Exploring HIV disease indicators at MDR-TB treatment initiation in South Africa.

BACKGROUND: Understanding relationships between HIV and multidrug-resistant TB (MDR-TB) is crucial for ensuring successful MDR-TB outcomes.METHODS: We used a cross-sectional analysis to evaluate sociodemographic and clinical characteristics as correlates of antiretroviral therapy (ART) use, having an HIV viral load (VL) result, and HIV viral suppression in a cross-sectional sample of people with HIV (PWH) and MDR-TB enrolled in a cluster-randomized trial of nurse case management to improve MDR-TB outcomes.RESULTS: Among 1,479 PWH, the mean age was 37.1 years; 809 (54.7%) were male, and 881 (59.6%) were taking ART. Housing location, employment status, and CD4 count differed significantly between those taking vs. those not taking ART. Among the 881 taking ART, 681 (77.3%) had available HIV VL results. Housing location, CD4 count, and prior history of TB differed significantly between those with and without a VL result. Among the 681 with a VL result, 418 (61.4%) were virally suppressed. Age, education level, CD4 count, TB history, housing location, and ART type differed significantly between those with and without viral suppression.CONCLUSION: PWH presenting for MDR-TB treatment with a history of TB, taking a protease inhibitor, or living in a township may risk poor MDR-TB outcomes.

Generalist palliative care for non-cancer patients : A review article.

BACKGROUND: Most patients in the last phase of life can be treated in the context of generalist palliative care, especially by general practitioners. In contrast to specialized palliative care, non-cancer patients predominate in this setting. OBJECTIVE: The aim of this article is to review the literature and elaborate current topics for non-cancer patients at the end-of-life in primary palliative care. MATERIALS AND METHODS: A literature search was carried out in the databases PubMed and Scopus from 2008 to 2013 followed by a qualitative content analysis according to the PRISMA statement. RESULTS: A total of 127 articles could be included in the qualitative content analysis and the final review whereby four core topics were identified: (1) specific target groups (e. g. elderly patients, patients with advanced heart failure and pain), (2) collaboration of general practitioners with other physicians and health professionals, (3) qualifications in palliative care and (4) provision of primary palliative care. Most articles found were related to the fourth topic and the subtopic of barriers and facilitators of palliative care. Insufficient coordination of the persons involved was a barrier often discussed. Advanced care planning including concrete palliative care aspects at an early stage can be beneficial for both patients and professionals. CONCLUSION: The current literature search highlights the importance of optimizing the processes and structures in providing palliative care and the discussion of end-of-life issues at an early stage in general practice. Therefore, a structured identification of palliative care needs identified by appropriate assessment instruments is crucial.

[Generalist palliative care for non-cancer patients: A review article]. / Hausärztliche Palliativversorgung bei nichtonkologischen Patienten: Eine Übersichtsarbeit.

BACKGROUND: Most patients in the last phase of life can be treated in the context of generalist palliative care, especially by general practitioners. In contrast to specialized palliative care, non-cancer patients predominate in this setting. OBJECTIVE: The aim of this article is to review the literature and elaborate current topics for non-cancer patients at the end of life in primary palliative care. MATERIAL AND METHODS: A literature search was carried out in the databases PubMed and Scopus from 2008 to 2013 followed by a qualitative content analysis according to the PRISMA statement. RESULTS: A total of 127 articles could be included in the qualitative content analysis and the final review whereby four core topics were identified: (1) specific target groups (e.g. elderly patients, patients with advanced heart failure and pain), (2) collaboration of general practitioners with other physicians and health professions, (3) qualifications in palliative care and (4) provision of primary palliative care. Most articles found were related to the fourth topic and the subtopic of barriers and facilitators of palliative care. Insufficient coordination of the persons involved was a barrier often discussed. Advanced care planning including concrete aspects of palliative care at an early stage can be beneficial for both patients and professionals. CONCLUSION: The current literature search elucidates the importance of optimizing the processes and structures in providing palliative care and the discussion of end of life issues at an early stage in general practice. Therefore, a structured identification of palliative care needs identified by appropriate assessment instruments is crucial.

Prognostic Value of Conventional Magnetic Resonance Imaging for Adult Patients with Brain Tumors.

