Nickel (II)-induced cytotoxicity and apoptosis in human proximal tubule cells through a ROS- and mitochondria-mediated pathway.
Nickel compounds are known to be toxic and carcinogenic in kidney and lung. In this present study, we investigated the roles of reactive oxygen species (ROS) and mitochondria in nickel (II) acetate-induced cytotoxicity and apoptosis in the HK-2 human renal cell line. The results showed that the cytotoxic effects of nickel (II) involved significant cell death and DNA damage. Nickel (II) increased the generation of ROS and induced a noticeable reduction of mitochondrial membrane potential (MMP). Analysis of the sub-G1 phase showed a significant increase in apoptosis in HK-2 cells after nickel (II) treatment. Pretreatment with N-acetylcysteine (NAC) not only inhibited nickel (II)-induced cell death and DNA damage, but also significantly prevented nickel (II)-induced loss of MMP and apoptosis. Cell apoptosis triggered by nickel (II) was characterized by the reduced protein expression of Bcl-2 and Bcl-xL and the induced the protein expression of Bad, Bcl-Xs, Bax, cytochrome c and caspases 9, 3 and 6. The regulation of the expression of Bcl-2-family proteins, the release of cytochrome c and the activation of caspases 9, 3 and 6 were inhibited in the presence of NAC. These results suggest that nickel (II) induces cytotoxicity and apoptosis in HK-2 cells via ROS generation and that the mitochondria-mediated apoptotic signaling pathway may be involved in the positive regulation of nickel (II)-induced renal cytotoxicity.


A classification system of radial polydactyly: inclusion of triphalangeal thumb and triplication.
Radial polydactyly is a congenital anomaly with a wide range of manifestations. Current classifications do not have the capacity to classify all different types of radial polydactyly when combined with triphalangeal components. The objective of this study was to test an adjusted classification and nomenclature that allows classification of triphalangeal components and triplication in radial polydactyly. Patients from 1993 to 2006 with radial polydactyly (N = 104), a total of 121 affected hands, were identified from the hospital database. All x-rays were carefully examined and classified according to the existing classifications for radial polydactyly and a modified classification. In the modified nomenclature, Wassel's level of duplication is preserved. Type VII and VIII are assigned for partial or complete duplication of the carpal bones according to Buck-Gramcko. Triplication and triphalangeal components can be assigned to each type of radial polydactyly by suffixes. Symphalangism, deviation, and hypoplasia can also be classified. Triplication on different levels of the thumb is classified by determining and including the different types of the original Wassel classification. Eighteen thumbs could not be classified according to existing classifications for radial polydactyly with triphalangeal components or triplication. Using the proposed classification, all patients could be classified. We propose a modified classification that is a practical and utilitarian scheme for nomenclature of radial polydactyly and that may assist comparison of treatment outcomes and individual cases. Diagnostic II.


One-trial olfactory learning enhances olfactory bulb responses to an appetitive conditioned odor in 7-day-old rats.
The expression of a conditioned odor preference and focal uptake of [14C]2-deoxyglucose (2-DG) within the olfactory bulb was assessed in neonatal rat pups that had undergone a single olfactory classical conditioning trial. At 6 days of age, rat pups were simultaneously exposed for 10 min to an odor (peppermint) and to a reinforcing tactile stimulation similar to that received from the dam. Three control groups received only the odor, only the stimulation, or neither of these stimuli. The next day, pups were either assessed for differential olfactory bulb activity using the 2-DG technique or tested for their olfactory preference behavior. Only pups that received simultaneous odor and tactile stimulation exhibited an attraction to the conditioned odor in the two-odor choice test. Furthermore, such pups had greater focal 2-DG uptake in the olfactory bulb glomeruli that were responsive to the odor than pups in all other groups. Thus, the olfactory bulb responds differentially to an odor which has acquired attractive value.


Cells of origin of ascending and descending as well as branching fibers in the cervical spinal cord of the pigeon.
Ascending and descending projections of spinal neurons (cervical enlargement) were studied with the retrograde transport of horseradish peroxidase (HRP) and with the fluorescent tracers Fast blue and rhodamine isothiocyanate (single and double labeling). Ascending and descending projections arise from the same laminae of the spinal grey except for neurons in contralateral lamina I and avian cervical Clarke's column which have ascending fibers only. A significant number of cervical nucleus proprius neurons (lamina IV) descends to the lumbar enlargement. Neurons with branching fibers were rare (less than 10 per cent).


Can renal infarction occur after renal cyst aspiration? Case report.
Renal infarction (RI) is a rarely seen disorder, and the diagnosis is often missed. The two major causes of RI are thromboemboli originhating from a thrombus in the heart or aorta, and in-situ thrombosis of a renal artery. We report a case of RI that developed due to renal artery and vein thrombosis, as confirmed by pathological evaluation of the nephrectomy material, three weeks after renal cyst aspiration.


Plasma dopamine-beta-hydroxylase and erythrocyte acetylcholinesterase in a group of patients with Parkinson disease.
In a group of patients with Parkinson disease there was no difference in plasma DBH activity between cases treated with L-Dopa and not treated. These patients tend to have an elevated activity of erythrocyte AChE.


Cardiac stem cells in the real world.
Cardiac stem cell transplantation as a potential means of regenerating infarcted myocardium is currently receiving a great deal of interest. However, data on these endogenous cardiac precursors are primarily derived from animal studies, and their clinical relevance still remains elusive. We prospectively screened 32 endomyocardial biopsies harvested from heart transplant recipients (off rejection episodes) and 18 right appendage biopsies collected during coronary artery bypass surgery, and processed the tissue specimens for the immunohistochemical detection of markers of stemness (c-kit, MDR-1, Isl-1), hematopoietic origin (CD45), mast cells (tryptase), endothelial cells (CD105), and cardiac lineage (Nkx2.5). Confocal microscopy was used for colocalization experiments. Three right appendage biopsies were also cultured for 2 to 3 weeks, at the completion of which c-kit-positive cells were sorted by flow cytometry. In endomyocardial biopsies, a median number of 2.7 (1.8-4) c-kit-positive cells/mm(2) were found, and this number was even significantly smaller in right appendage biopsies (1 [0.5-1.8] c-kit-positive cell/mm(2), P = .01). All of these c-kit-positive cells co-stained for CD45 and were more specifically identified as mast cells by their positive staining for the specific tryptase marker. However, none of the c-kit-positive cells expressed the markers of stemness MDR-1 and Isl-1 or colocalized with CD105. Flow cytometry confirmed the small number of c-kit-positive cells in cultured right atrial appendages. These data raise a cautionary note on the therapeutic exploitation of cardiac stem cells in patients with ischemic cardiomyopathy, who may be the elective candidates for regenerative therapy.


Ameliorating effects of low tidal volume ventilation with associated hypercapnia on pneumoperitoneum-induced lung injury by inhibition of Toll-like receptor 4.
Mechanical ventilation using lower tidal volume ventilation with associated hypercapnia is supported to avoid ventilator-induced lung injury, but the underlying mechanism is not clear. This study was intended to explore whether low tidal volume ventilation with associated hypercapnia would ameliorate pneumoperitoneum-induced lung injury and whether this protection strategy might work through mediating inflammation and oxidative stress via TLR 4 signaling pathway. 50 anesthetized Wistar Rats were randomized to be mechanically ventilated for 4 h at 7 groups: Group A, ventilated with 12 ml/kg; Group B, similar to Group A but injected with LPS (Toll receptor 4 agonist); Group C, similar to Group A but injected with Pam3Cys (Toll receptor 2 agonist); Group D, ventilated with 12 ml/kg and subjected to pneumoperitoneum; Group E, ventilated with 6 ml/kg and subjected to pneumoperitoneum; Group F, similar to Group E but injected with LPS; Group G, similar to Group E but injected with Pam3Cys. After animals were killed, indices of lung Injury, inflammation markers and oxidative stress markes of the lungs tissues, bronchoalveolar lavage fluid and blood were assessed. The group subjected to pneumoperitoneum (Group D) had elevated values of indices of lung Injury, inflammation oxidative stress markers compared with the controls (Group A). The low tidal volume ventilation group (Group E) had significantly decreased values of markers of lung Injury, inflammation and oxidative stress compared with the high tidal volume ventilation group (Group D). LPS treatment reversed all the results of Group E, while Pam3Cys treatment had no significant effect. Low tidal volume ventilation with associated hypercapnia ameliorated pneumoperitoneum-induced lung injury by reducing TLR 4-mediated inflammation and oxidative stress.


Efficiency of in vivo purging with rituximab prior to autologous peripheral blood progenitor cell transplantation in B-cell non-Hodgkin's lymphoma: a single institution study.
Rituximab induces clinical response in advanced B-cell lymphoma and is efficient in removing circulating B-cell from peripheral blood. We therefore postulated that rituximab might be a useful in vivo purging agent before high-dose therapy in this setting. Fourteen patients with relapsed follicular, marginal zone and mantle cell lymphomas (11, two and one cases, respectively) and a PCR-detectable molecular marker were treated first with rituximab, then a mobilization chemotherapeutic regimen, followed by high-dose therapy with peripheral blood stem cell transplantation. PCR analyses were performed in peripheral blood before rituximab and during follow-up, and in harvest. Harvests were free of PCR-detectable molecular marker in nine of the 11 studied cases (82%). After high-dose therapy, clinical complete remission was obtained in 13 (93%) patients and molecular remission in 11 (79%). With a median follow-up of 3 years, the 14 transplanted patients were alive, 11 of them remaining in clinical complete remission and eight in molecular remission at last follow-up. Rituximab treatment followed by high dose therapy appears to be effective in achieving complete clinical and molecular response. In vivo harvest purging is predictive of prolonged clinical and molecular remission.


Association of Hypovitaminosis D with Sleep Parameters in Rotating Shift Worker Drivers.
Objective To evaluate the association between sleep parameters and hypovitaminosis D in rotating shift drivers. Material and Methods We conducted a cross-sectional study on 82 male rotating shift workers (24-57 years old) with at least one cardiovascular risk factor (such as hyperglycemia, dyslipidemia, abdominal obesity, physical inactivity, hypertension, and smoking). Polysomnography was used to evaluate sleep parameters. Logistic regression was used to model the association between hypovitaminosis D and sleep parameters after adjustment for relevant covariates. Results Hypovitaminosis D (< 20 ng/mL) was seen in 30.5% of the workers. Shift workers with hypovitaminosis D had lower sleep efficiency (odds ratio [OR]: 3.68; 95% confidence interval [CI]: 1.95-5.53), lower arterial oxygen saturation (OR: 5.35; 95% CI: 3.37-6.12), and increased microarousal index (OR: 3.85; 95% CI: 1.26-5.63) after adjusting. Conclusion We suggest that hypovitaminosis D is associated with greater sleep disturbances in rotating shift workers.


