velocity of spermidine uptake in wild-type cells as well as in the polyamine transport-deficient pcp1 mutants. Exogenous spermidine rapidly inactivated spermidine transport with a half-life of approximately 10-15 min via a process that did not require de novo protein synthesis but was accelerated by cycloheximide addition. Conversely, reactivation of spermidine influx upon polyamine deprivation required active protein synthesis. The stability of polyamine carrier activity was increased 2-fold in polyamine-depleted spe2 deletion mutants, indicating that endogenous polyamines also contribute to the down-regulation of spermidine transport. Ligand-mediated repression of spermidine transport was delayed in end3 and end4 mutants that are deficient in the initial steps of the endocytic pathway, and spermidine uptake activity was increased 4- to 5-fold in end3 mutants relative to parental cells, although the stability of the transport system was similar in both strains. Disruption of the NPR1 gene, which encodes a putative Ser/Thr protein kinase essential for the reactivation of several nitrogen permeases, resulted in a 3-fold decrease in spermidine transport in NH4(+)-rich media but did not prevent its down-regulation by spermidine. The defect in spermidine transport was more pronounced in NH4(+)- than proline-grown npr1 cells, suggesting that NPR1 protects against nitrogen catabolite repression of polyamine uptake activity. These results suggest that (a) the polyamine carrier is an unstable protein subject to down-regulation by spermidine via a process involving ligand inactivation followed by endocytosis and that (b) NPR1 expression fully prevents nitrogen catabolite repression of polyamine transport, unlike the role predicted for that gene by the inactivation/reactivation model proposed for other nitrogen permeases.


Retrospective Evaluation of a Technique for Patient-Customized Placement of Precurved Cochlear Implant Electrode Arrays.
Objective Precurved electrode arrays (EAs) are commonly used in cochlear implants (CIs). Modiolar placement of such arrays has been shown to lead to better hearing outcomes. In this project, we retrospectively evaluated the modiolar positioning of EAs within a large CI imaging database. We aimed to discover the rate at which perimodiolar placement is successfully achieved and to evaluate a new technique we propose to preoperatively plan patient-customized EA insertion depths to improve perimodiolar placement at the time of surgery. Study Design Retrospective chart review and radiographic analysis. Setting Single tertiary academic referral center. Subjects and Methods Ninety-seven CI ears were evaluated. Perimodiolar positioning of electrodes was quantified using pre- and postimplantation computed tomography scans and automated image analysis techniques. Results Average perimodiolar distance was 0.59 ± 0.18 mm. Disagreement between the actual and our recommended insertion depth was found to be positively correlated with perimodiolar distance ( r = 0.49, P < .0001). Conclusions These results show that the average CI recipient with a precurved EA has a number of electrodes distant to the modiolus where they are not most effective. Our results also indicate the approach we propose for selecting patient-customized EA insertion depth would lead to better perimodiolar placement of precurved EAs.


Protease research in the era of systems biology.
Proteases are specific modulators of signaling molecules and their underlying pathways in addition to their degradative roles. However, proteases do not act alone, but form cascades, circuits and networks that all dynamically interconnect to form the protease web, which defines the proteolytic potential of a cell or tissue in a defined condition. To describe the protease web and its net activity several novel high-throughput proteomic techniques, in the field termed degradomics, have been developed. Emerging systems biology methods to evaluate the expression, activity and substrate discovery of proteases are presented. Understanding the protease web and its perturbations in pathology will help to develop new therapeutics for the treatment of diseases, such as cancer, arthritis and chronic obstructive pulmonary diseases.


Systems biology reveals uncoupling beyond UCP1 in human white fat-derived beige adipocytes.
Pharmaceutical induction of metabolically active beige adipocytes in the normally energy storing white adipose tissue has potential to reduce obesity. Mitochondrial uncoupling in beige adipocytes, as in brown adipocytes, has been reported to occur via the uncoupling protein 1 (UCP1). However, several previous in vitro characterizations of human beige adipocytes have only measured UCP1 mRNA fold increase, and assumed a direct correlation with metabolic activity. Here, we provide an example of pharmaceutical induction of beige adipocytes, where increased mRNA levels of UCP1 are not translated into increased protein levels, and perform a thorough analysis of this example. We incorporate mRNA and protein levels of UCP1, time-resolved mitochondrial characterizations, and numerous perturbations, and analyze all data with a new fit-for-purpose mathematical model. The systematic analysis challenges the seemingly obvious experimental conclusion, i.e., that UCP1 is not active in the induced cells, and shows that hypothesis testing with iterative modeling and experimental work is needed to sort out the role of UCP1. The analyses demonstrate, for the first time, that the uncoupling capability of human beige adipocytes can be obtained without UCP1 activity. This finding thus opens the door to a new direction in drug discovery that targets obesity and its associated comorbidities. Furthermore, the analysis advances our understanding of how to evaluate UCP1-independent thermogenesis in human beige adipocytes.


Intussusception in black children.
Seventy-six black patients with intussusception are reviewed. Infants (59%) presented with features similar to classic intussusception; ileocolic lesions were most common (80%) and a high resection rate (36%) was the sequel to delay in presentation. Children over 2 years of age (41%) presented with a pattern of 'tropical' intussusception in which primary colocolic lesions predominated (55%) and leading points were rare (3,5%). A high percentage of older children appears to characterize series from tropical areas. The relative proportions of these groups may vary between, and within, geographical regions and differing causes are likely. However, the management of both groups is similar. Hydrostatic reduction was not effective in those patients in whom it was attempted.


Defining a longitudinal survival model to examine forced treadmill running as a countermeasure for diet-induced weight gain.
Diet-induced weight gain increases disease risk via disruption of the innate immune system. Flow cytometry is commonly used to assess the immune system; however, in mice such measurements traditionally require terminal procedures and tissue collection to generate sufficient sample. The present study refined an existing flow cytometry method to reduce the number of mice needed to longitudinally measure monocytes. CD-1 male mice were randomly assigned to one of the three groups: DS (diet-induced weight gain + sedentary), DE (diet-induced weight gain + forced treadmill running [total distance 35,755 ± 1832 m]) or NS (normal weight gain + sedentary). DS and DE consumed a 60% fat diet and NS consumed a 10% fat diet ad libitum. Saphenous vein blood samples were collected weekly for a period of six weeks and three-colour flow cytometry was used to measure changes in monocyte (CD11b(+)/14(+)) concentration and cell-surface toll-like receptor 4 (TLR4) expression. DS (18%) and DE (17%) gained more weight than NS (P < 0.001). On a group basis, DS expressed 17% more TLR4 than DE and NS (P = 0.005). The present study demonstrates that a longitudinal survival model can be used to reduce the number of animals needed to complete flow cytometry experiments. Exercise during diet-induced weight prevented some (decreased monocyte TLR4 expression) but not all aspects of innate immune system function.