PURPOSE: Magnetic resonance imaging (MRI) is the pivotal diagnostic step in patients with brain tumors, and is performed before histological diagnosis is available. We hypothesized that conventional MRI is as accurate as tumor histology in differentiating malignant from benign clinical course. METHODS: Two neuroradiologists blinded to any clinical information evaluated the first diagnostic MRI of 244 brain tumor patients before any treatment, using a self-developed standardized list of image criteria and prospectively determined world health organization (WHO) tumor grade and tumor entity. All patients were examined with at least T1- and T2-weighted spin echo sequences before and after contrast injection on 1 and 1.5-T MRI scanners. Following the patients prospectively for 8-13 years after diagnosis, we were able to use nonsurvival at 5 years as a criterion for malignity and reference for the prognostic accuracy of both MRI and tumor tissue histology. RESULTS: The accuracy for predicting nonsurvival at 5 years was 91% (95% confidence interval (CI): 87-94%) for MRI and 92% (95% CI: 88-95%) for histology. The Kaplan-Meier survival curves of patients with benign and malignant brain tumors as diagnosed by MRI or histology differed significantly (p < 0.001). Histology confirmed benignity or malignity in 201 patients (82%, 95% CI: 77-87%). Sources of misdiagnosis were metastases diagnosed as astrocytoma WHO IV, atypical meningiomas, and low-grade astrocytoma with malignant transformation. CONCLUSION: MRI appears as accurate as histology in predicting survival at 5 years after diagnosis. Histological diagnosis may be more specific, however, and is needed to assess the tumor's specific biology.

Inpatient costs, mortality and 30-day re-admission in patients with central-line-associated bloodstream infections.

Previous work has suggested that central-line-associated bloodstream infection (CLABSI) is associated with increased costs and risk of mortality; however, no studies have looked at both total and variable costs, and information on outcomes outside of the intensive-care unit (ICU) is sparse. The aim of this study was to determine the excess in-hospital mortality and costs attributable to CLABSI in ICU and non-ICU patients. We conducted a retrospective cohort and cost-of-illness study from the hospital perspective of 398 patients at a tertiary-care academic medical centre from 1 January 2008 to 31 December 2010. All CLABSI patients and a simple random sample drawn from a list of all central lines inserted during the study period were included. Generalized linear models with log link and gamma distribution were used to model costs as a function of CLABSI and important covariates. Costs were adjusted to 2010 US dollars by use of the personal consumption expenditures for medical care index. We used multivariable logistic regression to identify independent predictors of in-hospital mortality. Among both ICU and non-ICU patients, adjusted variable costs for patients with CLABSI were c. $32 000 (2010 US dollars) higher on average than for patients without CLABSI. After we controlled for severity of illness and other healthcare-associated infections, CLABSI was associated with a 2.27-fold (95% CI 1.15-4.46) increased risk of mortality. Other healthcare-associated infections were also significantly associated with greater costs and mortality. Overall, CLABSI was associated with significantly higher adjusted in-hospital mortality and total and variable costs than those for patients without CLABSI.

[Sebaceous gland tumor with a rare gene mutation within a tumor syndrome: Muir-Torre syndrome]. / Talgdrüsenkarzinom mit seltener Genmutation im Rahmen eines Tumorsyndroms: Muir-Torre-Syndrom.

Muir-Torre syndrome is a rare autosomal dominant subtype of hereditary nonpolyposis colorectal carcinoma and is characterized by the simultaneous occurrence of sebaceous gland neoplasms with visceral and urogenital malignancies. This article describes the case of a 72-year-old patient who was referred to our clinic for removal of an upper eyelid tumor, showing the course from the clinical findings to the rare diagnosis of Muir-Torre syndrome.

Development and validation of an alternative disturbed skin model by mechanical abrasion to study drug penetration.

