[Relationship of TCM syndrome differentiation and manifestation of electrophysiology in patients with peripheral diabetic neuropathy].
To study the relationship between TCM syndrome type and electrophysiological changes of nerves in patients with peripheral diabetic neuropathy (PDN). TCM syndrome differentiation of 87 patients with PDN were performed, and the sensory nerve conduction velocity (SCV) of common peroneal nerve and the motor nerve conduction velocity (MCV) of sural nerve were measured as well using surface electrodes. Patients of yang-deficiency type showed the slowest MCV and SCV as well as the lowest compound muscular action potential (CMAP) and sensory nerve action potential (SNAP), with significant difference as compared with those in patients of qi-insufficiency type, heat type, and dampness type, respectively; also significant slower MCV and SCV and lower SNAP than those in patients with blood stasis type. Besides, the SCV and SNAP level in patients with yang-deficiency type were lower as compared with those in patients with yin-deficiency type (all P < 0.05). Obvious changes of MCV and SCV could be found in PDN patients of TCM yang-deficiency syndrome, so the abnormal velocity of nerve conduction could be taken as a referential index for diagnosis of patients belonging to that type.


Alternative criterion for two-dimensional wrapping percolation.
Based on the difference between a spanning cluster and a wrapping cluster, an alternative criterion for testing wrapping percolation is provided for two-dimensional lattices. By following the Newman-Ziff method, the finite size scalings of estimates for percolation thresholds are given. The results are consistent with those from Machta's method.


[Monoamine metabolism in children with hyperkinetic disorder].
In this review article, the authors consider a role of interaction between noradrenergic and dopaminergic systems in children with hyperkinetic disorder without impairment of the operational system of intelligence. The uneven development of higher mental functions observed in these cases is determined by the specificity of the formation of functional systems and the inclusion of compensatory mechanisms as well.


Treatment of AO/OTA Type C Pilon Fractures Through the Anterolateral Approach Combined With the Medial MIPO Technique.
The purpose of this study was to evaluate the clinical and radiographic results of the treatment of AO/OTA type C pilon fracture via the anterolateral approach using a low-profile plate combined with medial minimally invasive plate osteosynthesis (MIPO). We retrospectively reviewed 28 ankles with AO/OTA type C pilon fractures that were treated using the anterolateral approach combined with medial MIPO. Mean age was 46 years (range, 19 to 75), and the mean follow-up period was 25 months (range, 14 to 50). Clinical results were assessed using the visual analogue scale (VAS) and the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale. Range of motion (ROM) of the ankle joint was measured, and postoperative complications were investigated via chart review. The VAS and AOFAS Ankle-Hindfoot Scale were 2 and 89, respectively, at the last follow-up. Ankle ROM at the last follow-up was 13 degrees (range, 5 to 20) in dorsiflexion and 38 degrees (range, 35 to 40) in plantarflexion. All the fractures united without additional surgery. One patient (3.6%) had a deep infection at the fibular fracture site, and 1 patient (3.6%) had partial skin necrosis. This combined technique for AO/OTA type C pilon fracture resulted in good ROM of the ankle joint with reasonable function with a fairly low wound complication rate. However, further research on defined indications with a comparison group from multiple centers is necessary to determine if this technique is better than alternative surgical approaches. Level IV, case series.


Noise Exposure and Background Noise Tolerance in Listeners With Normal Audiograms.
Purpose Tolerance for background noise when listening to speech has been found to vary greatly between individuals, despite clinically similar audiograms. Recent work suggests that listeners at risk for noise-induced hearing loss (NIHL) self-report greater annoyance of background sounds compared with listeners at lower risk for NIHL. To date, the relationship between noise exposure levels and background noise tolerance has not been studied using objective noise exposure level measurements and quantitative (i.e., not questionnaire-based) background noise tolerance measures. Method Acceptable Noise Level (ANL; Nabelek, Tucker, & Letowski, 1991) scores and week-long noise dosimetry measurements were obtained for 56 normal-hearing college students, 22 of whom were routinely exposed to levels of noise that exceed recommended exposure limits (higher risk). The remaining 34 participants did not exceed recommended exposure limits (lower risk). Results The lower risk group's average daily noise dose was 26%, whereas the higher risk group accrued an average daily noise dose of 461%. The lower risk group was found to be more tolerant of background noise than the higher risk group, with mean ANL scores of 3.1 dB and 5.4 dB signal-to-noise ratio, respectively. A small but statistically significant relationship between ANL and noise dose was found, indicating that higher levels of noise exposure were associated with lower background noise tolerance. Conclusions Results suggest that young adults at higher risk for NIHL based on objective noise exposure data have a slightly lower tolerance for background noise when listening to speech. These findings open avenues for future work on background noise tolerance in more diverse noise-exposed populations.


Impact of safety valves on thermal runaway characteristics of 21 700-size lithium-ion cells.
To demonstrate the impact of safety valves on the thermal runaway characteristics of 21 700-size lithium-ion cells, this work carries out a series of abusive tests including over-heating tests, accelerating rate calorimetry (ARC) tests and overcharge tests; in the meantime, the impact of safety valves on cells with various states of charge (SOC) and states of health (SOH) is unveiled accordingly. Safety valves have a great impact on the thermal runaway behavior of 21 700-size cells, which effectively restrains the thermal runaway risks and hazards of cells under the over-heating conditions. The presence of a safety valve could even prevent a cell from the thermal runaway induced by overcharge. A cell with a larger SOC and/or a lower SOH is prone to the thermal runaway occurring, with an earlier thermal runaway, a lower temperature to thermal runaway and a lower mass loss demonstrated. Besides that, it is found that the advancement ratio of the time to thermal runaway between cells with and without a safety valve was maintained at around 15%; that is, the existence of a safety valve is helpful to delay the encounter of thermal runaway by ∼15%.


Medical ethics and torture.
There is growing evidence of widespread use of torture among political prisoners throughout the world. Medical personnel frequently become involved, sometimes directly, sometimes peripherally as in the examination or treatment of such prisoners. Physicians themselves may become victims of torture when the state attempts to subvert the doctor-patient relation for political purposes. Furthermore, recent studies demonstrate long lasting medical and psychologic effects of torture. For these reasons, physicians have a special opportunity and ethical obligation to resist and oppose torture as well as to support physicians whose lives or professional careers are jeopardized by their refusal to participate in torture. Codes of medical ethics need strengthening to provide clear guidance for the physician who becomes aware of or actively involved in these brutal practices.


HMG-CoA reductase promotes protein prenylation and therefore is indispensible for T-cell survival.
Statins are a well-established family of drugs that lower cholesterol levels via the competitive inhibition of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). In addition, the pleiotropic anti-inflammatory effects of statins on T cells make them attractive as therapeutic drugs in T-cell-driven autoimmune disorders. Since statins do not exclusively target HMGCR and thus might have varying effects on different cell types, we generated a new mouse strain allowing for the tissue-specific deletion of HMGCR. Deletion of HMGCR expression in T cells led to a severe decrease in their numbers with the remaining cells displaying an activated phenotype, with an increased proportion of regulatory T cells (Tregs) in particular. However, deletion of HMGCR specifically in Tregs resulted in severe autoimmunity, suggesting that this enzyme is also essential for the maintenance of Tregs. We were able to prevent the death of HMGCR-deficient lymphocytes by the addition of either the direct metabolite of HMGCR, namely mevalonate, or the downstream metabolite geranylgeranyl pyrophosphate, which is essential for protein prenylation. However, the addition of cholesterol, which is the final product of the mevalonate pathway, did not inhibit cell death, indicating that protein prenylation rather than the cholesterol biosynthesis pathway is indispensible for T-cell survival.


cis-Dichloro(dimethylaminomethylene)(triphenylphosphine)palladium(II) acetone solvate.
The synthesis and X-ray structural analysis of the title compound, [PdCl(2)(C(3)H(7)N)(C(18)H(15)P)].C(3)H(6)O, are described. The crystal structure contains discrete monomeric molecules of the carbene complex and solvent molecules separated by normal van der Waals distances. The Pd atom is four-coordinate in an essentially square-planar environment, with the chlorine ligands mutually cis; Pd-P = 2.2495 (7), Pd-Cl = 2.3508 (7) and 2.3600 (7), Pd-C 1.948 (2) and N-C(carbene) 1.274 (3) A.


Detection of Occult Arteriovenous Malformation With Annular Array Ultrasonography.
Retinal vascular tortuosity may occur in a wide range of ocular disorders. When retinal vascular tortuosity involves both arteries and veins, and presents unilaterally and without hemorrhage, a diagnosis of Wyburn Mason syndrome (WMS) should be considered due to the potential morbidity and mortality associated with cerebral involvement. Magnetic resonance imaging (MRI) and MRI angiography (MRA) are important tools for identifying cerebral arteriovenous malformations (AVMs), but these imaging modalities have limited spatial resolution to detect very small vascular lesions. Annular array contact ocular ultrasound is a new imaging modality capable of detecting small intraorbital AVMs. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:239-243.].


miR-142 regulates the tumorigenicity of human breast cancer stem cells through the canonical WNT signaling pathway.
MicroRNAs (miRNAs) are important regulators of stem and progenitor cell functions. We previously reported that miR-142 and miR-150 are upregulated in human breast cancer stem cells (BCSCs) as compared to the non-tumorigenic breast cancer cells. In this study, we report that miR-142 efficiently recruits the APC mRNA to an RNA-induced silencing complex, activates the canonical WNT signaling pathway in an APC-suppression dependent manner, and activates the expression of miR-150. Enforced expression of miR-142 or miR-150 in normal mouse mammary stem cells resulted in the regeneration of hyperproliferative mammary glands in vivo. Knockdown of endogenous miR-142 effectively suppressed organoid formation by BCSCs and slowed tumor growth initiated by human BCSCs in vivo. These results suggest that in some tumors, miR-142 regulates the properties of BCSCs at least in part by activating the WNT signaling pathway and miR-150 expression.


Comparison of gridded energy analyzer and laser induced fluorescence measurements of a two-component ion distribution.
We present ion velocity distribution function (IVDF) measurements obtained with a five grid retarding field energy analyzer (RFEA) and IVDF measurements obtained with laser induced fluorescence (LIF) for an expanding helicon plasma. The ion population consists of a background population and an energetic ion beam. When the RFEA measurements are corrected for acceleration due to the electric potential difference across the plasma sheath, we find that the RFEA measurements indicate a smaller background to beam density ratio and a much larger parallel ion temperature than the LIF. The energy of the ion beam is the same in both measurements. These results suggest that ion heating occurs during the transit of the background ions through the sheath and that LIF cannot detect the fraction of the ion beam whose metastable population has been eliminated by collisions.


Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in diabetic haemodialysis patients.
Patients with diabetic nephropathy are likely to have neurological complications including cardiovascular autonomic dysfunction, which is related to increased risk of mortality. We investigated whether cardiovascular autonomic neuropathy is associated with left ventricular hypertrophy (LVH) in diabetic haemodialysis patients. Holter electrocardiography was carried out for 24 h with time and frequency domain analyses of heart rate variability in 154 diabetic (age 62+/-11 years) and 63 non-diabetic haemodialysis patients (62+/-10 years). The left ventricular mass index (LVMI) was determined by echocardiography. We used the percentage of differences exceeding 50 ms between adjacent normal RR intervals (pNN50) in time domain analysis and the power in the high-frequency range (HF: 0.15-0.40 Hz) in frequency domain analysis as indicators of parasympathetic activity. The mean LVMI was greater in diabetic than in non-diabetic patients (168+/-63 vs 144+/-54 g/m(2), P<0.01). LVMI inversely correlated with pNN50 (r = -0.270, P = 0.0007, n = 154) and HF (r = -0.277, P = 0.0005, n = 154) in diabetic patients, but not in non-diabetic patients. By multiple logistic analysis, LVH was strongly associated with pNN50 (odds ratio 0.088; 0, <2%; 1, >/=2%) and HF (odds ratio 0.058; 0, <500 ms(2); 1, >/=500 ms(2)) in diabetic patients. Impaired parasympathetic activity, which indicates cardiovascular autonomic neuropathy, was associated with the presence of LVH in diabetic haemodialysis patients. The co-existence of cardiovascular autonomic neuropathy and LVH may be one of the key factors for the high incidence of cardiovascular events in diabetic haemodialysis patients.


The innate immune response in HIV/AIDS septic shock patients: a comparative study.
In recent years, the incidence of sepsis has increased in critically ill HIV/AIDS patients, and the presence of severe sepsis emerged as a major determinant of outcomes in this population. The inflammatory response and deregulated cytokine production play key roles in the pathophysiology of sepsis; however, these mechanisms have not been fully characterized in HIV/AIDS septic patients. We conducted a prospective cohort study that included HIV/AIDS and non-HIV patients with septic shock. We measured clinical parameters and biomarkers (C-reactive protein and cytokine levels) on the first day of septic shock and compared these parameters between HIV/AIDS and non-HIV patients. We included 30 HIV/AIDS septic shock patients and 30 non-HIV septic shock patients. The HIV/AIDS patients presented low CD4 cell counts (72 [7-268] cells/mm(3)), and 17 (57%) patients were on HAART before hospital admission. Both groups were similar according to the acute severity scores and hospital mortality. The IL-6, IL-10 and G-CSF levels were associated with hospital mortality in the HIV/AIDS septic group; however, the CRP levels and the surrogates of innate immune activation (cytokines) were similar among HIV/AIDS and non-HIV septic patients. Age (odds ratio 1.05, CI 95% 1.02-1.09, p=0.002) and the IL-6 levels (odds ratio 1.00, CI 95% 1.00-1.01, p=0.05) were independent risk factors for hospital mortality. IL-6, IL-10 and G-CSF are biomarkers that can be used to predict prognosis and outcomes in HIV/AIDS septic patients. Although HIV/AIDS patients are immunocompromised, an innate immune response can be activated in these patients, which is similar to that in the non-HIV septic population. In addition, age and the IL-6 levels are independent risk factors for hospital mortality irrespective of HIV/AIDS disease.


Concurrent chemoradiotherapy with S-1 in patients with stage III-IV oral squamous cell carcinoma: A retrospective analysis of nodal classification based on the neck node level.
The aim of the present study was to retrospectively evaluate the treatment outcomes of concurrent chemoradiotherapy (CCRT) with S-1, an oral fluoropyrimidine anticancer agent, for advanced oral squamous cell carcinoma (SCC). The study population consisted of 47 patients with clinical stage III or IV oral SCC, who underwent CCRT with S-1. Pretreatment variables, including patient age, clinical stage, T classification, midline involvement of the primary tumor and nodal status, were analyzed as predictors of survival. In addition to the N classification (node-positive, multiple and contralateral), the prognostic impact of the level of nodal involvement was assessed. Nodal involvement was mainly observed at levels Ib and II; involvement at levels Ia and III-V was considered to be anterior and inferior extension, respectively, and was recorded as extensive nodal involvement (ENI). The 3-year overall survival (OS) and progression-free survival (PFS) rates were 37 and 27%, respectively. A finding of ENI was a significant factor for OS [hazard ratio (HR)=2.16; 95% confidence interval (CI): 1.03-4.55; P=0.038] and PFS (HR=2.65; 95% CI: 1.32-5.33; P=0.005); the 3-year OS and PFS rates in patients with vs. those without ENI were 23 vs. 50% and 9 vs. 43%, respectively. The other variables were not significant. Therefore, CCRT with S-1 may be an alternative treatment for advanced oral SCC; favorable outcomes are expected in patients without ENI.


Effect of fluid load on the prognosis of children with sepsis-associated acute kidney injury undergoing continuous renal replacement therapy.
To evaluate the effect of fluid load on the prognosis of children with sepsis-associated acute kidney injury (AKI) undergoing continuous renal replacement therapy (CRRT). A total of 121 children who underwent CRRT for sepsis-associated AKI from August 2018 to March 2021 were enrolled in the retrospective study. According to the fluid load from admission or disease progression to CRRT, they were divided into three groups: low fluid load (fluid load: <5%; n=35), high fluid load (fluid load: 5% - <10%; n=35), and fluid overload (fluid load: ≥10%; n=51). Baseline data and clinical biochemical data before CRRT were collected for comparison and analysis. The Kaplan-Meier survival curve analysis was used for comparison of 28-day survival between groups. The multivariate logistic regression model was used to identify the influencing factors for the prognosis of the children. The survival analysis showed that the fluid overload group had a significantly higher 28-day mortality rate than the low fluid load and high fluid load groups (P<0.05). The multivariate logistic regression analysis showed that an increase in fluid overload volume was a risk factor for increased 28-day mortality in the fluid overload group, while earlier initiation of CRRT was a protective factor (P<0.05). Fluid overload before CRRT may increase the mortality in children with sepsis-associated AKI, and CRRT should be performed for these children as early as possible.


Intracranial metastases from malignant spinal-cord astrocytoma. Case report.
A patient with postoperative intracranial seeding from a malignant spinal-cord astrocytoma is presented. This case is compared with 17 previously cited cases of intracranial dissemination from spinal-cord astrocytoma. Factors associated with tumor dissemination include histological malignancy, proximity of the tumor to cerebrospinal fluid (CSF) pathways, and surgical manipulation. Hydrocephalus with infiltration of the basal cisterns also appears to be a consistent feature in these patients. Cytological studies of the CSF in this and previous cases were noted to be misleading, whereas intravenous contrast-enhanced cranial computerized tomography was invaluable for diagnosis of tumor dissemination in each case. Prophylactic irradiation of the entire neuraxis may limit intracranial metastases from malignant astrocytomas of the spinal cord.


Biodistribution and Dosimetry of 18F-Meta-Fluorobenzylguanidine: A First-in-Human PET/CT Imaging Study of Patients with Neuroendocrine Malignancies.
123I-meta-iodobenzylguanidine (123I-MIBG) imaging is currently a mainstay in the evaluation of many neuroendocrine tumors, especially neuroblastoma. 123I-MIBG imaging has several limitations that can be overcome by the use of a PET agent. 18F-meta-fluorobenzylguanidine (18F-MFBG) is a PET analog of MIBG that may allow for single-day, high-resolution quantitative imaging. We conducted a first-in-human study of 18F-MFBG PET imaging to evaluate the safety, feasibility, pharmacokinetics, and dosimetry of 18F-MFBG in neuroendocrine tumors (NETs). Methods: Ten patients (5 with neuroblastoma and 5 with paraganglioma/pheochromocytoma) received 148-444 MBq (4-12mCi) of 18F-MFBG intravenously followed by serial whole-body imaging at 0.5-1, 1-2, and 3-4 after injection. Serial blood samples (a total of 6) were also obtained starting at 5 min after injection to as late as 4 h after injection; whole-body distribution and blood clearance data, lesion uptake, and normal-tissue uptake were determined, and radiation-absorbed doses to normal organs were calculated using OLINDA. Results: No side effects were seen in any patient after 18F-MFBG injection. Tracer distribution showed prominent activity in the blood pool, liver, and salivary glands that decreased with time. Mild uptake was seen in the kidneys and spleen, which also decreased with time. Urinary excretion was prominent, with an average of 45% of the administered activity in the bladder by 1 h after injection; whole-body clearance was monoexponential, with a mean biologic half-life of 1.95 h, whereas blood clearance was biexponential, with a mean biologic half-life of 0.3 h (58%) for the rapid α phase and 6.1 h (42%) for the slower β phase. The urinary bladder received the highest radiation dose with a mean absorbed dose of 0.186 ± 0.195 mGy/MBq. The mean total-body dose was 0.011 ± 0.011 mGy/MBq, and the effective dose was 0.023 ± 0.012 mSv/MBq. Both skeletal and soft-tissue lesions were visualized with high contrast. The SUVmax (mean ± SD ) of lesions at 1-2 h after injection was 8.6 ± 9.6. Conclusion: Preliminary data show that 18F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. PET imaging with 18F-MFBG allows for same-day imaging of NETs. 18F-MFBG appears highly promising for imaging of patients with NETs, especially children with neuroblastoma.


Psychopharmacological treatment among adolescents with disabilities: Prevalence and predictors in a nationally representative sample.
Little is known about psychopharmacological treatment among adolescents with educational disabilities. This study (a) describes pharmacotherapy among adolescents who received special education, and (b) examines the relations to adolescents' disability type and sociodemographic characteristics. The sample was 9,230 adolescents who participated in the National Longitudinal Transition Study 2, a nationally representative study of students with disabilities. Descriptive statistics and logistic regression were used to estimate prevalence and predictors of pharmacotherapy. During the study period, 18.14% of adolescents received pharmacotherapy with 11.75% receiving monopharmacy, 6.39% receiving polypharmacy, and 5.86% simultaneously receiving multiple classes of medications. Stimulants and antidepressants were the most commonly used classes of psychotropic medication. After adjusting for sociodemographics, pharmacotherapy was highest among adolescents with other health impairments, emotional disturbance, and autism. Disability type, race/ethnicity, marital status, head of household education, urbanicity, and private insurance type were significant predictors of polypharmacy. Overall, these results indicated rates of psychopharmacological treatment exceeded those in the general population and disparities across sociodemographic groups existed. Implications for research and practice are discussed.