Mutation of a conserved hydrophobic patch prevents incorporation of ZP3 into the zona pellucida surrounding mouse eggs.
Three glycoproteins (ZP1, ZP2, and ZP3) are synthesized in growing mouse oocytes and secreted to form an extracellular zona pellucida that mediates sperm binding and fertilization. Each has a signal peptide to direct it into a secretory pathway, a "zona" domain implicated in matrix polymerization and a transmembrane domain from which the ectodomain must be released. Using confocal microscopy and enhanced green fluorescent protein (EGFP), the intracellular trafficking of ZP3 was observed in growing mouse oocytes. Replacement of the zona domain with EGFP did not prevent secretion of ZP3, suggesting the presence of trafficking signals and a cleavage site in the carboxyl terminus. Analysis of linker-scanning mutations of a ZP3-EGFP fusion protein in transient assays and in transgenic mice identified an eight-amino-acid hydrophobic region required for secretion and incorporation into the zona pellucida. The hydrophobic patch is conserved among mouse zona proteins and lies between a potential proprotein convertase (furin) cleavage site and the transmembrane domain. The cleavage site that releases the ectodomain from the transmembrane domain was defined by mass spectrometry of native zonae pellucidae and lies N-terminal to a proprotein convertase site that is distinct from the hydrophobic patch.


micro-RNA screening and prediction model construction for diagnosis of salt-sensitive essential hypertension.
Commonly used tests for diagnosis of salt-sensitive hypertension (SSH) are complex and time-consuming, so new methods are required. Many studies have demonstrated roles for miRNAs in hypertension; however, the diagnostic value of miRNAs has yet to be determined for human SSH. In this study, we examined miRNA expression profiles by initial high-throughput miRNA sequencing of samples from patients with salt-sensitive and salt-resistant hypertension (SSH and SRH, respectively; n = 6, both groups), followed by validation by quantitative real-time polymerase chain reaction (qRT-PCR) in a larger cohort (n = 91). We also evaluated differences in baseline characteristics (e.g., age, sex, body mass index, consumption of specific foods) between the SSH and SRH groups. Of 36 miRNAs identified as differentially expressed between SSH and SRH groups by RNA-Seq, 8 were analyzed by qRT-PCR. There were significant differences in the expression levels of hsa-miR-361-5p and hsa-miR-362-5p between the 2 groups (P = .023 and.049, respectively). In addition, there were significant differences in sauce and poultry consumption between the 2 groups (P = .004 and.001, respectively). The areas under the curve (AUC) determined by receptor operating characteristic (ROC) analysis for hsa-miR-361-5p and all 8 miRNAs were 0.793 (95% CI, 0.698-0.888; sensitivity = 73.9%, specificity = 74.4%; P < .001) and 0.836 (95% CI, 0.749-0.922; sensitivity = 80.4%, specificity = 81.4%; P < .001), respectively, when sauce and poultry consumption were included in the models. Assay feasibility and economic considerations make hsa-miR-361-5p combined with the dietary factors the preferred markers for diagnosis of SSH.


FL-QSAR: a federated learning-based QSAR prototype for collaborative drug discovery.
Quantitative structure-activity relationship (QSAR) analysis is commonly used in drug discovery. Collaborations among pharmaceutical institutions can lead to a better performance in QSAR prediction, however, intellectual property and related financial interests remain substantially hindering inter-institutional collaborations in QSAR modeling for drug discovery. For the first time, we verified the feasibility of applying the horizontal federated learning (HFL), which is a recently developed collaborative and privacy-preserving learning framework to perform QSAR analysis. A prototype platform of federated-learning-based QSAR modeling for collaborative drug discovery, i.e. FL-QSAR, is presented accordingly. We first compared the HFL framework with a classic privacy-preserving computation framework, i.e. secure multiparty computation to indicate its difference from various perspective. Then we compared FL-QSAR with the public collaboration in terms of QSAR modeling. Our extensive experiments demonstrated that (i) collaboration by FL-QSAR outperforms a single client using only its private data, and (ii) collaboration by FL-QSAR achieves almost the same performance as that of collaboration via cleartext learning algorithms using all shared information. Taking together, our results indicate that FL-QSAR under the HFL framework provides an efficient solution to break the barriers between pharmaceutical institutions in QSAR modeling, therefore promote the development of collaborative and privacy-preserving drug discovery with extendable ability to other privacy-related biomedical areas. The source codes of FL-QSAR are available on the GitHub: https://github.com/bm2-lab/FL-QSAR. Supplementary data are available at Bioinformatics online.


Antibacterial effects of blackberry extract target periodontopathogens.
Antimicrobial agents provide valuable adjunctive therapy for the prevention and the control of oral diseases. Limitations in their prolonged use have stimulated the search for new, naturally occurring agents with more specific activity and fewer adverse effects. Here we sought to determine the antibacterial properties of blackberry extract (BBE) in vitro against oral bacterial commensals and periodontopathogens. The effects of whole and fractionated BBE on the metabolism of 10 different oral bacteria were evaluated using the colorimetric water-soluble tetrazolium-1 assay. The bactericidal effects of whole BBE against Fusobacterium nucleatum were determined by quantitating the numbers of colony-forming units (CFUs). Cytotoxicity was determined in oral epithelial (OKF6) cells. BBE at 350-1400 μg/mL reduced the metabolic activity of Porphyromonas gingivalis, F. nucleatum and Streptococcus mutans. The reduced metabolic activity observed for F. nucleatum corresponded to a reduction in the numbers of CFUs following exposure to BBE for as little as 1 h, indicative of its bactericidal properties. An anthocyanin-enriched fraction of BBE reduced the metabolic activity of F. nucleatum, but not of P. gingivalis or S. mutans, suggesting the contribution of species-specific agents in the whole BBE. Oral epithelial cell viability was not reduced following exposure to whole BBE (2.24-1400 μg/mL) for ≤ 6 h. BBE alters the metabolic activity of oral periodontopathogens while demonstrating a minimal effect on commensals. The specific antibacterial properties of BBE shown in this study, along with its previously demonstrated anti-inflammatory and antiviral properties, make this natural extract a promising target as an adjunct for prevention and/or complementary therapy of periodontal infections.


Comparability of the WCST and WCST-64 in the assessment of first-episode psychosis.
The Wisconsin Card Sorting Test (WCST) was designed as a measure of executive functioning and is commonly used in the assessment of psychiatric disorders. The original WCST, consisting of 128 cards, has been criticized as being too lengthy for patients experiencing significant distress. Consequently, a shortened version consisting of a single 64-card deck (WCST-64) was created. The purpose of this study was to examine the comparability of the WCST and WCST-64 in 99 patients with first-episode psychosis. Findings showed the WCST-64 yielded a mean T score for perseverative responses (PR) that was 4.08 points lower than the corresponding variable from the WCST, and the correlation between the variables was r = .65. The mean discrepancy was only 2.34 for nonperseverative error (NPE) T scores and the correlation was also stronger, r = .82. Nearly half the sample (44%) had a T score discrepancy between the respective PR indexes that was greater than 1 SD, whereas this discrepancy was observed in only 4% of the sample for NPE. Based on a cut point of < 40T to define impaired versus normal performance for PR, 80% of the sample received the same classification. These findings suggest that NPE scores may be comparable across both tests. Conversely, whereas the PR score from the WCST-64 and WCST can be used as a gross measure of impairment, this score should not be used interchangeably to characterize the severity of perseverative tendencies in first-episode patients on a case-by-case basis. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Hospital leaders predict tighter finances, need for new initiatives.
National health care reform legislation will affect hospitals in ways as dissimilar as hospitals themselves. How prepared are they? Hospitals & Health Networks, in conjunction with Premier Hospitals Alliance, Westchester, IL, surveyed 402 CEOs and chief operating officers to gauge their responses to anticipated changes and garner their opinions on how reform will affect their hospitals.