Pharmaceuticals and cosmetics for dermal application are usually tested on healthy skin, although the primary permeation barrier, the stratum corneum, is often impaired by skin diseases or small skin lesions, especially on the hands. These skin conditions can considerably influence the permeation of chemicals and drugs. Furthermore, risk assessment for example of nanoparticles should be performed under various skin conditions to reflect the true circumstances. Therefore, an alternative and reproducible method for a high throughput of skin samples with impaired skin barrier was developed and verified by skin permeation studies (25 h) of caffeine, sorbic acid and testosterone compared to healthy (untreated) and tape-stripped skin. Skin barrier disruption was controlled by TEWL measurement. Skin permeation of the three substances was increased in tape-stripped and abraded skin compared to untreated skin due to the reduced barrier integrity. Enhancement of drug uptake was highest for the most hydrophilic substance, caffeine, followed by sorbic acid and lipophilic testosterone. No significant difference in drug uptake studies was observed between the new abrasion method with an aluminum-coated sponge and the tape-stripping method. The obtained results demonstrate that this abrasion method is an alternative way to achieve a disturbed skin barrier for drug and chemical uptake studies.

The prognostic value of IDH mutations and MGMT promoter status in secondary high-grade gliomas.

Reports about the prognostic value of IDH mutations and the promoter region of the O6-Methyl-guanyl-methyl-transferase gene in secondary high-grade gliomas (sHGG) are few in number. We investigated the prognostic value of IDH mutations and methylation of the promoter region of the MGMT gene in 99 patients with sHGG and analyzed the clinical course of those tumors. Patients with sHGG were screened for IDH mutations by direct sequencing, and, for promoter status of MGMT gene, by the methylation-specific polymerase chain reaction. A total of 48 of 99 patients (48.5 %) had secondary anaplastic gliomas (Group 1), while 51 patients had secondary glioblastomas (Group 2). The median survival time after malignant progression of all patients with sHGG and with an IDH mutation was 4 years, which is significantly longer than in patients with wild-type IDH (1.2 years, p = 0.009). Patients' survival was not significantly influenced by the tumors' MGMT promoter status, both in Group 1- 9.7 years vs. 6.1 years, methylated vs. unmethylated promoter (p = 0.330)-as well as in Group 2-1.5 years vs. 1.6 years, methylated versus unmethylated promoter (p = 0.829). In our population, the IDH mutation status was not associated with increased PFS or median survival time in sGBM patients. However, patients with secondary anaplastic glioma and IDH mutation had a significantly improved outcome. In addition, IDH mutations are a more powerful prognostic marker concerning both PFS and MS than the MGMT promoter status in those patients.

The prostate stem cell antigen represents a novel glioma-associated antigen.

Gliomas of WHO grades III-IV are malignant brain tumors mostly resistant to conventional therapies. Therefore, novel strategies for the treatment of gliomas are warranted. Although immunotherapy is gaining increased attention for the treatment of malignant gliomas and in particular of glioblastoma multiforme (GBM), this approach requires the identification of appropriate antigens. Our aim was to investigate the expression of the prostate stem cell antigen (PSCA), a highly N-glycosylated phosphatidylinositol (GPI)-anchored cell surface protein, in gliomas of different WHO grades in order to evaluate its potential as a diagnostic marker and as a target for immunotherapy. Tumor specimens and controls were assessed by quantitative RT-PCR, Western blotting and immunohistochemistry. The samples investigated in the study consisted of 210 human glial tumors, among which 31 were oligodendrogliomas, 9 ependymomas and 170 were astrocytomas (including 134 glioblastomas). PSCA was absent in normal brain tissue, but was detected in WHO grade III-IV gliomas. Weak PSCA protein expression was also recognized in some WHO grade I and WHO grade II tumors. The difference between WHO grade I-II tumors and WHO grade III-IV tumors was statistically significant (p<0.001). Our results suggest that increased PSCA expression levels are linked to gliomas of WHO grades III and IV, and may represent a suitable additional target for immunotherapy of gliomas.

[19-year-old asthma patient with pronounced eosinophilia and acute coronary syndrome]. / 19-jähriger Asthmatiker mit ausgeprägter Eosinophilie und akutem Koronarsyndrom.

Diagnosis of Churg-Strauss syndrome should be considered in young asthmatics with fatigue and eosinophilia. On the base of the etiopathology of a 19-year old man, who was initially admitted because of dyspnoea, fever and acute chest pain, we show that eosinophilia gives an important hint for further diagnostic and is the key trend parameter. Histologically an eosinophilic myocarditis could be shown in the myocardial biopsy. High dose prednisolone induced a clear improvement in symptoms, with decrease of the inflammatory signs and the eosinophilia and a clear improvement of the left ventricular function.