Beyond Head and Neck Cancer: The Relationship Between Oral Microbiota and Tumour Development in Distant Organs.
An altered oral microbiota has been linked with the development of several oral diseases, such as dental caries, periodontal disease, and oral stomatitis. Moreover, poor oral health has been linked to head and neck cancer, particularly oral cancer. In recent years a growing number of studies indicate that oral microbiota could be involved in the development of primary tumours outside of head and neck region. The aim of this article is to review the recent studies based on high-throughput technology to present evidences of a relationship between oral microbiota and "non-head and neck tumours." Oral dysbiosis seem to be more pronounced in patients with tumours of gastrointestinal tract, in particular oesophageal, gastric, pancreatic, and colorectal cancers, paving the way for developing specific oral microbiota test to allow early cancer detection. Regarding other tumour types, the results are promising but highly preliminary and still debated. Currently, there are several factors that limit the generalization of the results, such as the small sample size, the lack of adequate clinical information about patients, the different sequencing techniques used, and biological sample heterogeneity. Although only at the beginning, the analysis of oral microbiota could be the next step in the evolution of cancer therapy and will help clinicians to develop individualised approaches to cancer prevention and treatment.


[Selective denervation of the wrist joint].
The long-lasting pains of the wrist cause many times problems in the everyday trauma treatment. They are also frequently encountered by orthopedists, internists and rheumatologists. The pain is most frequently the characteristic symptom of osteoarthritis of the wrist, however it may appear without an accident (as a part of destructive and systemic disease, damaging the joints) too. Based on the paper published by WILHELM in 1966 we have performed in this Institute selective denervation of the wrist in 77 cases, with good results in 45 per cent. Our material is analysed in etiologic groups, giving light to the field of indication of this operation, that can be considered most generally as an alternative solution versus radiocarpal and intercarpal arthrodesis. This paper reports beside the description of the method on our favourable experiences, that are published in hope of a more wide spreading of the method.


A fast and simple approach to optimize the unit operation high pressure homogenization - a case study for a soluble therapeutic protein in E. coli.
Escherichia coli is one of the most commonly used host organisms for the production of recombinant biopharmaceuticals. E. coli is usually characterized by fast growth on cheap media and high productivity, but one drawback is its intracellular product formation. Product recovery from E. coli bioprocesses requires tedious downstream processing (DSP). A typical E. coli DSP for an intracellular product starts with a cell disruption step to access the product. Different methods exist, but a scalable process is usually achieved by high pressure homogenization (HPH). The protocols for HPH are often applied universally without adapting them to the recombinant product, even though HPH can affect product quantity and quality. Based on our previous study on cell disruption efficiency, we aimed at screening operational conditions to maximize not only product quantity, but also product quality of a soluble therapeutic protein expressed in E. coli. We screened for critical process parameters (CPPs) using a multivariate approach (design of experiments; DoE) during HPH to maximize product titer and achieve sufficient product quality, based on predefined critical quality attributes (CQAs). In this case study, we were able to gain valuable knowledge on the efficiency of HPH on E. coli cell disruption, product release and its impact on CQAs. Our results show that HPH is a key unit operation that has to be optimized for each product.


[Human Single Drug Exposures to Non-opioid Analgesics Reported to the Poisons Information Centre Erfurt from 2003 to 2012].
Because of their frequency, non-opioid analgesics (NOA) single drug exposures registered by Poisons Information Centre (PIC) Erfurt have been studied over a decade. A retrospective analysis of frequencies, circumstances of exposure, symptom severity, and age groups in NOA single drug exposures received by the PIC Erfurt from the beginning of 2003 to the end of 2012 was undertaken. Of all 4749 NOA single drug exposures, the 10 most frequent were caused by paracetamol (n=1 686), ibuprofen (n=1 439), acetylsalicylic acid (n=456), dipyrone (n=274), diclofenac (n=267), flupirtine (n=138), naproxen (n=41), etoricoxib (n=36), indomethacin (n=24), and dexketoprofen (n=19). Paracetamol single drug exposures increased from 158 in 2003 to 216 in 2007 and fell afterwards to 133 in 2012. Ibuprofen single drug exposures continously rose from 57 in 2003 to 258 in 2012. Adults were more often involved in NOA (53.8%) and all single drug exposures (54.1%) than children (45.9% and 45.6%, respectively). Suicidal attempts were more frequent in NOA (43.1%) than in all single drug exposures (34.2%), whereas accidental exposures or exposures in abuse were less often (33.4 and 0.2%, 46.0 and 0.9% respectively). NOA single drug exposures resulted mostly in none to minor symptoms (77.0%) and rarely in moderate (2.1%) or severe symptoms (1.0%). One adult was found dead after probable ingestion of 32 g of acetylsalicylic acid in suicidal intention. Because many NOA are over-the-counter drugs, it is difficult to obtain data on their use. PIC data could provide information on the NOA use in the population.


Hormonal regulation of ethylene response factors in tomato during storage and distribution.
Ethylene response factors (ERFs) play a critical role in regulating hormone interactions that affect the shelf life of tomatoes. Understanding their regulation during storage and distribution can be highly beneficial. This study examined the effects of treatment with ethylene (ET), brassinosteroid (BR), auxin (AUX), and gibberellin (GA) on fruit ripening and the expression of 18 ripening-associated ERFs in tomato stored at 20°C (room temperature) for 10 d or 4°C (cold storage) for 14 d followed by 2 d at 20°C (retailer conditions). The results showed that ripening was accelerated by ET and BR but was delayed by AUX and GA at room temperature. Cold storage delayed ripening in all groups, with ET and GA treatments showing the highest and lowest a* values, respectively. The effects of hormone treatment were consistent with room temperature when the fruits were transferred from cold storage to retail conditions. At room temperature, ERFs responsive to ET (ERF.B1, B2, B6, E2, and F1) and BR (ERF.E5, F2, and F3) were inhibited by AUX. ET-induced genes (ERF.C1, E1, F4, and H7) could be co-regulated by other hormones at cold storage. When the fruits were transferred from cold storage to retailer conditions, ERFs responsive to ET and BR were inhibited by GA. Additionally, ET-responsive ERFs could be inhibited by BR at room temperature, whereas ET could inhibit BR-responsive ERFs at retailer conditions. The same ERFs that were regulated by ET at room temperature were instead regulated by BR under retailer conditions, and vice versa. These findings can help provide a better understanding of the complex hormone interactions regulating the postharvest physiology of tomato and in maintaining its quality and shelf life during storage and distribution.


Native language shapes automatic neural processing of speech.
The development of the phoneme inventory is driven by the acoustic-phonetic properties of one's native language. Neural representation of speech is known to be shaped by language experience, as indexed by cortical responses, and recent studies suggest that subcortical processing also exhibits this attunement to native language. However, most work to date has focused on the differences between tonal and non-tonal languages that use pitch variations to convey phonemic categories. The aim of this cross-language study is to determine whether subcortical encoding of speech sounds is sensitive to language experience by comparing native speakers of two non-tonal languages (French and English). We hypothesized that neural representations would be more robust and fine-grained for speech sounds that belong to the native phonemic inventory of the listener, and especially for the dimensions that are phonetically relevant to the listener such as high frequency components. We recorded neural responses of American English and French native speakers, listening to natural syllables of both languages. Results showed that, independently of the stimulus, American participants exhibited greater neural representation of the fundamental frequency compared to French participants, consistent with the importance of the fundamental frequency to convey stress patterns in English. Furthermore, participants showed more robust encoding and more precise spectral representations of the first formant when listening to the syllable of their native language as compared to non-native language. These results align with the hypothesis that language experience shapes sensory processing of speech and that this plasticity occurs as a function of what is meaningful to a listener.


The prevention of neural tube defects.
The prevention of neural tube defects is a complex problem. The genetic associations may ultimately allow the prepregnancy identification of women at high risk of a neural tube defect. Education of both the public and healthcare providers has been shown to increase awareness, but the majority of women do not take folic acid before and in the early part of pregnancy. Food fortification will be effective in increasing the folate levels of the population and will have a benefit even at low doses of fortification.


Myoelectrical activity of muscles stabilizing the sacroiliac joints before and after the use of elastic tapes in women suffering from Pregnancy-related Pelvic Girdle Pain.
The aim of this study was the analysis of activity of selected muscles stabilizing the sacroiliac joints in pregnant women suffering from pelvic pain and changes in the pattern in response to the implementation of Kinesio Taping (elastic tape). Seventeen women with Pregnancy-related Pelvic Girdle Pain and 20 pregnant women without pain in the lumbar-pelvic complex were enrolled into the study. In patients with pelvic pain, the parameters describing the action of the muscles were assessed: before the tape was applied, immediately after application, 3 days into application and 5 days after the cessation of taping. In the control group, the test was carried out one time. The activity of the muscles was measured during extension of the hip from a four-point kneeling position. The gluteus maximus muscle shows higher resting activity values than in the control group, before and after application of the tape as well as five days after the removal of the tape. Before application, the gluteus maximus activates quicker than in the control group while the ipsilateral extensor spinae had a delayed activation when compared to the control group. The patterns of activation of tested muscles and their action potential values are different in the group of women with pelvic pain compared to the group without pelvic pain. The application of KT in the lumbar region appears to alter the activation of the GM muscle as well as improve activation of IES muscle during hip extension from the four-point-kneeling position.


Reduced baroreceptor sensitivity and elasticity of the carotid artery in a preeclamptic patient.
Baroreflex sensitivity, distensibility coefficient, and intima-media thickness (IMT) of the common carotid artery were determined in a preeclamptic patient during 1st and 3rd trimesters as well as after childbirth. From the beginning of her pregnancy, baroreflex sensitivity and distensibility coefficient of the carotid artery exhibited a parallel decline, whereas the IMT increased as compared with normotensive pregnancies. The values of all parameters examined returned to their initial levels after 14 weeks of delivery. These results suggest that augmented IMT and carotid stiffness coupled to baroreceptor dysfunction may have contributed to the perturbation of blood pressure control in our preeclamptic patient.


