Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone.
The disposition of the long-acting opioid methadone, used to prevent opiate withdrawal and treat short- and long-lasting pain, is highly variable. Methadone undergoes N -demethylation to the primary metabolite 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolinium (EDDP), catalyzed in vitro by intestinal, hepatic, and expressed cytochrome P450 (CYP) 3A4. However, the role of CYP3A4 in human methadone disposition in vivo is unclear. This investigation tested the hypothesis that CYP3A induction (or inhibition) would increase (or decrease) methadone metabolism and clearance in humans. Healthy volunteers were studied in a randomized, balanced, 4-way crossover study. They received intravenous (IV) midazolam (to assess CYP3A4 activity) and then simultaneous oral deuterium-labeled and IV unlabeled methadone after pretreatment with rifampin (INN, rifampicin) (hepatic/intestinal CYP3A induction), troleandomycin (hepatic/intestinal CYP3A inhibition), grapefruit juice (selective intestinal CYP3A inhibition), or nothing. Methadone effects were measured by dark-adapted pupil diameter. CYP isoforms catalyzing methadone metabolism by human liver microsomes and expressed CYPs in vitro were also evaluated. Methadone had high oral bioavailability (70%) and low intestinal (22%) and hepatic (9%) extraction, and there was a significant correlation ( r = 0.94, P <.001) between oral bioavailability and intestinal (but not hepatic) availability. Rifampin decreased bioavailability and oral and IV methadone plasma concentrations and increased IV clearance (4.42 +/- 1.00 mL. kg -1. min -1 versus 1.61 +/- 0.67 mL. kg -1. min -1, P <.05) and oral clearance (8.50 +/- 3.68 mL. kg -1. min -1 versus 2.05 +/- 0.92 mL. kg -1. min -1, P <.05), EDDP/methadone area under the curve (AUC) ratios, EDDP formation clearances, and hepatic extraction (0.27 +/- 0.06 versus 0.09 +/- 0.04, P <.05). Troleandomycin and grapefruit juice decreased the EDDP/methadone AUC ratio after oral methadone (0.17 +/- 0.10 and 0.14 +/- 0.06 versus 0.27 +/- 0.20, P <.05) but not IV methadone and had no effect on methadone plasma concentrations, IV clearance (1.29 +/- 0.41 mL. kg -1. min -1 and 1.48 +/- 0.55 mL. kg -1. min -1 ) or oral clearance (2.05 +/- 1.52 mL. kg -1. min -1 and 1.89 +/- 1.07 mL. kg -1. min -1 ), or other kinetic parameters. There was no correlation between methadone clearance and hepatic CYP3A4 activity. Pupil diameter changes reflected plasma methadone concentrations. In vitro experiments showed a predominant role for both CYP3A4 and CYP2B6 in liver microsomal methadone N -demethylation. First-pass intestinal metabolism is a determinant of methadone bioavailability. Intestinal and hepatic CYP3A activity only slightly affects human methadone N -demethylation but has no significant effect on methadone concentrations, clearance, or clinical effects. Greater rifampin effects, compared with troleandomycin and grapefruit juice, on methadone disposition suggest a major role for intestinal transporters and for other CYPs, such as CYP2B6. Interindividual variability and drug interactions affecting intestinal transporter and hepatic CYP3A and CYP2B6 activity may alter methadone disposition.


Characterization of Epoxy Composites Reinforced with Wax Encapsulated Microcrystalline Cellulose.
The effect of paraffin wax encapsulated microcrystalline cellulose (EMC) particles on the mechanical and physical properties of EMC/epoxy composites were investigated. It was demonstrated that the compatibility between cellulose and epoxy resin could be maintained due to partial encapsulation resulting in an improvement in epoxy composite mechanical properties. This work was unique because it was possible to improve the physical and mechanical properties of the EMC/epoxy composites while encapsulating the microcrystalline cellulose (MCC) for a more homogeneous dispersion. The addition of EMC could increase the stiffness of epoxy composites, especially when the composites were wet. The 1% EMC loading with a 1:2 ratio of wax:MCC demonstrated the best reinforcement for both dry and wet properties. The decomposition temperature of epoxy was preserved up to a 5% EMC loading and for different wax:MCC ratios. An increase in wax encapsulated cellulose loading did increase water absorption but overall this absorption was still low (<1%) for all composites.