Hypoxia induces apelin expression in human adipocytes.

Adipokines play a central role in the development of diseases associated with insulin resistance and obesity. Hypoxia in adipose tissue leads to a dysregulation of the expression of adipokines. The effect of hypoxia on the more recently identified adipokine apelin in human adipocytes is unclear. Therefore, we aimed at investigating the role of hypoxia on the expression of the adipokine apelin. Differentiated human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were cultured under hypoxic conditions for varying time periods. A modular incubator chamber was used to create a hypoxic tissue culture environment (defined as 1% O(2), 94% N, and 5% CO(2)). In addition, hypoxic conditions were mimicked by using CoCl(2). The effect of hypoxia on the expression of the investigated adipokines was measured by real-time PCR and the secretion of apelin was quantified by ELISA. Induction of hypoxia significantly induced mRNA expression of leptin and apelin in differentiated SGBS adipocytes compared with the normoxic control condition. Expression of adiponectin was significantly decreased by hypoxia. In addition, the amount of secreted apelin protein in response to hypoxia was elevated compared to untreated cells. Furthermore, we could demonstrate that the observed hypoxia-induced induction of apelin mRNA expression is in the first phase dependent on HIF-1α. In our study, we could demonstrate for the first time that apelin expression and secretion by human adipocytes are strongly induced under hypoxic conditions and that the early response on hypoxia with apelin induction is dependent on HIF-1α.

Rosette-forming glioneuronal tumor of the fourth ventricle in an elderly patient.

Rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) is a rare condition, which previously has been described predominantly in middle-aged patients. There is limited experience with this kind of tumor in the elderly. Clinical, neuroimaging, and histological features of an example in a 70-year-old male who presented initially with vertigo are detailed and compared with published cases. Neuroimaging studies demonstrated a 4-cm cystic lesion in posterior fossa containing a 1-cm contrast-enhancing nodule on its lateral margin. The lesion was confined to the fourth ventricle and initially thought to be a hemangioblastoma until angiography clarified the minimal tumor vascularization. Gross total resection was achieved. Pathological examination showed a rosette-forming low grade tumor with a cell proliferation rate of 2% being consistent with RGNT. The postoperative course was uneventful and clinical symptoms resolved completely. There was no tumor recurrence after 2 years follow-up. We confirm that the rare and only recently characterized tumor entity of RGNT can also be found in elderly patients; furthermore, it can be associated with a benign course. The main differential diagnosis of RGNT resulting from CNS-imaging modalities in elderly patients are pilocytic astrocytoma and hemangioblastoma of the posterior fossa, which after metastasis are the most common primary adult intra-axial posterior fossa tumors. Therefore, a subtle preoperative radiological diagnosis is warranted and surgery should be performed by experienced hands to avoid neurological deterioration.

[Teaching emergency medicine at the University Medical Center Freiburg: establishment of an integrative concept]. / Lehrveranstaltung Notfallmedizin am Universitätsklinikum Freiburg : Etablierung eines integrativen Gesamtkonzeptes.

Efforts to improve the quality of undergraduate medical education are commonly hampered by limited human and financial resources. This deficiency may be offset by the development of well structured and innovative teaching concepts, which optimize available assets. The newly conceived modular course "Emergency Medicine" at the University Medical Center Freiburg was conducted for the first time in the winter semester 2006/2007. The core of the course is a 3-day practical training period. It provides the possibility to teach a maximum number of medical students with only four lecturers using patient simulators, interactive case scenarios (simulation software MicroSim), and case scenarios with standardized patients. Evaluation of the course revealed standardized patients to be the best of all teaching methods with an overall average grade of 1.1 (patient simulators 1.2, computer simulation 1.4). Of the students, 88% stated that the practical training encouraged their interest in the speciality emergency medicine. The excellent student evaluation results show that the new course "Emergency Medicine" for medical students constitutes a successful balance between the constraint of resource limitation and the goal of excellent medical education.