3-Acetyl-Chlorophyll Formation in Light-Harvesting Complexes of Purple Bacteria by Chemical Oxidation.
Dedicated to the memory of Yuriy Nikolayevich Kozlov Oxidation of bacteriochlorophyll (BChl) with potassium ferricyanide in membranes and LH2 complexes (carotenoid-less and control samples) from the purple bacteria Allochromatium minutissimum and Rhodobacter sphaeroides as well as BChl photobleaching in a model system have been studied. The oxidation of BChl depended on the type of bacteria. BChl850 was rapidly oxidized in samples from Alc. minutissimum, and BChl800 and BChl850 were slowly oxidized in samples from Rb. sphaeroides. The carotenoids were not involved in protecting BChl from chemical oxidation in the light-harvesting complexes. The appearance of BChl oxidation product was registered in the absorption spectra (absorption maximum about 700 nm) and by HPLC analysis. The oxidized BChl was identified as 3-acetyl-chlorophyll. It differed from BChl by the presence of a double bond in pyrrole ring II at the 7-8 position. The extinction coefficient of 3-acetyl-chlorophyll was about 10 times less than that of BChl850 in the LH2 complex from Alc. minutissimum. In the BChl → 3-acetyl-chlorophyll transition, the binding constant of the latter with LH2 complex as compared with that of BChl did not change dramatically, as indicated by: (i) preserved electrophoretic mobility of the complex; (ii) the presence of 3-acetyl-chlorophyll in the complex after separation; (iii) the presence of a 3-acetyl-chlorophyll CD signal that was proportional to its absorption spectrum.


Porous Molybdenum-Based Hybrid Catalysts for Highly Efficient Hydrogen Evolution.
We have synthesized a porous Mo-based composite obtained from a polyoxometalate-based metal-organic framework and graphene oxide (POMOFs/GO) using a simple one-pot method. The MoO2 @PC-RGO hybrid material derived from the POMOFs/GO composite is prepared at a relatively low carbonization temperature, which presents a superior activity for the hydrogen-evolution reaction (HER) in acidic media owing to the synergistic effects among highly dispersive MoO2 particles, phosphorus-doped porous carbon, and RGO substrates. MoO2 @PC-RGO exhibits a very positive onset potential close to that of 20 % Pt/C, low Tafel slope of 41 mV dec(-1) , high exchange current density of 4.8×10(-4) A cm(-2) , and remarkable long-term cycle stability. It is one of the best high-performance catalysts among the reported nonprecious metal catalysts for HER to date.


Adventures in multivalency, the Harry S. Fischer memorial lecture CMR 2005; Evian, France.
This review discusses multivalency in the context of drug discovery, specifically the discovery of new diagnostic imaging and related agents. The aim is to draw attention to the powerful role that multivalency plays throughout research involving molecular biology, in general, and much of biochemically targeted contrast agent research, in particular. Two examples from the author's laboratory are described. We created small (approximately 5 kDa) peptide 'dimers' composed of two different, chemically linked peptides. The monomer peptides both bound to the same target protein with K(d) approximately 100 s nM, while the heterodimers had sub-nM K(d) values. Biological activity was evident in the heterodimers where none or very little existed in homodimers, monomers or monomer mixtures. Two different tyrosine kinases (KDR and C-Met) and four peptide families produced consistent results: multivalent heterodimers were uniquely different. The second example begins with making two micron ultrasound bubbles coated with the peptide, TKPPR (a Tuftsin antagonist) as a negative control for bubbles targeted with angiogenesis target-binding peptides. Unexpected binding of a 'negative' control, (TKPPR)-targeted bubble to endothelial cells expressing angiogenesis targets, led to the surprising result that TKPPR, only when multimerized, binds avidly, specifically and actively to neuropilin-1, a VEGF co-receptor. VEGF is the primary stimulator of angiogenesis. Tuftsin is a small peptide (TKPR) derived from IgG that binds to macrophages during inflammation, and has been studied for over 30 years. The receptor has never been cloned. The results led to new conclusions about Tuftsin, neuropilin-1 and the purpose, up to now unknown, of exon 8 in VEGF. Multivalency can be used rationally to solve practical problems in drug discovery. When targeting larger structures, multivalency is frequently unavoidable, and can lead to unpredictable and useful biochemical information, as well as to new drug candidates.


Comparison of some blood parameters of captured and farmed red deer (Cervus elaphus) hinds.
In studies on the adaptation of red deer (Cervus elaphus) to farm conditions, some blood parameters of 3- to 9-year-old captured and farmed hinds were compared. The test variable included blood plasma creatine kinase (CK), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) activities, the concentrations of glucose, urea, total protein (TP), serum cortisol, haemoglobin (Hb), and the blastogenic transformation of lymphocytes upon stimulation by the nonspecific mitogens Phaseolus vulgaris (PHA) and Concanavalin A (ConA) in the lymphocyte stimulation test (LST). The effects exerted by probiotic preparation (Ascogen) on the same parameters were studied in farmed deer. In hinds that had been kept under farm conditions for 10 months, CK activity was lower (P < 0.05) and blood urea concentration higher (P < 0.001) than at the time of capture, while their blood glucose concentration exceeded (P < 0.01) that of farmed hinds. Hinds treated with Ascogen had lower ALT activity (P < 0.001) and showed a higher increase in PHA-induced blastogenic transformation of lymphocytes than the control hinds.


Assessment of dog owner adherence to veterinarians' flea and tick prevention recommendations in the United States using a cross-sectional survey.
Adherence to a prescribed therapeutic regimen is a critical factor for achieving medication effectiveness and therefore treatment success. In the case of companion animal ectoparasite control, suboptimal owner adherence to medication recommendations is thought to be a common cause of treatment failure, and previous reports have found pet owners applying an average of 4.0-4.6 monthly flea and tick treatments per year to their dogs. This study investigated: US veterinary hospital self-reported flea and tick prevention recommendations; dog owner recollection of these recommendations; dog owner opinion on flea/tick recommendations and estimated owner flea and tick medication adherence based on veterinary hospital purchase records. Veterinarians at 24 veterinary hospitals in 4 United States regions provided their flea and tick prevention recommendations. Five hundred fifty-nine dog owners, clients of the 24 hospitals, completed a survey evaluating their recollection of the hospitals' recommendations and their opinions regarding required treatment frequency. Almost all veterinary hospitals in this study recommended 12 months of flea and tick prevention but only 62% of participating dog owners recalled this recommendation. The average owner response was that their dogs require 10.5 months of flea and tick prevention annually. Owner opinions were significantly different among U.S. regions with pet owners in the northeast U.S. believing that they needed significantly less canine flea and tick protection than pet owners in other parts of the United States. The estimated actual flea and tick prevention coverage was 6.1 months based on owner medication purchases over a 12-month period. In the United States, dog owner opinions and actions show that their flea and tick treatment adherence falls short of veterinarians' recommendations.


Guideline adherence for diagnostic faeces testing in primary care patients with gastroenteritis.
Gastroenteritis (GE) is a common reason for primary care consultation. Dutch clinical practice guidelines (CPG) recommend diagnostic faeces testing (DFT) only in primary care patients with severe illness, comprised immunity or increased transmission risk. For its superior accuracy, shorter turnaround time and ease of use, polymerase chain reaction (PCR)-based DFT has largely replaced conventional techniques. It is unknown whether this changed CPG adherence. To quantify the effect of PCR introduction on adherence to CPG indications for DFT in primary care patients with GE. We performed a cohort study using routine care data of 225 GPs. Episodes of GE where DFT was performed were extracted from electronic patient records. Presenting symptoms were identified and adherence to CPG indications for DFT assessed in two randomly drawn samples of each 500 patients, one from the period before PCR introduction (2010-11) and one after (2013). The association between PCR introduction and adherence was estimated using multivariable regression analysis. In 88% of all episodes relevant presenting symptoms were reported, most often 'frequent watery stool' (58%) and 'illness duration >10 days' (40%). DFT was performed in 15% of episodes before PCR introduction and in 18% after. Overall, in 17% the DFT request was considered adherent to the CPG, 16% before PCR introduction and 18% after (adjusted OR 1.2, 95% CI 0.9-1.7). Overall adherence to CPG indications when requesting DFT in primary care patient with GE was 17%. Implementation of PCR-based DFT was not associated with a change in CPG adherence.


Progression of aortic valve stenosis is associated with bone remodelling and secondary hyperparathyroidism in elderly patients--the COFRASA study.
There is currently no medical therapy that can prevent the progression of aortic valve stenosis (AS). Recent data highlight a possible relationship between bone metabolism and AS progression but prospective data are lacking. Serum levels of calcium, phosphorus, creatinine, 25-OH vitamin D, intact parathyroid hormon (iPTH), C-terminal-telopeptide of type-1-collagen (CTX) and osteocalcin were assessed at baseline in 110 elderly patients (age ≥70 years) with at least mild AS. CTX/osteocalcin ratio was calculated as a marker of bone remodelling balance. AS severity was assessed at baseline and 1-year based on the mean gradient. Two-thirds of patients had low 25-OH vitamin D and 20% had secondary hyperparathyroidism. AS progression was not associated with age, glomerular filtration rate (GFR), calcium and phosphorus levels, calcium-phosphorus product, but significantly with iPTH, CTX/osteocalcin and vitamin D status (all P < 0.01). There was no correlation between iPTH and CTX/osteocalcin (R = 0.04, P = 0.70) and AS progression was associated with CTX/osteocalcin (R = 0.42, P = 0.009), but not with iPTH (R = 0.10, P = 0.55) in patients with normal vitamin D levels, whereas it was associated with iPTH (R = 0.47, P < 0.001) and not with CTX/osteocalcin (R = 0.04, P = 0.73) in those with low vitamin D levels, especially if mild renal insufficiency was present (R = 0.61, P < 0.001). In elderly patients with AS, we observed an association between AS progression and vitamin D, iPTH and CTX/osteocalcin ratio and their respective influence varied according to the vitamin D status. In patients with normal vitamin D levels, AS progression was associated with a bone resorptive balance, whereas in patients with low vitamin D levels, AS progression was associated with iPTH and secondary hyperparathyroidism, especially if mild renal insufficiency was present. These findings may have important prognostic and therapeutic implications. Trial registration information: Clinicaltrials.gov identifier number: NCT00338676, funded by AP-HP, the COFRASA study.