The effect of fenugreek 4-hydroxyisoleucine on liver function biomarkers and glucose in diabetic and fructose-fed rats.
Fenugreek (Trigonella foenum graecum L) is a plant traditionally used for the treatment of diabetes. It contains an unusual amino acid, 4-hydroxyisoleucine, demonstrated to have insulinotropic and antidiabetic properties in animal models. Here we examine the effect of 4-hydroxyisoleucine on liver function and blood glucose in two rat models of insulin resistance, fructose-fed rats and streptozotocin-induced diabetes type 2. In fructose-fed rats, levels of glucose and liver damage marker aspartate transaminase were markedly (84% and 93%, respectively) and significantly elevated compared with controls (p < 0.001 for both). Alanine transaminase was elevated slightly (18%), and all markers were restored to near control values after treatment with 4-hydroxyisoleucine at 50 mg/kg per day for 8 weeks, the effect being significant (p < 0.01) for all markers. This prolonged exposure to 4-hydroxyisoleucine was well tolerated in control animals and did not alter levels of glucose or liver damage markers significantly. In diabetic rats, treatment with 4-hydroxyisoleucine did not affect glucose or liver damage markers, but did improve HDL-cholesterol levels (31% increase, p < 0.05). These findings indicate 4-hydroxyisoleucine as a useful and well-tolerated treatment for insulin resistance, both directly as a hypoglycaemic and also as a protective agent for the liver.


Vision and low self-rated health: the Blue Mountains Eye Study.
To assess the relationship between reduced vision and low self-rating of global health, after taking into account many other related factors. The Blue Mountains Eye Study examined 3654 residents aged > or =49 years (82.4% response) in an area west of Sydney, Australia. Presenting and best-corrected visual acuity (VA) were measured before and after refraction using a LogMAR chart. During a face-to-face interview, self-rated health was assessed by asking: "For someone of your age, how would you rate your overall health?: excellent, good, fair, or poor." Information about demography, socioeconomic status, need for assistance in daily living activities, medical history, and health risk behaviors was also collected. Logistic regression analyses were performed after dichotomizing self-rated health as poor or fair (low) versus good or excellent. Among persons without visual impairment (defined from best-corrected VA in the better eye), 24.5% rated their health as either poor or fair, compared with 35.5% and 48.8% of persons with mild or moderate-to-severe visual impairment, respectively. In multivariate logistic regression models that included 17 other related factors, reduced vision was statistically significantly associated with lower self-rated health in persons aged <80 years. For each one-line (5 letter) reduction in best-corrected VA, there was 20% increased likelihood of low self-rated health, after adjustment for other factors found associated with self-rated health (multivariate-adjusted odds ratio 1.2, 95% confidence interval 1.1-1.3). In persons aged 80 years or older, reduced vision had no impact on global health rating. Decreased vision was found to have an independent impact on global health ranking by persons younger than age 80 years, but not by older persons in this population. Taking into account many other factors affecting perceived health, people younger than age 80 years who see well are also more likely to say that they feel well!


Byzantine-robust federated learning via credibility assessment on non-IID data.
Federated learning is a novel framework that enables resource-constrained edge devices to jointly learn a model, which solves the problem of data protection and data islands. However, standard federated learning is vulnerable to Byzantine attacks, which will cause the global model to be manipulated by the attacker or fail to converge. On non-iid data, the current methods are not effective in defensing against Byzantine attacks. In this paper, we propose a Byzantine-robust framework for federated learning via credibility assessment on non-iid data (BRCA). Credibility assessment is designed to detect Byzantine attacks by combing adaptive anomaly detection model and data verification. Specially, an adaptive mechanism is incorporated into the anomaly detection model for the training and prediction of the model. Simultaneously, a unified update algorithm is given to guarantee that the global model has a consistent direction. On non-iid data, our experiments demonstrate that the BRCA is more robust to Byzantine attacks compared with conventional methods.