BM cells giving rise to MSC in culture have a heterogeneous CD34 and CD45 phenotype.

BACKGROUND: Mesenchymal stromal cells (MSC) isolated from adult human BM are characterized by their fibroblast-like morphology, adherent growth and capacity to differentiate into adipocytes, osteocytes, chondrocytes, cardiomyocytes and neuroprogenitors. After culturing these cells in vitro, they express the cell-surface molecules CD44, CD90, SH2 and SH3, and are negative for CD34 and the hematopoietic marker CD45. The aim of this study was to characterize the in vivo phenotype of MSC relative to the expression of CD34 and CD45. METHODS: BM mononuclear cells were stained with Ab against both molecules and separated into the CD34(+), CD34(-), CD45(+) CD34(+), CD45(high+) CD34(-), CD45(med,low+) CD34(-) and CD45(-) CD34(-) subpopulations, which were then cultured under the same conditions and analyzed for growth of MSC. RESULTS: A small population of MSC arose from the CD45(+) CD34(+) fraction, although the majority was obtained from the CD45(-) CD34(-) subpopulation. MSC from all fractions could be differentiated into adipocytes and osteocytes. In addition, MSC from the CD34(+) and CD34(-) fractions were shown to differentiate into chondrocytes. After in vitro culture, MSC from both fractions possessed the same phenotype, which was negative for CD34 and CD45. DISCUSSION: MSC from the CD45(+) CD34(+) fraction change their phenotype under in vitro conditions.

Infant carrying: the role of increased locomotory costs in early tool development.

Among the costs of reproduction, carrying one's infant incurs one of the greatest drains on maternal energy, simply because of the added mass alone. Because of the dearth of archaeological evidence, however, how early bipeds dealt with the additional cost of having to carry infants who were less able to support their body weight against gravity is not particularly well understood. This article presents evidence on the caloric drain of carrying an infant in one's arms versus having a tool with which to sling the infant and carry her passively. The burden of carrying an infant in one's arms is on average 16% greater than having a tool to support the baby's mass and seems to have the potential to be a greater energetic burden even than lactation. In addition, carrying a baby in one's arms shortens and quickens the stride. An anthropometric trait that seems to offset some of the increased cost of carrying a baby in the arms is a wider bi-trochanteric width.

FKHRL1-mediated expression of Noxa and Bim induces apoptosis via the mitochondria in neuroblastoma cells.

Protein kinase-B (PKB) and its target, the forkhead transcription factor like 1 (FKHRL1)/FoxO3a, have been suggested as regulators of neurotrophin-mediated cell survival in neuronal cells. We analyzed human neuroblastoma cells and found that FKHRL1 was phosphorylated, suggesting its inactivation. To study FKHRL1 function, we infected SH-EP and NB15 cells with a 4OH-tamoxifen-regulated FKHRL1(A3)ER(tm) transgene. Activation of FKHRL1 promoted cytochrome-c release and caspase-dependent apoptosis. FKHRL1 induced TRAIL and the BH3-only proteins Noxa and Bim, implicating both extrinsic and intrinsic death pathways. However, expression of dnFADD did not inhibit FKHRL1-induced cell death, whereas Bcl2 protected against apoptosis. This excluded the death-receptor pathway and suggested that cell death decision is regulated by Bcl2-rheostat. Importantly, RNAi knockdown of Noxa or Bim decreased apoptosis, indicating that Noxa and Bim cooperate to mediate FKHRL1-induced cell death. We conclude that Noxa and Bim establish a connection between FKHRL1 and mitochondria, and that both BH3-only proteins are critically involved in FKHRL1-induced apoptosis in neuroblastoma.

Neuronal and glial apoptosis in human traumatic brain injury.