Comparison of Wear Resistance of Hawley and Vacuum Formed Retainers: An in-vitro Study.
As a physical property, wear resistance of the materials used in the fabrication of orthodontic retainers play a significant role in the stability and long term use of the appliances. To evaluate the wear resistance of two commonly used materials for orthodontic retainers: Acropars OP, i.e. a polymethyl methacrylate based material, and 3A-GS060, i.e. a polyethylene based material. For each material, 30 orthodontic retainers were made according to the manufacturers' instructions and a 30×30×2 mm block was cut out from the mid- palatal area of each retainer. Each specimen underwent 1000 cycles of wear stimulation in a pin on disc machine. The depth of wear of each specimen was measured using a Nano Wizard II atomic force microscope in 3 random points of each specimen's wear trough. The average of these three measurements was calculated and considered as mean value wear depth of each specimen (µm). The mean wear depth was 6.10µm and 2.15µm for 3A-GS060 and Acropars OP groups respectively. Independent t-test showed a significant difference between the two groups (p < 0.001). The results show Polymethyl methacrylate base (Acropars) is more wear resistance than the polyethylene based material (3A-GS060). As the higher wear resistance of the fabrication material can improve the retainers' survival time and its cost-effectiveness, VFRs should be avoided in situations that the appliance needs high wear resistance such as bite blocks opposing occlusal forces.


RETRACTED: The long noncoding RNA CASC2 inhibits tumorigenesis through modulating the expression of PTEN by targeting miR-18a-5p in esophageal carcinoma.
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. In the article Figure 3A top and center panel are duplicated and in Figure 5A elements are duplicated from previous publications from the same authors in Tumor Biol. (2014) 35:12583–12592 DOI 10.1007/s13277-014-2579-4 (Figure 3) and Dig Dis Sci (2013) 58:706–714 DOI 10.1007/s10620-012-2395-x (Figure 8). The authors recognize mishandling of these images which affects the validation of the study and would like to apologize to readers.


Revisiting the taxonomy of Rhabdias fuelleborni Travassos, 1928 (Nematoda, Rhabdiasidae) with approaches to delimitation of species and notes on molecular phylogeny.
Rhabdias fuelleborni was described by Travassos (1926), who identified it in the lungs of Rhinella gr. marina (=Bufo marinus) from São Paulo. Later, Kloss (1971) added new information on the morphology and diagnosis of the species and new data on host and localities. However, its taxonomic status remains uncertain, due in particular to the morphological uniformity of Rhabdias spp., while the original description lacks important morphological data. In the present study, we found and reevaluated the type series of R. fuelleborni, as well as examining fresh material obtained from the type host and type locality, using light and scanning electron microscopy and molecular tools. The type series was deposited by Travassos (1926), and according to museum records the type locality is Paraty, Rio de Janeiro, Brazil. Our morphological and molecular analyses reinforce the taxonomic validity of this species, while molecular phylogeny identified a close relationship between R. fuelleborni and Rhabdias sp.4 and Rhabdias sp. from other studies, and from bufonids. Also R. fuelleborni are sister taxa with R. cf. stenocephala from Leptodactylidae from the northeast of Brazil and R. vencesi from Boophis madagascarariensis, Madagascar, according to mitochondrial COI gene.


The McCune-Albright syndrome without typical skin pigmentation.
This paper describes three girls with an incomplete form of the McCune-Albright syndrome. Polyostotic fibrous dysplasia and precocious puberty were present but the typical abnormal skin pigmentation was absent.


Comparison of macular buckling and vitrectomy for the treatment of macular schisis and associated macular detachment in high myopia: a randomized clinical trial.
To compare the efficacy and safety of macular buckling and vitrectomy for myopic traction maculopathy showing macular schisis (MS) and associated macular detachment (MD) but without full-thickness macular hole (FTMH). Prospective, randomized, parallel, open-label study. Patients were randomly assigned to either buckling or vitrectomy group. Macular buckling and intravitreal C3F8 gas injection were performed in the buckling group. Small gauge vitrectomy, internal limiting membrane peeling (ILMP) and C3F8 gas tamponade were performed in the vitrectomy group. The patients were followed for 12 months. Best-corrected visual acuity (BCVA) at 12 months. A total of 85 patients were randomized, 80 eyes were included (41 receiving buckling, 39 received vitrectomy), and 78 patients completed the study. There were less eyes determined as surgical failure and required a second surgery in the buckling group than vitrectomy the group (2.4% versus 18.4%, p = 0.021). After surgery, macular buckling achieved more improvement in BCVA (+21.7 versus +4.5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, p = 0.002). FTMH development was observed in only 1 (2.4%) eye, after removing of the implant due to recurrent conjunctival erosion, in the buckling group and 10 (26.3%) eyes (seven with-, three without MD) in the vitrectomy group (p < 0.001). More eyes developed cataracts in the vitrectomy group than did in the buckling group (28.9% versus 7.5%, p = 0.014). Macular buckling-associated strabismus (esotropia), binocular diplopia and implant exposure were observed in limited cases. Macular buckling is superior to vitrectomy with ILM peeling plus gas injection for surgical treatment of MS and associated MD in high myopia.


Observations on Echinococcus multilocularis in the definitive host.
Six dogs were found to be susceptible to experimental infections with a European isolate of Echinococcus multilocularis from southern Germany. Two cats were only poorly susceptible. Adult worms were not evenly distributed throughout the small intestine and the majority of parasites were found in the posterior region. The mode of attachment of E. multilocularis in the dog was similar to that for E. granulosus with the adult worm extending its rostellum deep within a crypt of Lieberkühn. In cats only few worms were found to have penetrated deeply between the villi. E. multilocularis was found to possess a modified group of rostellar tegumental cells, morphologically and functionally identical to those described in E. granulosus and previously referred to as the "rostellar gland". By studying development in vivo and in vitro, the time required for the production of shelled eggs was demonstrated to be only 28 days. Concurrent experimental infections in dogs with E. multilocularis and E. granulosus revealed that both species will develop together in the same host. Their development was not retarded in any way by the presence of the other and both species were able to coexist in the same area of the intestine.


Can hyperthermic intraperitoneal chemotherapy efficiency be improved by blocking the DNA repair factor COP9 signalosome?
A frequently used chemotherapeutic agent in hyperthermic intraperitoneal chemotherapy (HIPEC) is mitomycin C (MMC) which induces DNA damage and apoptosis in tumor cells. In addition, MMC activates DNA damage response (DDR) leading to repair mechanisms counteracting the effect of chemotherapy. COP9 signalosome (CSN) positively influences the DDR pathway by its intrinsic deneddylating and associated kinase activities. In an in vitro HIPEC model, we studied the impact of curcumin, an inhibitor of CSN-associated kinases, and of the microRNA (miRNA) let-7a-1, an inhibitor of CSN subunit expression, on the MMC-induced apoptosis in human HT29 colon cancer cells. Cells were incubated at 37 °C and indicated concentrations of MMC in a medium preheated to 42 °C as under HIPEC conditions for 1 or 4 h. HT29 cells were cotreated with 50 μM curcumin or transfected with let-7a-1 miRNA mimic. After incubation, cells were analyzed by Western blotting, densitometry, and caspase-3 ELISA. An increase of CSN subunits in response to MMC treatment was detected. Apoptosis was only measured after 4 h with 50 μM MMC. MMC-induced apoptosis was elevated by cotreatment with curcumin. Transfection of HT29 cells with let-7a-1 reduced the expression of tested CSN subunits associated with the accumulation of the pro-apoptotic factors p27 and p53. In response to MMC treatment, the CSN is elevated as a regulator of DDR retarding apoptosis in tumor cells. The therapeutic effect of HIPEC can be increased by inhibiting CSN-associated kinases via curcumin or by blocking CSN expression with let-7a-1 miRNA.


Role of the electrocardiogram in identifying the patient at increased risk for sudden death.
Published data dealing with the electrocardiogram as a means of identifying individuals at increased risk for sudden death are meager. The available information suggests that the sensitivity of the electrocardiogram in association with other signs of heart disease is relatively good and that this may vary with the severity of the underlying disease. In contrast, its specificity for sudden death is poor; many patients with abnormal electrocardiograms do not die suddenly or of cardiac causes. The prognosis of any electrocardiographic abnormality is that of the underlying disease.


Poor mitochondrial health and systemic inflammation? Test of a classic hypothesis in the Baltimore Longitudinal Study of Aging.
Although a persistent inflammatory state has long been associated with aging and negative health outcomes, the underlying mechanisms remain unclear. Mitochondrial dysfunction has been proposed as a cause of inflammaging, but evidence of an association in humans is lacking. In this study, we analyzed the cross-sectional association between inflammatory biomarkers and mitochondrial oxidative capacity in skeletal muscle, assessed as post-exercise phosphocreatine recovery time constant by phosphorus magnetic resonance spectroscopy, in a population of 669 adults (mean age 67 years) from the Baltimore Longitudinal Study of Aging. We observed that participants with lower mitochondrial oxidative capacity exhibited hallmarks of inflammation, specifically markedly higher levels of interleukin-6 and C-reactive protein, as well as increased erythrocyte sedimentation rate when compared with participants with better oxidative capacity, independent of age and sex. We speculate that this association reflects the observation that products of damaged mitochondria, such as mitochondrial DNA, activate multiple pathways that lead to inflammation. Furthermore, excess production of oxidative species (ROS) by dysfunctional mitochondria could trigger inflammation either directly via NF-κB or through oxidative damage to proteins, lipids, and nucleic acids. Longitudinal studies are necessary to ascertain whether and through which mechanisms mitochondrial dysfunction activate inflammation or whether both these phenomena derive from a common root.


High ejaculate volume: a distinct entity?
In this study clinical, andrological and endocrinological data of a group of 101 patients with ejaculate volume of at least 8.0 ml are compared with data of 100 consecutive patients attending our infertility clinic. Within both groups correlations between different parameters are observed. Between both groups a significant difference in total sperm output is noted suggesting a 'dilution oligozoospermia' in the high ejaculate volume group. We suggest that, in order to avoid a falsely unfavourable fertility prognosis for those patients, total sperm output should be considered rather than sperm density. From the point of view of nomenclature, the term 'relative oligozoospermia' seems justified in cases with very high ejaculate volumes.