[The neuronal reactions of the perinuclear zone of the hypothalamic supraoptic nucleus in rats to stimulation of the hypophyseal stalk and the hippocampus].
The orthodromically activated neurons (OAN) were recorded in the hypothalamic supraoptic area under the hypophysial stalk stimulation. They were distinguished by the pattern of the orthodromic activation and the recording sites. More than a half of OAN responded to the stimulation of ventral hippocampus and the responses were primary excitatory in all cases. The similarity in most OAN responses to the hippocampal and the hypophysial stalk stimulation was found. The peculiar influence of the hippocampus on OAN was analyzed, their location in the supraoptic nucleus or perinuclear zone and the supposed morphofunctional connections with the antidromically identified neurosecretory cells being taken into account.


Using cementochronology to assess the seasonality of catastrophic events in medieval mass graves (Kutná Hora-Sedlec, Czechia, 14th century): Preliminary results.
While season-of-death estimation using cementochronology is routine in archaeozoology, its use is much less frequent in bioarchaeology. Based on the character of the outermost increment (bright or dark), two seasons (spring/summer, autumn/winter) can be distinguished. Although many studies mention its potential and possible use in forensic anthropology or bioarchaeology, few exist with estimation results. This study aimed to apply cementochronology-a histological method based on counting and assessing regular circa-annual acellular cementum increments-to 42 individuals from medieval mass graves from Kutná Hora-Sedlec (Czechia, 14th century) to estimate the season-of-death. The mass graves belong to two stratigraphically distinct groups; written and archaeological sources relate them to two catastrophic events (the famine of 1318 and the plague epidemic of 1348-1350). Using cementochronology, we distinguished two distinct seasons corresponding to the two groups of graves, with individuals from the first group dying predominantly in spring/summer, while those from the second group died in autumn/winter. Taking into account the typical seasonal dynamics of epidemics, the results would be more in line with written sources. However, during the evaluation, we faced difficulties identifying the outermost increment and detecting the dark (thinner) increment; we recommend including only young and middle-aged adults in future studies, due to the difficulty of evaluation, and to consider the readability of the tissue (often affected by diagenesis). In conclusion, cementochronology has potential in the context of estimating the season-of-death, but the technical possibilities for enhancing the outermost increment need to be addressed, and the amount of data analysed expanded.


Penetrating bladder injury caused by a medially placed acetabular screw.
Cancellous bone screws are frequently used to improve the early stability of HA coated acetabular components during total hip arthroplasty. Avoidance of the anterosuperior and anteroinferior quadrants is recommended for transacetabular screw placement to minimize the risk of injury to intrapelvic structures. Revision arthroplasty in rheumatoid patients presents additional hazards in that the acetabular bone is often soft and deficient, and the protective depth of obturator internus and psoas is usually reduced. I report a case of delayed, but fatal, perforation of the bladder associated with a medially placed acetabular screw during revision arthroplasty in a rheumatoid patient. Unless directed safely into the superior pubic ramus, anterior quadrant screws should be avoided in these circumstances.


Diversity of monomers in nonribosomal peptides: towards the prediction of origin and biological activity.
Nonribosomal peptides (NRPs) are molecules produced by microorganisms that have a broad spectrum of biological activities and pharmaceutical applications (e.g., antibiotic, immunomodulating, and antitumor activities). One particularity of the NRPs is the biodiversity of their monomers, extending far beyond the 20 proteogenic amino acid residues. Norine, a comprehensive database of NRPs, allowed us to review for the first time the main characteristics of the NRPs and especially their monomer biodiversity. Our analysis highlighted a significant similarity relationship between NRPs synthesized by bacteria and those isolated from metazoa, especially from sponges, supporting the hypothesis that some NRPs isolated from sponges are actually synthesized by symbiotic bacteria rather than by the sponges themselves. A comparison of peptide monomeric compositions as a function of biological activity showed that some monomers are specific to a class of activities. An analysis of the monomer compositions of peptide products predicted from genomic information (metagenomics and high-throughput genome sequencing) or of new peptides detected by mass spectrometry analysis applied to a culture supernatant can provide indications of the origin of a peptide and/or its biological activity.


Conversion from Nonshockable to Shockable Rhythms and Out-of-Hospital Cardiac Arrest Outcomes by Initial Heart Rhythm and Rhythm Conversion Time.
The conversion from a nonshockable rhythm (asystole or pulseless electrical activity (PEA)) to a shockable rhythm (pulseless ventricular tachycardia or ventricular fibrillation) may be associated with better out-of-hospital cardiac arrest (OHCA) outcomes. There are insufficient data on the prognostic significance of such conversions by initial heart rhythm and different rhythm conversion time. Among 24,849 adult OHCA patients of presumed cardiac etiology with initial asystole or PEA in the Resuscitation Outcomes Consortium Cardiac Epidemiologic Registry (version 3, 2011-2015), we examined the association of shockable rhythm conversion with prehospital return of spontaneous circulation (ROSC), survival, and favorable functional outcome (modified Rankin Scale score ≤3) at hospital discharge by initial rhythm and rhythm conversion time (time from cardiopulmonary resuscitation (CPR) initiation by emergency medical providers to first shock delivery), using logistic regression adjusting for key clinical characteristics. Of 16,516 patients with initial asystole and 8,333 patients with initial PEA, 16% and 20% underwent shockable rhythm conversions; the median rhythm conversion time was 12.0 (IQR: 6.7-18.7) and 13.2 (IQR: 7.0-20.5) min, respectively. No difference was found in odds of prehospital ROSC across rhythm conversion time, regardless of initial heart rhythm. Shockable rhythm conversion was associated with survival and favorable functional outcome at hospital discharge only when occurred during the first 15 min of CPR, for those with initial asystole, or the first 10 min of CPR, for those with initial PEA. The associations between shockable rhythm conversion and outcomes were stronger among those with initial asystole compared with those with initial PEA. The conversion from a nonshockable rhythm to a shockable rhythm was associated with better outcomes only when occurred early in initial nonshockable rhythm OHCA, and it has greater prognostic significance when the initial rhythm was asystole.