Nitrification in the intertidal zone: influence of effluent type and effect of tannin on nitrifiers.
Nitrification by intertidal sediments was measured by using a tide simulator that approximated the cycle of seawater on tidal flats. Sediments were chosen from sites affected by industrial and municipal effluents and pastoral seepage and runoff. The ability of sediments from different sites to nitrify endogenous nitrogen varied markedly. All sites exhibited an initial lag before activity commenced. The duration of this lag and the rate of nitrate production were different at each site. The sediments were also capable of oxidizing NH3-N supplied to them in seawater. This "nitrification potential" was highest at sites receiving nitrogenous effluents (slaughterhouse and sewage), but was also substantial in sediments affected by bark extract effluent and pasture runoff. The lowest potential and the longest lag were exhibited by sediments in an apple cannery effluent area. Enrichment cultures of nitrifying microorganisms were obtained from all sites using NH4+ as a source of energy, but enrichments for nitrite oxidizers were unsuccessful. Concentrated pine bark tannins, similar in origin to those in effluents at the well-nitrifying chipmill site, were tested for toxicity to pure cultures of nitrifying bacteria. Two Nitrobacter strains and one Nitrosomonas strain were unaffected by tannins even at 5 mg/ml. A Nitrosolobus and a Nitrosospira strain were inhibited partially at 5 mg/ml and only slightly or not at all at 1 mg/ml.


Platelet-targeted pharmacologic treatments as anti-cancer therapy.
Platelets act as multifunctional cells participating in immune response, inflammation, allergy, tissue regeneration, and lymphoangiogenesis. Among the best-established aspects of a role of platelets in non-hemostatic or thrombotic disorders, there is their participation in cancer invasion and metastasis. The interaction of many different cancer cells with platelets leads to platelet activation, and on the other hand platelet activation is strongly instrumental to the pro-carcinogenic and pro-metastatic activities of platelets. It is thus obvious that over the last years a lot of interest has focused on the possible chemopreventive effect of platelet-targeted pharmacologic treatments. This article gives an overview of the platelet-targeted pharmacologic approaches that have been attempted in the prevention of cancer development, progression, and metastasis, including the application of anti-platelet drugs currently used for cardiovascular disease and of new and novel pharmacologic strategies. Despite the fact that very promising results have been obtained with some of these approaches in pre-clinical models, with the exclusion of aspirin, clinical evidence of a beneficial effect of anti-platelet agents in cancer is however still largely missing. Future studies with platelet-targeted drugs in cancer must carefully deal with design issues, and in particular with the careful selection of patients, and/or explore novel platelet targets in order to provide a solution to the critical issue of the risk/benefit profile of long-term anti-platelet therapy in the prevention of cancer progression and dissemination.


Intervertebral disc cell-mediated mesenchymal stem cell differentiation.
Low back pain is one of the largest health problems in the Western world today, and intervertebral disc degeneration has been identified as a main cause. Currently, treatments are symptomatic, but cell-based tissue engineering methods are realistic alternatives for tissue regeneration. However, the major problem for these strategies is the generation of a suitable population of cells. Adult bone marrow-derived mesenchymal stem cells (MSCs) are undifferentiated, multipotent cells that have the ability to differentiate into a number of cell types, including the chondrocyte-like cells found within the nucleus pulposus (NP) of the intervertebral disc; however, no method exists to differentiate these cells in an accessible monolayer environment. We have conducted coculture experiments to determine whether cells from the human NP can initiate the differentiation of human MSCs with or without cell-cell contact. Fluorescent labeling of the stem cell population and high-speed cell sorting after coculture with cell-cell contact allowed examination of individual cell populations. Real-time quantitative polymerase chain reaction showed significant increases in NP marker genes in stem cells when cells were cocultured with contact for 7 days, and this change was regulated by cell ratio. No significant change in NP marker gene expression in either NP cells or stem cells was observed when cells were cultured without contact, regardless of cell ratio. Thus, we have shown that human NP and MSC coculture with contact is a viable method for generating a large population of differentiated cells that could be used in cell-based tissue engineering therapies for regeneration of the degenerate intervertebral disc.


Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia-associated autoimmune hemolytic anemia: a multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS).
We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response.


Cardiac autonomic recovery after strength exercise in lower and upper limbs.
Introduction Strength exercises influence the cardiovascular system by promoting autonomic adjustments induced by the increased metabolic demand and consequent increase in local blood flow. However, it is unclear whether there are differences between upper and lower limbs. We aimedto evaluate recovery of cardiac autonomic modulation afterstrengthexercise in upper and lower limbs. Methods We analysed 29 healthy male subjects physically active but not professional athletes aged between 20 and 35 years old. We analysed heart rate variability (HRV) in the time and frequency domain 0-10 minutes before exercise (T1), 0-10 minutes after exercise (T2), 10-20 minutes after exercise (T3) and 20-30 minutes after exercise (T4). Results Regarding the time domain we observed that the SDNN, pNN50 and RMSSD were reduced (P < 0.0001) in T2, T3, T4 in relation to T1 with no difference between upper and lower limbs. In the frequency domain analysis, we observed stronger significancefor the increased values of LF (nu) (P = 0.0008) and LF/HF ratio (P = 0.0008) and for reduction in HF (nu) (P = 0.0008) in the lower limbs compared to upper limbs (LF (nu) - P = 0.0015, LF/HF ratio - P = 0.0028 and HF (nu) - P = 0.0028). Conclusion Strength exercise acutely induced more pronounced cardiac autonomic responses in lower limbs compared to upper limbs.


Tracheal stenosis or agenesis in association with tracheo-oesophageal fistula and oesophageal atresia.
Two babies are described with oesophageal atresia, a tracheo-oesophageal fistula and severe subglottic tracheal stenosis. A third baby, who did not survive, had a tracheal agenesis associated with bronchi arising from the oesophagus. A review of the types of tracheal stenosis and agenesis associated with various forms of tracheo-oesophageal fistula is included.


High-throughput ultraviolet photoacoustic microscopy with multifocal excitation.
Ultraviolet photoacoustic microscopy (UV-PAM) is a promising intraoperative tool for surgical margin assessment (SMA), one that can provide label-free histology-like images with high resolution. In this study, using a microlens array and a one-dimensional (1-D) array ultrasonic transducer, we developed a high-throughput multifocal UV-PAM (MF-UV-PAM). Our new system achieved a 1.6 ± 0.2 μm lateral resolution and produced images 40 times faster than the previously developed point-by-point scanning UV-PAM. MF-UV-PAM provided a readily comprehensible photoacoustic image of a mouse brain slice with specific absorption contrast in ∼16 min, highlighting cell nuclei. Individual cell nuclei could be clearly resolved, showing its practical potential for intraoperative SMA.


Temporal expression of L-Maf and RaxL in developing chicken retina are arranged into mosaic pattern.
Members of the maf gene family encode basic/leucine zipper transcription factors and play important roles during cell differentiation in vertebrate and Drosophila development. To investigate the possible roles of chicken lens-specific Maf (L-Maf)/MafA in retinal development, we analyzed its expression in the developing chicken retina. We first determined that L-Maf is expressed in a subset of ganglion cells, amacrine cells and rod cells during retinal development. To characterize further the L-Maf expressing cells during photoreceptor development, we compared the expression patterns of L-Maf and RaxL, a marker of cone cells. We found the L-Maf proteins are detectable from E10 between RaxL positive cone cells in outer nuclear layer (ONL). Subsequently, the expression of L-Maf is restricted to the innermost nuclear cells in the ONL during rod differentiation. In contrast, RaxL positive cone cells are distributed in the outermost layer of ONL. Furthermore, tangential retinal sections showed that L-Maf positive rods and RaxL positive cones form a mosaic pattern during photoreceptor development.


Psoriasis sparing the polio-affected limb: is it merely the koebner phenomenon?
Psoriasis being a common skin condition, atypical forms and unusual localizations of this disease are quite frequently seen. However, psoriasis sparing a polio-affected limb is extremely rare. We report a case of an adult male, who presented with psoriasis distributed all over the body but with almost complete sparing of the polio-affected left lower limb.


Factors Influencing Dental Students' Interest in Advanced Periodontal Education: Perspectives of Department Chairs.
The number of graduates of U.S. dental schools enrolled in U.S. postdoctoral programs in periodontics has been decreasing. The aims of this study were to determine the perspectives of periodontics department chairs regarding 1) features of a school's predoctoral curriculum that promote student interest in advanced periodontal education and 2) characteristics of a periodontal residency program that make it more attractive to dental students over other specialty programs. In 2015, a 14-question survey was designed and sent to chairs of periodontics departments at all 65 U.S. dental schools at the time. Questions addressed number of instructional hours; specialty clinic rotations; elective courses; number of applicants to periodontal residency; existence of a residency program; length of the residency program; and externships, fellowships, and financial stipends offered. The survey response rate was 73.8%. The results showed that departments offering more than seven clinical credit hours in periodontics to predoctoral students had the greatest number of residency applicants. Most of the applicants were from institutions that offered specialty clinic rotations, elective courses, and residency programs in periodontics. The number of applicants did not change significantly if a stipend or fellowship was offered. However, the availability of an externship was significantly associated with a greater number of applicants (p=0.042). These results suggest that offering periodontal clinical rotations, elective courses, and especially externships in periodontics during predoctoral education may encourage more graduating students to pursue postdoctoral periodontal education.


Poor sleep quality is independently associated with physical disability in older adults.
We aimed to evaluate the association between sleep quality and physical disability in community-dwelling older adults. There were 213 community-dwelling adults (76 men and 137 women) aged 65 years and above participated into this investigation. The Groningen Activity Restriction Scale and the Pittsburgh Sleep Quality Index were utilized to evaluate physical disability and subjective sleep quality, respectively. Global functional capacity was measured by the 6-minute walk test (6MWT). The Mini Mental State Examination and the Chinese Geriatric Depression Screening Scale were used to evaluate cognitive function and depression. Univariate analysis revealed a correlation between physical disability and poor sleep quality, older age, 2 or more comorbidities, depression, functional capacity, and poor cognitive function. However, in the multivariate analyses, depression failed to show significant association with physical disability. In contrast, an independent association was observed between poor sleep quality and physical disability (OR = 2.03; 95% CI: 1.02-4.05). In community-dwelling older adults, subjective poor sleep was significantly associated with physical disability, even after controlling for the effects of other established risk factors.