Site of Deep Venous Thrombosis and Age in the Selection of Patients in the Emergency Department for Hospitalization Versus Home Treatment.
Despite apparent advantages of home treatment of deep venous thrombosis (DVT) based upon results of randomized controlled trials, physicians maintain a conservative approach, and a large proportion of patients with DVT are hospitalized. In the present investigation we assess whether selection of patients for hospitalization for acute DVT was related to the site of the DVT or to age. This was a retrospective cohort study based on administrative data from the Nationwide Emergency Department Sample, 2016. Patients were identified by International Classification of Diseases-10-Clinical Modification codes. Most, 87,436 of 133,414 (66%), had proximal DVT. A minority of patients with isolated distal DVT were hospitalized, 10,621 of 37,592 (28%). However, hospitalization was selected for 47,459 of 87,436 (54%) with proximal DVT; 4,867 of 7,599 (64%) with pelvic vein DVT; and 611 of 788 (78%) with DVT involving the inferior vena cava. Hospitalization for patients with distal DVT, proximal DVT, and pelvic vein DVT was age-dependent. In conclusion, both the site of acute DVT and age were factors affecting the clinical decision of emergency department physicians to select patients for hospital treatment.


Selective management of iatrogenic femoral artery injuries.
Increased femoral artery catheterization for therapy and diagnosis has resulted in a concomitant increase in iatrogenic femoral artery injuries. A 33-month experience at two affiliated institutions was reviewed to evaluate the results of a selective approach to management of these complications. During this period, 9576 femoral artery catheterizations were performed. Eighty-nine femoral artery injuries were treated surgically or by ultrasound-guided compression therapy. Cardiac catheterization procedures predominated and 61% of patients were anticoagulated. Thirty-eight cases were treated surgically: 14 pseudoaneurysms, 16 hematomas, 6 arteriovenous fistulas, 2 thromboses. Local anesthesia was used in 28 cases (74%). Arterial repair was required in 34 cases, with control being achieved below the inguinal ligament in 33 cases (97%). Punctures were found in the superficial femoral or profunda femoral rather than the common femoral artery in 17 of 38 cases (44%, P < 0.001 compared with the ultrasound group). There were two deaths (5.3%), six wound infections (16%), and no limb loss. Ultrasound-guided compression was preferentially used for stable or slowly expanding pseudoaneurysms. Cases with large hematomas causing skin ischemia were treated surgically. The pseudoaneurysms ranged from 2 to 7 cm in diameter. This technique was effective in 46 of 51 cases (90%). A single thromboembolic complication was treated by thrombolysis. There were no late recurrences. We conclude that (1) iatrogenic femoral artery injuries are associated with postcatheterization anticoagulation and punctures not located in the common femoral artery; (2) injuries requiring surgery can usually be treated under local anesthesia with infrainguinal arterial control; (3) ultrasound-guided compression is an effective method for treating iatrogenic pseudoaneurysms not associated with large hematomas.


