Biological hydrogen production using a membrane bioreactor.
A cross-flow membrane was coupled to a chemostat to create an anaerobic membrane bioreactor (MBR) for biological hydrogen production. The reactor was fed glucose (10,000 mg/L) and inoculated with a soil inoculum heat-treated to kill non-spore-forming methanogens. Hydrogen gas was consistently produced at a concentration of 57-60% in the headspace under all conditions. When operated in chemostat mode (no flow through the membrane) at a hydraulic retention time (HRT) of 3.3 h, 90% of the glucose was removed, producing 2200 mg/L of cells and 500 mL/h of biogas. When operated in MBR mode, the solids retention time (SRT) was increased to SRT = 12 h producing a solids concentration in the reactor of 5800 mg/L. This SRT increased the overall glucose utilization (98%), the biogas production rate (640 mL/h), and the conversion efficiency of glucose-to-hydrogen from 22% (no MBR) to 25% (based on a maximum of 4 mol-H(2)/mol-glucose). When the SRT was increased from 5 h to 48 h, glucose utilization (99%) and biomass concentrations (8,800 +/- 600 mg/L) both increased. However, the biogas production decreased (310 +/- 40 mL/h) and the glucose-to-hydrogen conversion efficiency decreased from 37 +/- 4% to 18 +/- 3%. Sustained permeate flows through the membrane were in the range of 57 to 60 L/m(2) h for three different membrane pore sizes (0.3, 0.5, and 0.8 microm). Most (93.7% to 99.3%) of the membrane resistance was due to internal fouling and the reversible cake resistance, and not the membrane itself. Regular backpulsing was essential for maintaining permeate flux through the membrane. Analysis of DNA sequences using ribosomal intergenic spacer analysis indicated bacteria were most closely related to members of Clostridiaceae and Flexibacteraceae, including Clostridium acidisoli CAC237756 (97%), Linmingia china AF481148 (97%), and Cytophaga sp. MDA2507 AF238333 (99%). No PCR amplification of 16s rRNA genes was obtained when archaea-specific primers were used.


[MICROBIOLOGICAL ASPECTS OF INFECTIOUS BALANOPOSTHITIS].
Treatment and prevention of diseases of the male reproductive organs largely influence male population fertility and the health of the future generations. This review summarizes current views on the problem of infectious balanoposthitis and presents generalized information on its pathogens. Refined classification and diagnostic workup are provided. The important role of pathogenic microflora in the formation of the glans penis and foreskin inflammation is shown. Importance of Enterococcus spp. in the etiology of balanoposthitis is demonstrated. The modern treatment regimens and prevention of balanoposthitis are described.


How do we manage asthma? Assessment of knowledge, attitude, and practice patterns among pulmonologists and allergists.
Objective: The objective of this study was to evaluate and compare knowledge, attitude, and practice patterns between pulmonologists and allergists for adult asthma in Turkey.Methods: Questionnaire-based data were gathered from 236 pulmonologists and 62 allergists, who had been members of the Turkish Thoracic Society and Turkish National Society of Allergy and Clinical Immunology in January-March 2021. Univariate and multivariate statistics were used to determine the factors associated with primary reliever preferences.Results: Of the 298 physicians, 39% encountered at least five asthma patients daily. Spirometer was used frequently by both the allergists (82.3%) and pulmonologists (77.5%) for asthma diagnosis. Budesonide was the most preferred inhaler corticosteroid. Formoterol/budesonide was the most preferred ICS/LABA combination, followed by beclomethasone/formoterol and fluticasone/salmeterol for asthma treatment. For mild asthmatics, formoterol/ICS was the most preferred (72.6%) reliever among allergists, whereas salbutamol was the most preferred (66.1%) among pulmonologists (p < 0.001). Age and workplace were associated with salbutamol preference of doctors for mild asthmatics. Age, specialty, and patient examination time were significantly associated with salbutamol preference for severe asthmatics.Conclusions: The use of diagnostic tools, such as a spirometer, for asthma diagnosis was compatible with the guidelines. While recent updates of the guidelines indicate that salbutamol should not be used solely in mild asthmatics due to its harmful effects in long-term use, it still was the most preferred drug by pulmonologists. Postgraduate education programs are needed to improve compliance with the guidelines.


Toe blood pressure. A valuable adjunct to ankle pressure measurement for assessing peripheral arterial disease.
Ankle pressure measurements fail to reflect the severity of peripheral ischemia when the underlying vessels are calcified or when there is extensive pedal or digital arterial disease. These problems may be obviated by measuring pressures at toe level. In this study, toe pressures were correlated with ankle pressures, clinical symptoms, and the presence or absence of diabetes in 294 limbs. The relationship of toe pressures to healing of ulcers or amputations of the foot was investigated in 58 limbs. Measurements were made with a digital pneumatic cuff and a photoplethysmograph. The ability of absolute toe pressure, ankle/brachial index, toe/brachial index, toe/ankle index, and the brachial pressure minus the toe pressure to differentiate between asymptomatic, claudicating, and ischemic limbs was determined. The toe/brachial index, arm minus toe pressure, and the absolute toe pressure had an average sensitivity and specificity of 85% and 88% for asymptomatic limbs and 89% and 86% for ischemic limbs. A toe pressure greater than 30 mmHg was indicative of a good healing potential, and ankle pressure less than 80 mmHg was associated with poor healing. The correlation between ankle and toe pressures was essentially the same in both diabetic (r = 0.60) and non-diabetic limbs (r = 0.62).


[Tetracycline and the primary immune response].
The effect of tetracycline on proliferation of plate- and rossette-forming cells in the spleen and mesenterial lymph nodes of rats in case of the primary immune response with respect to the sheep erythrocytes was studied using the methods of Jerne, Notta and Zaalberg. It was found that tetracycline acted as an inhibitor when it was administered 48 hours before introduction of the antigen. When they were administered simultaneously its inhibiting effect decreased. When tetracycline was injected 24 hours after the antigen administration it had induced stimulation of immunogenesis. The inhibiting effect of the antibiotic was more pronounced with respect to the plate-forming cells and less pronounced with respect to the rossette-forming cells. The inhibiting effect of the antibiotic was lower in the mesenterial lymph nodes than in the spleen. The problem of independent antibody genesis in the lymph nodes is discussed.


ATP-induced spectral changes in cytochrome c oxidase. A kinetic investigation.
Mixing ATP with soluble oxidized cytochrome c oxidase induces a spectral perturbation in the Soret region of the enzyme. This spectral perturbation is observed at ATP concentrations similar to those found to modulate the catalytic activity of cytochrome c oxidase [Malatesta, Antonini, Sarti & Brunori (1987) Biochem. J. 248, 161-165]. The process is reversible and corresponds to a simple binding with Kd = 0.2 mM at 25 degrees C. The absorbance change follows a first-order time course, and analysis of the ATP-concentration-dependence indicates the presence of a rate-limiting monomolecular step that governs the process. From the temperature-dependence of this process, studied at saturating concentrations of ATP, an activation energy of 44 kJ/mol (10.6 kcal/mol) was measured. The spectral perturbation also occurs when cytochrome c oxidase is reconstituted into artificial phospholipid vesicles, with equilibria and kinetics similar to those observed with the soluble enzyme. Mixing ATP with soluble oxidized cyanide-bound cytochrome c oxidase induces a different spectral perturbation, and the apparent affinity of ATP for the enzyme is substantially increased. There is no absolute specificity for ATP, because EGTA, inositol hexakisphosphate, sulphate and phosphate are all able to induce an identical spectral perturbation with the same kinetics, although the value of the apparent Kd is different for the various anions. The presence of Mg2+ ions decreases, in a saturation-dependent fashion, the apparent affinity of cytochrome c oxidase for ATP. The absorbance change can be correlated to the displacement of the Ca2+ bound to cytochrome c oxidase.


Growing Apart: A Longitudinal Assessment of the Relation Between Post-traumatic Growth and Loneliness Among Combat Veterans.
The aftermath of war-related trauma may entail psychological devastation and is typically accompanied by various deleterious phenomena. These include, but are not limited to, high rates of loneliness. However, trauma may also result in positive outcomes such as personal, spiritual, and relational prosperity, which are typically considered under the conceptual framework of post-traumatic growth (PTG). PTG may theoretically contribute to either loneliness amelioration (e.g., via increasing one's appreciation of close relationships) or exacerbation (e.g., by increasing one's sense of undergoing experiences that others do not share). Loneliness, on the other hand, may potentially hinder PTG by fostering negative social cognitions and behaviors, or otherwise lead to personal growth. The relations between the two phenomena, however, have yet to be investigated. Filling this gap, the current study examined the aforementioned potentialities by utilizing an autoregressive cross-lagged modeling strategy (ARCL) with a cohort of 260 Israeli combat veterans assessed 30, 35, and 42 years after their participation in the 1973 Yom Kippur War. Results indicated that higher rates of PTG were consistently related to higher rates of loneliness both cross-sectionally and longitudinally. Loneliness, however, did not longitudinally predict PTG rates. It is suggested that these findings may be understood in light of the observation that veterans' loneliness is primarily related to the experience of being experientially out of sync with people who have not endured war experiences. It is suggested that this experiential loneliness may include not only the negative but also the positive ramifications of undergoing such traumas (i.e., PTG). We, therefore, argue that while PTG may include authentic positive transformations it may also lead to more negative ramifications, and these should be identified and addressed by researchers and clinicians alike. Thus, as study limitations are acknowledged, clinical implications, and future research directions are suggested.


Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial.
Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism of this benefit is unclear. To better understand the effects of vitamin D on endothelial function, blood pressure, albuminuria, and inflammation in patients with chronic kidney disease (2 patients stage 2, remaining stage 3), we conducted a pilot trial in 24 patients who were randomly allocated equally to 3 groups to receive 0, 1, or 2 microg of paricalcitol, a vitamin D analog, orally for 1 month. Placebo-corrected change in flow mediated dilatation with a 1-microg dose was 0.5% and 0.4% with a 2-microg dose (P>0.2). At 1 month, the treatment:baseline ratio of high sensitivity C-reactive protein was 1.5 (95% CI: 1.1 to 2.1; P=0.02) with placebo, 0.8 (95% CI: 0.3 to 1.9; P=0.62) with a 1-microg dose, and 0.5 (95% CI: 0.3 to 0.9; P=0. 03) with a 2-microg dose of paricalcitol. At 1 month, the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (95% CI: 1.08 to 1.69; P=0.01) with placebo, 0.52 (95% CI: 0.40 to 0.69; P<0.001) with a 1-microg dose, and 0.54 (95% CI: 0.35 to 0.83; P=0. 01) with a 2-microg dose (P<0.001 for between group changes). No differences were observed in iothalamate clearance, 24-hour ambulatory blood pressure, or parathyroid hormone with treatment or on washout. Thus, paricalcitol-induced reduction in albuminuria and inflammation may be mediated independent of its effects on hemodynamics or parathyroid hormone suppression. Long-term randomized, controlled trials are required to confirm these benefits of vitamin D analogs.


How to get proteomics to the clinic? Issues in clinical proteomics, exemplified by CE-MS.
Clinical proteomics is defined as application of proteome analysis aiming at improving the current clinical situation. As such, the success of clinical proteomics should be assessed based on the clinical impact following implementation of the findings. While we have experienced significant technological advancements in mass spectrometry in the last years, based on the above measure, this has not at all resulted in similar advancements in clinical proteomics. Although a large number of proteomic biomarkers have been described, most of them were not subsequently validated, and certainly have had no impact in clinical decision making as yet. Under the current conditions, it appears likely that the situation will not change significantly: we will be flooded by reports on biomarkers, but not see any implementation. In this article, some key issues in proteomic biomarker research are pinpointed, based on the experience with CE-MS, likely also holding true for biomarkers resulting from other analysis domains.


Nanodiamond Effects on Cancer Cell Radiosensitivity: The Interplay between Their Chemical/Physical Characteristics and the Irradiation Energy.
Nanoparticles are being increasingly studied to enhance radiation effects. Among them, nanodiamonds (NDs) are taken into great consideration due to their low toxicity, inertness, chemical stability, and the possibility of surface functionalization. The objective of this study is to explore the influence of the chemical/physical properties of NDs on cellular radiosensitivity to combined treatments with radiation beams of different energies. DAOY, a human radioresistant medulloblastoma cell line was treated with NDs-differing for surface modifications [hydrogenated (H-NDs) and oxidized (OX-NDs)], size, and concentration-and analysed for (i) ND internalization and intracellular localization, (ii) clonogenic survival after combined treatment with different radiation beam energies and (iii) DNA damage and apoptosis, to explore the nature of ND-radiation biological interactions. Results show that chemical/physical characteristics of NDs are crucial in determining cell toxicity, with hydrogenated NDs (H-NDs) decreasing either cellular viability when administered alone, or cell survival when combined with radiation, depending on ND size and concentration, while OX-NDs do not. Also, irradiation at high energy (γ-rays at 1.25 MeV), in combination with H-NDs, is more efficient in eliciting radiosensitisation when compared to irradiation at lower energy (X-rays at 250 kVp). Finally, the molecular mechanisms of ND radiosensitisation was addressed, demonstrating that cell killing is mediated by the induction of Caspase-3-dependent apoptosis that is independent to DNA damage. Identifying the optimal combination of ND characteristics and radiation energy has the potential to offer a promising therapeutic strategy for tackling radioresistant cancers using H-NDs in conjunction with high-energy radiation.


Monocyte-derived dendritic cells as a model for the study of HIV-1 infection: productive infection and phenotypic changes during culture in human serum.
Dendritic cells (DC) have been implicated in the initial selection for macrophage-tropic HIV-1 during transmission and in the generation of high-level virus replication during interactions with CD4 T cells. The role of DC as viral reservoirs and the extent of productive infection is unclear, but the ability to generate large numbers of DC from blood monocytes has produced a tractable model for study of DC-HIV-1 interactions. When cultured in granulocyte-macrophage colony stimulating factor and IL-4, sorted CD14+ monocytes rapidly lost phagocytic function for both 93 nm and 977 nm latex particles and developed the surface markers and function of DC. After 7 days, when returned to medium containing human serum without cytokines, some monocyte-derived dendritic cells (MDDC) became adherent, but retained the costimulatory markers CD80 and CD86 and continued to express CD83 and CD40. The MDDC stimulated allogeneic CD4 T cells, did not express new macrophage markers and remained non-phagocytic. With or without TNF-alpha, MDDC generated in cytokines were infected by macrophage and T cell-tropic virus and produced higher reverse transcriptase levels than did the autologous monocyte-derived macrophages (MDM). When added to T cells, the infected MDDC were able to infect T cells with a wider range of viral isolates than were MDM.


Tec family kinases in inflammation and disease.
Over the last decade, the Tec family of nonreceptor tyrosine kinases (Btk, Tec, Bmx, Itk, and Rlk) have been shown to play a key role in inflammation and bone destruction. Bruton's tyrosine kinase (Btk) has been the most widely studied due to the critical role of this kinase in B-cell development and recent evidence showing that blocking Btk signaling is effective in ameliorating lymphoma progression and experimental arthritis. This review will examine the role of TFK in myeloid cell function and the potential of targeting these kinases as a therapeutic intervention in autoimmune disorders such as rheumatoid arthritis.


Sex Modulates the Pathological Aging Effect on Caudate Functional Connectivity in Mild Cognitive Impairment.
To assess the pathological aging effect on caudate functional connectivity among mild cognitive impairment (MCI) participants and examine whether and how sex and amyloid contribute to this process. Two hundred and seventy-seven functional magnetic resonance imaging (fMRI) sessions from 163 cognitive normal (CN) older adults and 309 sessions from 139 participants with MCI were included as the main sample in our analysis. Pearson's correlation was used to characterize the functional connectivity (FC) between caudate nuclei and each brain region, then caudate nodal strength was computed to quantify the overall caudate FC strength. Association analysis between caudate nodal strength and age was carried out in MCI and CN separately using linear mixed effect (LME) model with covariates (education, handedness, sex, Apolipoprotein E4, and intra-subject effect). Analysis of covariance was conducted to investigate sex, amyloid status, and their interaction effects on aging with the fMRI data subset having amyloid status available. LME model was applied to women and men separately within MCI group to evaluate aging effects on caudate nodal strength and each region's connectivity with caudate nuclei. We then evaluated the roles of sex and amyloid status in the associations of neuropsychological scores with age or caudate nodal strength. An independent cohort was used to validate the sex-dependent aging effects in MCI. The MCI group had significantly stronger age-related increase of caudate nodal strength compared to the CN group. Analyzing women and men separately revealed that the aging effect on caudate nodal strength among MCI participants was significant only for women (left: P = 6.23 × 10-7, right: P = 3.37 × 10-8), but not for men (P > 0.3 for bilateral caudate nuclei). The aging effects on caudate nodal strength were not significantly mediated by brain amyloid burden. Caudate connectivity with ventral prefrontal cortex substantially contributed to the aging effect on caudate nodal strength in women with MCI. Higher caudate nodal strength is significantly related to worse cognitive performance in women but not in men with MCI. Sex modulates the pathological aging effects on caudate nodal strength in MCI regardless of amyloid status. Caudate nodal strength may be a sensitive biomarker of pathological aging in women with MCI.


Construction and validation of the My Medicines and Me Questionnaire for assessment of the self-reported side effects of psychotropic medication.
We aimed to construct and assess the psychometric properties of the My Medicines and Me Questionnaire (M3Q), a self-report side-effect questionnaire for mental health patients. Thirty individuals taking a psychotropic medication completed the M3Q side-effect checklist along with the Liverpool University Neuroleptic Side Effect Rating Scale. Thirty healthy comparison individuals also completed the M3Q checklist. Data were analyzed using factorial analysis. Psychometric evaluations including validity and reliability testing were carried out on the questionnaire's checklist. The original 54-item checklist of the M3Q was shortened to include only those items found to be significant in the factorial analysis. The revised 32-item checklist of the M3Q was found to be valid and reliable. The M3Q is a simple, valid and reliable questionnaire that can be used routinely in clinical practice for detecting bothersome side effects of a range of psychotropic medications. This will provide a platform for improved communication between the clinician and the patient.


One Thousand and One Software for Proteomics: Tales of the Toolmakers of Science.
Proteomics is a highly dynamic field driven by frequent introduction of new technological approaches, leading to high demand for new software tools and the concurrent development of many methods for data analysis, processing, and storage. The rapidly changing landscape of proteomics software makes finding a tool fit for a particular purpose a significant challenge. The comparison of software and the selection of tools capable to perform a certain operation on a given type of data rely on their detailed annotation using well-defined descriptors. However, finding accurate information including tool input/output capabilities can be challenging and often heavily depends on manual curation efforts. This is further hampered by a rather low half-life of most of the tools, thus demanding the maintenance of a resource with updated information about the tools. We present here our approach to curate a collection of 189 software tools with detailed information about their functional capabilities. We furthermore describe our efforts to reach out to the proteomics community for their engagement, which further increased the catalog to >750 tools being about 70% of the estimated number of 1097 tools existing for proteomics data analysis. Descriptions of all annotated tools are available at https://proteomics.bio.tools.