Predictive ability of C-reactive protein for early mortality after ischemic stroke: comparison with NIHSS score.
We aimed to compare the association of high-sensitivity C-reactive protein (CRP) and National Institutes of Health Stroke Scale (NIHSS) score with mortality risk and to determine the optimal threshold of CRP for prediction of mortality in ischemic-stroke patients. A series of 162 patients with first-ever ischemic-stroke admitted within 24 h after onset of symptoms was enrolled. CRP and NIHSS score were estimated on admission and their predictive abilities for mortality at 7 days were determined by logistic-regression analyses. Receiver-Operating Characteristic (ROC) curves were depicted to identify the optimal cut-off of CRP, using the maximum Youden-index and the shortest-distance methods. Deceased patients had higher levels of CRP and NIHSS on admission (8.87 ± 7.11 vs. 2.20 ± 4.71 mg/l for CRP, and 17.31 ± 6.36 vs. 8.70 ± 4.85 U for NIHSS, respectively, P < 0.01). CRP and NIHSS were correlated with each other (r (2) = 0.39, P < 0.001) and were also independently associated with increased risk of mortality [odds ratios (95 % confidence interval) of 1.16 (1.05-1.28) and 1.20 (1.07-1.35) for CRP and NIHSS, respectively, P < 0.01]. The areas under the ROC curves of CRP and NIHSS for mortality were 0.82 and 0.84, respectively. The CRP value of 2.2 mg/l was identified as the optimal cut-off value for prediction of mortality within 7 days (sensitivity: 0.81, specificity: 0.80). Thus, CRP as an independent predictor of mortality following ischemic-stroke is comparable with NIHSS and the value of 2.2 mg/l yields the optimum sensitivity and specificity for mortality prediction.


Exploration of metal-organic framework MOF-177 coated fibers for headspace solid-phase microextraction of polychlorinated biphenyls and polycyclic aromatic hydrocarbons.
Metal-organic frameworks (MOFs) have received much attention in analytical science for their large langmuir surface and high thermostability. Herein MOF-177-coated solid-phase micro-extraction (SPME) fibers were fabricated on etched stainless steel by an adhensive method, and applied to the enrichment of polychlorinated biphenyls (PCB01, PCB05, PCB29, PCB47, PCB98, PCB154, PCB171, PCB201) and polycyclic aromatic hydrocarbons (ANY, ANA, FLU, PHE, ANT, FLT, PYR) from environmental water samples. Several parameters affecting the extraction efficiency were optimized prior to the gas chromatography-mass spectrometry analysis, including extraction temperature and time, desorption time, stirring rate and salt addition. The results indicated that the coated fiber gave low detection limits (0.69-4.42 ng L(-1)) and good repeatability with the RSD ranging from 1.47% to 8.67% for PCBs and PAHs. The recoveries were between 81.8% and 113% with the spiked level of 10 ng L(-1) for the real water samples. Besides, the MOF-177 coated fiber was stable enough over 100 extraction cycles and the RSD for fiber-to- fiber reproducibility was less than 9.82% during the experiment.


Reversed end-diastolic flow in the umbilical artery at 10-14 weeks of gestation is associated with absent pulmonary valve syndrome.
To determine the incidence of reversed end-diastolic flow (REDF) in the umbilical artery in high-risk first-trimester pregnancies and evaluate associated conditions. This was a prospective evaluation of the umbilical artery Doppler waveforms of 614 consecutive high-risk pregnancies between 10 and 14 weeks of gestation, to determine those with REDF. The associated anomalies and characteristics of these fetuses were then investigated. In 278/614 (45.3%) fetuses, there was positive end-diastolic flow in the umbilical artery; in 331/614 (53.9%) end-diastolic flow was absent and in 5/614 (0.8%) there was REDF. Three of the five fetuses with REDF had tetralogy of Fallot (TOF) with absent pulmonary valve syndrome (APVS) and a patent ductus arteriosus, and all three showed signs of cardiac failure, with reversed blood flow in the ductus venosus during atrial systole and generalized skin edema. Another fetus had a large ventricular septal defect and the remaining fetus had agenesis of the ductus venosus. Three fetuses had trisomy 18 and one had trisomy 13. REDF in the umbilical artery is very rare in early pregnancy and mostly occurs in association with major fetal vascular anomalies and cardiac defects, particularly TOF with APVS and patent arterial duct. We propose that the patency of the arterial duct in TOF with APVS leads to heart failure with subsequent demise early in pregnancy. Therefore, the frequent absence of the arterial duct observed in APVS in later pregnancy is more likely to be a result of early selection than a prerequisite for the development of this lesion as has been proposed previously.


Hypomagnesemic hypocalcemia. Early serum calcium and late parathyroid hormone increase with magnesium therapy.
A patient with short-bowel syndrome developed severe hypomagnesemia (0.2 mEq/liter) associated with symptomatic hypocalcemia (6.1 mg/100 ml). Parathyroid hormone (PTH) levels were normal but inappropriately low. During therapy with magnesium sulfate, an initial hypocalcemia was followed by a calcemic response without a change in PTH levels. This indicates improved bone responsiveness to circulating low levels of endogenous PTH with magnesium replenishment, which appears to be related to the restoration of magnesium-dependent cellular mechanisms. The additional observation of a slow and delayed increase in PTH, despite normal calcium levels, indicates improvement of hormone synthesis.


[Secondary gout and pseudo-Bartter syndrome in females with laxative abuse].
Four females (27-54 y), presenting with a history of long-term laxative abuse, were admitted to the Medizinische Poliklinik for evaluation of generalized weakness. Laboratory findings revealed signs of Bartter's syndrome, including hypokalemia, systemic alkalosis and normal blood pressure. Three of the four females showed impaired renal function and elevated serum uric acid levels, two of them suffered from recurrent gouty attacks. In our patients the incidence of hyperuricemia and impaired renal function, as a consequence of chronic hypokalemia, was much higher than known from patients with Bartter's syndrome. Hyperuricemia is related to some pathophysiological features of Pseudo-Bartter's syndrome, (e.g. systemic alkalosis, elevated angiotensin) and combined with additional factors (e.g. catabolism, reduced plasma volume) may lead to gouty attacks. Gallstones were found in two of the four females. Long term surreptitious laxative ingestion frequently is observed in females. Hypokalemia, induced by the laxatives, causes reduced intestinal motility and leads to augmented laxative intake. These patients are prone to develop Pseudo-Bartter's syndrome, causing eventually a hyperuricemia and gouty attacks.


[Sudden deafness as a consequence of rupture of a basilar artery aneurysm (author's transl)].
A sixty-eight year old female patient died from a subarachnoid hemorrhage three days after experiencing sudden hearing loss in her right ear. Autopsy showed that the cause of death was a large aneurism of the basilar artery. Temporal bone sections uncovered a massive infiltrate of erythrocytes about the nerves in the internal auditory canal. The blood cells had extended along the nerve bundles to enter Rosenthal's canal and the other fluid channels of the modiolus, and could be found within all perilymphatic spaces. The presence of hemosiderin within the inner ear correlates clinically with the onset of sudden deafness three days prior to demise, and is substantial evidence for the loss of hearing due to rupture of the basilar aneurism.


Identifying risk factors for HIV-positive test results in walk-in and hospitalized patients in a Mexico City HIV clinic: a descriptive study.
The objective of this study was to analyze risk factors for HIV-positive tests in walk-in users and in hospitalized patients in a Mexico City hospital. We undertook a cross-sectional study based on routine HIV testing and counseling service data in adults undergoing an HIV test from January 2015 to July 2017. Multivariate analysis was performed to determine risk factors for walk-in and hospitalized patients. The results showed that 2040 people tested during the period; hospitalized patients were more likely to test HIV-positive than walk-in users (18 versus 15%; p < 0.05). HIV risk factors for hospitalized patients included being men who have sex with men (MSM) (adjusted odds ratio [aOR] 7.2, 95% CI 2.0-26.5), divorced (aOR 4.4, 95% CI 1.3-14.4), having 3-5 lifetime sexual partners (aOR 2.7, 95% CI 1.0-7.4), and being in the emergency room (aOR 3.6, 95% CI 1.1-11.3), intensive care (aOR 27.2, 95% CI 3.4-217.2), or clinical pneumology wards (aOR 33.4, 95% CI 9.7-115.2). In the walk-in group, HIV risk factors included being male (aOR 2.8, 95% CI 1.3-5.9), being MSM (aOR 4.3, 95% CI 2.0-9.5), having sex while using drugs (aOR 2.3, 95% CI 1.3-4.0), being referred by a physician for testing (aOR 3.2, 95% CI 1.6-6.3), and perceiving oneself at risk (aOR 3.8, 95% CI 2.3-6.3). Differential risk factors found among hospitalized patients and walk-in testers can be helpful in designing better HIV testing strategies to increase early diagnosis and linkage to care.


Brønsted acid mediated cyclization of enaminones. Rapid and efficient access to the tetracyclic framework of the Strychnos alkaloids.
The development of an efficient diastereoselective method that permits rapid construction of the tetracyclic core 17 of the Strychnos-Aspidosperma alkaloids is described. Enaminone 16, synthesized in high yield, has been cyclized under the influence of a Brønsted acid to provide the core tetracyclic framework 17 of the Strychnos alkaloids in optically active form or alternatively to the β-ketoester tetrahydro-β-carboline (THBC) unit 18, by varying the equivalents of acid and the molar concentration. Attempts to utilize 18 to form the C₇-C₁₆ bond of the akuammiline related alkaloids represented by strictamine (22), using metal-carbenoid chemistry, are also described.


Nucleotide sequence and secondary structure of potato spindle tuber viroid.
The viroid of the potato spindle tuber disease (PSTV) is a covalently closed ring of 359 ribonucleotides. As a result of intramolecular base pairing, a serial arrangement of double-helical sections and internal loops form a unique rod-like secondary structure. PSTV is the first pathogen of a eukaryotic organism for which the complete molecular structure has been established.


Broad-spectrum inhibitor of viruses in the Flaviviridae family.
The viruses in the Flaviviridae family have been associated with human and animal diseases. In this report, we demonstrate that compound 2-amino-8-(beta-D-ribofuranosyl) imidazo [1,2-a]-s-triazine-4-one (ZX-2401) was capable of inhibiting the production in culture of at least five members of the Flaviviridae family with minimal cytotoxicity. This compound inhibited yellow fever virus, dengue virus, bovine viral diarrhea virus, banzi virus and West Nile virus with EC50 of 10, 10, 5, 5 and 3 microg/ml, respectively, and the CC50 in these experiments were greater than 1000 microg/ml. The activity of ZX-2401 is comparable to or better than the control drugs in these studies and was not affected by MOI variation. In addition, ZX-2401 inhibited HCV replication in a dose response fashion in the replicon assay system. Furthermore, ZX-2401 exhibited a synergistic antiviral activity in combination with IFN in tissue culture. The data described herein suggest that ZX-2401 is a broad-spectrum inhibitor of the RNA viruses, which has merit for development of treatments for the emerging infections caused by the viruses in the Flaviviridae family.