Role of toll-like receptors in changes in gene expression and NF-kappa B activation in mouse hepatocytes stimulated with lipopolysaccharide.
The liver is an important site of host-microbe interaction. Although hepatocytes have been reported to be responsive to lipopolysaccharide (LPS), the global gene expression changes by LPS and mechanism(s) by which LPS stimulates cultured hepatocytes remain uncertain. Cultures of primary mouse hepatocytes were incubated with LPS to assess its effects on the global gene expression, hepatic transcription factors, and mitogen-activated protein (MAP) kinase activation. DNA microarray analysis indicated that LPS modulates the selective expression of more than 80 genes and expressed sequence tags. We have shown previously that hepatocytes express CD14, which is required both for uptake and responsiveness to LPS. In other cells, responsiveness to microbial products requires expression of Toll-like receptors (TLR) and their associated accessory molecules. Hepatocytes expressed TLR1 through TLR9 as well as MyD88 and MD-2 transcripts, as shown by reverse transcriptase PCR analysis, indicating that hepatocytes express all known microbe recognition molecules. The MAP kinase extracellular signal-regulated kinase 1/2 was phosphorylated in response to LPS in mouse hepatocytes, and the levels of phosphorylation were lower in hepatocytes from TLR4-null mice. NF-kappa B activation was reduced in TLR4-mutant or -null hepatocytes compared to control hepatocytes, and this defect was partially restored by adenoviral transduction of mouse TLR4. Thus, hepatocytes respond to nanogram concentrations of LPS through a TLR4 response pathway.


New role of E3 ubiquitin ligase in the regulation of necroptosis.
Necroptosis is a well-known form of caspase-independent cell death. Necroptosis can be triggered by various extrinsic stimuli, including death ligands in the presence of receptorinteracting protein kinase 3 (RIPK3), a key mediator of necroptosis induction. Our recent studies have revealed that C-terminus HSC-70 interacting protein (CHIP), an E3 ligase, can function as an inhibitor of necroptosis. CHIP-/- mouse embryonic fibroblast showed higher sensitivity to necrotic stimuli than wild-type mouse embryonic fibroblast cells. Deleterious effects of CHIP knockout MEFs were retrieved by RIPK3 depletion. We found that CHIP negatively regulated RIPK3 and RIPK1 by ubiquitylation- and lysosome- dependent degradation. In addition, CHIP-/- mice showed postnatal lethality with intestinal defects that could be rescued by crossing with RIPK3-/- mice. These results suggest that CHIP is a negative regulator of RIPK1 and RIPK3, thus inhibiting necroptosis. [BMB Reports 2016; 49(5): 247-248].


Resolution No. 16, 20 November 1987.
This Venezuela Resolution requires the performance of a cytological study in all medical offices providing family planning, pre- and postnatal care, adult hygiene, treatment for sexually transmitted diseases, and gynecological services and, in general, all medical offices in the public sector that treat women between the ages of 25 and 64. It also requires all patients treated in these offices who for any reason have to be admitted for hospitalization to undergo a cytological exam. The purpose of these activities is the prevention of uterine cancer.


A Possible Role for TNF-α in Coordinating Inflammation and Angiogenesis in Chronic Liver Disease and Hepatocellular Carcinoma.
Increasing evidence supports the hypothesis that chronic and persistent inflammation contributes to cancer development. However, the molecular mechanisms that lead to cancer in chronic inflammation and the role of angiogenesis in inflammation-associated cancer remain poorly understood. NINETY PATIENTS WERE ENROLLED: 30 cases of CHC without cirrhosis, 28 cases of CHC with liver cirrhosis, and 32 cases of HCC and hepatitis C virus infection. Ten wedge liver biopsies, taken during laparoscopic cholecystectomy, served as normal controls. Serum TNF-α levels were measured using the ELISA technique; in situ hybridization and immunohistochemical studies were used to detect hepatic levels of messenger RNA (mRNA) transcripts and mature protein, respectively, for both TNF-α and VEGF. The highest hepatic expression of TNF-α was noticed in liver cirrhosis specimens compared to noncirrhotic CHC and HCC. Hepatic expression of VEGF and serum level of TNF-α revealed significant increases in the progression of the disease. Moreover, cases with higher grades of inflammation or stages of fibrosis showed significant increases in serum TNF-α and expression of TNF-α and VEGF. Expression of mRNA of both TNF-α and VEGF shows increasing expression with positive correlation to progression of viral hepatitis to cirrhosis with more positivity in cases developed HCC. VEGF signaling could be one of the molecular signaling pathways involved in TNF-α induced angiogenesis which might pose an important link between inflammation and fibrosis in CHC and HCC development and progression. Moreover, serum inflammatory biomarkers can be used to monitor the disease progression.