Importance of Surface Coating to Accumulation Dynamics and Acute Toxicity of Copper Nanomaterials and Dissolved Copper in Daphnia magna.
We evaluated the effect of copper oxide nanomaterials (CuO NMs), uncoated and with 3 different surface coatings (carboxylated, pegylated, and ammonia groups), on acute toxicity and accumulation dynamics in Daphnia magna. With the use of biodynamic modelling, biosorption and elimination rate constants were determined for D. magna following waterborne exposure to dissolved Cu and CuO NMs. The relationship between modeled parameters and acute toxicity endpoints was evaluated to investigate whether accumulation dynamics parameters could be used as a predictor of acute toxicity. The Langmuir equation was used to characterize the biosorption dynamics of Cu NMs and Cu chloride, used as dissolved Cu control. Uptake rates showed the following NM rankings: pristine-CuO > NH3 -CuO > aqueous Cu > polyethylene glycol (PEG)-CuO > COOH-CuO. To determine Cu elimination by D. magna, a one-compartment model was used. Different elimination rate constants were estimated for each chemical substance tested. Those that were easily biosorbed were also easily removed from organisms. Biosorption and depuration properties of NMs were correlated with zeta potential values and diameters of NM agglomerates in the suspensions. No link was found between biosorption and toxicity. Waterborne exposures to more difficult-to-biosorb CuO NMs were more likely to induce adverse effects than those that biosorbed easily. It is proposed that some physicochemical properties of NMs in media, including zeta potential and agglomerate diameter, can lead to higher biosorption but do not necessarily affect toxicity. The mode of interaction of the NMs with the organism seems to be complex and to depend on chemical speciation and physicochemical properties of the NMs inside an organism. Moreover, our findings highlight that coating type affects the biosorption dynamics, depuration kinetics, and dissolution rate of NMs in media. Environ Toxicol Chem 2020;39:287-299. © 2019 SETAC.


A brewing understanding of the regulation of Bax function by Bcl-xL and Bcl-2.
Bcl-2 family members form a network of protein-protein interactions that regulate apoptosis through permeabilization of the mitochondrial outer membrane. Deciphering this intricate network requires streamlined experimental models, including the heterologous expression in yeast. This approach had previously enabled researchers to identify domains and residues that underlie the conformational changes driving the translocation, the insertion and the oligomerization of the pro-apoptotic protein Bax at the level of the mitochondrial outer membrane. Recent studies that combine experiments in yeast and in mammalian cells have shown the unexpected effect of the anti-apoptotic protein Bcl-xL on the priming of Bax. As demonstrated with the BH3-mimetic molecule ABT-737, this property of Bcl-xL, and of Bcl-2, is crucial to elaborate about how apoptosis could be reactivated in tumoral cells.


Stakeholders' perceptions of appropriate nature-based solutions in the urban context.
The concept of nature-based solutions (NBSs) has become increasingly popular among urban policymakers and planners to help them tackle the urban challenges arising from urban expansion and climate change. Stakeholders' involvement is a fundamental step, and stakeholders' perceptions and preferences can affect the development of NBS projects. This study aims to identify stakeholders' perceptions of the most critical urban challenges, the priority interventions, the preferred NBSs and the benefits of the NBSs, and to identify the determinants of these perceptions. A survey was administered to assess stakeholders' perceptions and views on implementing NBSs in two Portuguese cities with distinct urban, geographical, and socio-economic contexts. A binary logistic regression model was used to understand the determinants of the likelihood of the stakeholders' answers. According to the stakeholders, climate change is one of the main concerns in the urban context. It is usually associated with the incidence of heatwaves and water scarcity. Additionally, stakeholders are concerned about the low quantity and poor management of green spaces (GSs). They believe that it will be necessary to increase the GS, to recover some degraded areas, and to increase mobility. The preferred NBSs were planting more urban trees, making green shaded areas, and rehabilitating riverbanks. The main expected benefits were benefits for leisure and relaxation, reductions in air temperature, purer air, and improvements in public health. The results showed mostly coherent connections between the main concerns/priorities of the stakeholders and the perceived NBS benefits; however, some stakeholders did not present coherent connections, indicating low awareness of the current policy for implementing NBSs to overcome existing and future urban challenges.


Prenatal and postnatal exposure to DDT by breast milk analysis in Canary Islands.
The use of p,p'-dichlorodiphenyltrichloroethane (DDT) has been banned since the late 1970s due to its toxicity. However, its long half-life makes it persistent in the environment and, consequently, almost everyone has DDT residues in the body. Human milk constitutes an ideal non-conventional matrix to investigate environmental chronic exposure to organochlorine compounds (OCs) residues. The study aimed to identify potential population risk factors of exposure to DDT due to the proximity to countries where it is still used. Seventy-two consecutive lactating women were prospectively included in Tenerife, Canary Islands (Spain). A validated questionnaire was used to obtain socioeconomic, demographics data, and daily habits during pregnancy. DDT levels in breast milk were measured by gas chromatography with-electron capture detector (GC-ECD). Anthropometrics measurements in newborns were obtained. Thirty-four out of 72 (47.2%) of the analysed milk samples presented detectable levels of DDT (mean: 0.92 ng/g), ranging between 0.08 to 16.96 ng/g. The socio-demographic variables did not significantly differ between detectable DDT and non-detectable DDT groups. We found positive association between DDT levels and vegetables (OR (95%CI): 1.23 (1.01-1.50)) and poultry meat (OR (95%CI): 2.05 (1.16-3.60)) consumption, and also between the presence of DDT in breast milk and gestational age (OR (95%CI): 0.59 (0.40-0.90)). DDT is present in breast milk of women at the time of delivery. Residual levels and the spread from countries still using DDT explain DDT detection from vegetables and from animal origin food. The presence of this compound in breast milk represents a pre- and postnatal exposure hazard for foetuses and infants due to chronic bioaccumulation and poor elimination, with possible deleterious effects on health. This data should be used to raise awareness of the risks of OCs exposure and to help establish health policies in order to avoid its use worldwide and thus, to prevent its propagation.


Hepatic resection combined with portal vein or hepatic artery reconstruction for advanced carcinoma of the hilar bile duct and gallbladder.
Hepatectomy with vascular reconstruction for biliary malignancy remains controversial. This study aimed to clarify the indications for surgery. Patients with advanced hilar bile duct cancer (HBDC) (n = 26) and gallbladder cancer (GBC) involving the hepatoduodenal ligament (n = 13) who underwent hepatectomy were enrolled. They were divided into two groups on the basis of whether vascular reconstruction was performed (HBDC, 10 yes vs. 16 no; GBC, 5 yes vs. 8 no). Portal vein (PV) reconstruction was performed on the right branch in seven patients and on the left branch in two; hepatic artery (HA) reconstruction was done on the right branch in 11 patients and on the left branch in 1. Five patients with HBDC and one with GBC underwent both PV and HA reconstruction. Patency rates were 88.0% and 83.3% for PV and HA reconstructions, respectively. Vascular reconstruction-related morbidity occurred in one patient with fatal liver failure owing to a portal thrombus and in two patients with multiple liver abscesses caused by arterial obstruction. Microsurgery eliminated reconstruction-related morbidity. Mortality in vascular reconstruction cases was 13.3% (2/15), and in those without reconstruction it was 8.3% (2/24). Curability rates (R0 and R1+R2) were 50.0% and 56.0% for HBDC and 40.0% and 62.5% for GBC, respectively. The 3-year survivals of HBDC patients were, respectively, 33% and 42%, and the 5-year survivals were 18% and 25%, whereas for GBC the 1-year survivals were 20% and 60% and the 2-year survivals 0% and 25%. Two patients with vascular involvement who underwent PV with HA reconstruction survived more than 3 years. Hepatectomy with vascular reconstruction for selected HBDC patients offers low surgical risk and increased survival by curable resection, but it is not recommended for advanced GBC.


Low-grade endometrial stromal sarcoma with inferior vena cava tumor thrombus and intracardiac extension: radical resection may improve recurrence free survival.
Endometrial stromal sarcoma (ESS) represents 0.2% of all uterine malignancies. Based on the mitotic activity, a distinction is made between low and high-grade ESS. Although the overall five-year survival rate for low-grade ESS exceeds 80%, about 50% of the patients show tumor recurrence, mostly after a long latency period. Tumor invasion of the great vessels is extremely rare. We describe a patient with advanced low-grade ESS with tumor invasion of the infrarenal aorta and the inferior vena cava. The patient presented with a large tumor thrombus extending from the inferior vena cava into the right atrium. Review of literature and identification of 19 patients, including our own case report, with advanced low-grade ESS with invasion of the great vessels and formation of an inferior vena cava tumor thrombus. All 19 patients presented with an abdominal tumor mass and a tumor thrombus protruding into the inferior vena cava. The tumor thrombus extended into the right heart cavities in nine patients reaching the right atrium in four, the right ventricle in three and the pulmonary artery in two patients. There were 5 patients with an advanced primary tumor and 14 patients with an advanced recurrent tumor. Seven patients presented with synchronous metastatic disease and six patients with a pelvic tumor infiltrating the bladder, the rectosigmoid colon or the infrarenal aorta. Mean age at surgery was 45.9+/-12.3 years (median 47, range 25-65 years). Tumor thrombectomy was accomplished by cavatomy or by right atriotomy after installation of a cardiopulmonary bypass. There was no peri-operative mortality and a very low morbidity. Radical tumor resections were achieved in 10 patients. The follow-up for these 10 patients was 2+/-1.3 years (median 2, range 0.3-4.5 years). Nine patients remained recurrence free whereas one patient suffered an asymptomatic local recurrence. Low-grade ESS is a rare angioinvasive tumor with a high recurrence rate. Resection of an inferior vena cava tumor thrombus, even with extension into the right heart cavities, can be performed safely. Extensive radical surgery is therefore justified in the treatment of advanced tumor manifestations of a low-grade ESS potentially improving recurrence free survival.


[Congenital lobar emphysema - a radiological diagnosis at first glance?].
Congenital lobar emphysema (CLE) is a malformation of the lung of unknown etiology. The characteristic overdistension of the affected lobe leads to compression and displacement of adjacent normal lung tissue and mediastinum. In the majority of cases, symptoms appear during the neonatal period or in early childhood. Clinically, children present with signs of respiratory distress, frequently occurring with a superimposed lower respiratory tract infection that aggravates air trapping and renders the patient symptomatic. Rarely, CLE is diagnosed in adult patients who did not experience any symptoms during childhood. Knowledge of the disease is of importance because in the majority of cases a plain chest radiograph together with clinical signs is sufficient to diagnose the disease correctly. The article draws attention to this condition by presenting two children and one adult with congenital lobar emphysema. Possible clinical symptoms and diagnostic strategies are reviewed.