TNF-alpha signaling in glaucomatous neurodegeneration.
Growing evidence supports the role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of neurodegeneration in glaucoma. Glial production of TNF-alpha is increased, and its death receptor is upregulated on retinal ganglion cells (RGCs) and optic nerve axons in glaucomatous eyes. This multifunctional cytokine can induce RGC death through receptor-mediated caspase activation, mitochondrial dysfunction, and oxidative stress. In addition to direct neurotoxicity, potential interplay of TNF-alpha signaling with other cellular events associated with glaucomatous neurodegeneration may also contribute to spreading neuronal damage by secondary degeneration. Opposing these cell death-promoting signals, binding of TNF receptors can also trigger the activation of survival signals. A critical balance between a variety of intracellular signaling pathways determines the predominant in vivo bioactivity of TNF-alpha as best exemplified by differential responses of RGCs and glia. This review focuses on the present evidence supporting the involvement of TNF-alpha signaling in glaucomatous neurodegeneration and possible treatment targets to provide neuroprotection.


Serum concentration of pregnancy-associated plasma protein A in the first trimester of pregnancy.
Serial assays of pregnancy-associated plasma protein A were done in 12 subjects before the first missed menstrual period through 10 to 16 weeks' gestation. It was found that the concentration of pregnancy-associated plasma protein A remained at prepregnancy levels until 6 to 10 weeks after the last menstrual period. Thereafter the concentration increased rapidly. It is surmised that pregnancy-associated plasma protein A is a maternal protein, the synthesis of which is stimulated by pregnancy.


Single versus dual pathways to functional outcomes in schizophrenia: Role of negative symptoms and cognitive function.
The functional outcomes for many patients with schizophrenia remain poor, and the specific determinants for and pathways to functional outcomes are not well understood to date. It is unknown whether major determinants of outcomes are achieved via a motivated single pathway or by the motivation and capacity defined in dual pathways. This study investigated whether different aspects of functional outcomes, such as residential, social, and vocational outcomes, are the main determinants of the experience factors for negative symptoms or whether the experience factors and cognitive function are the determinants. We enrolled 107 patients with schizophrenia. The Social Functioning Scale domains were used to examine whether a single or dual pathway is appropriate for each domain based on the model fit using structural equation modeling. The model goodness of fit criterion showed a dual pathway for residential and vocational outcomes. In contrast, social and recreational outcomes showed a single pathway. The major determinants were clearly different for each outcome. Therefore, we emphasize the importance of using different treatment strategies for each outcome. Irrespective of the factors approached, social and recreational outcomes should ultimately focus on motivation. The findings also suggest that interventions should be combined for vulnerable cognitive functions and motivational interventions for residential and vocational outcomes.


Genomic organisation and expression of BCL6 in murine B-cell lymphomas.
BCL6 encodes a transcription factor deregulated by chromosomal translocations in human diffuse large cell B lymphomas (DLCL). This study was designed to determine whether Bcl6 might also be involved in lymphomas of mice. BCL6 protein was expressed at high levels in 90% or more of DLCL but not in low grade B lymphomas. Southern hybridisation studies demonstrated altered organisation of Bcl6 in three primary DLCL and the WEHI 231 B-cell lymphoma cell line but not in low grade tumours. Chromosomal painting and fluorescence in situ hybridisation (FISH) analyses of the WEHI 231 metaphase spreads revealed a T(5;16) translocation with Bcl6 on Chromosome 16 at the translocation breakpoint. Deregulated expression of BCL6 is thus likely to contribute to the genesis of DLCL of mice as well as of humans.


A randomised, double-blind, placebo-controlled trial of a herbal medicinal product containing Tropaeoli majoris herba (Nasturtium) and Armoraciae rusticanae radix (Horseradish) for the prophylactic treatment of patients with chronically recurrent lower urinary tract infections.
The aim of this study was to verify the efficacy and safety of a herbal medicinal product containing Tropaeoli majoris herba and Armoraciae rusticanae radix in the prophylactic treatment of chronically recurrent urinary tract infections (UTIs), and to test whether the medicinal product decreases the incidence of relapses over the study period. A total of 219 adults aged between 18 and 75 years were screened and 174 patients enrolled. Of these 174 patients, a group of 45 patients were screening failures. Patients were randomised to receive either the study drug or placebo twice daily for 90 days. A UTI is confirmed by defined symptoms together with a laboratory result. The diagnosis of a new episode of a recurrent UTI included urine analysis from a central laboratory. The primary efficacy criterion - the number of recurrent UTIs over the study period - was tested between the treatment groups. For the per-protocol population, the mean number of recurrent UTIs in the study period was 0.43 versus 0.77 for the placebo group. This result is statistically significant (p = 0.035). A total of 36 patients in the test group and 37 patients in the placebo group reported adverse events. Two serious adverse events were reported in the placebo group and one serious adverse event in the treatment group (not associated with the study medication). This randomised, double-blind, placebo-controlled trial demonstrates the efficacy and safety of the herbal medicinal product Angocin Anti-Infekt N* in the prophylactic treatment of chronically recurrent UTIs.


Differences between intra- and extracellular interleukin-1.
The intracellular (IC) and extracellular (EC) pools of interleukin 1 (IL-1) of human monocyte cultures were found to differ in their molecular size and charge characteristics. EC activity was found by Sephadex G-75 chromatography to consist mainly of a single peak in the 15,000-17,000 mol. wt range. In contrast, IC activity was distributed in four peaks (mol. wts of approx. 15,000, 26,000, 45,000 and greater than 70,000). Treatment of a pool of the IC 26,000, 45,000 and greater than 70,000 mol. wt species with CHAPS, a zwitterionic detergent, yielded a large amount of the 15,000 mol. wt species, thus suggesting that a portion of the larger species consists of aggregates of the 15,000 mol. wt molecule. Both IL-1 pools were found by isoelectrofocusing to be composed of three molecular species with pIs of 5.5, 6.7. However, the proportions of these species differed markedly between the EC and IC pools. The large majority of IC activity (approximately 90%) was found at pI 5.5, while 55-60% of EC activity had a pI of 6.7 and 35-40% had a pI of 5.5. The differences in their biophysical properties support the notion that the IC and EC pools of IL-1 also differ in their functions.


Experience with 170 cases of posterior urethral strictures during 7 years.
Various types of urethroplasty and visual urethrotomy should not be regarded as competitive with each other for a particular case of urethral stricture. Rather, they should be regarded as complementary procedures available for the cure of different types of strictures, with each having its indications as well as limitations. In cases of post-traumatic strictures and disruption the best solution is complete excision of the pathological segment and bulboprostatic anastomosis, either through the perineum when prostatic displacement is absent or minimal, or by the transpubic route when the displacement is great. Post-inflammatory strictures should be corrected by a 2-stage urethroplasty with exteriorization of the diseased urethra. Internal visual urethrotomy is reserved for short post-traumatic strictures that are limited in length, circumference and depth. Free skin grafts are best suited to cover small defects after urethroplasty.


Information for decision making by post-menopausal women with hormone receptor positive early-stage breast cancer considering adjuvant endocrine therapy.
To identify the information that post-menopausal women with hormone-receptor positive, early-stage breast cancer want, to help them decide among six treatment options for adjuvant-endocrine therapy. We surveyed women with early-stage breast cancer who were eligible for adjuvant endocrine-therapy 3-18 months earlier. Participants rated the importance of getting each of 95 questions answered before this decision is made (options: essential/desired/not important/avoid). For questions rated essential or desired, participants identified the purpose(s) for having the question answered: to help them understand, make the decision, plan, or other. Participants indicated the role they played in their actual decision and the role they would prefer if the decision was made today. They also indicated whether they felt they had had a choice of endocrine therapy treatments. 188 of 343 questionnaires were returned (response rate 55%). Mean age was 67 yr (range 38-88 yr); 76% were married, and 39% had secondary school education or less. On average, respondents rated 18 questions (range 0-94) essential for decision making. Each question was rated essential for decision making by ≥ 7% of participants but only 1 question by >50%. Regarding roles, 89% of respondents had participated in their actual decision and would want to again; an additional 9% had not participated in their actual decision but would want to at the time of the survey. The percentage of respondents who felt they had no choice of endocrine therapy treatments varied between centres, 25% vs 41% and 49%. Most patients want to participate in the decision but they vary widely in the amount and which specific details they want to help them make the decision. The wide variation in questions considered important means the support should be tailored to the needs of the individual patient.


Impact of the spread of mass education on married women's experience with domestic violence.
This paper investigates the association between mass education and married women's experience with domestic violence in rural Nepal. Previous research on domestic violence in South Asian societies emphasizes patriarchal ideology and the widespread subordinate status of women within their communities and families. The recent spread of mass education is likely to shift these gendered dynamics, thereby lowering women's likelihood of experiencing domestic violence. Using data from 1775 currently married women from the Chitwan Valley Family Study in Nepal, we provide a thorough analysis of how the spread of mass education is associated with domestic violence among married women. The results show that women's childhood access to school, their parents' schooling, their own schooling, and their husbands' schooling are each associated with their lower likelihood of experiencing domestic violence. Indeed, husbands' education has a particularly strong, inverse association with women's likelihood of experiencing domestic violence. These associations suggest that the proliferation of mass education will lead to a marked decline in women's experience with domestic violence in Nepal.


Exosome-Shuttled circSHOC2 from IPASs Regulates Neuronal Autophagy and Ameliorates Ischemic Brain Injury via the miR-7670-3p/SIRT1 Axis.
The aim of the present study was to investigate the neuroprotective roles and mechanisms of the circular RNA circSHOC2 in ischemic-preconditioned astrocyte-derived exosomes (IPAS-EXOs) against ischemic stroke. We established an ischemia model based on oxygen glucose deprivation (OGD) in vitro and isolated resultant exosomes from astrocytes. Neuronal viability and apoptosis were determined by Cell Counting Kit-8 (CCK-8) assays and TUNEL (terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling) staining, respectively. Autophagy-related proteins were analyzed by western blotting. We found that exosomes derived from IPAS-preconditioned medium (IPAS-CM) exerted neuroprotection. Furthermore, circSHOC2 expression was significantly upregulated in exosomes released from IPAS-CM. Overexpression of circSHOC2 in neurons yielded the same protective effects as those from IPAS-EXOs in vitro, and similar results were also observed in the middle cerebral artery occlusion (MCAO) mouse model. Mechanistically, circSHOC2 reduced neuronal apoptosis via regulating autophagy. Furthermore, circSHOC2 was found to sponge miR-7670-3p, which regulated SIRT1 expression. Transfection with an miR-7670-3p small interfering RNA (siRNA) (siRNA-7670-3p) and incubation with circSHOC2 extracellular vesicles attenuated ischemia-induced neuronal apoptosis in vivo and in vitro, while silencing of SIRT1 reversed the protective effects of exosomal circSHOC2 on hypoxic cerebral neurons. Taken together, our findings indicate that circSHOC2 in IPAS-EXOs suppressed neuronal apoptosis and ameliorated neuronal damage by regulating autophagy and acting on the miR-7670-3p/SIRT1 axis, which might contribute to a therapeutic strategy for ischemic stroke treatment.