Desulfotomaculum thermobenzoicum subsp. thermosyntrophicum subsp. nov., a thermophilic, syntrophic, propionate-oxidizing, spore-forming bacterium.
From granular sludge from a laboratory-scale upflow anaerobic sludge bed reactor operated at 55 degrees C with a mixture of volatile fatty acids as feed, a novel anaerobic, moderately thermophilic, syntrophic, spore-forming bacterium, strain TPO, was enriched on propionate in co-culture with Methanobacterium thermoautotrophicum Z245. The axenic culture was obtained by using pyruvate as the sole source of carbon and energy. The cells were straight rods with pointed ends and became lens-shaped when sporulation started. The cells were slightly motile. The optimum growth temperature was 55 degrees C and growth was possible between 45 and 62 degrees C. The pH range for growth of strain TPO was 6-8, with an optimum at pH 7-7.5. Propionate was converted to acetate, CO2 and CH4 by a co-culture of strain TPO with Methanobacterium thermoautotrophicum Z245. In pure culture, strain TPO could grow fermentatively on benzoate, fumarate, H2/CO2, pyruvate and lactate. Sulphate could serve as inorganic electron acceptor when strain TPO was grown on propionate, lactate, pyruvate and H2/CO2. The G+C content was 53.7 mol%. Comparison of 16S rDNA sequences revealed that strain TPO is related to Desulfotomaculum thermobenzoicum (98%) and Desulfotomaculum thermoacetoxidans (98%). DNA-DNA hybridization revealed 88.2% reassociation between strain TPO and D. thermobenzoicum and 83.8% between strain TPO and D. thermoacetoxidans. However, both organisms differ physiologically from strain TPO and are not capable of syntrophic propionate oxidation. It is proposed that strain TPO should be classified as new subspecies of D. thermobenzoicum as D. thermobenzoicum subsp. thermosyntrophicum.


A vaccine against CCR5 protects a subset of macaques upon intravaginal challenge with simian immunodeficiency virus SIVmac251.
As an alternative to targeting human immunodeficiency virus (HIV), we have developed vaccines targeting CCR5, a self-protein critically involved in HIV replication and pathogenesis. By displaying peptides derived from CCR5 at high density on the surface of virus-like particles, we can efficiently induce high-titer IgG antibodies against this self-molecule. Here, we investigated whether prophylactic immunization of rhesus macaques with a particle-based vaccine targeting two regions of macaque CCR5 could prevent or suppress vaginal infection with highly virulent SIVmac251. Twelve macaques were vaccinated with a bacteriophage Qß-based vaccine targeting macaque CCR5 (Qß.CCR5). Six control animals were immunized with the Qß platform alone. All animals immunized with Qß.CCR5 developed high-titer anti-CCR5 antibody responses. Macaques were vaginally challenged with a high dose of SIVmac251. The mean peak viral RNA levels in the vaccinated groups were 30-fold lower than in the control group (10(6.8) versus 10(8.3) copies/ml plasma). Three of the 12 vaccinated macaques dramatically suppressed simian immunodeficiency virus (SIV) replication: peak viral loads were low (10(3) to 10(4) RNA copies/ml), and SIV RNA became undetectable from 6 weeks onward. No viral RNA or DNA could be detected in colon and lymph node biopsy specimens collected 13 months after challenge. In vivo depletion of CD8(+) cells failed to induce a viral rebound. However, once anti-CCR5 antibody responses had waned, the 3 animals became infected after intravaginal and/or intravenous rechallenge. In conclusion, vaccination against CCR5 was associated with dramatic suppression of virus replication in a subset (25%) of macaques. These data support further research of vaccination against CCR5 to combat HIV infection.


[The synthetic peptide D-(iEW) (thymodepressin) protects bone marrow CFU-S from ionizing radiation exposure].
Synthetic polypeptide D-(iEW) (Thymodepressin) was shown to reduce the bone marrow CFU-S in the S-phase of cell cycle. Apparently, due to this property the agent being administered 2 days before the irradiation with 4 Gy causes a prominent restoration of the CFU-S population afterwards. The 3-5 times higher value of this parameter as compared to the control (irradiation only) is likely to be connected to the increased "survival" of the Thymodepressin-protected CFU-S after the treatment with ionizing irradiation.


[Health resources--potentials and how to utilise them].
Studies analysing resources refer to Aaron Antonovsky's salutogenetic theory. Contrasting risk research and salutogenesis, three problems concerning methodology and concepts are illustrated in this paper: the lack of a positive definition of health, the conceptual gap between indicators of health and influencing factors, and the relation between risk and resources. Starting points to promote health focussing on personal, micro, meso and macro levels are discussed in the second section of the paper. Future interventions will have to interact on different levels and in theory and practice interfaces with other experts will have to be defined. The paper concludes with a plea for developing a health promotion scheme based on evidence.


Classic IgA-Vasculitis With Nephrotic Range Proteinuria - Rare Presentation in an Adult.
IgA vasculitis formerly known as Henoch-Schonlein Purpura is characterized by leukocytoclastic vasculitis and IgA immune complex in small vessels of the affected organ. IgA vasculitis can involve any organ system depending upon the deposition of the IgA immune complex. IgA vasculitis is a clinical diagnosis which manifest with abdominal pain, arthralgia/arthritis, palpable purpura, and kidney involvement. Occasionally, serum IgA levels or skin or kidney biopsy can help in confirming the diagnosis. Treatment is usually supportive, but studies have proved that prednisone or immunosuppressive agents can help in the prevention or progression of the disease. Hereby we present a case of 54-year-old Caucasian male who developed classic tetrad findings of IgA vasculitis most likely after receiving monkeypox vaccine which patient received three weeks prior to presentation to the hospital. Kidney involvement was present but surprisingly proteinuria was above nephrotic range making it as a rare presentation of IgA vasculitis.


Compression-plate fixation in acute diaphyseal fractures of the radius and ulna.
At the Campbell Clinic and City of Memphis Hospital from 1960 to 1970, 244 patients (216 with closed and twenty-eight with open fractures) had 330 acute diaphyseal fractures of the radius and ulna which were treated with ASIF compression plates and followed for from four months to nine years. One hundred and twelve patients had fractures of both bones of the forearm; fifty, single fractures of the ulna; and eighty-two, single fractures of the radius. In all, 193 fractures of the radius and 137 fractures of the ulna were treated by compression plating. Sixty-three patients (25.9 per cent) with severely comminuted fractures also had iliac-bone grafts. The over-all rate of union for the radius was 97.9 per cent and for the ulna, 96.3 per cent. ASIF compression plates, therefore, provided a successful method for obtaining union and restoring optimum function after acute diaphyseal fractures of the forearm.


Simultaneous measurement of noise and spatial resolution in PET phantom images.
As an aid to evaluating image reconstruction and correction algorithms in positron emission tomography, a phantom procedure has been developed that simultaneously measures image noise and spatial resolution. A commercially available (68)Ge cylinder phantom (20 cm diameter) was positioned in the center of the field-of-view and two identical emission scans were sequentially performed. Image noise was measured by determining the difference between corresponding pixels in the two images and by calculating the standard deviation of these difference data. Spatial resolution was analyzed using a Fourier technique to measure the extent of the blurring at the edge of the phantom images. This paper addresses the noise aspects of the technique as the spatial resolution measurement has been described elsewhere. The noise measurement was validated by comparison with data obtained from multiple replicate images over a range of noise levels. In addition, we illustrate how simultaneous measurement of noise and resolution can be used to evaluate two different corrections for random coincidence events: delayed event subtraction and singles-based randoms correction. For a fixed number of iterations of the maximum-likelihood expectation-maximization algorithm, the singles-based correction gave rise to higher noise than delayed event subtraction. However, when noise and resolution were measured simultaneously it was shown that singles-based randoms correction gave rise to lower noise than delayed event subtraction for a fixed spatial resolution. The proposed method of simultaneously measuring image noise and spatial resolution is useful for evaluating reconstruction algorithms and may aid standardization of data collection between centers.


