A Drug Repurposing Approach Reveals Targetable Epigenetic Pathways in Plasmodium vivax Hypnozoites.

Radical cure of Plasmodium vivax malaria must include elimination of quiescent 'hypnozoite' forms in the liver; however, the only FDA-approved treatments are contraindicated in many vulnerable populations. To identify new drugs and drug targets for hypnozoites, we screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) library and a collection of epigenetic inhibitors against P. vivax liver stages. From both libraries, we identified inhibitors targeting epigenetics pathways as selectively active against P. vivax and P. cynomolgi hypnozoites. These include DNA methyltransferase (DNMT) inhibitors as well as several inhibitors targeting histone post-translational modifications. Immunofluorescence staining of Plasmodium liver forms showed strong nuclear 5-methylcystosine signal, indicating liver stage parasite DNA is methylated. Using bisulfite sequencing, we mapped genomic DNA methylation in sporozoites, revealing DNA methylation signals in most coding genes. We also demonstrated that methylation level in proximal promoter regions as well as in the first exon of the genes may affect, at least partially, gene expression in P. vivax. The importance of selective inhibitors targeting epigenetic features on hypnozoites was validated using MMV019721, an acetyl-CoA synthetase inhibitor that affects histone acetylation and was previously reported as active against P. falciparum blood stages. In summary, our data indicate that several epigenetic mechanisms are likely modulating hypnozoite formation or persistence and provide an avenue for the discovery and development of improved radical cure antimalarials.

The challenges and possibilities of public access defibrillation.

Out-of-hospital cardiac arrest (OHCA) is a major health problem that affects approximately four hundred and thousand patients annually in the United States alone. It is a major challenge for the emergency medical system as decreased survival rates are directly proportional to the time delay from collapse to defibrillation. Historically, defibrillation has only been performed by physicians and in-hospital. With the development of automated external defibrillators (AEDs), rapid defibrillation by nonmedical professionals and subsequently by trained or untrained lay bystanders has become possible. Much hope has been put to the concept of Public Access Defibrillation with a massive dissemination of public available AEDs throughout most Western countries. Accordingly, current guidelines recommend that AEDs should be deployed in places with a high likelihood of OHCA. Despite these efforts, AED use is in most settings anecdotal with little effect on overall OHCA survival. The major reasons for low use of public AEDs are that most OHCAs take place outside high incidence sites of cardiac arrest and that most OHCAs take place in residential settings, currently defined as not suitable for Public Access Defibrillation. However, the use of new technology for identification and recruitment of lay bystanders and nearby AEDs to the scene of the cardiac arrest as well as new methods for strategic AED placement redefines and challenges the current concept and definitions of Public Access Defibrillation. Existing evidence of Public Access Defibrillation and knowledge gaps and future directions to improve outcomes for OHCA are discussed. In addition, a new definition of the different levels of Public Access Defibrillation is offered as well as new strategies for increasing AED use in the society.

Assessment strategies and decision criteria for pesticides with endocrine disrupting properties relevant to humans.

There is growing concern that environmental substances with a potential to modulate the hormonal system may have harmful effects on human health. Consequently, a new EU regulation names endocrine disrupting properties as one of the cut-off criteria for the approval of plant protection products, although it currently fails to provide specific science-based measures for the assessment of substances with such properties. Since specific measures are to be presented by the European Commission in 2013 the development of assessment and decision criteria is a key challenge concerning the implementation of this new EU regulation. Proposals of such decision criteria for substances with potential endocrine disrupting properties in human health risk assessment were developed by the German Federal Institute for Risk Assessment (BfR) and discussed at an expert workshop in November 2009. Under consideration of the requirements laid down within the new plant protection product legislation and the scientific discussions during the workshop, a conceptual framework on evaluation of substances for endocrine disrupting properties in a regulatory context is presented in this paper. Central aspects of the framework include assessment of adversity of effects, establishment of a mode/mechanism of action in animals, considerations concerning the relevance of effects to humans and two options for a regulatory decision.

High-intensity resistance and cardiovascular training improve physical capacity in cancer patients undergoing chemotherapy.