Prediction of attendance at fitness center: a comparison between the theory of planned behavior, the social cognitive theory, and the physical activity maintenance theory.
In the processes of physical activity (PA) maintenance specific predictors are effective, which differ from other stages of PA development. Recently, Physical Activity Maintenance Theory (PAMT) was specifically developed for prediction of PA maintenance. The aim of the present study was to evaluate the predictability of the future behavior by the PAMT and compare it with the Theory of Planned Behavior (TPB) and Social Cognitive Theory (SCT). Participation rate in a fitness center was observed for 101 college students (53 female) aged between 19 and 32 years (M = 23.6; SD = 2.9) over 20 weeks using a magnetic card. In order to predict the pattern of participation TPB, SCT and PAMT were used. A latent class zero-inflated Poisson growth curve analysis identified two participation patterns: regular attenders and intermittent exercisers. SCT showed the highest predictive power followed by PAMT and TPB. Impeding aspects as life stress and barriers were the strongest predictors suggesting that overcoming barriers might be an important aspect for working out on a regular basis. Self-efficacy, perceived behavioral control, and social support could also significantly differentiate between the participation patterns.


Risk assessment of high concentrations of molybdenum in forage.
Molybdenum is toxic to ruminants when present in high levels in forage, causing physiological copper deficiency. A critical level for ruminants is 3-10 mg Mo kg-1 dry matter. The average Mo level varies considerably between different arable soils, depending mainly on soil parent material. This study investigated the possibility of using various existing sources of geospatial information (geophysical, biogeochemical and soil chemical) to develop a geography-based risk assessment system. Forage samples (n = 173) were collected in 2006-2007. Three types of national geoscientific datasets were tested: (1) SEPA topsoil, comprising data from arable land within the Swedish environmental monitoring programme; (2) SGU biogeochemical, containing data from aquatic plant root material collected in small streams; and (3) SGU geophysical, consisting of data from airborne gamma-ray scanning. The digital postcode area map was used for geocoding, with Mo concentrations in forage assigned to arable parts of the corresponding postcode area. By combining this with the three national geoscientific databases, it was possible to construct a risk map using fuzzy classification depicting High-risk, Intermediate-risk, Low-risk and Very-low-risk areas. The map was validated using 42 randomly selected samples. All samples but one with Mo > 3 mg kg-1 were found in postcode areas designated High risk. Thus, the risk map developed seems to be useful as a decision support system on where standard forage analyses need to be supplemented with Mo analyses.


Limitations and Management of Dynamic Navigation System for Locating Calcified Canals Failure.
Nonsurgical endodontic teeth treatment with severe pulp canal obliteration poses challenges, primarily locating canals. By combining 3-dimensional reconstruction and spatial location registration, the dynamic navigation technique uses an optical tracking system to guide the clinician to drill in real time according to the predesigned path until access to the canal is established. Several in vitro studies and case reports have shown that calcified canal location with dynamic navigation system (DNS) is more accurate and efficient, yet the technique has limitations. In 4 cases with 7 teeth, this work presents manipulation process and clinical outcomes of DNS helping in calcified canal location. We performed handpiece adaptation and elucidated the failure to locate the canals with DNS in 2 teeth, resulting in canal geometry alteration and canal path deviation. Subsequently, the more experienced endodontist located the canals by combining cone-beam computed tomographic imaging and dental operating microscopy. All patients were completely asymptomatic after treatment. At the 1-year follow-up visit, the bone healing of periapical lesions progressed well according to the periapical radiography or cone-beam computed tomographic imaging. These findings indicate that DNS is a promising technique for locating calcified canals; however, it needs to be refined before clinical use.


The calcium channel α2/δ1 subunit interacts with ATP5b in the plasma membrane of developing muscle cells.
The α2/δ1 and α(1)1.1 subunits are present at a 1:1 ratio in the dihydropyridine receptor (DHPR) from adult skeletal muscle. In contrast, during early myotube development α2/δ1 is present at higher levels than α(1)1.1 and localizes at the ends of the cells, suggesting that α2/δ1 may have a role independent from DHPRs. We sought to identify binding partners of α2/δ1 at a period when levels of α(1)1.1 are low. Analysis of protein complexes in their native configuration established that α2/δ1 may be associating with ATP5b, a subunit of a mitochondrial ATP synthase complex. This interaction was confirmed with fluorescence resonance energy transfer and coimmunoprecipitation. The association of α2/δ1 and ATP5b occurs in intracellular membranes and at the plasma membrane, where they form a functional signaling complex capable of accelerating the rate of decline of calcium transients. The acceleration of decay was more evident when myotubes were stimulated with a train of pulses. Our data indicate that the α2/δ1 subunit is not only part of the DHPR but that it may interact with other cellular components in developing myotubes, such as the ATP5b in its atypical localization in the plasma membrane.


Expression and phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 in B-cell lymphomas and reactive lymphoid tissues.
Cap-mediated messenger RNA translation controlled by the eukaryotic initiation factor 4F (eIF-4F) complex plays a key role in human cancer. eIF-4F activity is controlled by a repressor binding protein (4E-BP1), which promotes translation when phosphorylated. To examine the level of expression and phosphorylation of 4E-BP1 in various subtypes of B-cell lymphoma and reactive lymphoid tissues. Archival formalin-fixed, paraffin-embedded B-cell lymphoma samples and reactive lymphoid tissues were immunostained and examined for expression of 4E-BP1 and phosphorylated 4E-BP1. Expression of components of the eIF-4F complex and unphosphorylated and phosphorylated 4E-BP1 was confirmed using Western immunoblotting on lysates of frozen lymphoma samples and reactive tissues. Immunohistochemical analysis demonstrated weak to undetectable 4E-BP1 staining within benign, reactive germinal centers (N = 10). In contrast, 4E-BP1 was consistently expressed (moderate to strong staining) in 98% of various subtypes of mature B-cell lymphoma (N = 50). 4E-BP1 expression was also demonstrable in all 4 lymph nodes with in situ or partial involvement by follicular lymphoma and in all 12 cases of BCL2-negative lymphoma. The level of phosphorylation of 4E-BP1 in lymphomas, evaluated by immunohistochemistry, was heterogeneous. The immunohistochemical expression pattern of 4E-BP1 exhibits regional and cellular specificity in reactive lymphoid tissues and may offer a diagnostic tool for distinguishing reactive follicles from neoplastic B-cell proliferations.


Decreased retinoblastoma protein expression in gamma-irradiated mouse ovarian follicles.
We immunohistochemically examined the effect of gamma-radiation on immature mouse ovarian follicles. Mice were Jirradiated with a dose of LD80 (8.3 Gy) in KAERI. At 0 h, 6 h, 12 h, 1 d, 2 d, 4 d and 8 d postirradiation, the ovaries were excised and fixed in neutral buffered formalin. We performed immunohistochemistry for protein retinoblastoma (pRb), terminal deoxynucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) and routine hematoxylin-eosin staining in the largest cross sections. Radiation-induced follicular degeneration increased before 6 h, and most irradiated ovarian follicles became acutely atretic. The immunohistochemical staining for pRb was strong in the nuclei of granulosa cells of normal follicles and weak in atretic ones which were, conversely, strong for TUNEL staining. It was shown that pRb expression became lower with the degeneration of the ovarian follicles, which was inhibited by gamma-radiation. In the present study, pRb immunohistochemistry was proven to be a useful tool for the identification of follicular status.


Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates.
Long-term survival is reported in patients with liver metastases of colorectal cancer. Recently, an increased number of reports on liver resection following neoadjuvant chemotherapy in patients with initially unresectable liver metastases has been published. We analysed all published or presented trials and retrospective studies that report the rate of objective response and the rate of resection of initially unresectable metastases to correlate objective response and the rate of resection of metastases. In studies that enrolled patients with metastases confined to the liver, 24-54% of patients were resected following chemotherapy, compared to 1-26% of patients in trials that included non-selected patients with metastatic colorectal cancer. A strong correlation was found between response rates and the resection rate in studies with patients with isolated liver metastases (r = 0.96, P=0.002). Likewise, in studies with non-selected patients, the resection rate of metastases also was associated with the objective response rate (r = 0.74, P <0.001). Patient selection and efficacy of pre-operative chemotherapy are both strong predictors for resectability of liver metastases. Resectability is a novel endpoint focusing on the curative potential of treatment compared with classical endpoints of response or progression-free survival that are important if palliation is the aim. Therefore, patients with potentially resectable liver metastases should be investigated in special trials and interdisciplinary teams.


[Inorganic pyrophosphatase activity of the mouse spleen in the immune response and after treatment with bis-phosphonates].
The inorganic pyrophosphatase activity was determined in different tissues of mice. The immunization of mice by sheep erythrocytes increased the inorganic pyrophosphatase activity of the spleen. The in vivo administration of bisphosphonates (40 mg per 1 g of mass), which are structural analogs of inorganic pyrophosphate (methylene bisphosphonic acid--MBPA, hydroxyethylidene bisphosphonic acid--HEBPA and aminomethylene bisphosphonic acid--AMBPA), inhibited the inorganic pyrophosphatase activity only by MBPA in the thymus and spleen but not in liver. The addition of MBPA, HEBPA as well as of phosphonoacetic acid, imidobisphosphate, bis(phosphonomethyl)-phosphonic acid, MBPA and phosphoric acid monoanhydride to cytosol from the mouse spleen led to the competitive (relative to the [Mg (PPi)2-] complex) inhibition of the inorganic pyrophosphatase activity. AMBPA didn't possess the analogous effect.


Computational analysis of enhanced magnetic bioseparation in microfluidic systems with flow-invasive magnetic elements.
A microfluidic design is proposed for realizing greatly enhanced separation of magnetically-labeled bioparticles using integrated soft-magnetic elements. The elements are fixed and intersect the carrier fluid (flow-invasive) with their length transverse to the flow. They are magnetized using a bias field to produce a particle capture force. Multiple stair-step elements are used to provide efficient capture throughout the entire flow channel. This is in contrast to conventional systems wherein the elements are integrated into the walls of the channel, which restricts efficient capture to limited regions of the channel due to the short range nature of the magnetic force. This severely limits the channel size and hence throughput. Flow-invasive elements overcome this limitation and enable microfluidic bioseparation systems with superior scalability. This enhanced functionality is quantified for the first time using a computational model that accounts for the dominant mechanisms of particle transport including fully-coupled particle-fluid momentum transfer.