Sedentary death syndrome.
Sedentary death syndrome (SeDS) is a major public health burden due to its causing multiple chronic diseases and millions of premature deaths each year. Despite the impact of physical inactivity, very little is known about the actual causes of physical inactivity-induced chronic diseases. It is important to study the mechanisms underlying molecular changes related to physical inactivity in order to better understand the scientific basis of individualized exercise prescription and therapies for chronic diseases, and to support improved public health efforts by providing molecular proof that physical inactivity is an actual cause of chronic diseases. Physical activity has a genetic basis. A subpopulation of genes, which have functioned to support physical activity for survival through most of humankind's existence, require daily exercise to maintain long-term health and vitality. Type 2 diabetes (T2D) is an example of a SeDS condition, as it is almost entirely preventable with physical activity. To determine the true role of physical inactivity in the development and progression of T2D, information is presented which indicates that comparisons should be made to physically active controls, rather than sedentary controls, as this population is the healthiest. Use of sedentary subjects as the control group has led to potentially misleading interpretations. If physically active individuals were designated as the control group, a different interpretation would have been drawn. It is thought that there is no difference in GLUT4 concentration between T2D and sedentary groups. However, GLUT4 expression is higher in active controls than in sedentary and T2D groups. Therefore, to obtain causal mechanisms for SeDS in order to allow for scientifically based prevention and therapy strategies, physically active subjects must serve as the control group.


Stabilization and characterization of a heme-oxy reaction intermediate in inducible nitric-oxide synthase.
Nitric-oxide synthases (NOS) are heme-thiolate enzymes that N-hydroxylate L-arginine (L-Arg) to make NO. NOS contain a unique Trp residue whose side chain stacks with the heme and hydrogen bonds with the heme thiolate. To understand its importance we substituted His for Trp188 in the inducible NOS oxygenase domain (iNOSoxy) and characterized enzyme spectral, thermodynamic, structural, kinetic, and catalytic properties. The W188H mutation had relatively small effects on l-Arg binding and on enzyme heme-CO and heme-NO absorbance spectra, but increased the heme midpoint potential by 88 mV relative to wild-type iNOSoxy, indicating it decreased heme-thiolate electronegativity. The protein crystal structure showed that the His188 imidazole still stacked with the heme and was positioned to hydrogen bond with the heme thiolate. Analysis of a single turnover L-Arg hydroxylation reaction revealed that a new heme species formed during the reaction. Its build up coincided kinetically with the disappearance of the enzyme heme-dioxy species and with the formation of a tetrahydrobiopterin (H4B) radical in the enzyme, whereas its subsequent disappearance coincided with the rate of l-Arg hydroxylation and formation of ferric enzyme. We conclude: (i) W188H iNOSoxy stabilizes a heme-oxy species that forms upon reduction of the heme-dioxy species by H4B. (ii) The W188H mutation hinders either the processing or reactivity of the heme-oxy species and makes these steps become rate-limiting for l-Arg hydroxylation. Thus, the conserved Trp residue in NOS may facilitate formation and/or reactivity of the ultimate hydroxylating species by tuning heme-thiolate electronegativity.


Ethics in Telehealth: Comparison between Guidelines and Practice-based Experience -the Case for Learning Health Systems.
To understand ethical issues within the tele-health domain, specifically how well established macro level telehealth guidelines map with micro level practitioner perspectives. We developed four overarching issues to use as a starting point for developing an ethical framework for telehealth. We then reviewed telemedicine ethics guidelines elaborated by the American Medical Association (AMA), the World Medical Association (WMA), and the telehealth component of the Health Professions council of South Africa (HPCSA). We then compared these guidelines with practitioner perspectives to identify the similarities and differences between them. Finally, we generated suggestions to bridge the gap between ethics guidelines and the micro level use of telehealth. Clear differences emerged between the ethics guidelines and the practitioner perspectives. The main reason for the differences were the different contexts where telehealth was used, for example, variability in international practice and variations in the complexity of patient-provider interactions. Overall, published guidelines largely focus on macro level issues related to technology and maintaining data security in patient-provider interactions while practitioner concern is focused on applying the guidelines to specific micro level contexts. Ethics guidelines on telehealth have a macro level focus in contrast to the micro level needs of practitioners. Work is needed to close this gap. We recommend that both telehealth practitioners and ethics guideline developers better understand healthcare systems and adopt a learning health system approach that draws upon different contexts of clinical practice, innovative models of care delivery, emergent data and evidence-based outcomes. This would help develop a clearer set of priorities and guidelines for the ethical conduct of telehealth.


Exosome-Based Vaccines: Pros and Cons in the World of Animal Health.
Due to the emergence of antibiotic resistance and new and more complex diseases that affect livestock animal health and food security, the control of epidemics has become a top priority worldwide. Vaccination represents the most important and cost-effective measure to control infectious diseases in animal health, but it represents only 23% of the total global animal health market, highlighting the need to develop new vaccines. A recent strategy in animal health vaccination is the use of extracellular vesicles (EVs), lipid bilayer nanovesicles produced by almost all living cells, including both prokaryotes and eukaryotes. EVs have been evaluated as a prominent source of viral antigens to elicit specific immune responses and to develop new vaccination platforms as viruses and EVs share biogenesis pathways. Preliminary trials with lymphocytic choriomeningitis virus infection (LCMV), porcine reproductive and respiratory syndrome virus (PRRSV), and Marek's disease virus (MDV) have demonstrated that EVs have a role in the activation of cellular and antibody immune responses. Moreover, in parasitic diseases such as Eimeria (chickens) and Plasmodium yoelii (mice) protection has been achieved. Research into EVs is therefore opening an opportunity for new strategies to overcome old problems affecting food security, animal health, and emerging diseases. Here, we review different conventional approaches for vaccine design and compare them with examples of EV-based vaccines that have already been tested in relation to animal health.


Management of incarcerated inguinal hernia in a patient with yellow nail syndrome.
While abdominal wall hernias are often seen in cirrhotic patients, they have not been previously reported following chylous ascites secondary to yellow nail syndrome. In general, repairing abdominal wall hernias in patients with ascites are associated with significant morbidity, recurrence rate and mortality, and are therefore often managed expectantly. Hernial incarceration or strangulation in these patients is a life-threatening complication, and requires urgent surgical intervention. To highlight this difficult issue and its emergency management and repair, we present this report of a 46-year-old man, who was known to have yellow nail syndrome and who was hospitalised for incarcerated inguinal hernia, massive chylous ascites, severe lower limbs oedema, hypoproteinaemia, hypoalbuminaemia and hypocalcaemia.


Around-the-World Atomic Clocks: Observed Relativistic Time Gains.
Four cesium beam clocks flown around the world on commercial jet flights during October 1971, once eastward and once westward, recorded directionally dependent time differences which are in good agreement with predictions of conventional relativity theory. Relative to the atomic time scale of the U.S. Naval Observatory, the flying clocks lost 59 +/- 10 nanoseconds during the eastward trip and gained 273 +/- 7 nanoseconds during the westward trip, where the errors are the corresponding standard deviations. These results provide an unambiguous empirical resolution of the famous clock "paradox" with macroscopic clocks.