Intensive early screen exposure as a causal factor for symptoms of autistic spectrum disorder: The case for «Virtual autism».
Intensive Early Screen Exposure (IESE) has been associated with detrimental outcomes on different variables including attention, language, emotion regulation and socialisation, some of which are central to the diagnosis of neurodevelopmental disorders, such as ADHD and learning disorders. Following Bradford-Hill's recommendations, we argue that there is growing clinical and empirical evidence supporting a causal relationship between intensive early screen exposure (more than 4 h a day) and subsequent symptoms of Autism Spectrum Disorders in some possibly vulnerable younger children (less than 6 years old). Clinicians should also be aware of the existence of cases of recovery or dramatic improvement after parents accept to stop screen exposure for a few months, associated with daily moments of dyadic interaction, since this intervention has repeatedly been found to be effective with no known side-effects.


Purification and characterization of a Ca2+-dependent actin filament severing protein from bovine adrenal medulla.
We describe the purification of an actin regulatory protein from bovine adrenal medulla. This protein caused a dose-dependent decrease of the specific viscosity of actin solution within 30 s of its addition in a Ca2+-sensitive way. Sedimentation assays and the observation by electron microscopy showed that this effect was ascribable to the fragmentation of actin filaments. This protein apparently promoted nucleation of actin polymerization and increased the critical concentration of actin for polymerization nearly 5-fold, suggesting its binding to the barbed end of actin filaments. The inhibitory effect of this protein on the elongation of actin from the barbed end of the myosin subfragment S1-labeled actin seeds confirmed this suggestion. These properties are similar to those of gelsolin. However, the physicochemical properties of this protein having a single polypeptide chain with a molecular weight of 74,000, a Stokes radius of 3.9 nm, a sedimentation coefficient (s0(20),w) of 4.5 S, and an immunological characterization showed that this protein is different from gelsolin.


Nutrients' behavior and removal in an activated sludge system receiving Olive Mill Wastewater.
This work aims to monitor inorganic nutrients (phosphorus and ammonium) behavior during the injection of Olive Mill Wastewater (OMWW) in an activated sludge process. The system was fed firstly with urban wastewater (UWW) and was alimented after its stabilization with OMWW (at 0.1% (v/v) and 1%) for 100 days. Total polyphenols, chemical oxygen demand (CODT), nutrients, and biomass behavior against OMWW injection were investigated. The results showed a satisfactory biomass growth of 7.12 gMLVSS.L-1 and a high microbial activity of 21.88 mg O2.gMLVSS-1.h-1. An overall removal reached 90%, 92%, 59% and 93% respectively for, CODT, total polyphenols, PO43- and NH4+. Adding OMWW at 1% seems to improve the nutrients elimination, especially phosphorus by the biological process probably though bringing more biodegradable organics. The chemical processes (precipitation/complexation) could also be involved in phosphorus removal, due to the OMWW wealth on salts elements such as calcium.


Yarrowia lipolytica dehydrogenase/reductase: an enzyme tolerant for lipophilic compounds and carbohydrate substrates.
Yarrowia lipolytica short chain dehydrogenase/reductase (YlSDR) was expressed in Escherichia coli, purified and characterized in vitro. The substrate scope for YlSDR mediated oxidation was investigated with alcohols and unprotected carbohydrates spectrophotometrically, revealing a preference for secondary compared to primary alcohols. In reduction direction, YlSDR was highly active on ribulose and fructose, suggesting that the enzyme is a mannitol-2-dehydrogenase. In order to explore substrate tolerance especially for space-demanding, lipophilic protecting groups, 5-O-trityl-D-ribitol and 5-O-trityl-α,β-D-ribose were investigated as substrates: YlSDR oxidized 5-O-trityl-D-ribitol and 5-O-trityl-α,β-D-ribose and reduced the latter at the expense of NADP(H).


Antidopaminergic activity of estrogens on prolactin release at the pituitary level in vivo.
Treatment of female or male rats with estradiol benzoate led to an almost complete reversal of the inhibitory effect of low doses of dopamine on prolactin secretion. These data indicate that estrogens which have previously been shown to exert a potent antidopaminergic activity on prolactin secretion in anterior pituitary cells in primary culture have similar effects in vivo.


Clinical features of hypertrophic cardiomyopathy caused by a Lys183 deletion mutation in the cardiac troponin I gene.
Mutations that cause hypertrophic cardiomyopathy (HCM) have been identified in 9 genes that code proteins in the sarcomere. Previous reports have demonstrated that cardiac troponin I (cTnI) gene mutations may account for familial HCM; however, the clinical characteristics and prognosis of patients with HCM caused by cTnI gene mutations are not known. We analyzed cTnI gene mutations in 130 unrelated probands with HCM and their families to clarify the genotype-phenotype correlations. We identified 25 individuals in 7 families with a Lys183 deletion (Lys183 del) mutation in exon 7 of the cTnI gene. The disease penetrance in subjects aged >20 years was 88% by echocardiography and 96% by ECG. Sudden death occurred in 7 individuals of 4 families at any age. Overall, 7 (43.8%) of 16 individuals aged >40 years had left ventricular systolic dysfunction, and 3 (18.8%) displayed dilated cardiomyopathy-like features. Of affected individuals, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up. The Lys183 del mutation in the cTnI gene in patients with HCM is associated with variable clinical features and outcomes. HCM caused by the Lys183 del mutation has a significant disease penetrance. This mutation is associated with sudden death at any age and dilated cardiomyopathy-like features in those aged >40 years. However, it remains unclear whether screening of families with HCM for this mutation will be useful in patient management and counseling.


Robotically assisted minimally invasive biliary surgery in a porcine model.
A robotic surgery system has the potential both to reduce the effects of tremor and fatigue and to enhance dexterity in the performance of complex, fine endosurgical tasks. We report a prospective study of robotically assisted minimally invasive biliary surgery in a porcine model using the Zeus robotic surgical system (Computer Motion, Goleta, Ca, USA). For this study, 50-kg domestic swine were used. Minimally invasive robotically assisted cholecystectomy was performed in 16 animals, either longitudinal or transverse common bile duct incision, T-tube placement, and suture repair of the common bile duct. Retrieval of 12 simulated bile duct calculi was attempted. Eight animals were monitored for 6 weeks postoperatively. Liver function tests and cholangiography were performed 2 and 6 weeks after surgery. The median setup time for the robotic system was 45 min (range, 10-120 min). The median operative time was 40 min (range, 25-60 min) for cholecystectomy and 80 min (range, 40-165 min) for bile duct dissection, exploration, and repair. Of 12 bile duct calculi, 11 were retrieved successfully. Cholangiography demonstrated no leaks, and the anastomotic stenotic index (diameter of the proximal bile duct divided by the diameter of distal bile duct) at 6 weeks was 0.98. The results of the liver function tests remained normal in all animals. One postoperative death unrelated to operative technique occurred. Complications included one minor splenic laceration and two intraoperative gallbladder perforations. Robotically assisted minimally invasive biliary surgery in this animal model is both feasible and safe. The Zeus system provides enhanced dexterity, which facilitates precise laparoscopic suture repair of small bile ducts.


Long Non-coding RNA H19 Deteriorates Hypoxic-Ischemic Brain Damage by Interacting with MicroRNA-140-5p and STAT3.
Even though extensive studies have surveyed long non-coding RNA (lncRNA)-related networks in hypoxic-ischemic brain damage (HIBD), the concrete function of lncRNA H19 (H19) in HIBD is still in ambiguity. Therein, this work intends to decipher H19-related network of microRNA (miR)-140-5p and signal transducer and activator of transcription 3 (STAT3) in HIBD. Brain microvascular endothelial cells (BMECs) from BALB/c mice were isolated and induced by oxygen glucose deprivation (OGD). OGD-induced BMECs were transfected with depleted or restored H19, miR-140-5p or STAT3, and cell apoptosis, migration and angiogenesis were examined. H19, miR-140-5p and STAT3 expression and their internal connections were tested. H19 and STAT3 were overexpressed while miR-140-5p was down-regulated in OGD-induced BMECs. H19 or STAT3 knockdown, or miR-140-5p restoration repressed apoptosis and improved migration and angiogenesis of OGD-induced BMECs. MiR-140-5p restoration negated the impacts of up-regulated H19 on OGD-induced BMECs. H19 bound to miR-140-5p to modulate STAT3 expression. The work illustrates that depleting H19 or STAT3 or restoring miR-140-5p attenuates HIBD and supplies a novel perspective for HIBD management.


The decreased cyclic-AMP dependent-protein kinase A function in the nucleus accumbens: a role in alcohol drinking but not in anxiety-like behaviors in rats.
The nucleus accumbens (NAc) brain structures have been implicated in the reward and reinforcing properties of ethanol. The present study investigated the role of nucleus accumbal cyclic AMP (cAMP)-dependent protein kinase A (PKA) signaling in alcohol drinking and anxiety-like behaviors of rats. It was found that infusion of PKA inhibitor (Rp-cAMP) into the NAc shell significantly increased the alcohol but not the sucrose intake, without modulating the anxiety-like behaviors, as measured by elevated plus maze test in rats. PKA inhibitor infusion into the NAc shell significantly decreased the protein levels of alpha-catalytic subunit of PKA (PKA-Calpha) and phosphorylated cAMP response element-binding protein (p-CREB) as well as decreased the protein levels of neuropeptide Y (NPY) in the shell but not in the NAc core of rats. On the other hand, infusion of PKA activator (Sp-cAMP) or NPY alone into the NAc shell did not produce any changes in alcohol intake; however, when these agents were coinfused with PKA inhibitor, they significantly attenuated the increases in alcohol preference induced by pharmacological inhibition of PKA. Interestingly, PKA activator coinfusion with PKA inhibitor into the NAc shell significantly normalized the PKA inhibitor-induced decreases in the protein levels of PKA-Calpha and p-CREB as well as of NPY in the NAc shell of rats. Taken together, these results provide the first evidence that decreased PKA function in the NAc shell is involved in alcohol drinking but not in anxiety-like behaviors of rats. Furthermore, decreased function of PKA may regulate alcohol drinking behaviors via CREB-mediated decreased expression of NPY in the NAc shell of rats.