The purpose of the study was to examine the effects of a supervised high- and low-intensity structured training program in cancer patients concurrently undergoing chemotherapy. Seventy patients, in different stages of the disease and with different diagnoses (48 females, 22 males), between 18 and 65 years of age (mean age 42.8) participated in a 9-h weekly training program over 6 weeks. The intervention involved physical exercise, relaxation, massage, and body-awareness training. Physical capacity (one-repetition maximum tests (1RM), VO2max) and body composition (weight, skin-fold) were compared before and after the exercise intervention. The average increase in muscular strength was 41.3% (P<0.001) and 14.5% in aerobic fitness (pre: 2.27+/-0.597 L/min, post: 2.56+/-0.644 L/min, (P<0.001). The exercise intervention significantly increased the weight of the subjects by 1% (pre: 72.62+/-13.42 kg, post: 73.25+/-13.44 kg, P=0.016). There was a significant decrease in skin-fold measurements by 3% (P=0.031). The exercise intervention was well tolerated, provided that daily screening criteria were adhered to. The effects of resistance and cardiovascular training observed in this short-term study support the theory that exercise is a beneficial intervention strategy for increasing muscle strength and aerobic fitness during antineoplastic chemotherapy. This type of exercise program can be an important component of complementary treatment for cancer patients undergoing chemotherapy.

Transforming the nature of fatigue through exercise: qualitative findings from a multidimensional exercise programme in cancer patients undergoing chemotherapy.

The objective of this study was to explore the nature of fatigue in cancer patients with advanced stages of disease undergoing chemotherapy and concurrently participating in a 6-week multidimensional exercise programme (physical exercise, relaxation, massage and body-awareness training). Semi-structured qualitative interviews were conducted with 23 patients between 18 and 65 years of age prior to, during, and at termination of the programme. The findings endorsed that physical debilitation, fatigue, and uncertainty of physical capacity were the patients' motivation for participation. Throughout the programme the patients experienced exercise-induced fatigue, which they associated with a sense of increased physical strength, improvement in energy and physical well-being. This positive sense of fatigue can be seen as a contrast to the negative chemotherapy-induced fatigue, which is characterized by physical discomfort and uncontrollable exhaustion. The patients learned to manoeuvre through periods of intense fatigue by using exercise as a strategy to adjust their sense of physical debilitation. Visibility of fatigue's qualitative aspects is necessary if patients are to be encouraged to stay active and to set realistic goals. The transformation process of fatigue identified in this study supports the theory of exercise as a beneficial intervention strategy in the treatment of cancer-related fatigue.

Salt intake and hypertension in renal transplant patients.

BACKGROUND: Dietary salt restriction is currently widely recommended as an important non-pharmacological measure for the treatment of hypertension. However, the relationship between dietary salt intake and post-transplant hypertension has not been extensively investigated. PATIENTS AND METHODS: We examined the relationship between dietary salt intake and the prevalence of hypertension in 129 renal transplant patients with stable allograft function (serum creatinine < 400 micromol/l, variation in serum creatinine during the preceding two months < 20%). Salt intake was assessed by measuring 24-hour urinary excretion of sodium on an unrestricted diet. Hypertension was defined based on the prescription of antihypertensive medication, and the number of antihypertensive drugs was considered a surrogate marker for severity of hypertension. Patients were divided into tertiles based on urinary sodium excretion and analyzed by chi2-testing. RESULTS: The prevalence of hypertension was 74% and the mean sodium excretion was 178 mmol/d (range: 56 to 603). There was no statistical difference in the frequency of antihypertensive medication between patients with low (76%, UNa = 107 mmol/d), medium (73%, UNa = 178 mmol/d), or high sodium (73%, UNa = 272 mmol/d) excretion. Furthermore, the number of antihypertensive drugs (in treated patients) was similar between the tertiles. There was also no correlation between urinary sodium excretion and systolic (r = -0.05) or diastolic (r = 0.08) blood pressure levels. CONCLUSION: We conclude that dietary salt intake in transplant patients with stable allograft function is higher than currently recommended. There is, however, no relationship between salt intake and the prevalence of hypertension in these patients. These data do not support the hypothesis that the prevalence or severity of post-transplant hypertension is markedly affected by dietary salt intake.