Functional recovery after discharge in enhanced recovery video-assisted thoracoscopic lobectomy: a pilot prospective cohort study.
Little is known about functional recovery following patient discharge in an established enhanced recovery programme after video-assisted thoracoscopic lobectomy. We conducted a single-centre pilot prospective observational cohort study. We hypothesised that patients achieved early functional recovery after discharge. A total of 32 patients aged ≥ 18 years were enrolled. A digital device was used for objective activity measurements, and patient-reported outcomes were collected as subjective measurements. Primary outcomes were the difference in physical activity; sleep duration; pain; fatigue; and average quality of life scores between pre-operative baseline and 7 days following discharge. The secondary outcome was the reason for reduced daily activity during the first 7 days after discharge. Median (IQR [range]) length of stay was 3 (2-5 [1-13]) days. Up to post-discharge day 7, total, lower intensity and moderate-to-vigorous activities were lower than pre-operative activity (p < 0.001; p = 0.005 and p = 0.027, respectively). Numerical rating scale (0-10) pain scores increased postoperatively at rest (mean difference 1.2, p < 0.001) and during walking (mean difference 1.4, p < 0.001). Fatigue assessed by the Christensen Fatigue Scale (1-10) was also increased postoperatively (mean difference 1.7, p = 0.001). There was a reduction in quality of life scores, while sedentary activity and sleep duration were unchanged postoperatively. Dominant reasons for not recovering daily activity included fatigue in 43% and pain in 33% of patients. Despite compliance with an enhanced recovery programme with a median length of hospital stay of 3 days after video-assisted thoracoscopic lobectomy, functional recovery was not achieved within 7 days after hospital discharge. Reduction in postoperative pain and fatigue are important factors to enhance functional recovery.


Prediabetes Is Associated with Increased Prevalence of Sleep-Disordered Breathing.
Type 2 diabetes leads to severe nocturnal hypoxemia, with an increase in apnea events and daytime sleepiness. Hence, we assessed sleep breathing parameters in the prediabetes stage. A cross-sectional study conducted on 966 middle-aged subjects without known pulmonary disease (311 patients with prediabetes and 655 controls with normal glucose metabolism) was conducted. Prediabetes was defined by glycated hemoglobin (HbA1c), and a nonattended overnight home sleep study was performed. Participants with prediabetes (n = 311) displayed a higher apnea−hypopnea index (AHI: 12.7 (6.1;24.3) vs. 9.5 (4.2;19.6) events/h, p < 0.001) and hypopnea index (HI: 8.4 (4.0;14.9) vs. 6.0 (2.7;12.6) events/h, p < 0.001) than controls, without differences in the apnea index. Altogether, the prevalence of obstructive sleep apnea was higher in subjects with prediabetes than in controls (78.1 vs. 69.9%, p = 0.007). Additionally, subjects with prediabetes presented impaired measurements of the median and minimum nocturnal oxygen saturation, the percentage of time spent with oxygen saturations below 90%, and the 4% oxygen desaturation index in comparison with individuals without prediabetes (p < 0.001 for all). After adjusting for age, sex, and the presence of obesity, HbA1c correlated with the HI in the entire population (r = 0.141, p < 0.001), and the presence of prediabetes was independently associated with the AHI (B = 2.20 (0.10 to 4.31), p = 0.040) as well as the HI (B = 1.87 (0.61 to 3.14), p = 0.004) in the multiple linear regression model. We conclude that prediabetes is an independent risk factor for an increased AHI after adjusting for age, sex, and obesity. The enhanced AHI is mainly associated with increments in the hypopnea events.