Asymmetric hydrogenation catalyzed by a rhodium complex of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane: scope of enantioselectivity and mechanistic study.
The rhodium complex of (R)-(tert-butylmethylphosphino)(di-tert-butylphosphino)methane used in Rh-catalyzed asymmetric hydrogenation of representative substrates 3-14 demonstrated high catalytic activity coupled with wide scope and nearly perfect enantioselectivity. Mechanistic studies (NMR and DFT computations) were carried out in order to investigate the mechanism of the enantioselection in the asymmetric hydrogenation of (Z)-alpha-acetamidocinnamate (3). Although catalyst-substrate complexes 15a,b with the double bond coordinated near the non-"chiral" phosphorus atom were formed as kinetic products upon the addition of 3 to solvate complex 2 at -100 degrees C, they rapidly rearranged to more stable isomers 15c,d with the double bond coordinated near the "chiral" phosphorus atom. The thermodynamic and kinetic parameters of the interconversion between 15c and 15d were determined by NMR; mainly, the interconversion occurred intramolecularly via nonchelating catalyst-substrate complexes 16. The equilibrium between 15d and 16d was directly observed from NMR line shape changes at temperatures ranging from -100 to -40 degrees C, whereas no such equilibrium was observed for 15c. This result was accounted for computationally by determining the corresponding transition states for the methanol insertion into 15c,d. Three sets of experiments of the low-temperature hydrogenation of different catalyst-substrate complexes gave the same order and sense of enantioselectivity (97% ee (R)) even in the case when 15c, having Re-coordinated double bond, was hydrogenated under the conditions precluding its isomerization to 15d. It was concluded that the hydrogenation of 15c,d does not occur directly, but is preceded by the dissociation of the double bond to result in the more reactive species 16. This indicates that enantioselection must occur at a later step of the catalytic cycle. DFT computations of association and migratory insertion steps suggest that enantioselection takes place during the association step when chelating dihydride 19d.MeOH is formed from nonchelating dihydride 18d.


The B cell antigen receptor and overexpression of MYC can cooperate in the genesis of B cell lymphomas.
A variety of circumstantial evidence from humans has implicated the B cell antigen receptor (BCR) in the genesis of B cell lymphomas. We generated mouse models designed to test this possibility directly, and we found that both the constitutive and antigen-stimulated state of a clonal BCR affected the rate and outcome of lymphomagenesis initiated by the proto-oncogene MYC. The tumors that arose in the presence of constitutive BCR differed from those initiated by MYC alone and resembled chronic B cell lymphocytic leukemia/lymphoma (B-CLL), whereas those that arose in response to antigen stimulation resembled large B-cell lymphomas, particularly Burkitt lymphoma (BL). We linked the genesis of the BL-like tumors to antigen stimulus in three ways. First, in reconstruction experiments, stimulation of B cells by an autoantigen in the presence of overexpressed MYC gave rise to BL-like tumors that were, in turn, dependent on both MYC and the antigen for survival and proliferation. Second, genetic disruption of the pathway that mediates signaling from the BCR promptly killed cells of the BL-like tumors as well as the tumors resembling B-CLL. And third, growth of the murine BL could be inhibited by any of three distinctive immunosuppressants, in accord with the dependence of the tumors on antigen-induced signaling. Together, our results provide direct evidence that antigenic stimulation can participate in lymphomagenesis, point to a potential role for the constitutive BCR as well, and sustain the view that the constitutive BCR gives rise to signals different from those elicited by antigen. The mouse models described here should be useful in exploring further the pathogenesis of lymphomas, and in preclinical testing of new therapeutics.


Differences in non-enzymatic glycation and collagen cross-links between human cortical and cancellous bone.
It is important to establish the relationship between pentosidine and advanced glycation endproducts (AGEs) in bone. We found the relationship between pentosidine and AGEs and their magnitude of accumulation were dependent on bone's surface-to-volume ratio. Results illustrate the importance of measuring pentosidine and AGEs separately in cancellous and cortical bone. Accumulation of collagen cross-links (AGEs) produced by non-enzymatic glycation deteriorates bone's mechanical properties and fracture resistance. Although a single AGE, pentosidine, is commonly used as a representative marker, it is unclear whether it quantitatively reflects total fluorescent AGEs in bone. The goal of this study was to establish the relationship between pentosidine and total AGEs in cancellous and cortical bone. Pentosidine and total AGEs were quantified in 170 human bone samples. Total fluorescent AGEs were measured in 28 additional cancellous and cortical bone specimens of the same apparent volume that were incubated in control or in vitro glycation solutions. Correlations between pentosidine and total AGEs and differences between cortical and cancellous groups were determined. Pentosidine was correlated with total AGEs in cancellous bone (r = 0.53, p < 0.0001) and weakly correlated in cortical bone (r = 0.23, p < 0.05). There was more pentosidine (p < 0.01) and total AGEs (p < 0.001) in cancellous than in cortical bone. The in vitro glycation substudy showed that cancellous bone accumulated more AGEs than cortical bone (p < 0.05). The relationship between pentosidine and total AGEs and their magnitude of accumulation differed in cancellous and cortical bone of the same apparent volume, and were dependent on the surface-to-volume ratios of each sample. It is important to consider the bone types as two separate entities, and it is crucial to quantify total AGEs in addition to pentosidine to allow for more comprehensive analysis of the effects of non-enzymatic glycation in bone.


Superior Mesenteric Artery Syndrome due to a Vertebral Hemangioma and Postpartum Osteoporosis following Treatment.
In pregnancy, advanced vertebral hemangiomas may be seen, and these require treatment. The case reported here is of a 35-year-old female in the 32nd week of pregnancy who was admitted to the orthopaedics clinic with a history of backache and difficulty walking. A burst fracture of L1 associated with a vertebral hemangioma was identified with an L3 compression fracture secondary to osteoporosis. The local kyphosis angle between T12 and L2 was 27°. Kyphotic deformity was corrected and postoperatively, the measured T12-L2 local kyphotic angle was 9°. Twelve hours postoperatively, oral nutrition was allowed, but she developed nausea and vomiting and twenty-four hours postoperatively, an electrolyte imbalance developed. Postoperatively, the patient was diagnosed with superior mesenteric artery syndrome. To the best of our knowledge, this is the first reported case of superior mesenteric artery syndrome, which occurred following the correction of a kyphotic deformity that had developed secondary to an advanced hemangioma in pregnancy.


Detection methods for milk pathogenic bacteria by loop-mediated isothermal amplification.
Milk is a common food, which is consumed all over the world. It is an important source of calcium. Meanwhile, it provides abundant protein, minerals and vitamins. However, pathogenic bacteria which exist in milk not only causes nutrition loss, but also produces toxins which may cause diarrhea, food poisoning, and even death. In order to control the microbial level of raw milk and eliminate the contamination of materials, this assay applied loop-mediated isothermal amplification to explore a new way to detect enterotoxigenic Escherichia coli (ETEC) in raw milk. The best reaction condition in detecting ETEC from raw milk was confirmed to be: 0.016 μM each of forward outer primer (primer F3) and backward outer primer (primer B3), 0.128 μM each of forward inner primer (primer FIP) and backward inner primer (primer BIP), 0.45 μM deoxy-ribonucleoside triphosphate (dNTPs), 2IU Bst DNA polymerase large fragment and template DNA were incubated at 63°C for 60 min. LAMP was proved to be specific, rapid and sensitive in detecting pathogenic bacteria which exist in milk.


The Influence of Social Relationships on Men's Weight.
To explore how men's social relationships influence their dietary, physical activity, and weight loss intentions and behaviors. Qualitative study using semistructured interviews. One county in the southwest of England. Men (n = 19) aged 18-60 years with a body mass index ≥24 kg/m2 who were otherwise healthy. Men's perceptions of dieting, physical activity and weight loss, and how social relationships influence these behaviors. Interviews were audiorecorded and transcribed verbatim. Transcripts were coded line by line using NVivo software. Themes and subthemes were inductively generated using thematic analysis. Four themes were derived: (1) how experiences shape beliefs, (2) being a proper bloke, (3) adapting to family life, and (4) support from outside the home. Men discussed how partners were a greater influence on diet than physical activity. Attitudes toward diet and physical activity were influenced by life events such as becoming a father. It was framed as acceptable for men to talk to their friends about exercise and food intake in general, but they emphasized that this was not for "support." Family members were key influences on men's behaviors. Future qualitative research could include interviews with men's families. Findings may inform family weight loss interventions.


Transplacental transmission of Toxoplasma gondii in minipigs infected with strains of different virulence.
Infections with the zoonotic protozoan Toxoplasma gondii during pregnancy can result in severe fetal infections. To investigate the use of pigs as animal models for congenital toxoplasmosis, tachyzoites of 5 T. gondii strains, with low to intermediate virulence in mice, were intravenously inoculated into pregnant minipig gilts. Two strains caused abortions of uninfected fetuses following severe disease of the mothers. One strain caused no disease in the gilts but slightly elevated anti-T. gondii antibodies in 2 of 9 fetuses. One strain produced clinical disease with 4 mummified fetuses and 2 full-term, congenitally infected piglets in 1 gilt and no clinical disease but elevated specific fetal antibodies in both piglets of the other gilt. Infection with the fifth strain (SVS-O14), which was considered apathogenic to both pigs and mice based on the clinical course of this and previous experiments, resulted in significant numbers of congenitally infected piglets, as indicated by production of anti-T. gondii antibodies in all 12 fetuses; the parasite was identified in 3 of these fetuses. This pattern of infection indicates that pigs infected with SVS-O14 (or a similar strain) are relevant animal models for studies of transplacental transmission and pathogenesis of congenital toxoplasmosis.