Ca2+ channel antagonists and neuroprotection from cerebral ischemia.
Stroke is the third leading cause of death and the main disabling neurologic disease. The finding in experimental studies that neuronal death does not occur immediately after ischemic injury has encouraged the development of neuroprotective agents. Various Ca2+ channel antagonists, that is, L-type-selective or non-selective derivatives from classical Ca2+ channel antagonists, have been examined for their ability of neuroprotection through improvement of cerebral blood circulation or inhibition of Ca2+ overload induced by excessive glutamate release. Although some of the antagonists showed efficient neuroprotection in animal models, systemic hypotension limited the utility of these drugs, and none of the compounds showed beneficial effects in treatments for acute ischemic stroke in clinical trials. Drugs other than Ca2+ channel antagonists developed on the basis of the glutamate-Ca2+ overload hypothesis were shown also to lack clinical benefit. Recently, some mechanisms have been proposed to interpret neuronal death in relation to hyperexcitability or apoptosis after ischemic insult. In these hypotheses, activation of the Ca2+ channel types selectively expressed in neuronal tissues is proposed as a critical step of the pathways toward neurodegeneration. Thus, it is increasingly recognized that developing highly selective compounds for neuronal Ca2+ channels is not only important for treatment of stroke but also for elucidation of mechanisms that underlie neurodegeneration.


Effect of poly-γ-glutamic acid on the phytoremediation of ramie (Boehmeria nivea L.) in the Hg-contaminated soil.
Farmlands around the Hg mining areas have suffered from severe Hg contamination issues, triggering a phenomenon of high Hg content in crops, and subsequently threatening human health. In this study, ramie (Boehmeria nivea L.) assisted with poly-γ-glutamic acid (γ-PGA) was employed to remediate the Hg-contaminated soil through incubation experiments. After the soil was amended with γ-PGA, the leaf Hg content increased by 4.4-fold, and the translocation factor value even reached 3.5, indicating that γ-PGA could dramatically enhance the translocation of Hg from root and stem to leaf. γ-PGA could induce the transformation of potentially available Hg to available fractions, resulting in the soil Hg being more bioavailable. Batch trials verified that γ-PGA could mask the adsorption function of Hg ions by soil organic matter, significantly stimulating the desorption of Hg ions from the soil. As a result, the soil Hg would transfer to the aqueous phase and be assimilated by the root of ramie more easily and effectively. The γ-PGA chelated Hg is hydrophilic and has a high affinity with -SH and -S-; thereby, it can easily stride over the Casparian strip, enter the vessel, be translocated upwards, be sequestered in the tissues of leaf, and be incorporated irreversibly. This study can provide a new method for the remediation of Hg-contaminated soil.


Prenatal exposure to phthalates and gender-specific play behavior at seven years of age in the SELMA study.
A growing body of evidence shows that prenatal exposure to phthalates affects child development. Since many phthalates have been shown to alter endocrine signaling, they may influence reproductive development, neurodevelopment, and child behavior. Indeed, a few studies reported associations between prenatal phthalate exposure and gender-specific play behavior. However, evidence for this relationship is limited, and previous findings are based on single phthalates, while human exposure entails mixtures of chemicals. We aimed to investigate the associations between prenatal exposure to single phthalates, as well as a phthalate mixture, and gender-specific play behavior. A total of 715 mother-child pairs from the Swedish Environmental Longitudinal, Mother and Child, Asthma and Allergy (SELMA) study were included. In the median week 10 of pregnancy, phthalate metabolites were measured in urine. Gender-specific play behavior was measured with Preschool Activities Inventory at the age of seven years. Linear and weighted quantile sum regressions were used; data was stratified by sex. Models were adjusted for child and maternal age, maternal education, parental attitudes toward play behavior, and urinary creatinine concentration. For boys, single compound analyses revealed negative associations of prenatal exposure to di-isononyl phthalate (DINP) concentrations with masculine (β = -1.44; 95% CI = -2.72, -0.16) and composite (β = -1.43; 95% CI = -2.72, -0.13) scores. Suggestive associations were also observed with a mixture approach identifying DINP as the main contributor of the association of decreased masculine play. Among girls, higher urinary concentrations of 2,4-methyl-7-oxyooctyl-oxycarbonyl-cyclohexane carboxylic acid (MOiNCH) was associated with decreased feminine (β = -1.59; 95% CI = -2.62, -0.57) and masculine scores (β = -1.22; 95% CI = -2.14, -0.29), whereas the mixture analyses did not yield conclusive results for girls. Our findings suggest associations of prenatal exposure to DINP with decreased masculine play behavior in boys while the results for girls were not fully conclusive.


Genomic alterations as independent prognostic factors to predict the type of lung cancer recurrence.
33-70% of lung cancer (LC) patients develop recurrence after radical treatment. Previous studies have shown the importance of clinical-pathological characteristics for the risk of recurrence. The role of molecular mechanisms remains unclear. The aim was analyzing genomic features in LC patients with local (LR) versus distant recurrence (DR) to predict the risk and type of recurrence. Patients previously curatively treated with LC recurrences from 2015 to 2017 were retrospectively enrolled. Histological specimens collected at the time of LC diagnosis were sent for whole exome sequencing (WES). Genomic data was analyzed for single nucleotide polymorphisms (SNPs) and insertion-deletion mutations (INDELs). 191 patients were included. 33% of patients had LR and 67% DR, with median recurrence-free survival (RFS) 15.4 versus 11.2 months (p = 0.20) and overall survival (OS) after recurrence 12.9 versus 8.5 months (p = 0.007), respectively. Of various laboratory parameters studied, lymphocytes were significantly decreased at recurrence (p < 0.0001) in the DR group. In genetic analysis, significantly enriched INDEL mutations were found in 38 and 98 genes and SNP mutations in 63 and 179 genes in DR and LR groups, respectively. DMXL2 and ABCC9 gene mutations caused by INDELs appeared exclusively in the DR group. Enrichment analysis detected genes, like KNTC1, CLASP1, CLASP2 and CENPE, responsible of microtubule disturbance in the DR group. Furthermore, genes related to cytosolic Ca2+ such as STIM1, ITPR3 and RYR3, were significantly enriched in DR group whereas in LR group enrichment of pathways related to endoplasmic/sarcoplasmic reticulum Ca2+ was observed. Our findings indicate distinct genomic signatures in the LR and DR cohorts, with microtubule disturbance and calcium regulation playing a crucial role in invasiveness in DR of LC. Understanding molecular mechanisms of LC recurrence may lead to the discovery of novel drug targets that could potentially stop spread of cancer cells.


A full digital workflow to prefabricate an implant-supported interim restoration: case report and a novel technique.
This article describes a case with a full digital procedure to prefabricate an implant-supported interim restoration based on the preoperative digital implant planning. A fully guided surgical template is designed and printed, and then an interim restoration is fabricated based on the planned implant position through a dental computer-aided design (CAD) software. Once the implant was placed at the predetermined position through the fully guided surgical guide, the prefabricated interim restoration could be inserted immediately after the surgery, which can guide the healing of the soft tissue and enhance the esthetic outcomes. This novel technique eliminates the conventional impression making to insert an implant-supported interim restoration immediately after the implant placement surgery, which can guide the healing of the soft tissue, minimize the chairside time and optimize the clinical workflow.


Infliximab for the treatment of psoriasis: clinical experience at the State University of New York at Buffalo.
Infliximab has shown promising results for the treatment of moderate to severe psoriasis and psoriatic arthritis. We conducted a retrospective study of all 52 patients treated with intravenous infliximab for severe psoriasis at a single practice site. These patients had recalcitrant plaque psoriasis (>33% body surface area), which was unresponsive to multiple conventional systemic therapies. Intravenous infliximab was administered at a dose of 5 mg/kg at 0, 2, 6, and 14 weeks and every 8 weeks thereafter. Patients were monitored for infections, infusion reactions, side effects, and response to therapy. Fifty-two patients (men = 32, women = 20) with a mean age of 47 (range, 22-76 years old) were included in this study. They were followed for a minimum of 4 months and a maximum of 33 months (median, 22 months). Patients received a mean total number of 12 infusions (range, 3-22). Forty-six of 52 patients (88%) had a clear or almost clear improvement based on the Physician's Global Assessment done by a single physician. Twelve patients (23%) required infliximab dose escalation to maintain control of their disease. Nine patients experienced infusion reactions. Thirteen patients experienced nonopportunistic infections; however, only one infection required temporary cessation of infliximab. This was a retrospective study at a single practice site. Infliximab was extremely effective and well tolerated in this group of patients with severe, recalcitrant psoriasis. Thirty-nine of 52 patients have continued receiving treatment for a median duration of 25 months with excellent disease control. Infliximab can provide control of extensive psoriasis with continued intermittent infusions.


Fundamental comments on cell polarography according to Velazquez and Rosado.
Some fundamental comments are made on cell polarography according to Velázquez and Rosado (Fertil Steril 23:562, 1972). The results which they have obtained cannot be reliable because fundamental mistakes are made against the principles of the electroanalytic techniques used. We comment upon the conductometry, the amperometric titrations, and the alternating-current polarography as carried out by Velázquez and Rosado.


Sensitization to human milk.
Allergy to milk is one of the earliest manifestations of IgE-mediated allergies and affects about 2.5% of newborn children. Several reports indicate that milk-allergic patients may be sensitized also to human milk proteins. To analyse the specificity and possible biological relevance of IgE reactivity to human milk antigens in milk-allergic patients. The specificity of IgE reactivity to cow's milk and human milk antigens was analysed with sera from milk-allergic children and adults by IgE immunoblotting. IgE cross-reactivity between milk antigens was studied by immunoblot inhibition experiments. That IgE reactivity to human milk antigens is not due to alloreactivity or due to the transmission of foreign antigens into mother's milk was demonstrated through the analysis of milk samples from genetically unrelated mothers before and after intake of dietary milk products. The biological relevance of IgE reactivity to human milk was confirmed by skin testing. Results IgE antibodies to human milk were found in more than 80% of the tested milk-allergic patients. Cross-reactive IgE-reactive human antigens such as alpha-lactalbumin and non-cross-reactive human milk antigens were identified. Immediate-type skin reactions could be elicited with human milk samples in patients with IgE reactivity to human milk. IgE reactivity to human milk in milk-allergic patients can be due to cross- sensitization and genuine sensitization to human milk and may cause allergic symptoms. IgE-mediated sensitization to human milk is common in milk-allergic patients and may require diagnostic testing and monitoring.