[Various aspects of Parkinson syndrome in the aged].
The author defines this syndrome with symptoms and diagnostics and describes its aetiopathogenesis, pathological and anatomical changes in the patient, course, treatment and epidemiology as well as primary and secondary measures to prevent it.


Role of CD8+ T Cells in the Selection of HIV-1 Immune Escape Mutations.
Human immunodeficiency virus type-1 (HIV-1) infection represents one of the biggest public health problems worldwide. The immune response, mainly the effector mechanisms mediated by CD8+ T cells, induces the selection of mutations that allows the virus to escape the immune control. These mutations are generally selected within CD8+ T cell epitopes restricted to human leukocyte antigen class I (HLA-I), leading to a decrease in the presentation and recognition of the epitope, decreasing the activation of CD8+ T cells. However, these mutations may also affect cellular processing of the peptide or recognition by the T cell receptor. Escape mutations often carry a negative impact in viral fitness that is partially or totally compensated by the selection of compensatory mutations. The selection of either escape mutations or compensatory mutations may negatively affect the course of the infection. In addition, these mutations are a major barrier for the development of new therapeutic strategies focused on the induction of specific CD8+ T cell responses.


Calcium store sensor stromal-interaction molecule 1-dependent signaling plays an important role in cervical cancer growth, migration, and angiogenesis.
Store-operated Ca(2+) entry (SOCE) is the principal Ca(2+) entry mechanism in nonexcitable cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca(2+) sensor that triggers SOCE activation. However, the role of STIM1 in regulating cancer progression remains controversial and its clinical relevance is unclear. Here we show that STIM1-dependent signaling is important for cervical cancer cell proliferation, migration, and angiogenesis. STIM1 overexpression in tumor tissue is noted in 71% cases of early-stage cervical cancer. In tumor tissues, the level of STIM1 expression is significantly associated with the risk of metastasis and survival. EGF-stimulated cancer cell migration requires STIM1 expression and EGF increases the interaction between STIM1 and Orai1 in juxta-membrane areas, and thus induces Ca(2+) influx. STIM1 involves the activation of Ca(2+)-regulated protease calpain, as well as Ca(2+)-regulated cytoplasmic kinase Pyk2, which regulate the focal-adhesion dynamics of migratory cervical cancer cells. Because of an increase of p21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cells significantly inhibits cell proliferation by arresting the cell cycle at the S and G2/M phases. STIM1 also regulates the production of VEGF in cervical cancer cells. Interference with STIM1 expression or blockade of SOCE activity inhibits tumor angiogenesis and growth in animal models, confirming the crucial role of STIM1-mediated Ca(2+) influx in aggravating tumor development in vivo. These results make STIM1-dependent signaling an attractive target for therapeutic intervention.


Self-organized rod undulations on pre-stretched textiles.
Textile technology is a traditional approach to additive manufacturing based on one-dimensional yarn. Printing solid rods onto pre-stretched textiles creates internal stresses upon relaxation of the pre-stretch, which leads to buckling-induced out-of-plane deformation of the textile. Similar behaviours are well known to occur also in biological systems where differential growth leads to internal stresses that are responsible for the folding or wrinkling of leaves, for example. Our goal was to get a quantitative understanding of this wrinkling by a systematic experimental and numerical investigation of parallel rods printed onto a pre-stretched textile. We vary rod thickness and spacing to obtain wavelength and phase coherence of the wrinkles as a function of these parameters. We also derive a simple analytical description to rationalize these observations. The result is a simple analytical estimate for the phase diagram of behaviours that may be used for design purposes or to describe wrinkling phenomena in biological or bioinspired systems.