Radioiodine-Induced Salivary Gland Damage Detected by Ultrasonography in Patients Treated for Papillary Thyroid Cancer: Radioactive Iodine Activity and Risk.
Background: An important side effect of radioactive iodine (RAI) therapy in patients treated for papillary thyroid cancer (PTC) is chronic sialadenitis. Neck ultrasonography (US) easily recognizes radioiodine-induced salivary gland abnormalities. The objectives of this study were to determine the prevalence of US-detected sialadenitis caused by RAI and to identify the risk factors associated with this damage. Methods: This nonconcurrent cohort study includes all PTC-operated patients who were treated with RAI between 2007 and 2017 and were systematically evaluated with preoperative and follow-up neck US that included targeted exploration of the major salivary glands. Patients with pre-existing salivary gland diseases were excluded. The anatomical damage (diminished glandular volume, wavy contours, hypoechogenicity, and heterogeneity) was qualitatively assessed and compared with the preoperative study. RAI activity, sex, age, and preparation method were evaluated as risk factors using univariate and multivariate analyses with logistic regression. Results: Enrolled in this study were 570 patients who received a median RAI activity of 3700 MBq (100 mCi). On US, we found 143 patients (25.1%) with damage in at least one of their salivary glands: all had parotid damage (77 bilaterally) and 14 (9.8%) also had submandibular gland damage (7 of them bilaterally). The multivariate analysis indicated that the risk of sialadenitis was significantly (p < 0.01) correlated with both RAI activity and sex (14.1% of males vs. 28.5% of females). However, the main risk factor was RAI activity; no injury was detected in 156 patients who received 1110 MBq (30 mCi) and 1850 MBq (50 mCi) of RAI. In the groups of patients receiving 3700 MBq (100 mCi), 5550 MBq (150 mCi) and ≥7400 MBq (≥200 mCi), atrophy was found in 21%, 46.9%, and 77.7% of patients, respectively. Age and preparation method were not related to an increased risk of atrophy in this study. Conclusions: Chronic sialadenitis is common and affects approximately one fourth of patients who receive 3700 MBq (100 mCi) or higher RAI activity. The main risk factor for this injury is the total RAI activity administered. By using the lowest effective activity possible, irreversible anatomical damage in salivary glands can be minimized. US is an excellent tool to diagnose post-RAI atrophy.


Targeting tumor O-glycosylation modulates cancer-immune-cell crosstalk and enhances anti-PD-1 immunotherapy in head and neck cancer.
Cells in the tumor microenvironment (TME) communicate via membrane-bound and secreted proteins, which are mostly glycosylated. Altered glycomes of malignant tumors influence behaviors of stromal cells. In this study, we showed that the loss of core-1 β1,3-galactosyltransferase (C1GALT1)-mediated O-glycosylation suppressed tumor growth in syngeneic head and neck cancer mouse models. O-glycan truncation in tumor cells promoted the M1 polarization of macrophages, enhanced T-cell-mediated cytotoxicity, and reduced interleukin-6 (IL-6) levels in the secretome. Proteasomal degradation of IL-6 was controlled by the O-glycan at threonine 166. Both IL-6/IL-6R blockade and O-glycan truncation in tumor cells induced similar pro-inflammatory phenotypes in macrophages and cytotoxic T lymphocytes (CTLs). The combination of the O-glycosylation inhibitor itraconazole and anti-programmed cell death protein 1 (anti-PD-1) antibody effectively suppressed tumor growth in vivo. Collectively, our findings demonstrate that O-glycosylation in tumor cells governs their crosstalk with macrophages and CTLs. Thus, targeting O-glycosylation successfully reshapes the TME and consequently enhances the efficacy of anti-PD-1 therapy.


Resting-state electroencephalography theta predicts neurofeedback treatment 4-month follow-up response in nicotine addiction.
The high rate of long-term relapse is a major cause of smoking cessation failure. Recently, neurofeedback training has been widely used in the treatment of nicotine addiction; however, approximately 30% of subjects fail to benefit from this intervention. Our previous randomised clinical trial (RCT) examined cognition-guided neurofeedback and demonstrated a significant decrease in daily cigarette consumption at the 4-month follow-up. However, significant individual differences were observed in the 4-month follow-up effects of decreased cigarette consumption. Therefore, it is critical to identify who will benefit from pre-neurofeedback. We examined whether the resting-state electroencephalography (EEG) characteristics from pre-neurofeedback predicted the 4-month follow-up effects and explored the possible mechanisms. This was a double-blind RCT. A total of 60 participants with nicotine dependence were randomly assigned to either the real-feedback or yoked-feedback group. They underwent 6 min closed-eye resting EEG recordings both before and after two neurofeedback sessions. A follow-up assessment was conducted after 4 months. The frontal resting-state theta power spectral density (PSD) was significantly altered in the real-feedback group after two neurofeedback visits. Higher theta PSD in the real-feedback group before neurofeedback was the only predictor of decreased cigarette consumption at the 4-month follow-up. Further reliability analysis revealed a significant positive correlation between theta PSD pre-neurofeedback and post-neurofeedback. A leave-one-out cross-validated linear regression of the theta PSD pre-neurofeedback demonstrated a significant correlation between the predicted and observed reductions in cigarette consumption at the 4-month follow-up. Finally, source analysis revealed that the brain mechanisms of the theta PSD predictor were located in the orbital frontal cortex. Our study demonstrated changes in the resting-state theta PSD following neurofeedback training. Moreover, the resting-state theta PSD may serve as a prognostic marker of neurofeedback effects. A higher resting-state theta PSD predicts a better long-term response to neurofeedback treatment, which may facilitate the selection of individualised interventions. ChiCTR-IPR-17011710.


Neurobiological background for performing surgical intervention in the inferior thalamic peduncle for treatment of major depression disorders.
To present a review of evidence for an inhibitory thalamo-orbitofrontal system related to physiopathology of major depression disorders (MDDs) and to postulate that interfering with hyperactivity of the thalamo-orbitofrontal system by means of chronic high-frequency electrical stimulation of its main fiber connection, the inferior thalamic peduncle (ITP), may result in an improvement in patients with MDD. Experimentally, the thalamo-orbitofrontal system has been proposed as part of the nonspecific thalamic system. Under normal conditions, the nonspecific thalamic system induces characteristic electrocortical synchronization in the form of recruiting responses that mimic some sleep stages. It also inhibits input of irrelevant sensory stimuli, thus facilitating the process of selective attention. Permanent disruption of the system, via lesioning or temporary inactivation through cooling of the ITP with cryoprobes, results in a state of hyperkinesia, increased attention, and cortical desynchronization. Surgical lesioning of the medial part of orbitofrontal cortex and white matter overlying area 13, which includes the ITP, may result in significant improvement in MDD. Imaging studies (functional magnetic resonance imaging and positron emission tomography) consistently demonstrate hyperactivity in the orbitofrontal cortex and midline thalamic regions during episodes of MDD. This hyperactivity decreases with efficient control of MDD by medical treatment, indicating that orbitofrontal cortex and midline thalamic overactivity are related to the depressive condition. Conversely, noradrenergic and serotoninergic systems in the frontal lobes have been implicated in the pathophysiology of MDD. Although noradrenergic receptor density in the frontal lobe is consistently increased in depressed patients who commit suicide, 5-hydroxytryptamine reuptake blockers, which are potent antidepressive drugs, decrease hypermetabolism in the orbital frontal cortex in MDD. Therefore, the serotonin hypothesis for depression postulates that norepinephrine and serotonin in the frontal lobes are required to maintain antidepressive responsiveness. Dysregulation of the secretion of both neurotransmitters initiates overactivity of orbitofrontal cortex, resulting in depression. It is possible that surgical interventions in this region, including electrical stimulation of ITP, disrupt adrenergic and serotoninergic dysregulation in patients with MDD. Circumscribed lesions or electrical stimulation of the ITP, a discrete target easily identified by electrophysiological studies, may improve MDD. Electrical stimulation may have the advantage of being less invasive and more adjustable to patient needs.


Cytomegalovirus (CMV) viremia and the CD4+ lymphocyte count as predictors of CMV disease in patients infected with human immunodeficiency virus.
We screened 192 patients infected with human immunodeficiency virus (HIV) to examine the relation between CD4+ lymphocyte counts and cytomegalovirus (CMV) viremia and the occurrence of CMV disease and subsequent duration of survival. When we stratified the viremic patients by CD4+ lymphocyte counts, the proportions were as follows: <50/mm3, 20 (25%) of 80 patients; 50-100/mm3, 2 (5.5%) of 36; 101-150/mm3, none of 14; and >150/mm3, 1 (1.5%) of 62. After a mean follow-up period of 8.5 months, 21 (11%) of 192 patients developed CMV disease. The probability of developing CMV disease at 6 months was 13% when the CD4+ lymphocyte count was <50/mm3, 3% when the CD4+ lymphocyte count was 50-100/mm3, and 0 when the CD4+ lymphocyte count was >100/mm3; this probability was 46% for viremic patients and 1% for nonviremic patients. In a multivariate analysis, CMV viremia was independently prognostic of CMV disease (relative risk, 22.03; 95% confidence interval, 6.49-78.97; P < .001), whereas a CD4+ lymphocyte count of <50/mm3 was not (P = .26). These results support the value of CMV viremia for predicting which HIV-infected patients are at risk of developing CMV disease and should therefore receive primary prophylaxis.


Reducing attrition bias with an instrumental variable in a regression model: results from a panel of rheumatoid arthritis patients.
This study proposes an econometric technique to reduce attrition bias in panel data. In the simplest case, one estimates two regressions. The first is a probit regression based on sociodemographic and clinical characteristics measured at baseline. The probit regression estimates the probability that subjects stay or leave over the duration of the study. We insert the predicted probabilities from the probit regression into an inverse Mills ratio (IMR) or hazard rate to form an instrumental variable. We use this instrumental variable subsequently as an additional covariate in a second regression model that attempts to explain fluctuations in the dependent variable. The second regression, which is linear, includes only subjects who remained in the study. In alternative models, instrumental variables are created using predicted values from least squares and logit regressions estimating the probability that subjects stay or leave. The use of the instrumental variables reduces the effects of attrition bias in the linear regression model. We applied the technique to a panel of patients with rheumatoid arthritis (RA) enrolled in 1981 and followed through 1990. We attempted to predict values for a measure of functional disability recorded in 1990 with use of covariates measured in 1981. The dependent variable was an index of disability in 1990 and the independent variables (covariates) included the disability index from 1981, the years of duration of RA, gender, marital status, education, and age in 1981. The correction technique suggested that ignoring attrition bias would underestimate the strength of associations between being female and the subsequent disability index, and overestimate the strength of associations between being married spouse present, age, and the initial disability index on the one hand and the subsequent disability index on the other.