Cancer Collaboration Aims to Boost Detection.
A new collaboration sponsored by Cancer Research UK will attempt to boost early cancer detection. The partnership involves five institutions in the UK and United States that will to team up to develop and validate new technologies and biomarkers.


Permanent improvement of renal dysfunction and proteinuria with colchicine in a patient with tumoral amyloidosis and basal cell carcinoma.
Basal cell carcinoma and amyloid deposition was reported not uncommonly, but renal failure and nephrotic syndrome were rare. Here in, we reported a 72 years old male patient with nephrotic syndrome, renal failure and relatively small basal cell carcinoma. In this patient toumoral excision caused temporary improvement. When the proteinuria reappeared, due to amyloid deposition in toumoral tissue, colchicine was began. With colchicine therapy permanent improvement of nephrotic syndrome was achieved in follow-up 18 months.


Analysis of Salmonella typhi isolates from Southeast Asia by pulsed-field gel electrophoresis.
Pulsed-field gel electrophoresis (PFGE) revealed that multiple genetic variants of Salmonella typhi are simultaneously present in Southeast Asia and are associated with sporadic cases of typhoid fever and occasional outbreaks. Comparative analysis of PFGE patterns also suggested that considerable genetic diversity exists among S. typhi strains and that some PFGE patterns are shared between isolates obtained from Malaysia, Indonesia, and Thailand, implying movement of these strains within these regions of Southeast Asia, where they are endemic.


Growth hormone isoforms, segments/fragments: does a link exist with multifunctionality?
Understanding the relationship between growth hormone (GH) structure (its molecular fragments) and function via interaction with single or multiple receptors is of particular importance in clinical diagnostics and physiologic biochemistry. Direct and indirect actions of GH are numerous ranging from carbohydrate and lipid metabolism to growth effects at muscle and vessels. To this end, we have focused on the influence of physical exercise on GH synthesis and release into the circulation. Physical exercise is a physiological condition to which GH multifunctionality is inextricably linked and is thus important physiologically and pathologically. This review describes the potential human GH fragments with respect to protein hormone multifunctionality and the molecular regions of potential action. The intent of the review is to highlight human GH fragments and hypothesize their potential physiologic role. GH fragmentation is also reviewed in relation to the effects of physical exercise and hormone multifunctionality.


Depression stigma and management of suicidal callers: a cross-sectional survey of crisis hotline counselors.
Crisis hotlines play a key role in suicide prevention worldwide following different approaches regarding risk assessment and management of suicidality. This is to our knowledge the first study investigating depression stigma in crisis hotline counselors. The association between stigma and self-rated knowledge and their exploration of suicide risk and consecutive management of suicidal callers is being investigated. Data on depression stigma, self-rated knowledge, self-reported exploration and management of suicidality was collected from 893 counselors working for the German crisis hotline. Stigma in counselors had been compared to matched population sample (1002). Crisis hotline counselors reported significantly lower depression stigma compared to the general population. Depression stigma and age associations differed in both samples. The reported exploration of suicide risk in callers differed depending on the self-rated knowledge about suicidality and depending on the personal depression stigma, but not the reported consecutive management. Compared to the general population, crisis hotline counselors seem to have fewer stigmatizing attitudes toward depression. Attitudes and self-rated knowledge seem to influence the confidence in counselors regarding the exploration of suicidal callers, but not the consecutive management. The results indicate that a profound training and hands-on information about depression and suicide risk seem to be essential.


Molecular characterization of ochratoxin A producing penicillia.
Sixty-six strains classified as P. verrucosum based on morphological criteria were characterized by RAPD analysis. Two groups could be identified which differed in their ability to produce ochratoxin A (OTA). Group I originating from proteinacious foods containing mainly high OTA producing strains, and group II originating from plants containing moderate to non-producing strains. The differences at the RAPD level are consistent with the recent reclassification of ochratoxin A producing penicillia to be either P. verrucosum or P. nordicum.


High amplitude T-wave alternans precedes spontaneous ventricular tachycardia or fibrillation in ICD electrograms.
T-wave alternans (TWA) increases acutely prior to ventricular tachycardia (VT) or fibrillation (VF) in animal studies, suggesting that it may provide a warning for VT/VF in implantable cardioverter defibrillator (ICD) patients. Clinically, measurement of surface ECG TWA requires preprocessing the input signal to reduce noise and/or analyzing more sinus beats than are recorded in ICDs as pre-onset, stored intracardiac electrograms (EGMs) before VT/VF. Our objective was to measure TWA from the few sinus EGMs stored in ICDs before spontaneous VT/VF in humans. The purpose of this study was to evaluate the technical feasibility of measuring TWA from pre-onset ICD EGMs and to measure EGM TWA before spontaneous VT/VF in humans. We developed a method to measure EGM TWA as a simple average (AVE) of peak-to-peak alternans. Using simulation, we determined the effect of ICD signal processing on EGM TWA for durations comparable to those in pre-onset EGMs. We then applied this method to pre-onset ICD EGMs that preceded 101 episodes of sustained VT/VF in 10 patients. In 6 of these patients, EGM recordings in atrial pacing and sinus rhythm provided control data. In simulation, the AVE method discriminated input TWA differences > or = 15 microV. In patients, EGM TWA was 78 +/- 62 microV prior to VT/VF vs. 13 +/- 10 microV in control recordings (p< .0001). Eighty percent of pre-onset measurements exceeded 30 microV, while 95% of control measurements were less than 30 microV. A simple averaging method can measure TWA preceding VT/VF in stored ICD EGMs. Pilot data indicate that high-amplitude EGM TWA usually precedes spontaneous VT/VF and is infrequent in control recordings. They provide a rationale for developing ICD technology to measure EGM TWA continuously, both to warn patients and to initiate pacing algorithms to prevent VT/VF.


The quality evaluation of frankfurter-type sausages from hand and mechanically deboned turkey meat.
A quality evaluation was made of frankfurter-type sausages made from hand and mechanically deboned meat from various parts of turkey carcasses. The results led to the conclusions that despite some differences in objective measurements of the sausage quality, mechanically deboned turkey meat can be considered as an exclusive meat raw material for the production of frankfurter-type sausages. The quality of sausages from mechanically deboned turkey meat from wings and frames with skin was the least satisfactory.


Early abnormality detected by speckle-tracking echocardiography in a patient with suspected cardiac sarcoidosis.
A 56-year-old female was admitted to our hospital because of respiratory symptoms. Her admission ECG showed normal sinus rhythm and standard echocardiographic evaluation showed no structural or functional abnormalities. She was diagnosed as having sarcoidosis by imaging modalities and mediastinum lymph node biopsy. In this case, 2-dimensional speckle-tracking echocardiography (STE) demonstrated abnormal regional myocardial function and delayed enhancement cardiac magnetic resonance imaging revealed a high intensity area in the same segments. This case suggests that STE is potentially useful for the detection of cardiac sarcoidosis in the early phase.


Effects of B-HT 920 on nigrostriatal and mesolimbic dopamine systems in normosensitive and supersensitive rats.
1. B-HT 920, a D2 dopamine receptor agonist, was tested for its ability to exert presynaptic actions in normosensitive rats, and for possible postsynaptic actions in rats made 'supersensitive' to apomorphine. 2. In normosensitive rats, B-HT 920 (0.01-0.3 mg kg-1, i.p.) increased dopamine concentrations and lowered metabolite levels to a similar extent in all four terminal regions examined (medial prefrontal cortex, olfactory tubercle, nucleus accumbens, caudate-putamen). Analogous effects were seen for 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid. 3. Rats which received bilateral 6-hydroxydopamine (6-OHDA) infusions into the caudate-putamen showed signs of postsynaptic dopamine receptor activation (stereotyped behaviour) in response to B-HT 920 (0.1 and 1.0 mg kg-1, i.p.) and to apomorphine (0.2 mg kg-1, s.c.). Similarly, B-HT 920 (0.1 mg kg-1) induced contralateral circling in rats that had received unilateral 6-OHDA infusions into the medial forebrain bundle; the rate of circling increased gradually over several weeks. 4. In contrast, bilateral 6-OHDA infusions into the nucleus accumbens resulted in a supersensitive (locomotor stimulant) response to a low dose of apomorphine (0.1 mg kg-1, s.c.), but not to B-HT 920 (0.01 and 0.1 mg kg-1). 5. In intact rats, withdrawal of chronic haloperidol treatment induced behavioural supersensitivity to apomorphine but not to B-HT 920.


Auranofin targets UBA1 and enhances UBA1 activity by facilitating ubiquitin trans-thioesterification to E2 ubiquitin-conjugating enzymes.
UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Decreased or insufficient ubiquitination can cause or drive aging and many diseases. Therefore, a small-molecule enhancing UBA1 activity could have broad therapeutic potential. Here we report that auranofin, a drug approved for the treatment of rheumatoid arthritis, is a potent UBA1 activity enhancer. Auranofin binds to the UBA1's ubiquitin fold domain and conjugates to Cys1039 residue. The binding enhances UBA1 interactions with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest that auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.


The disposal of an oral glucose load in healthy subjects. A quantitative study.
Although it is an established concept that the liver is important in the disposition of glucose, the quantitative contribution of the splanchnic and peripheral tissues, respectively, to the disposal of an oral glucose load is still controversial. In the present investigation, we have employed the hepatic venous catheter technique in combination with a double-tracer approach (in which the glucose pool is labeled with 3H-glucose and the oral glucose load is labeled with 14C-glucose) to quantitate the four determinants of oral glucose tolerance: rate of oral glucose appearance, splanchnic glucose uptake, peripheral glucose uptake, and suppression of hepatic glucose production. Studies were carried out in 11 normal volunteers in the overnight-fasted state and for 3.5 h after the ingestion of glucose (1 g/kg body wt; range, 55-93 g). In the postabsorptive state, the rate of endogenous (hepatic) glucose production, evaluated from the 3H-glucose infusion, was 2.34 +/- 0.06 mg/min X kg. Glucose ingestion was accompanied by a prompt reduction of endogenous glucose output, which reached a nadir of 0.62 +/- 0.23 mg/min X kg at 45 min and remained suppressed after 3.5 h (0.85 +/- 0.22 mg/min X kg). The average inhibition of hepatic glucose output during the absorptive period was 53 +/- 5%. The appearance of ingested glucose in arterial blood, as derived from the 14C-glucose measurements after correction for recycling 14-C radioactivity, reached a peak after 15-30 min, and 14C-glucose continued to enter the systemic circulation throughout the observation period. The rate of appearance of ingested glucose was 2.47 +/- 0.45 mg/min X kg at 3.5 h. A total of 73 +/- 4% of the oral load was recovered in the systemic circulation within 3.5 h.(ABSTRACT TRUNCATED AT 250 WORDS)


Document of revision and updating of medication overuse headache (MOH).
Medication overuse headache is a secondary headache in which the regular or frequent use of analgesics can increase the frequency of the episodes, causing the transition from episodic to chronic headache. The prevalence of medication overuse headache is approximately 1-2%, with higher rates among women aged 30-50 years and with comorbid psychiatric disorders such as depression or anxiety, or other chronic pain disorders. It is important to be familiar with the management of this disease. To this end, the Spanish Society of Neurology's Headache Study Group has prepared a consensus document addressing this disorder. These guidelines were prepared by a group of neurologists specialising in headache after a systematic literature review and provides consensus recommendations on the proper management and treatment of medication overuse headache. The treatment of medication overuse headache is often complex, and is based on 4 fundamental pillars: education and information about the condition, preventive treatment, discontinuation of the drug being overused, and treatment for withdrawal symptoms. Follow-up of patients at risk of recurrence is important. We hope that this document will be useful in daily clinical practice and that it will update and improve understanding of medication overuse headache management.