[Contrast media in MR mammography]. / Kontrastmittel in der MR-Mammographie.

A standardized relationship between concentration of contrast media and normalized signal intensity should be the basis of a diagnostic evaluation of MR-mammography at different sites and with different sequences. In this work we compared the dynamic range of the MR-compatible contrast medium Magnevist at different sequences and machines. For this purpose we made measurements with a phantom, consisting of MR-compatible glass tubes filled with contrast medium of different concentrations. The glass tubes were placed in a water bath. All measurements were made with breast coils. The signal intensity of the glass tubes was normalized to the signal intensity of the native probe (water = 1). These normalized dynamic curves were compared with each other in order to find, for the different machines, the sequence which is nearest to a defined "Standard-Curve". As this task proved not possible for all machines, we measured how the dynamic curves of the different machines related to the "Standard-Curve". For all sequences we made also measurements with a female student to assure the quality of the pictures. Thus the participating radiologists can now compare their dynamic measurements of breast lesions with each other.

[Radiation protection through cytokine release by N-acetylcysteine]. / Radioprotektion durch Zytokinfreisetzung unter N-Acetylcystein.

BACKGROUND: Interleukin-1, tumornecrosisfactor-alpha and interferon-gamma endogenously provide protection of the hematopoietic system against radiation. Thiols have already been used successfully as radioprotective agents. In this study the effect von N-acetylcysteine (NAC) on the release of interleukin-1 alpha and beta (IL-1), interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and tumornecrosisfactor-alpha (TNF-alpha) was assessed in an in vitro assay. PATIENTS AND METHODS: Whole blood samples from 8 healthy volunteers were stimulated with 7.5 micrograms/ml PHA. NAC was added at concentrations of 0.6, 6, 12 and 24 mmol/l. Subsequently the samples were irradiated with a dose of 18 Gy according to preceding validation experiments. RESULTS: IL-1 alpha, IL-1 beta b and IL-2: In comparison to stimulation and radiation alone the addition of 0.6 and 6 mmol/l, with IL-2 also 12 mmol/l, NAC resulted in a significant increase of the cytokine-concentrations. The highest concentration of 24 mmol/l NAC, however, resulted in a decrease beyond control levels. IFN-gamma and TNF-alpha: Until 12 mmol/l NAC no changes were observed. 24 mmol/l NAC resulted in a significant decrease, too. CONCLUSION: N-acetylcysteine is capable to co-stimulate radioprotective cytokines like IL-1 alpha and IL-1 beta and to enhance IL-2 in vitro, whereas higher doses result in a suppression.

The combined effects of physical, sexual, and emotional abuse during childhood: long-term health consequences for women.

The long-term health effects of physical, sexual, and emotional abuse during childhood were studied in a sample of 668 middle class females in a gynecologic practice who responded to a self-administered, anonymous questionnaire covering demographic information, family history, physical and psychological health, as well as stressful events and abusive experiences as a child. Half (53%) of the sample reported childhood abuse, with 28.9% recounting exposure to one type of abuse, 18.7% to two types of abuse, and 5.4% to all three types of abuse. In comparison to women not abused during childhood, the abused reported significantly more hospitalizations for illnesses, a greater number of physical and psychological problems, and lower ratings of their overall health. The greater the number of childhood abuses, the poorer one's adult health and the more likely one was to have experienced abuse as an adult. Thus, in addition to the deleterious psychological consequences of abuse described in the literature, physical health also appears to be adversely affected in women abused as children.

[Functional testing of the immunotoxicity of the phenoxyalkane acid mecoprop in rats and prevention of immunotoxic effects by adrenalectomy]. / Funktionelle Testung der Immunotoxizität der Phenoxyalkansäure Mecoprop an Ratten und Ausschaltung immuntoxischer Effekte durch Adrenalektomie.