Career satisfaction, practice patterns and burnout among surgical oncologists: report on the quality of life of members of the Society of Surgical Oncology.
Studies show that 30-50% of medical oncologists experience burnout, but little is known about burnout among surgical oncologists. We hypothesized that wide variation in burnout and career satisfaction exist among surgical oncologists. In April 2006, members of the Society of Surgical Oncology (SSO) were sent an anonymous, cross-sectional survey evaluating demographic variables, practice characteristics, career satisfaction, burnout, and quality of life (QOL). Burnout and QOL were measured using validated instruments. Of the 1519 surgical oncologists surveyed, 549 (36%) responded. More than 50% of respondents worked more than 60 hours per week while 24% performed more than 10 surgical cases per week. Among the respondents, 72% were academic surgical oncologists and 26% spent at least 25% of their time to research. Seventy-nine percent stated that they would become a surgical oncologist again given the choice. Overall, 28% of respondents had burnout. Burnout was more common among respondents age 50 years or younger (31% vs 22%; P = .029) and women (37% vs 26%; P = .031). Factors associated with a higher risk of burnout on multivariate analysis were devoting less than 25% of time to research, had lower physical QOL, and were age 50 years or younger. Burnout was associated with lower satisfaction with career choice. Although surgical oncologists indicated a high level of career satisfaction, nearly a third experienced burnout. Factors associated with burnout in this study may inform efforts by program directors and SSO members to promote personal health and retain the best surgeons in the field of surgical oncology. Additional research is needed to inform evidenced-based interventions at both the individual and organizational level to reduce burnout.


Restoration of wild-type p53 activity in p53-null HL-60 cells confers multidrug sensitivity.
HL-60 cells that stably express transfected wild-type (wt) p53 were used to determine whether restoration of wt p53 increased the chemosensitivity of cells that normally lack p53 activity. The wt p53 HL-60 transfectants (SN3 cells) were more sensitive than the parental (S) cells to a number of common anticancer drugs representing various mechanisms of action, whereas HL-60 cells transfected with p53 genes mutated at codons 248 and 143 were not sensitized. The sensitization ratio due to the transfected wt p53 varied from about 2-fold for cisplatin to over 50-fold for thymidine. Cells treated with the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FdUrd) were used to study changes in various p53-associated gene expressions. A higher percentage of apoptotic cells among the SN3 cells was observed than among the S cells at each concentration of FdUrd. The S cells had undetectable levels of bax and high levels of bcl-2, whereas the SN3 cells had undetectable levels of bcl-2 levels and appreciable basal levels of bax. After FdUrd treatment of SN3 cells, both p53 and bax levels increased, but the induction of bax was faster than that of p53 and paralleled the appearance of apoptotic DNA laddering. FdUrd treatment induced p21 expression and increased the G1 fraction of the SN3 cells but did not induce p21 or change the phase distribution in the S cells. FdUrd treatment also induced the expression and phosphorylation of cyclin D1 in the SN3 cells but not in the S cells. These results show that transfected wt p53 confers multidrug sensitivity to HL-60 cells by re-adjustment of the expressions of apoptosis genes and displays other properties characteristic of endogenously originated wt p53.


Dielectric relaxation time of bulk water at 136-140 K, background loss and crystallization effects.
Dielectric relaxation time, tau, of ultraviscous bulk water has been determined by analyzing its loss tangent, tan delta, data, which had been measured on heating the vapor-deposited amorphous solid water and hyperquenched glassy water in our earlier studies. [Johari, Hallbrucker, and Mayer, J. Chem. Phys. 95, 2955 (1991); 97, 5851 (1992)]. As for glasses and liquids generally, the measured tan delta of water is the sum of a frequency-independent background loss and a frequency-dependent relaxational loss. A two-frequency method is provided for determining the background loss and used for obtaining the relaxational part of tan delta. After considering the structural relaxation and crystal-nuclei growth effects, tau for water has been determined. At 136+/-1 K, it is 2.5+/-0.6 s when a single relaxation time is (untenably) assumed, and 42+/-14 s when a distribution of relaxation times, a characteristic of viscous liquids, is assumed, with Davidson-Cole distribution parameter of 0.75. Structural relaxation time of approximately 70 s for water at 136 K, which was originally estimated from the DSC endotherm [Johari, Hallbrucker, and Mayer, Nature (London) 330, 552 (1987)], has been revised to approximately 33 s. Temperature dependence of tau could not be determined because ultraviscous water crystallizes too rapidly to cubic ice containing stacking faults and intergranular water. The study demonstrates that water is a liquid over the 136-155 K range, thus removing the basis for a recent contention on its state.


Roadmap for advanced aqueous batteries: From design of materials to applications.
Safety concerns about organic media-based batteries are the key public arguments against their widespread usage. Aqueous batteries (ABs), based on water which is environmentally benign, provide a promising alternative for safe, cost-effective, and scalable energy storage, with high power density and tolerance against mishandling. Research interests and achievements in ABs have surged globally in the past 5 years. However, their large-scale application is plagued by the limited output voltage and inadequate energy density. We present the challenges in AB fundamental research, focusing on the design of advanced materials and practical applications of whole devices. Potential interactions of the challenges in different AB systems are established. A critical appraisal of recent advances in ABs is presented for addressing the key issues, with special emphasis on the connection between advanced materials and emerging electrochemistry. Last, we provide a roadmap starting with material design and ending with the commercialization of next-generation reliable ABs.


[A case of tuberculous meningitis complicated with multiple drug hypersensitivity to antituberculosis agents].
Multiple drug hypersensitivity (MDH) is an allergy to two or more chemically unrelated drugs. We present a case of MDH caused by antituberculosis agents during the treatment of tuberculous meningitis (TBM). A 64-year-old man without a history of drug allergy developed fever and severe headache. Examination of cerebrospinal fluid showed lymphocytosis, a low glucose level, and a high ADA activity, suggestive of TBM. The patient was treated with isoniazid, rifampicin, pyrazinamide, and ethambutol, and his symptoms resolved quickly. However, 20 days after the initiation of therapy, he developed remittent fever without mucocutaneous lesions. A drug-induced lymphocyte stimulation test was positive for isoniazid, rifampicin, and pyrazinamide, which was consistent with a diagnosis of MDH. All the antituberculosis drugs were replaced with levofloxacin and ethionamide, both of which have excellent cerebrospinal fluid penetration, and the fever subsided. The patient made a full recovery from TBM. Because standard antituberculosis regimens include three or four antituberculosis drugs, it is difficult to determine the culprit drug when hypersensitivity occurs. Moreover, there can be multiple causative drugs as illustrated by the present case. During a time-consuming desensitization therapy, TBM could flare up, leading to permanent neurological damage. Thus, treatment with suitable alternative drugs should be started immediately.