Objective assessment of visual pursuit in patients with disorders of consciousness: an exploratory study.
Visual pursuit is a key marker of residual consciousness in patients with disorders of consciousness (DOC). Currently, its assessment relies on subjective clinical decisions. In this study, we explore the variability of such clinical assessments, and present an easy-to-use device composed of cameras and video processing algorithms that could help the clinician to improve the detection of visual pursuit in a clinical context. Visual pursuit was assessed by an experienced research neuropsychologist on 31 patients with DOC and on 23 healthy subjects, while the device was used to simultaneously record videos of both one eye and the mirror. These videos were then scored by three researchers: the experienced research neuropsychologist who did the clinical assessment, another experienced research neuropsychologist, and a neurologist. For each video, a consensus was decided between the three persons, and used as the gold standard of the presence or absence of visual pursuit. Almost 10% of the patients were misclassified at the bedside according to their consensus. An automatic classifier analyzed eye and mirror trajectories, and was able to identify patients and healthy subjects with visual pursuit, in total agreement with the consensus on video. In conclusion, our device can be used easily in patients with DOC while respecting the current guidelines of visual pursuit assessment. Our results suggest that our material and our classification method can identify patients with visual pursuit, as well as the three researchers based on video recordings can.


Local anesthetics differentiate dihydropyridine calcium antagonist binding sites in rat brain and cardiac membranes.
Local anesthetics were used to probe differences in the binding of [3H]nitrendipine to dihydropyridine calcium antagonist binding sites on rat brain and cardiac membranes. Local anesthetics inhibited [3H]nitrendipine binding to brain and cardiac membranes with the rank order of potency, dibucaine = proadifen much greater than tetracaine greater than meproadifen greater than RAC-109 (S) greater than RAC-109 (R) greater than benzocaine. Lidocaine, procaine, piperocaine and bupivacaine produced either a small potentiation or inhibition of [3H]nitrendipine binding. Dibucaine inhibited [3H]nitrendipine binding to brain membranes (IC50, 4.9 +/- 0.5 microM) by increasing the Kd, whereas in cardiac membranes (IC50, 8.5 +/- 0.9 microM) it both increased the Kd and decreased the maximum binding site capacity of [3H]nitrendipine. The potency of dibucaine to inhibit [3H]nitrendipine binding was reduced in both tissues by monovalent (Li+ greater than Na+ = K+ = Rb+; EC50, 40-50 mM) and divalent (Ca++, Mg++ and Mn++; EC50, 10-50 microM) cations. These cations reduced the effect of dibucaine on the Kd of [3H]nitrendipine in brain and on the maximum binding site capacity of [3H]nitrendipine in cardiac membranes. Inhibition of [3H]nitrendipine binding by dibucaine was best described by high (2 microM) and low (50 microM) affinity sites. The apparent affinities of these sites, but not the fractional occupancies, were similar in brain and cardiac membranes. Na+ modulated the occupancies of these sites in brain, but not in cardiac membranes, whereas Ca++ inhibited occupancy of the high affinity site in both tissues. The effects of Li+ were similar to those of Ca++. These findings indicate that brain and cardiac dihydropyridine calcium antagonist binding sites are coupled to different allosteric effectors or exist in a different membrane environment.


[Prevalence of hepatitis C virus genotypes in the area of El Ferrol (La Coruña, Spain)].
To determine the prevalence of hepatitis C virus (HCV) genotypes in the area of El Ferrol, as well as their distribution according to risk factors. A total of 479 patients with hepatitis C were studied, including 254 with no known risk factors, 161 intravenous drug abusers (IVDA) and 64 with a history of blood transfusions. The presence of HCV RNA was studied by RT-PCR, and a reverse hybridization method (INNO-LiPA) was used for genotyping. Genotype distribution was as follows: 1b, 269 (56.2%); 1a, 79 (16.5%); 3a, 59 (12.3%); 4c/4d, 35 (7.3%); 1, 19 (4.0%); 2a/2c, 3 (0.6%); 4, 3 (0.6%); 2b, 2 (0.4%). In 10 patients (2.1%) genotype could not be determined. In patients with no known risk factor, the predominant genotype was 1b, detected in 191 of the 254 patients in this group (75.2%). Distribution of genotypes was more varied in the IVDA group, with the most frequent being 1a in 49 (30.4%) and 3a in 43 (26.7%). In the 64 patients who had received transfusions, 1b was predominant, detected in 54 of 64 patients (84.4%). The predominant HCV genotype in our area is 1b. Differences in genotype distribution were observed in the population groups studied, according to their underlying risk factors.


S100P as a potential biomarker for immunosuppressive microenvironment in pancreatic cancer: a bioinformatics analysis and in vitro study.
Immunosuppression is a significant factor contributing to the poor prognosis of cancer. S100P, a member of the S100 protein family, has been implicated in various cancers. However, its role in the tumor microenvironment (TME) of pancreatic cancer remains unclear. This study aimed to investigate the potential impact of S100P on TME characteristics in patients with pancreatic cancer. Multiple data (including microarray, RNA-Seq, and scRNA-Seq) were obtained from public databases. The expression pattern of S100P was comprehensively evaluated in RNA-Seq data and validated in four different microarray datasets. Prognostic value was assessed through Kaplan-Meier plotter and Cox regression analyses. Immune infiltration levels were determined using the ESTIMATE and ssGSEA algorithms and validated at the single-cell level. Spearman correlation test was used to examine the correlation between S100P expression and immune checkpoint genes, and tumor mutation burden (TMB). DNA methylation analysis was performed to investigate the change in mRNA expression. Reverse transcription PCR (RT-PCR) and immunohistochemical (IHC) were utilized to validate the expression using five cell lines and 60 pancreatic cancer tissues. This study found that S100P was differentially expressed in pancreatic cancer and was associated with poor prognosis (P < 0.05). Notably, S100P exhibited a significant negative-correlation with immune cell infiltration, particularly CD8 + T cells. Furthermore, a close association between S100P and immunotherapy was observed, as it strongly correlated with TMB and the expression levels of TIGIT, HAVCR2, CTLA4, and BTLA (P < 0.05). Intriguingly, higher S100P expression demonstrated a negative correlation with methylation levels (cg14323984, cg27027375, cg14900031, cg14140379, cg25083732, cg07210669, cg26233331, and cg22266967), which were associated with CD8 + T cells. In vitro RT-PCR validated upregulated S100P expression across all five pancreatic cancer cell lines, and IHC confirmed high S100P levels in pancreatic cancer tissues (P < 0.05). These findings suggest that S100P could serve as a promising biomarker for immunosuppressive microenvironment, which may provide a novel therapeutic way for pancreatic cancer.


Remarkably stable inclusion complexes with heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-beta-cyclodextrin.
Complexes of heptakis-[6-deoxy-6-(2-aminoethylsulfanyl)]-beta-cyclodextrin (1) and a series of common cyclodextrin guests were studied by NMR, fluorescence spectroscopy, and ITC experiments. NMR conformational analysis shows that the thioethers of 1 are positioned over the hydrophobic cavity of the cyclodextrin, increasing potential hydrophobic interactions with guest molecules. The combination of the increased hydrophobic character, the electrostatic complementarity and a hypothesized conformational change in 1 lead to a complex with the dye 2,6-ANS (5) that is over 2000 times more stable than with the native beta-cyclodextrin. One of the most stable host-guest complexes between a cyclodextrin and a small molecule measured to date was revealed between 1 and lithocholic acid (4) with an association constant of 5.5 x 10(7) M(-1).


A Systematic Review of Response Styles Among Latinx Populations.
Culture influences responses to psychological measurements in ways unrelated to target constructs, thus biasing test scores and potentially contributing to under- and over-diagnosis of mental health problems in populations for which measures have not yet been normed. We conducted a systematic review of publications addressing response style among Latinx population groups in North and South America. In a final corpus of 24 studies, Latinx/Latin American populations were generally found to exhibit higher levels of extreme response style (n = 17), acquiescent response style (n = 10), and socially desirable responding (n = 5). The few publications (n = 3) that investigated midpoint responding reported no differences. Seven publications (29%) attempted to adjust scores to mitigate response style bias, using both scale design and statistical techniques. Findings suggest that researchers and clinicians should directly assess culturally patterned response style as a construct, rather than inferring style indirectly using other measures. For clinicians, knowledge of response style represents another facet of case conceptualization.


Coping strategies among caregivers of people with Alzheimer disease: a systematic review.
Caregivers of people with Alzheimer disease (PwAD) report significant stress, burden and depression compared to caregivers of people with other dementias, especially when neuropsychiatric symptoms are prominent. Adequate coping strategies can modify the impact of stressful situations and increase the caregivers' quality of life. To systematically review the different coping strategies used by caregivers of PwAD to manage neuropsychiatric symptoms. We carried out electronic searches using MEDLINE (PubMed), SciELO, Web of Knowledge Cross Search (Thomson Scientific/ISI Web Services) and PsycINFO databases to select studies on coping in PwAD caregivers published from January 2005 to July 2017. The search terms were coping, caregivers, strategy, onset, adaptation, family, behavior, dementia and Alzheimer. The studies were organized in three categories: problem-focused, emotion-focused and dysfunctional coping strategies. We found 2,277 articles. After application of exclusion criteria and exclusion of redundant references, 24 articles were analyzed. Emotion-focused coping was the most commonly used strategy among PwAD caregivers. The use of this strategy associated with religion and spirituality may help reduce symptoms of depression and anxiety. Problem-focused coping strategies were mostly used with active coping interventions. Problem-solving coping may have buffered the impact of acute psychological stressors on procoagulant activity. Dysfunctional coping strategies were associated with increase of caregiver burden. The evaluated studies showed that the use and development of coping strategies may have ameliorated the depressive symptoms, anxiety and burden of caregivers. However, longitudinal studies are still needed that clearly describe the type of coping strategy used in relation to the presented results.