Mecoprop caused in former toxicological examinations time and dose dependent changes of structural components of the immune system. By investigation of humoral and cell immunity was to test, if functional parameter are also influenced by the substance. Mecoprop decreased the delayed hypersensitivity as parameter of cell immunity. The haemagglutination titer against sheep erythrocytes was not influenced by the substance. But the decrease of IgG-concentration in the serum shows also an effect of Mecoprop on the humoral immunity. Adrenalectomy was carried out to test, if there is an indirect mechanism of the action on the immune system, which is mediated by the activity of adrenals. The results show a nearly complete elimination of substance effects in adrenalectomized animals.

[Predictive value of a combined physiologic-therapeutic oriented score system in patients of intensive internal medicine]. / Aussagefähigkeit eines kombinierten physiologisch-therapeutisch orientierten Score-Systems (KOPT) bei Patienten der internen Intensivmedizin.

171 consecutive patients of a medical intensive care unit (age 18 to 81 years, mortality 24.6%) who were treated in the ICU for at least 72 hours were investigated in order to test the hypothesis, that the combination of therapeutic scoring (TISS) and physiologic scoring (APS) may improve the prognostic significance of score systems and/or the severity of disease classification in critically ill patients. Discrimination of survivors and non-survivors of the combined score was comparable to the results of isolated scores. A higher weighting of the physiology parameters in the combined score did not improve its prognostic significance. On the other hand, only the combined score implicated a linear increase of mortality with increasing score point values. - We conclude, that the combined score system improves the severity of disease classification in critically ill medical patients.

[Pathomorphologic and hematologic studies of the immunotoxicity of the phenoxyalkane acid mecoprop in rats]. / Pathomorphologische und hämatologische Untersuchungen zur Immuntoxizität der Phenoxyalkansäure Mecoprop an Ratten.

For a first estimation of the influence of the as herbicide used phenoxy acid Mecoprop on the immune system pathomorphological and haematological investigations were carried out. Histological results are completed by results of morphometrical--stereological investigations. Mecoprop causes structural changes in spleen and thymus and changes of the number of blood lymphocytes and granulocytes. The possibility, that the effects are induced by chemical stress, is discussed.

Sensory changes in the elderly.

Altered attitudes and improved physical surroundings can do much to create a more supportive environment for older persons. Changed attitudes are critical in reducing the impatience, rudeness, lack of understanding, and insensitivity faced by many older persons as a consequence of sensory changes. These attitudes compound the sensory barriers encountered in homes and public buildings, in the work place, on the streets and in recreational areas. Public education and awareness are needed to facilitate the daily life of older persons and to create a greater sense of dignity in the later years.

Childhood sexual abuse and the consequences in adult women.

This paper reviews the literature on childhood sexual abuse and its implications for women. It is estimated that at least 15-38% of adults have been sexually abused as children, with figures higher for women than for men. Failure to report abuse is common, and only 20-50% of incidents may come to the attention of authorities. Although childhood sexual abuse is present in all socioeconomic groups, more severe forms of abuse appear to be associated with lower socioeconomic status. After the age of ten, a sharp increase is observed in vaginal intercourse, sexual assaults accompanied by physical violence, and abuse committed by strangers. Although fathers are frequently cited as the primary perpetrators, not all studies support this finding. Other relatives have been reported to account for 20-70% of the sexual abuse occurring within the family. A history of childhood abuse may contribute to sexual problems or multiple chronic complaints in the adult woman. Moreover, some of these women may experience depression, anxiety, and low self-esteem. The gynecologist should use empathetic questioning with all patients regarding abuse, and integrate the patient's history of abuse with current health care. Physicians who are uncomfortable with this topic or who observe ongoing distress in their patients should refer these women to a mental health practitioner who is familiar with the issues common to women who have experienced childhood sexual abuse.

Hospital--nursing home collaboration.

In the present health care environment, the provision of quality care for the elderly depends on collaboration between hospitals and nursing homes. Nathan Miller Center for Nursing Care, Inc, a skilled nursing facility in White Plains, New York, and Montefiore Medical Center, a tertiary care hospital in Bronx, New York, developed a variety of joint educational programs in geriatrics for their staffs and for the local medical community. These programs not only helped improve patient care directly in such areas as development of care plans but also led to joint projects for research on geriatric care issues.