Computational methods for birth-death processes.
Many important stochastic counting models can be written as general birth-death processes (BDPs). BDPs are continuous-time Markov chains on the non-negative integers in which only jumps to adjacent states are allowed. BDPs can be used to easily parameterize a rich variety of probability distributions on the non-negative integers, and straightforward conditions guarantee that these distributions are proper. BDPs also provide a mechanistic interpretation - birth and death of actual particles or organisms - that has proven useful in evolution, ecology, physics, and chemistry. Although the theoretical properties of general BDPs are well understood, traditionally statistical work on BDPs has been limited to the simple linear (Kendall) process. Aside from a few simple cases, it remains impossible to find analytic expressions for the likelihood of a discretely-observed BDP, and computational difficulties have hindered development of tools for statistical inference. But the gap between BDP theory and practical methods for estimation has narrowed in recent years. There are now robust methods for evaluating likelihoods for realizations of BDPs: finite-time transition, first passage, equilibrium probabilities, and distributions of summary statistics that arise commonly in applications. Recent work has also exploited the connection between continuously- and discretely-observed BDPs to derive EM algorithms for maximum likelihood estimation. Likelihood-based inference for previously intractable BDPs is much easier than previously thought and regression approaches analogous to Poisson regression are straightforward to derive. In this review, we outline the basic mathematical theory for BDPs and demonstrate new tools for statistical inference using data from BDPs.


Sub-atomic resolution X-ray crystallography and neutron crystallography: promise, challenges and potential.
The International Year of Crystallography saw the number of macromolecular structures deposited in the Protein Data Bank cross the 100000 mark, with more than 90000 of these provided by X-ray crystallography. The number of X-ray structures determined to sub-atomic resolution (i.e. ≤1 Å) has passed 600 and this is likely to continue to grow rapidly with diffraction-limited synchrotron radiation sources such as MAX-IV (Sweden) and Sirius (Brazil) under construction. A dozen X-ray structures have been deposited to ultra-high resolution (i.e. ≤0.7 Å), for which precise electron density can be exploited to obtain charge density and provide information on the bonding character of catalytic or electron transfer sites. Although the development of neutron macromolecular crystallography over the years has been far less pronounced, and its application much less widespread, the availability of new and improved instrumentation, combined with dedicated deuteration facilities, are beginning to transform the field. Of the 83 macromolecular structures deposited with neutron diffraction data, more than half (49/83, 59%) were released since 2010. Sub-mm(3) crystals are now regularly being used for data collection, structures have been determined to atomic resolution for a few small proteins, and much larger unit-cell systems (cell edges >100 Å) are being successfully studied. While some details relating to H-atom positions are tractable with X-ray crystallography at sub-atomic resolution, the mobility of certain H atoms precludes them from being located. In addition, highly polarized H atoms and protons (H(+)) remain invisible with X-rays. Moreover, the majority of X-ray structures are determined from cryo-cooled crystals at 100 K, and, although radiation damage can be strongly controlled, especially since the advent of shutterless fast detectors, and by using limited doses and crystal translation at micro-focus beams, radiation damage can still take place. Neutron crystallography therefore remains the only approach where diffraction data can be collected at room temperature without radiation damage issues and the only approach to locate mobile or highly polarized H atoms and protons. Here a review of the current status of sub-atomic X-ray and neutron macromolecular crystallography is given and future prospects for combined approaches are outlined. New results from two metalloproteins, copper nitrite reductase and cytochrome c', are also included, which illustrate the type of information that can be obtained from sub-atomic-resolution (∼0.8 Å) X-ray structures, while also highlighting the need for complementary neutron studies that can provide details of H atoms not provided by X-ray crystallography.


Antiurolithiatic effect of lithocare against ethylene glycol-induced urolithiasis in Wistar rats.
This study is aimed to investigate the protective effect of Lithocare (LC) (a polyherbal formulation) against ethylene glycol (EG) induced urolithiasis in Wistar rats. The protective effect of LC (400 and 800 mg/kg) was evaluated using EG-induced urolithiasis in rats. Administration of EG in drinking water resulted in hyperoxaluria, hypocalcemia as well as an increased renal excretion of phosphate. Supplementation with LC significantly reduced the urinary calcium, oxalate, and phosphate excretion dose-dependently. There was a significant reduction in the levels of calcium, oxalate as well as a number of calcium oxalate crystals deposits in the kidney tissue of rats administered with LC in EG-treated rats. There was a significant reduction in creatinine, urea, uric acid, and blood urea nitrogen when LC was administered in EG-treated rats. From this study, it was concluded that the supplementation of LC protected EG-induced urolithiasis as it reduced the growth of urinary stones. The mechanism underlying this effect might be due to its antioxidant, diuretic, and reduction in stone-forming constituents.


Job Loss and Attempts to Return to Work: Complicating Inequalities across Gender and Class.
Drawing on data from 100 qualitative interviews with the recently unemployed, this study examines how participants made decisions about attempting to return to work and identifies how class and gender shape these decisions. Middle-class men were most likely to take time to attempt to return to work, middle-class women were most likely to begin a deliberate job search, working-class men were most likely to report an urgent search, and working-class women were most likely to have diverted searches. Financial resources, gendered labor force attachments, and family responsibilities shaped decision making. Ultimately, those in the middle-class appear doubly advantaged-both in their financial capabilities and in their ability to respond to the crisis with greater gender flexibility.


On the use of log-transformation vs. nonlinear regression for analyzing biological power laws.
Power-law relationships are among the most well-studied functional relationships in biology. Recently the common practice of fitting power laws using linear regression (LR) on log-transformed data has been criticized, calling into question the conclusions of hundreds of studies. It has been suggested that nonlinear regression (NLR) is preferable, but no rigorous comparison of these two methods has been conducted. Using Monte Carlo simulations, we demonstrate that the error distribution determines which method performs better, with NLR better characterizing data with additive, homoscedastic, normal error and LR better characterizing data with multiplicative, heteroscedastic, lognormal error. Analysis of 471 biological power laws shows that both forms of error occur in nature. While previous analyses based on log-transformation appear to be generally valid, future analyses should choose methods based on a combination of biological plausibility and analysis of the error distribution. We provide detailed guidelines and associated computer code for doing so, including a model averaging approach for cases where the error structure is uncertain.


Convective forcing of mercury and ozone in the Arctic boundary layer induced by leads in sea ice.
The ongoing regime shift of Arctic sea ice from perennial to seasonal ice is associated with more dynamic patterns of opening and closing sea-ice leads (large transient channels of open water in the ice), which may affect atmospheric and biogeochemical cycles in the Arctic. Mercury and ozone are rapidly removed from the atmospheric boundary layer during depletion events in the Arctic, caused by destruction of ozone along with oxidation of gaseous elemental mercury (Hg(0)) to oxidized mercury (Hg(II)) in the atmosphere and its subsequent deposition to snow and ice. Ozone depletion events can change the oxidative capacity of the air by affecting atmospheric hydroxyl radical chemistry, whereas atmospheric mercury depletion events can increase the deposition of mercury to the Arctic, some of which can enter ecosystems during snowmelt. Here we present near-surface measurements of atmospheric mercury and ozone from two Arctic field campaigns near Barrow, Alaska. We find that coastal depletion events are directly linked to sea-ice dynamics. A consolidated ice cover facilitates the depletion of Hg(0) and ozone, but these immediately recover to near-background concentrations in the upwind presence of open sea-ice leads. We attribute the rapid recoveries of Hg(0) and ozone to lead-initiated shallow convection in the stable Arctic boundary layer, which mixes Hg(0) and ozone from undepleted air masses aloft. This convective forcing provides additional Hg(0) to the surface layer at a time of active depletion chemistry, where it is subject to renewed oxidation. Future work will need to establish the degree to which large-scale changes in sea-ice dynamics across the Arctic alter ozone chemistry and mercury deposition in fragile Arctic ecosystems.


Do patients with lymphoedema cholestasis syndrome 1/Aagenaes syndrome need dietary counselling outside cholestatic episodes?
Patients with lymphoedema cholestasis syndrome 1/Aagenaes Syndrome need a fat reduced diet when cholestatic. We wanted to assess the need for dietary counselling outside cholestatic episodes, and hypothetized that no counselling was needed. Fifteen patients above 10 years of age without symptoms of cholestasis were compared with a sex and age matched control group. Diet from a four-day weighed record and blood samples were compared between the two groups and with general Norwegian recommendations. The patients had a similar diet to the healthy controls, except for statistically significant lower intake of energy from total fat (p=0.04) and saturated fat (0.02), and fish (0.05). The patients met the dietary recommendations for macronutrients, except for saturated fat, monounsaturated fat, refined sugar and fibre. Supplements were needed to meet the micronutrient recommendations. Patients had a significantly lower serum level of alpha-tocopherol (0.01) compared with the control group, and the serum 25-OH D level was below reference ranges. The patients would benefit from counselling on fat quality, carbohydrates including fibre intake, and individual needs for vitamins D and E. To secure serum 25-OH D and alpha-tocopherol levels within reference ranges, regular examinations to determine the need for supplementary vitamins D and E are recommended.


Role of a mitogen-activated protein kinase pathway during conidial germination and hyphal fusion in Neurospora crassa.
Mitogen-activated protein (MAP) kinase signaling pathways are ubiquitous and evolutionarily conserved in eukaryotic organisms. MAP kinase pathways are composed of a MAP kinase, a MAP kinase kinase, and a MAP kinase kinase kinase; activation is regulated by sequential phosphorylation. Components of three MAP kinase pathways have been identified by genome sequence analysis in the filamentous fungus Neurospora crassa. One of the predicted MAP kinases in N. crassa, MAK-2, shows similarity to Fus3p and Kss1p of Saccharomyces cerevisiae, which are involved in sexual reproduction and filamentation, respectively. In this study, we show that an N. crassa mutant disrupted in mak-2 exhibits a pleiotropic phenotype: derepressed conidiation, shortened aerial hyphae, lack of vegetative hyphal fusion, female sterility, and autonomous ascospore lethality. We assessed the phosphorylation of MAK-2 during conidial germination and early colony development. Peak levels of MAK-2 phosphorylation were most closely associated with germ tube elongation, branching, and hyphal fusion events between conidial germlings. A MAP kinase kinase kinase (NRC-1) is the predicted product of N. crassa nrc-1 locus and is a homologue of STE11 in S. cerevisiae. An nrc-1 mutant shares many of the same phenotypic traits as the mak-2 mutant and, in particular, is a hyphal fusion mutant. We show that MAK-2 phosphorylation during early colony development is dependent upon the presence of NRC-1 and postulate that phosphorylation of MAK-2 is required for hyphal fusion events that occur during conidial germination.