Fecal S100A12 concentration predicts a lack of response to treatment in dogs affected with chronic enteropathy.
S100A12 is a potential biomarker of gastrointestinal inflammation in dogs and fecal S100A12 concentrations are correlated with disease severity and outcome. The aim of the present study was to investigate whether there was any association between pre-treatment fecal S100A12 concentrations in dogs affected with chronic enteropathy (CE) and the response to treatment. Dogs affected with CE were recruited into the study and were classified as antibiotic-responsive diarrhea (ARD; n = 9), food-responsive diarrhea (FRD; n = 30) or idiopathic inflammatory bowel disease (IBD; n = 25). They were also grouped based on their response to treatment as complete remission (n = 35), partial response (n = 25) or no response (n = 4). Fecal S100A12 concentrations, measured by ELISA, were elevated in dogs affected with IBD compared with those from dogs affected with FRD (P = 0.010) or ARD (P = 0.025). Dogs with IBD that did not respond to treatment (n = 4) had significantly greater fecal S100A12 concentrations than dogs in complete remission (P = 0.009). Measurement of fecal S100A12 at the time of diagnosis discriminated between dogs with IBD that were refractory to therapy (≥2700 ng/g fecal S100A12) from those with at least a partial response (<2700 ng/g fecal S100A12), with a sensitivity of 100% and a specificity of 76%. These preliminary results suggest that testing of fecal S100A12 may be useful for predicting the lack of response to treatment in dogs affected with CE. The utility of serial fecal S100A12 measurements for monitoring dogs undergoing treatment for CE warrants further investigation.


Opioid receptors mediate inotropic and depressor effects of apelin in rats with 2K1C-induced chronic renovascular hypertension.
Apelin receptors (APJ) cross-talk with other G-protein-coupled receptors. However, the role of APJ interaction with opioid receptors (OPR) on the cardiovascular effects of apelin in hypertension is not clear. Renovascular hypertension was induced by placing a Plexiglas clip on the left kidney of rats. After 16 weeks, F13A (an APJ antagonist), naloxone (a general OPR inhibitor), and nor-binaltorphimine dihydrochloride (nor-BNI; a selective inhibitor of KOR) were given prior to injections of apelin at doses of 40 and 60 μg/kg. The arterial systolic/diastolic blood pressure and left ventricular contractility responses were then evaluated. The arterial systolic/diastolic blood pressure in sham and 2K1C rats was 110/71 mm Hg and 171/124 mm Hg, respectively. The hypotensive effects of apelin at both doses were inhibited by F13A and naloxone. Nor-BNI completely inhibited the effects of apelin 40 on arterial pressure, and decreased the effects of 60 μg/kg. KOR inhibition also prevented the compensation for the decrease in the left ventricle +dp/dt max and -dp/dt max caused by apelin 60. The simultaneous inhibition of OPR and APJ reduced arterial pressure and increased cardiac contractility. Findings showed that the OPR, particularly KOR, mediate the inotropic, lusitropic, and depressor effects of apelin. The interaction of the OPR and APJ augments the inotropic and vasodepressor effects of apelin. This interaction may have potential clinical applications in cardiac failure since opioids are currently used in the treatment of myocardial infarction and stroke, and apelin has been introduced as a potential therapeutic agent in cardiovascular complications.


Sertraline treatment for generalized anxiety disorder: a randomized, double-blind, placebo-controlled study.
This study assessed the efficacy and safety of sertraline in the treatment of generalized anxiety disorder (GAD). The study was conducted from April 2000 to May 2002. Outpatients with DSM-IV GAD (N = 326) who satisfied inclusion/exclusion criteria and completed a 1-week screening phase were randomly assigned to 10-week double-blind treatment with flexible dosing of sertraline (50-200 mg/day) or placebo. The primary efficacy measure was change from baseline in Hamilton Rating Scale for Anxiety (HAM-A) total score. Response was defined as a 50% or greater decrease in HAM-A total score at endpoint. Sertraline produced a statistically significant reduction in anxiety symptoms, as measured by HAM-A total change scores (p = .032), HAM-A psychic anxiety subscale (p = .011), and Hospital Anxiety and Depression Scale-anxiety subscale (p = .001). Response rates were significantly higher (p = .05) for the sertraline group (59.2%) compared to the placebo group (48.2%). Sertraline was well tolerated, with only sexual side effects reported significantly more often by subjects receiving sertraline than those receiving placebo. Despite the relatively small between-group differences, study findings suggest a role for sertraline in the acute treatment of GAD.


Human T-cell lymphotropic virus type III shares sequence homology with a family of pathogenic lentiviruses.
The etiologic agent of the acquired immune deficiency syndrome, human T-cell lymphotropic virus type III (HTLV-III), has recently been shown to morphologically resemble and share sequence homology with visna virus, a pathogenic lentivirus. Molecular hybridization, heteroduplex mapping, and DNA sequence analyses were used to compare HTLV-III to other lentiviruses of domestic animals, including visna, caprine arthritis encephalitis, and equine infectious anemia viruses. Hybridization results showed that a substantial amount of sequence homology exists between each of these viruses and HTLV-III. In addition, a closer relationship was found between visna and caprine arthritis encephalitis viruses than for any of the other lentiviruses studied. These results, along with nucleotide and amino acid sequence comparisons, have been used in a comprehensive effort to derive a systematic relationship for lentiviruses and to provide further evidence for classifying HTLV-III with the Lentivirinae subfamily of retroviruses. This relationship predicts that similarities in biology and disease process can be expected between HTLV-III and other Lentivirinae members.


Inhibition of CCR2 ameliorates insulin resistance and hepatic steatosis in db/db mice.
Recently, adipose tissue inflammation induced by macrophage infiltration through MCP-1/C-C chemokine receptor-2 (CCR2) pathway is considered to play a role in the development of visceral obesity and insulin resistance. In the present study, to further examine the role of CCR2 in the development of obesity and type 2 diabetes, we studied the effect of pharmacological inhibition of CCR2 from the early stage of obesity in db/db mice. Db/+m (lean control) and db/db mice were fed with a standard diet with or without 0.005% propagermanium, as a CCR2 inhibitor for 12 weeks from 6 weeks of age. Propagermanium treatment decreased body weight gain, visceral fat accumulation, and the size of adipocytes only in db/db mice. Further, propagermanium suppressed macrophage accumulation and inflammation in adipose tissue. Propagermanium treatment also ameliorated glucose tolerance and insulin sensitivity, and decreased hepatic triglyceride contents in db/db mice. Propagermanium improved obesity and related metabolic disorders, such as insulin resistance and hepatic steatosis by suppressing inflammation in adipose tissue. Our data indicate that inhibition of CCR2 could improve obesity and type 2 diabetes by interfering adipose tissue inflammation, and that propagermanium may be a beneficial drug for the treatment of the metabolic syndrome.


Anthocyanin accumulation and expression of anthocyanin biosynthetic genes in radish (Raphanus sativus).
Radish [Raphanus sativus (Rs)] is an important dietary vegetable in Asian countries, especially China, Japan, and Korea. To elucidate the molecular mechanisms of anthocyanin accumulation in radish, the gene expression of enzymes directly involved in anthocyanin biosynthesis was analyzed. These genes include phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), 4-coumarate-CoA ligase (4CL), chalcone synthase (CHS), chalcone isomerase (CHI), flavanone 3-hydroxylase (F3H), dihydroflavonol reductase (DFR), and anthocyanidin synthase (ANS). RsDFR and RsANS were found to accumulate in the flesh or skin of two radish cultivars (Man Tang Hong and Hong Feng No.1). Radish skin contained higher CHS, CHI, and F3H transcript levels than radish flesh in all three cultivars. In the red radish, 16 anthocyanins were separated and identified by high-performance liquid chromatography (HPLC) and elctrospray ionization-tandem mass spectrometry (ESI-MS/MS). Some of them were acylated with coumaroyl, malonoyl, feruoyl, and caffeoyl moieties. Furthermore (-)-epicatechin and ferulic acid were also identified in the three cultivars.