miR-181b-5p Modulates Cell Migratory Proteins, Tissue Inhibitor of Metalloproteinase 3, and Annexin A2 During In Vitro Decidualization in a Human Endometrial Stromal Cell Line.
Decidualization is essential for successful embryo implantation and is regulated by concerted actions of growth factors and hormones. More recently, microRNAs, small RNA molecules that regulate posttranscriptional gene expression, have been implicated to play a role in the decidualization process. Of these microRNAs, miR-181b-5p has been associated with decidualization but its precise role and targets are not well established. To address this gap in our knowledge, we assessed the expression of miR-181b-5p, and its target tissue inhibitor of metalloproteinase 3 (TIMP-3), during in vitro decidualization using the well-characterized human endometrial stromal cell line, t-HESC. miR-181b-5p expression was highest prior to decidualization and significantly decreased in response to decidualization stimulus. In contrast, TIMP-3 expression was absent prior to in vitro decidualization and increased during decidualization. Regulation of TIMP-3 expression by miR-181b-5p was confirmed in vitro by quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blot analysis, and 3' untranslated region reporter constructs. To identify unforeseen targets of miR-181b-5p during in vitro decidualization, t-HESC cells were transfected with pre- miR-181b-5p, and protein profiles were determined by 2-dimensional differential in-gel electrophoresis followed by matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI TOF/TOF) tandem mass spectrometry. Of these proteins, several downregulated proteins associated with cell migration were identified including annexin A2, which we subsequently confirmed by qRT-PCR and Western blot analysis to be regulated by miR-181b-5p. In conclusion, miR-181b-5p is downregulated during the process of in vitro decidualization and may regulate the expression of proteins associated with cell migration including TIMP-3 and annexin A2.


Molecular Modeling and Active Site Binding Mode Characterization of Aspartate β-Semialdehyde Dehydrogenase Family.
The enzyme aspartate β-semialdehyde dehydrogenase (ASADH) plays a vital role in biosynthesis of essential amino acids and several important metabolites in microbes and some higher plants. So this key enzyme can be targeted selectively in these microbes to exhibit anti-bacterial and fungicidal effects. In this work, molecular modeling and comparative active site binding mode studies were performed for understanding the mode of action, in silico insight into the 3D structure, enzyme-substrate interactions with natural substrate in this homologous enzyme family. During comparative sequence analysis, high diversity was found in the sequences of different ASADHs and exhibited the same key binding interactions with the substrate. Both, the functional carboxylic and the phosphate group of the substrate are engaged in a bidentate interaction with the guanidinium N atom of two key arginyl active site residues of ASADHs. These structural and active site binding mode characterization studies can further be used for designing the more potent and selective substrate analogues inhibitors against ASADH family.


Modulation of epinephrine-stimulated gluconeogenesis by insulin in hepatocytes isolated from genetically obese (fa/fa) Zucker rats.
Genetically obese (fa/fa) Zucker rats present an impaired response of hepatic glucose production to the inhibition by insulin. In this work, we have investigated the modulation by this hormone of epinephrine-stimulated gluconeogenesis, in hepatocytes isolated from obese (fa/fa) rats and their lean (Fa/-) littermates. Epinephrine (1 microM) caused a maximal stimulation of [14C]lactate conversion to [14C]glucose in hepatocytes isolated from either obese or lean animals. The stimulation of gluconeogenesis by epinephrine was accompanied by a significant reduction of fructose 2,6-bisphosphate levels, an inactivation of both pyruvate kinase and 6-phosphofructo 2-kinase, and by a 2-fold increase in the cellular concentrations of cAMP. The presence of insulin in the incubation medium antagonized, in a concentration-dependent manner, the effects of epinephrine. In hepatocytes isolated from lean rats, the reversion caused by insulin was complete, the concentration required for half-maximal insulin action ranging from 0.22 to 0.56 nM. In contrast, in obese rat hepatocytes, insulin only partially blocked epinephrine-mediated effects, and the sensitivity to insulin was 2- to 4-fold lower, as indicated by the corresponding half-maximal insulin action values. Furthermore, insulin (10 nM) almost completely blocked the increase in cAMP levels induced by epinephrine in lean rat hepatocytes, whereas it only provoked a small and nonsignificant reduction of epinephrine-stimulated levels of the cyclic nucleotide in hepatocytes obtained from obese rats.


A collaborative approach to improving patient access in general practice: impact of three different pilot schemes in 12 general practices in Greenwich.
With rising patient demand and expectations, many practices are struggling to respond to the demand for appointments. To investigate different approaches to improving access to general practice and assess the impact on (i) patient experience, (ii) practice staff experience and (iii) activity in A&E and walk-in centres. Greenwich CCG piloted three approaches in 12 volunteer practices. The schemes were:(1) Systematic GP telephone triage of all appointment requests.(2) Analysis and comparison of practice data including demand and capacity to identify opportunities for improvement.(3) Online consultations. Qualitative and quantitative evaluation was undertaken. Overall results were inconclusive and no one pilot scheme was overwhelmingly successful in improving patient experience of access or reducing practice workload. Scheme 1 telephone triage: In some cases, overall demand on clinician time through the day reduced as face-to-face consultations were replaced with shorter telephone consultations. However, in other practices, total consulting time went up when telephone consultations took longer than the suggested average 5 min. Scheme 2 practice analysis and benchmarking: The pilot practices implemented no significant changes. Scheme 3 online consultations: Take up was low, with users as a percentage of total list size dropping significantly to even lower levels in the second half of the pilot - from 3.13% in the first three months to 1.20% in the second three months. As the pilots did not improve the overall patient experience of access or practice workload, the pilot schemes were not rolled out by the CCG. From the CCG's point of view, it was valuable to test out the effect of a scheme before committing further resources.


ECA, the enterobacterial common antigen.
Enterobacterial common antigen (ECA) is a family-specific surface antigen shared by all members of the Enterobacteriaceae and is restricted to this family. It is found in freshly isolated wild-type strains as well as in laboratory strains like Escherichia coli K-12. The family specificity of ECA can be used for taxonomic and diagnostic purposes. ECA is located in the outer leaflet of the outer membrane. It is a glycophospholipid built up by an aminosugar heteropolymer linked to an L-glycerophosphatidyl residue. In a few rough mutants, in addition, the sugar chain can be bound to the complete lipopolysaccharide (LPS) core. Recently, for Shigella sonnei a lipid-free cyclic form of ECA was reported. The genetical determination of ECA is closely related to that of lipopolysaccharide. For biosynthesis of ECA and LPS partly the same sugar precursors and the same carrier lipid is used.


[Active uptake of oxalate in a renal tubular cell line (LLC-PK1)].
The oxalate uptake was studied in LLC-PK1 cells, an epithelial cell line originated in proximal tubular cells of porcine kidney. It was clear that the cells contain an oxalate exchanger highly sensitive to 4,4-diisothio-cyanostilbene-2-' disulfonic acid (DIDS). The uptake was inhibited by the addition of inorganic anions (chloride, sulphate and bicarbonate) to the reaction system, but was unaffected by sodium ion. The data suggest the possibility that it should be consistent with at least two transport systems for oxalate in LLC-PK1 cells, a SO4-/oxalate/HCO3- exchanger and a Cl-/oxalate exchanger.


Physical performance measures as a useful indicator of multiple geriatric syndromes in women aged 75 years and older.
To identify whether individual physical performance measures or a combination of measures is a better indicator of multiple geriatric syndromes (MGS) defined as the concomitant presence of more than one geriatric syndrome in an individual. We carried out cross-sectional analyses on data from 340 community-dwelling women aged 75 years and older (mean 80.0 years). We examined the following geriatric syndromes: urinary incontinence, falls, underweight, depression and functional decline. Trained testers measured usual gait speed (UGS), hand-grip strength and lower extremity performance (LEP) score derived from four LEP measures: tandem stance, chair stand test, alternate step and timed up-and-go (TUG). We categorized UGS to distinguish high- and low-performing participants using the established 1.0 m/s cut-off point. Applying the same population percentile (35.8%), we determined cut-off points for all individual measures and the LEP score. The UGS, TUG and LEP score had similar discriminating powers for MGS (each with area under receiver-operator curves [AUC] of 0.80), which were more significant than the discriminating powers of other individual measures (AUC = 0.69-0.76) when considered as continuous variables. A slow UGS, especially less than 1.0 m/s, was more strongly associated with MGS (odds ratio [OR] = 7.6, 95% confidence interval [CI] = 3.6-15.9) than the same percentiles for TUG (OR = 3.9, 95% CI = 1.9-7.8) and LEP score (OR = 5.2, 95% CI = 2.5-10.6). The UGS test alone might be sufficient in detecting MGS in women aged 75 years and older compared with a more comprehensive test battery.


Limb preference in the gallop of dogs and the half-bound of pikas on flat ground.
During fast locomotion--gallop, half-bound, bound--of quadruped mammals, the ground contact of the limbs in each pair does not alternate symmetrically. Animals using such asymmetrical gait thus choose whether the left or the right limb will contact the ground first, and this gives rise to limb preference. Here, we report that dogs (Mammalia, Carnivora) and pikas (Mammalia, Lagomorpha) prefer one forelimb as trailing limb and use it as such almost twice as often as the other. We also show that this choice depends on the individual and is not a characteristic of the species, and that the strength of the preference was not dependent on the animal's running speed.


Overcoming Oncogenic Mediated Tumor Immunity in Prostate Cancer.
Immunotherapy is being tested intensively in clinical trials for prostate cancer; it includes immune checkpoint inhibition, prostate specific antigen (PSA) vaccines and dendritic cell-based strategies. Despite increasing evidence for clinical responses, the consensus of multiple trials is that prostate cancers are poorly responsive to immunotherapy. Prostate cancer has a high degree of pathological and genetic heterogeneity compared to other cancer types, which may account for immunotherapeutic resistance. This hypothesis also implies that select types of prostate tumors may be differentially responsive to immune-based strategies and that the clinical stage, pathological grade and underlying genetic landscape may be important criteria in identifying tumors that respond to immune therapies. One strategy is to target oncogenic driver pathways in combination with immunotherapies with the goal of overcoming tumor immunity and broadening the number of patients achieving a clinical response. In this analysis, we address the hypothesis that driver oncogenic signaling pathways regulate cancer progression, tumor immunity and resistance to current immune therapeutics in prostate cancer. We propose that increased responsiveness may be achieved through the combined use of immunotherapies and inhibitors targeting tumor cell autonomous pathways that contribute towards anti-tumor immunity in patients with prostate cancer.