Feasibility study of adjuvant chemotherapy with S-1 plus cisplatin for gastric cancer.
To evaluate the feasibility of S-1 plus cisplatin as adjuvant chemotherapy for stage III gastric cancer after curative resection. Japanese patients with stage III gastric cancer who underwent gastrectomy with D2 lymph node resection were enrolled. Treatment consisted of 3 cycles of S-1 (80 mg/m(2)/day, b.i.d.) for 21 days followed by a 14-day rest, and cisplatin (60 mg/m(2) iv) on day 8. After that, S-1 monotherapy was given on days 1-28 every 6 weeks until 1-year postsurgery. After protocol amendment, the first chemotherapy cycle consisted of S-1 monotherapy; cisplatin was added to cycles 2, 3, and 4, followed by S-1 monotherapy up to 1-year postsurgery. The primary endpoint was the completion rate of three cycles of S-1 plus cisplatin. A total of 63 enrolled patients have been evaluated. Grade 3/4 toxicities included neutropenia (40%), anorexia (28%), and febrile neutropenia (4%) before protocol amendment (n = 25), and neutropenia (37%), anorexia (8%), and febrile neutropenia (3%) after amendment implementation (n = 38). Excluding ineligible cases, treatment completion rates were 57% (12/21) before and 81% (30/37) after the protocol amendment. The amended S-1 plus cisplatin is more feasible than the original protocol because of early dose reduction of S-1 prior to cisplatin addition and greater recovery time from surgery prior to cisplatin. This treatment should be considered as a feasible experimental arm for the next postoperative adjuvant phase III trial.


The role of de-excitation electrons in measurements with graphite extrapolation chambers.
A method is described for determining the absorbed dose to graphite formedium energy x-rays (50-300 kV). The experimental arrangement consists of an extrapolation chamber which is part of a cylindrical graphite phantom of 30 cm diameter and 13 cm depth. The method presented is an extension of the so-called two-component model. In this model the absorbed dose to graphite is derived from the absorbed dose to the air of the cavity formed by the measuring volume. Considering separately the contributions of the absorbed dose to air in the cavity from electrons produced in Compton and photoelectric interactions this dose can be converted to the absorbed dose to graphite in the limit of zero plate separation. The extension of the two-component model proposed in this paper consists of taking into account the energy transferred to de-excitation electrons, i.e. Auger electrons, which are produced as a consequence of a photoelectric interaction or a Compton scattering process. For the system considered, these electrons have energies in the range between about 200 eV and 3 keV and hence a range in air at atmospheric pressure of 0.2 mm or less. As the amount of energy transferred to the de-excitation electrons is different per unit mass in air and in graphite, there is a region, about 0.2 mm thick, of disturbed electronic equilibrium at the graphite-to-air interface. By means of the extension proposed, the x-ray tube voltage range over which a graphite extrapolation chamber can be used is lowered from 100 kV in the case of the two-component model down to at least 50 kV.


Bone turnover markers predict changes in bone mineral density after parathyroidectomy in patients with renal hyperparathyroidism.
Patients on long-term dialysis may develop secondary hyperparathyroidism (SHPT), which causes varying degrees of bone mass loss. This condition is treated with parathyroidectomy (PTX). We investigated whether serial serum bone turnover markers could predict changes in bone mineral density (BMD) after PTX. Renal patients on maintenance haemodialysis who received PTX for refractory SHPT (n = 26, male/female: 13/13; mean age: 48·6 ± 10·7 year) and control subjects without SHPT (n = 25) were prospectively followed for 1 year at two tertiary hospitals in Taiwan. Serum intact parathyroid hormone (iPTH), bone-specific alkaline phosphatase (BAP) and type 5b tartrate-resistant acid phosphatase (TRAP) were measured serially. Additionally, femoral neck (FN) and lumbar spine (LS) BMD were measured before and 1 year after PTX. After PTX, iPTH levels decreased markedly and persistently. BMDs increased in both the FN and LS, but particularly in the LS. Serum BAP progressively increased to a peak at 2 weeks after PTX. Serum TRAP levels progressively decreased over 6 months after PTX. In univariate correlation analyses, baseline iPTH correlated positively with T-score changes in FN (r = 0·45, P = 0·021) and LS (r = 0·48, P = 0·013). In multivariate regression models, changes in FN T-scores were negatively predicted by baseline BAP levels (r = -0·615, P = 0·005) and baseline FN T-scores (r = -0·563, P = 0·012), and they were positively predicted by baseline TRAP(r = 0·6, P = 0·007). Changes in LS T-scores were positively predicted by baseline TRAP values (r = 0·528, P = 0·01) and negatively predicted by the percentage change in BAP after 2 weeks (r = -0·501, P = 0·015). Parathyroidectomy provided marked, sustained improvements in BMD for up to 1 year. Furthermore, markers of bone turnover predicted 1-year changes in FN and LS BMDs after PTX.


Extracorporeal treatments in sepsis: are there new perspectives?
Sepsis continues to provide a major challenge to clinicians. Despite vast advancements achieved in the understanding of its pathways and mechanisms, the incidence of sepsis is increasing and the mortality and morbidity rates remain high, generating a considerable burden to health budgets worldwide. Unfortunately, no definitive therapy yet exists that can successfully treat sepsis and its complications. At variance with targeting single mediators, therapeutic intervention aimed at the non-selective removal of pro- and anti-inflammatory mediators seems a rational concept and a possible key to successful extra-corporeal therapies. A further advantage may lie in the continuous nature of such therapy. With such continuous therapy, sequentially appearing peaks of systemic mediator overflow may be attenuated and persistently high plasma levels reduced. This theoretical framework is proposed as the underlying biological rationale for a series of innovative modalities in sepsis. In this editorial, we will review recent animal and human trials which lend support to this concept. We will also review the importance of treatment dose during continuous renal replacement therapy as a major factor affecting survival in critically ill patients with acute renal failure. We will also review novel information related to other blood purification techniques using largo pore membranes or plasma filtration with adsorbent perfusion. Although these approaches are still in the early stages of clinical testing, they are conceptually promising and might represent an important advance.


[Role of vagal intestinal glucoreceptors in insulin regulation].
This paper summarizes recent data on the existence of insulin nervous regulation by duodenal glucoreceptors which are connected to non-medullated fibres included in the vagal nerves. These glucoreceptors respond to intestinal perfusion of glucose or other carbohydrates, but other conventional mechanical stimuli are unable to activate them; therefore, they must be considered as true specific glucoreceptors. Their activation produces an immediate increase of insulin which precedes changes in glycemia. From bivagotomy experiments and from experiments which pharmacologically exclude the efferent parasympathetic or sympathetic fibres, it has been shown that this regulation is chiefly mediated by the vagal nerves. On the other hand, it was found that glucoreceptor afferents project on the hypothalamic nuclei (VMH and LHA) like the whole splanchnic and vagal afferents. The physiological importance and the role of insulin nervous regulation are discussed.


Unusual pattern of antibodies to human T-cell leukemia virus type-I in family members of adult T-cell leukemia patients.
Detection methods for the human T-cell leukemia virus type-I (HTLV-I) for blood screening and diagnosis generally rely on antibody tests that use the structural proteins of HTLV-I as antigen. We have found an unusual pattern of antibody reactivity among people who are at high risk of HTLV infection due to being a family member of an adult T-cell leukemia (ATL) patient: a specific antibody reaction exclusively directed to the HTLV regulatory protein tax, and not to the HTLV-I structural proteins. Sera from 7 of 82 (8.5%) structural antibody-undetectable family members of ATL patients had the anti-tax reactivity. Two seroconverters were observed. One seroconverter a healthy resident of Miyazaki, tested negative for structural antibody, but positive for tax antibody. Two years later she tested positive for both. The other seroconverter, an Israeli hemophiliac, tested negative for both antibodies, but converted to tax antibody-positive/structural antibody-negative. The HTLV-I tax-only antibody profile was also observed in sera sets from two other populations at risk for HTLV infection, human immunodeficiency virus-1-infected patients at the Bronx-Lebanon Hospital in New York and Israeli hemophiliacs. DNA samples from lymphocytes of four individuals with antibody reactivity only to HTLV-I tax were tested in polymerase chain reaction experiments; no HTLV-I or -II DNA was detected.


Recruitment of Young Adults: Lessons Learned From Research on Rural E-Cigarette Use and Cessation.
Electronic nicotine delivery system (ENDS) use continues to grow in rural areas of the United States. In particular, young adults (18-24 years) in rural areas are a hard-to-reach population in regard to understanding the growing ENDS use trend. The purpose of this article was to describe recruitment strategies that were used for a series of ENDS-relevant projects for young adults in rural areas, report recruitment yields from these strategies, and provide methodological considerations to aid researchers in improving recruitment. We used descriptive statistical methods to characterize recruitment yields (responses to screening vs initial invites, and number of individuals who fully met eligibility criteria vs responses to screening) from 2 ENDS studies that focused on 3 main recruitment strategies, including student directories, leadership offices (eg, Student Affairs), and regional tobacco control support networks (eg, Area Health Education Centers) for reaching young adults in rural communities. The recruitment yield rates varied and ranged from 2% to 14% depending on strategy with leadership offices resulting in the highest recruitment yield. Methodological considerations by strategy are described in detail. Results of this study can be used to inform tailored recruitment strategies to increase the representation of rural young adults in ENDS or other tobacco research.