Cell kinetics as a prognostic indicator in node-negative breast cancer.
The consistency of the prognostic role of cell kinetics (evaluated as the [3H]thymidine labeling index, LI) over a period of years has been assessed in 354 patients with resectable node-negative breast cancer subjected only to Halsted or modified radical mastectomy. The risk of disease recurrence and death was proportional to LI values and the pattern was superimposable, regardless of menopausal status, in the two consecutive case series entered in this retrospective study. In particular, tumors with high LI (greater than 2.8%) had a higher 6-year probability (41% vs. 25%, P less than 0.0001) of manifesting local-regional and distant metastases and of dying (19% vs. 5%, P = 0.0005) as compared to tumors with low LI. In tumors with high LI the risk of relapse within the first 2 years from mastectomy was twofold compared to that of tumors with low LI. Multiple regression analysis showed that LI also retained its prognostic significance in both relapse-free and overall survival when tumor size and estrogen receptor status were considered. The present findings confirm that LI can substantially contribute to the selection of high risk node-negative patients who could be candidates for adjuvant chemotherapy.


Cricket Fast Bowling Technique and Lumbar Bone Stress Injury.
Lumbar bone stress injuries (LBSI) are the most prevalent injury in cricket. Although fast bowling technique has been implicated in the etiology of LBSI, no previous study has attempted to prospectively analyze fast bowling technique and its relationship to LBSI. The aim of this study was to explore technique differences between elite cricket fast bowlers with and without subsequent LBSI. Kinematic and kinetic technique parameters previously associated with LBSI were determined for 50 elite male fast bowlers. Group means were compared using independent-samples t-tests to identify differences between bowlers with and without a prospective LBSI. Significant parameters were advanced as candidate variables for a binary logistic regression analysis. Of the 50 bowlers, 39 sustained a prospective LBSI. Significant differences were found between injured and noninjured bowlers in rear knee angle, rear hip angle, thoracolumbar side flexion angle, and thoracolumbar rotation angle at back foot contact; the front hip angle, pelvic tilt orientation, and lumbopelvic angle at front foot contact; and the thoracolumbar side flexion angle at ball release and the maximal front hip angle and ipsilateral pelvic drop orientation. A binary logistic model, consisting of rear hip angle at back foot contact and lumbopelvic angle at front foot contact, correctly predicted 88% of fast bowlers according to injury history and significantly increased the odds of sustaining an LBSI (odds ratio, 0.88 and 1.25, respectively). Lumbopelvic motion is implicated in the etiology of LBSI in fast bowling, with inadequate lumbopelvifemoral complex control as a potential cause. This research will aid the identification of fast bowlers at risk of LBSI, as well as enhancing coaching and rehabilitation of fast bowlers from LBSI.


Survey of eye practitioners' attitudes towards diagnostic tests and therapies for dry eye disease.
There is a wide variation in the use of diagnostic tests for dry eye disease. The purpose of this study was to survey the attitudes of eye practitioners towards both tests and therapies available for dry eye disease. An anonymous, web-based questionnaire was used, containing both quantitative and qualitative sections. Thirty-eight respondents, evenly distributed in experience, confirmed the wide variation of diagnostic tests in use. History and staining techniques were significantly preferred to tests of tear flow (P < 0.05). 'Evidence' was the most valued test characteristic, and was regarded as significantly more important than 'comfort' or 'cost' (P < 0.003). However, 'evidence' was not valued significantly higher than 'ease of use' or 'time taken to perform'. Overall, there was poor satisfaction with diagnostic and therapeutic options in dry eye, for both quantitative and qualitative measures. This is the first qualitative study of attitudes towards dry eye disease. Attitudes towards the adequacy of diagnostic tests vary considerably. As evidence supporting a diagnostic test's validity is the most highly valued test characteristic, a systematic review of the topic is justified.


Characterization of basic p-coumaryl and coniferyl alcohol oxidizing peroxidases from a lignin-forming Picea abies suspension culture.
A Norway spruce (Picea abies) tissue culture line that produces extracellular lignin into the culture medium has been used as a model system to study the enzymes involved in lignin polymerization. We report here the purification of two highly basic culture medium peroxidases, PAPX4 and PAPX5, and isolation of the corresponding cDNAs. Both isoforms had high affinity to monolignols with apparent K(m) values in microM range. PAPX4 favoured coniferyl alcohol with a six-fold higher catalytic efficiency (V(max)/K(m)) and PAPX5 p-coumaryl alcohol with a two-fold higher catalytic efficiency as compared to the other monolignol. Thus coniferyl and p-coumaryl alcohol could be preferentially oxidized by different peroxidase isoforms in this suspension culture, which may reflect a control mechanism for the incorporation of different monolignols into the cell wall. Dehydrogenation polymers produced by the isoforms were structurally similar. All differed from the released suspension culture lignin and milled wood lignin, in accordance with previous observations on the major effects that e.g. cell wall context, rate of monolignol feeding and other proteins have on polymerisation. Amino acid residues shown to be involved in monolignol binding in the lignification-related Arabidopsis ATPA2 peroxidase were nearly identical in PAPX4 and PAPX5. This similarity extended to other peroxidases involved in lignification, suggesting that a preferential structural organization of the substrate access channel for monolignol oxidation might exist in both angiosperms and gymnosperms.


Neurasthenic symptoms in workers occupationally exposed to jet fuel.
Long-term exposure to petroleum distillation products (e.g. jet fuel) has been suggested to cause chronic mental and neurological symptoms. In the present "cross-sectional epidemiological study" the extent of neuropsychiatric ill-health in 30 workers exposed to jet fuel was compared with that in 60 non-exposed matched controls. Standardized medical interviews showed a higher occurrence of neurasthenic symptoms in exposed subjects (P less than 0.001). The result was confirmed by examination of the medical records kept by the factory physician (P less than 0.01). The prevalence of psychiatric symptoms was assessed with a rating scale of 37 items (a modified CPRS). Again, the exposed workers scored higher than the controls (P less than 0.001), particularly regarding the neurasthenic symptoms, i.e. fatigue, anxiety, mood changes, memory difficulties, and various psychosomatic symptoms (P less than 0.01). The results could neither be explained by observer's bias, nor by a greater susceptibility for mental disorders in the exposed subjects. We therefore conclude that occupational exposure to jet fuel vapours around the present threshold limit values may induce a neurasthenic syndrome.


The COVID-19 pandemic in Italy: Depressive symptoms immediately before and after the first lockdown.
Italy was one of the first countries to be heavily hit by the spread of the new Coronavirus. Longitudinal studies are needed to investigate the real effect of COVID-19 on adult mental health. The Italian Twin Registry carried out a study to investigate, over time, the course of depressive symptoms in the general population. The study relies on data collected just before the beginning (February 2020) and the end (June 2020) of the first lockdown. Symptoms of depression were assessed using the Patient Health Questionnaire, and total scores or categorized depression scores were considered in the analyzes. A total of 1690 adult twins were recruited. The study showed a mean depression score of 1.11 immediately before lockdown and 1.20 immediately after, with an overall prevalence of depressive symptoms increasing from 33.6 to 38.9%. Depressive symptoms immediately after the restriction period were associated with Covid-19 symptoms affecting households, financial problems due to the pandemic and poor social support. Independently of the baseline risk of depressive symptoms, we observed an increased risk among younger and less educated people. Compared to the pre-lockdown period, women and middle-aged people also were found to be at greater risk of developing depressive symptoms. Possible participation bias and residual selection bias. The study shows that the COVID-19 pandemic was associated with an increased depressive symptomatology and that, in such health emergency times, the most vulnerable persons are young adults, women, and those living in a socially, culturally, or economically disadvantaged environment.


Heat treatment reduced the expression of miR-7-5p to facilitate insulin-stimulated lactate secretion by targeting IRS2 in boar Sertoli cells.
Insulin dysfunction of diabetes mellitus (DM) disorders the glucose metabolism in Sertoli cells (SCs), resulting in the impairment of spermatogenesis.Insulin signaling system in Sertoli cells (SCs) plays an important role in regulating lactate secretion. Heat treatment could increase the lactate secretion of boar SCs, but whether heat treatment participates in lactate secretion by improving the sensitivity of insulin is unknown. In the current study, the primary SCs from 21-day-old boar were employed to treat with 100 nM insulin for 24 h or heat treatment (43 °C, 30 min). Heat treatment strengthened the effect of insulin on the effect of lactate secretion. In addition, heat treatment increased the expression of insulin-induced insulin receptor substrate 2 (IRS2), but reduced the expression of miR-7-5p. Using dual luciferase reporter assay and Western blot, the study found that IRS2 is a potential target gene of miR-7-5p. Heat treatment also enhanced the Phosphorylation of insulin-stimulated PI3K/Akt, and increased lactate secretion by promoting the expression of Glucose Transporter 3 (GLUT3), Lactate Dehydrogenase-A (LDHA) and monocarboxylate transporter 1 (MCT1). Furthermore, miR-7-5p inhibitor could partly mimic the effects of heat treatment on lactate production of SCs, indicating that heat treatment improves insulin sensitivity by regulating the expression of miR-7-5p/IRS2/PI3K/Akt. These results reveal a novel miRNA-mediated mechanism of heat treatment on the regulation of lactate metabolism production, and suggest that targeting miR-7-5p is a probably therapeutic method to insulin dysfunction-induced metabolic diseases.