N-glycans from Paramecium bursaria chlorella virus MA-1D: Re-evaluation of the oligosaccharide common core structure.
Paramecium bursaria chlorella virus MA-1D is a chlorovirus that infects Chlorella variabilis strain NC64A, a symbiont of the protozoan Paramecium bursaria. MA-1D has a 339-kb genome encoding ca. 366 proteins and 11 tRNAs. Like other chloroviruses, its major capsid protein (MCP) is decorated with N-glycans, whose structures have been solved in this work by using nuclear magnetic spectroscopy and matrix-assisted laser desorption ionization-time of flight mass spectrometry along with MS/MS experiments. This analysis identified three N-linked oligosaccharides that differ in the nonstoichiometric presence of three monosaccharides, with the largest oligosaccharide composed of eight residues organized in a highly branched fashion. The N-glycans described here share several features with those of the other chloroviruses except that they lack a distal xylose unit that was believed to be part of a conserved core region for all the chloroviruses. Examination of the MA-1D genome detected a gene with strong homology to the putative xylosyltransferase in the reference chlorovirus PBCV-1 and in virus NY-2A, albeit mutated with a premature stop codon. This discovery means that we need to reconsider the essential features of the common core glycan region in the chloroviruses.


Anatomical subsegmentectomy in the lateral segment for hepatocellular carcinoma.
In this article, we describe a safe technique and the outcome of anatomical subsegmentectomies of segments 2 and 3 in patients with chronic liver disease. In cases of subsegmentectomy of segment 2, Arantius duct is transected at the side of umbilical portion and then the liver parenchyma located just above the root of the glissonean pedicle feeding segment 2 is transected. This procedure allows to encircle and dissect the root of the glissonean pedicle feeding segment 2 safely even in cirrhotic patients. After marking the discolored area on the liver surface, parenchymal transection between segment 2 and segment 3 was performed. In cases of subsegmentectomy of segment 3, the root of the glissonean pedicle feeding subsegment 3 is encircled and dissected from the ventral side of the umbilical portion before liver parenchymal resection. Using our technique, we performed subsegmentectomies of segment 3 in four hepatocellular carcinoma (HCC) patients and of segment 2 in two HCC patients. There was no postoperative liver failure and remnant liver function was adequate in all six of our cases. Although three of the six patients had HCC recurrence after hepatectomy, various and multiple treatments for HCC recurrence could be performed in these three patients. Subsegmentectomies for HCC located in the lateral segment were performed safely and could contribute to preservation of remnant liver function.


Integrative analysis of competing endogenous RNA network focusing on long noncoding RNA associated with progression of cutaneous melanoma.
Cutaneous melanoma (CM) is the most malignant tumor of skin cancers because of its rapid development and high mortality rate. Long noncoding RNAs (lncRNAs), which play essential roles in the tumorigenesis and metastasis of CM and interplay with microRNAs (miRNAs) and mRNAs, are hopefully considered to be efficient biomarkers to detect deterioration during the progression of CM to improve the prognosis. Bioinformatics analysis was fully applied to predict the vital lncRNAs and the associated miRNAs and mRNAs, which eventually constructed the competing endogenous RNA (ceRNA) network to explain the RNA expression patterns in the progression of CM. Further statistical analysis emphasized the importance of these key genes, which were statistically significantly related to one or few clinical features from the ceRNA network. The results showed the lncRNAs MGC12926 and LINC00937 were verified to be strongly connected with the prognosis of CM patients.


Transfusion in critical care - a UK regional audit of current practice.
A consistent message within critical care publications has been that a restrictive transfusion strategy is non-inferior, and possibly superior, to a liberal strategy for stable, non-bleeding critically ill patients. Translation into clinical practice has, however, been slow. Here, we describe the degree of adherence to UK best practice guidelines in a regional network of nine intensive care units within Wessex. All transfusions given during a 2-month period were included (n = 444). Those given for active bleeding or within 24 h of major surgery, trauma or gastrointestinal bleeding were excluded (n = 148). The median (IQR [range]) haemoglobin concentration before transfusion was 73 (68-77 [53-106]) g.l-1 , with only 34% of transfusion episodes using a transfusion threshold of < 70 g.l-1 . In a subgroup analysis that did not study patients with a history of cardiac disease (n = 42), haemoglobin concentration before transfusion was 72 (68-77 [50-98]) g.l-1 , with only 36% of transfusion episodes using a threshold of < 70 g.l-1 (see Fig. 3). Most blood transfusions given to critically ill patients who were not bleeding in this audit used a haemoglobin threshold > 70 g.l-1 . The reason why recommendations on transfusion triggers have not translated into clinical practice is unclear. With a clear national drive to decrease usage of blood products and clear evidence that a threshold of 70 g.l-1 is non-inferior, it is surprising that a scarce and potentially dangerous resource is still being overused within critical care. Simple solutions such as electronic patient records that force pause for thought before blood transfusion, or prescriptions that only allow administration of a single unit in non-emergency circumstances may help to reduce the incidence of unnecessary blood transfusions.


Bronchoalveolar lavage.
In formulating a reasonable position about the clinical use of BAL and its analysis, one must acknowledge that it is still an experimental procedure that needs further assessment, and it must continue to be included as part of patient research protocols. Therefore, neither the patient nor his/her insurance carrier should foot the bill, yet. The cost involved in analysis of BAL fluid and serum raises another consideration about how many things need to be measured and what tests give the essential information and are the most discriminating. Clearly, all of the assays suggested by some of the BAL results given in table 2 are not necessary. The cell count and the differential count, indicating the relative percentage of lymphocytes among the respiratory cells, and monoclonal antibody staining to distinguish the various T-cell subtypes give most of the essential cell information that relates to activity of alveolitis and to diagnosis in the interstitial lung diseases. Finding a very high percentage of lymphocytes in BAL fluid shifts the differential diagnosis in an unknown diffuse interstitial lung disease to the possibility of a granulomatous process, especially sarcoidosis or hypersensitivity pneumonitis; whereas elevated PMN with about 3% eosinophils also present suggests possible idiopathic pulmonary fibrosis. Many of the protein and enzyme assays have a role in describing immunopathogenesis, but are rarely measured until a few days after the procedure. Some quite sophisticated cell mediators can be measured, such as interleukin-2 produced by helper T-lymphocytes and many macrophage effector substances that may give more precise information than just cell counts and various immunoglobulin values. These assays require complex biochemical and cell culture work and are only available in special research laboratories, limiting the availability of such tests. Thus, it is not easy to suggest just what tests should be conducted with BAL cells and fluid to tailor costs yet give comprehensive clinical information, too. The use of BAL to obtain cells and proteins lining the alveolar space in many ways is still in its infancy, and new applications are being sought for a substantial list of lung diseases. Just the tip of the iceberg has been investigated, and much more may remain to be uncovered.