Renal dysfunction in cirrhosis: acute kidney injury and the hepatorenal syndrome.
Renal dysfunction is a common complication of liver cirrhosis and of utmost clinical and prognostic relevance. Patients with cirrhosis are more prone to developing acute kidney injury (AKI) than the non-cirrhotic population. Pre-renal AKI, the hepatorenal syndrome type of AKI (HRS-AKI, formerly known as 'type 1') and acute tubular necrosis represent the most common causes of AKI in cirrhosis. Correct differentiation is imperative, as treatment differs substantially. While pre-renal AKI usually responds well to plasma volume expansion, HRS-AKI and ATN require different specific approaches and are associated with substantial mortality. Several paradigms, such as the threshold of 2.5 mg/dL for diagnosis of HRS-AKI, have recently been abolished and novel urinary biomarkers are being investigated in order to facilitate early and correct diagnosis and treatment of HRS-AKI and other forms of AKI in patients with cirrhosis. This review summarizes the current diagnostic criteria, as well as pathophysiologic and therapeutic concepts for AKI and HRS-AKI in cirrhosis.


Membrane-permeable cygnets: rapid cellular internalization of fluorescent cGMP-indicators.
We have recently developed genetically encoded cGMP-indicators (cygnets) which have enabled us to study the spatial and temporal dynamics of intracellular cGMP in single cultured cells (1). However, primary mammalian cell types (dissociated cells or acute tissue samples) are often difficult to maintain undifferentiated in culture and the current established methods of introducing molecular reporters in single cells are laborious (micro-injection) and/or require cell culture techniques to accommodate the 1-2 day lag time of genetically mediated reporter expression. Here, we present an alternative, non-genetic method to rapidly introduce cGMP-indicators into cells and intact tissues using membrane permeable peptides (MPP). Five different 125 kDa MPP-cygnets were expressed and purified from insect SF9 cells. Three constructs showed high level cGMP-dependent FRET in vitro. One of the probes, Ant7-Cygnet, demonstrated emission ratio changes identical to the unmodified indicator. Ant7-Cygnet was rapidly (3 hours) and efficiently internalized in cultured smooth muscle cells and intact cerebral arteries. Furthermore, the internalized Ant7-Cygnet detected nitric oxide mediated elevations of intracellular cGMP in cultured smooth muscle cells and sensed increased levels of intracellular cGMP derived from C-type natriuretic peptide (CNP) induced guanylyl cyclase stimulation in intact arteries. These results demonstrate that MPP-cygnets provide a novel and potentially powerful technique to study intracellular cGMP in intact tissue.


Incidence of dominant spinocerebellar and Friedreich triplet repeats among 361 ataxia families.
To determine the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich's ataxia (FA) among a large panel of ataxia families. The ataxias are a clinically and genetically heterogeneous group of neurodegenerative diseases that variably affect the cerebellum, brainstem, and spinocerebellar tracts. Trinucleotide repeat expansions have been shown to be the mutational mechanism for five dominantly inherited SCAs as well as FA. We collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded from our collection. Among the 178 dominant kindreds, we found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. FA alleles were found in 11.4% of apparently recessive and 5.2% of apparently sporadic patients. Among these patients the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients is atypical for FA, with one or more of the following characteristics: adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensory perceptions. Pathogenic trinucleotide repeat expansions were found among 61% of the dominant kindreds. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4 and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Because of the significant implications that a dominant versus recessive inheritance pattern has for future generations, it is important to screen patients who do not have a clearly dominant inheritance pattern for expansions at both the FA and the dominant ataxia loci.


Transient receptor potential channel polymorphisms are associated with the somatosensory function in neuropathic pain patients.
Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients.


Validation of ApneaLink Ox™ for the diagnosis of obstructive sleep apnea.
The aim of the study was to validate the automatic and manual analysis of ApneaLink Ox™ (ALOX) in patients with suspected obstructive sleep apnea (OSA). All patients with suspected OSA had a polysomnography (PSG) and an ALOX performed in the sleep laboratory. For automatic analysis, hypopnea was defined as a decrease in airflow ≥30 % of baseline for at least 10 s plus oxygen desaturation ≥3 or 4 %. While for the manual analysis, hypopnoea was considered when a reduction of airflow ≥30 % of ≥10 s plus oxygen desaturation ≥3 % or increase in cardiac rate ≥5 beats/min were identified or, when only a reduction of airflow ≥50 % was observed. OSA was defined as a respiratory disturbance index (RDI) ≥5. The apnea/hypopnea automatic index (AHI3-a, AHI4-a) and manual index were estimated. Receiver operating characteristics (ROC) analysis and the agreement between ALOX and PSG were performed. Fifty-five patients were included (38 men; mean age, 48.2; median, RDI 15.1; median BMI, 30 Kg/m(2)). The automatic analysis of ALOX under-estimated the RDI from PSG, mainly for the criterion of oxygen desaturation ≥4 % (AHI3-a-RDI, -3.6 ± 10.1; AHI4-a-RDI, -6.5 ± 10.9, p < 0.05). The autoscoring from ALOX device showed a better performance when it was set up to identify hypopneas with an oxygen desaturation criterion of ≥3 % than when it was configured with an oxygen desaturation criterion of ≥4 % (area under the receiver operator curves, 0.87 vs. 0.84). Also, the manual analysis was found to be better than the autoscoring set up with an oxygen desaturation of ≥3 % (0.923 vs. 0.87). The manual analysis showed a good interobserver agreement for the classification of patients with or without OSA (k = 0.81). The AHI obtained automatically from the ApneaLink Ox™ using oxygen desaturation ≥3 % as a criterion of hypopnea had a good performance to diagnose OSA. The manual scoring from ApneaLink Ox™ was better than the automatic scoring to discriminate patients with OSA.


Postural baroreflex stimuli may affect EEG arousal and sleep in humans.
Past research has shown that baroreceptor stimulation can induce sleep. The present study investigated whether the upright posture inhibits sleep by reducing baroreceptor firing. Twenty-eight men were each exposed to four conditions on separate days: 40 degrees head-up tilt with (TP) and without (TN) 45 mmHg positive pressure on the legs and the supine position with (SP) and without (SN) leg pressure. Heart rate and blood pressure changes indicated that baroreceptor firing was strongly reduced by TN and only mildly reduced by TP in 24 subjects. Baroreceptor effects of SP were unclear. SN and SP did not differ significantly in their effects on electroencephalogram (EEG) sleep. Among subjects who showed a normal baroreflex response to tilt, both TN and TP inhibited sleep, but TN caused a persistent elevation of EEG beta activity that did not occur in TP plus a greater delay in sleep onset. TN had no such arousing effects in four subjects who showed little or no baroreflex response to tilt. These results are consistent with the hypothesis that the fall in baroreceptor firing produced by the upright posture contributes to EEG arousal.


Effect of 1,25 dihydroxyvitamin D3 on insulin secretion.
Recent autoradiographic studies demonstrated that B-cells concentrate 1,25 (OH)2 D3 in their nuclei, suggesting a genomic action on B-cell function. This study was undertaken to investigate the effects of 1,25 (OH)2 D3 on insulin secretion in vitamin D-deficient rats. Mature vitamin D-deficient rats were injected with 1,25 (OH)2 D3 or the ethanol-isotonic saline vehicle. Administration of 1,25 (OH)2 D3 to 10 rats resulted in a 17 microunits/ml (113%) increase in insulin levels and 0.9 mg/dl (16%) increase in plasma calcium. No changes were found in insulin or calcium levels in 5 control rats given vehicle alone. A group of vitamin D-deficient rats with plasma calcium levels of 5.4 +/- 0.1 mg/dl had insulin levels that were the same as those observed in a group of vitamin D-deficient rats with plasma calcium levels of 6.3 +/- 0.1 mg/dl. The difference in calcium levels between these two groups is similar to the increase in plasma calcium found after 1,25 (OH)2 D3 administration. The results of these studies indicate that 1,25 (OH)2 D3 action on pancreatic B-cells affects insulin secretion. Since insulin increases synthesis of 1,25 (OH)2 D3, the existence of a feedback loop between B-cells and kidney proximal tubule cells is suggested.


Erythropoietin levels in posterior fossa haemangioblastoma.
Using an in vitro bioassay, erythropoiesis stimulating activity has been measured in serum, cyst fluids and tumour homogenates from fourteen patients with cerebellar haemangioblastoma. Only two patients had elevated peripheral blood red cell counts and haemoglobin concentrations. Significantly elevated serum erythropoiesis stimulating activity was found in only one patient. High level, however, were detected in seven out of the fourteen cyst fluids and in the two homogenates tested. The dose response lines from these paralleled those of normal human erythropoietin. It was possible to neutralise the erythropoiesis stimulating activity in the cyst fluids with anti-human erythropoietin serum, indicating its similarity to erythropoietin, the normal erythropoietic regulating hormone. Significant release of the erythropoietic stimulating factor from the cyst fluids into the blood seemed to be an uncommon occurrence.


[Bone marrow structure and HIV infection].
Bone marrow hematopoietic tissue and stromal elements were characterized histologically on iliac bone trepanobioptats from 8 HIV infected patients. Signs of dyserythropoiesis, dysgranulocytopoiesis, dysmegakaryocytosis, focal accumulations of plasmocytes lymphoid and histiocytic cells were demonstrated. Changes of hematopoietic tissue were accompanied by reorganization of stromal microenvironment. Growth of intramedullar reticuline cells quantity and decline in number of endosteal stromal cells were found.


A novel approach for coronoid fractures.
The coronoid process serves as an important constraint that provides ulnohumeral joint stability. We describe a novel approach to coronoid fractures that minimizes surgical dissection, without compromising fracture visualization. We present the case of a 65-year-old woman who sustained an anteromedial facet fracture of the coronoid process. The elbow demonstrated intractable posteromedial instability and the inability to maintain reduction even up to 90 degrees. This report describes a surgical approach to the coronoid process that minimizes extensive soft tissue dissection. It is a variation of the previously described approach by Taylor and Scham, although it can achieve a similar exposure without elevation of the entirety of the flexor-pronator mass. Our approach involves a limited skin incision, followed by elevation of enough of the flexor-pronator mass such that adequate visualization of the posterior medial collateral ligament (which was repaired), anteromedial facet, and the fractured fragment of coronoid were achieved. Moreover, this approach enables the course of the ulnar nerve to remain unaltered.