To establish reliable methods to aid the timing of brain damage after traumatic brain injury (TBI), brain tissue from 56 autopsy cases with TBI and known survival times, ranging from a few minutes to 126 days, were tested for apoptotic changes to the neuronal and glial cells. Apoptosis was established using the TdT-mediated dUTP nick end labelling (TUNEL) method of in-situ labelling and immunohistochemical reaction of caspase 3. In addition, cellular reaction and astroglial cell differentiation were investigated using histological and immunohistochemical markers. From a survival time of 120 min up to 12 days, TUNEL-positive apoptotic neuronal cells were frequently detected in the contusion zone. The earliest positive caspase 3 reaction in cortical neurons was evident after a posttraumatic interval of 80 min. Detection of apoptotic glial cells using the TUNEL technique showed that as in the case of neuronal cells, the earliest positive TUNEL reaction was obtained after 110 min. In cases of survival times of 120 min up to 4 days, apoptotic glial cells could frequently be detected. However, the first caspase 3-positive glial cells appeared 5 h after injury. Cerebral apoptosis was significantly associated with TBI cases as compared to control cases (P<0.001). The reference histological findings of neutrophilic granulocytes, CD3-positive T-lymphocytes, CD68-positive activated microglial cells/macrophages and TUNEL-positive neuronal cells increases the degree of certainty in determining the probable age of traumatic brain injury to 87.5%.

Increased polysialic acid neural cell adhesion molecule expression in human hippocampus of heroin addicts.

Chronic exposure to heroin is known to cause cognitive deficits. However, little is known about the underlying molecular mechanisms. It has been suggested that opiate-induced neurotoxicity as well as impaired plasticity and regeneration may be relevant. One of the target regions where regeneration still can be observed in the adult brain is the hippocampus. Since polysialic acid neural cell adhesion molecule is regarded as one of the key players involved in plasticity and regeneration of neural tissue, we analyzed polysialic acid neural cell adhesion molecule expression in the fascia dentate hilus of the human hippocampus of 29 lethally intoxicated heroin addicts and matched controls. Immunohistochemistry with an antibody directed against polysialic acid neural cell adhesion molecule revealed its expression in differently sized cells which could be identified as neurons and glial cells. We observed an increase in the percentage of polysialic acid neural cell adhesion molecule positive neurons in hippocampal hilus of heroin addicts compared with controls (P = 0.001).Interestingly, we also observed polysialic acid neural cell adhesion molecule expression in glial cells as evidenced by double immunofluorescence with glial fibrillary acidic protein and polysialic acid neural cell adhesion molecule using confocal laser scanning microscopy. The fraction of polysialic acid neural cell adhesion molecule positive glial cells was also higher in heroin addicts compared with controls (P = 0.009). In addition, within the group of addicts morphine blood concentrations showed a positive correlation with the percentage of polysialic acid neural cell adhesion molecule positive neurons (P = 0.04; r = 0.547). In conclusion, we observed an increase in polysialic acid neural cell adhesion molecule positive neurons and glial cells in hippocampi of heroin addicts. This might reflect an attempt to repair cell damage due to heroin exposure.

Impact of inspired substance concentrations on the results of breath analysis in mechanically ventilated patients.

A well-defined relationship has to exist between substance concentrations in blood and in breath if blood-borne volatile organic compounds (VOCs) are to be used as breath markers of disease or health. In this study, the impact of inspired substances on this relationship was investigated systematically. VOCs were determined in inspired and expired air and in arterial and mixed venous blood of 46 mechanically ventilated patients by means of SPME, GC/MS. Mean inspired concentrations were 25% of expired concentrations for pentane, 7.5% for acetone, 0.7% for isoprene and 0.4% for isoflurane. Only if inspired concentrations were <5% did substance disappearance rates from blood and exhalation rates correlate well. Exhaled substance concentrations depended on venous and inspired concentrations. Patients with sepsis had higher n-pentane and lower acetone concentrations in mixed venous blood than patients without sepsis (2.27 (0.37-8.70) versus 0.65 (0.33-1.48) nmol L-1 and 69 (22-99) versus 18 (6.7-56) micromol L-1). n-Pentane and acetone concentrations in breath showed no differences between the patient groups, regardless whether or not expired concentrations were corrected for inspired concentrations. In mechanically ventilated patients, concentration profiles of volatile substances in breath may considerably deviate from profiles in blood depending on the relative amount of inspired concentrations. A simple correction for inspired substance concentrations was not possible. Hence, substances having inspired concentrations>5% of expired concentrations should not be used as breath markers in these patients without knowledge of concentrations in blood and breath.