Study on ultrasonic wave propagation in equine leg bone for screening bucked shin.
For simple, safe, portable, and inexpensive evaluation suitable for leg bone diseases of racehorses in the field, an ultrasonic measurement technique was applied to evaluate wave velocities. A digital model of the third metacarpal bone with the bucked shin was fabricated using high-resolution peripheral quantitative computerized tomography data of a racehorse. This model was anisotropic and heterogeneous, and was constructed using the measured ultrasonic wave velocities in the bone. With this model, ultrasonic wave propagation along the bone axis was simulated using the elastic finite-difference time-domain method. We found two main waves with different propagation velocities. The fast-waves showed a wave velocity close to the longitudinal wave in the axial direction. However, the apparent velocities changed dramatically owing to bone surface irregularities (changes of the shape) in the area of bucked shin. The slow-waves showed a wave velocity close to the shear wave, which was unaffected by the bone surface irregularities. The simple comparison of different wave behaviors may be a suitable parameter for the initial in vivo screening of bucked shin in the legs of racehorses, which can be performed in the field.


Design and Test of a Graphic Medication Dosage Calculator in Paramedic Practice With Children.
Children are more vulnerable to medication errors during prehospital care because of paramedic staff having less experience with pediatric patients. One of the possible solutions to this problem is the use of technologies as cognitive aids to medication dosage calculation. Design and empirically test a graphic dosage calculator tailored for pediatric medication calculation in prehospital emergency care. The design and development of the calculator followed an iterative user-centered design process. Fourteen novice and 16 experienced paramedics participated in the empirical test of the graphic calculator by running 3 pediatric medication scenarios with both the graphic calculator and a pocket handbook used currently to aid calculations. It took significantly less time to complete the scenarios with the graphic calculator compared with the handbook. Both novice and experienced paramedics expressed similar levels of confidence with using the graphic calculator. Participants expressed a strong preference for the graphic calculator. Finally, the graphic calculator was scored significantly above a standard usability benchmark. The results show that the graphic calculator was usable, more effective, efficient, and preferred compared with the current dosage calculation method. Technologies such as the graphic calculator designed and tested in this study can help not only with the rare cases, such as pediatrics, but might also mitigate skill decay.


Modulation of the human hair follicle pigmentary unit by corticotropin-releasing hormone and urocortin peptides.
Human skin is a local source of corticotropin-releasing hormone (CRH) and expresses CRH and CRH receptors (CRH-R) at mRNA and protein levels. Epidermal melanocytes respond to CRH by induction of cAMP with up-regulation of pro-opiomelanocortin gene expression and subsequent production of adrenocorticotropin hormone. However, the role of CRH/CRH-R in melanocyte biology is complicated by the significant heterogeneity of cutaneous melanocyte subpopulations, from continuously active and UV-responsive melanocytes in epidermis to UV nonresponsive, hair growth cycle-coupled melanogenesis in hair follicles. In the present study we report that normal human scalp hair follicle melanocytes express CRH at the mRNA level. Furthermore, CRH, urocortin and CRH-R 1 and 2 were differentially expressed in follicular melanocytes, fibroblasts, and keratinocytes depending on anatomic location and differentiation status in situ and in vitro. Stimulation of follicular melanocytes with CRH and CRH peptides, modified for selectivity for CRH-R1 and/or CRH-R2, variably induced cell melanogenesis, dendricity, and proliferation. CRH-peptides also stimulated the expression and activity of Tyrosinase, and expression of Tyrosinase-related protein-1 and-2. However, a modified urocortin peptide highly selective for CRH-R2 down-regulated melanocyte differentiation phenotype. This study indicates that CRH peptides can differentially influence hair follicle melanocyte behavior not only via CRH-R1 signaling but also by complex cross-talk between CRH-R1 and CRH-R2.


The area under the waveform of electromyography for monitoring the external branches of the superior laryngeal nerve during thyroid surgery.
Injuries to the external branches of the superior laryngeal nerve (EBSLN) are difficult to identify during thyroidectomy. Monitoring the low amplitudes of the EBSLN during surgery has proven to be complicated. Therefore a new parameter, the area under the waveform (AUW), was designed to improve monitoring efficiency. The aim of this study was to determine the effectiveness of using AUW to monitor the EBSLN during thyroidectomy. A total of 927 patients and 927 recurrent laryngeal nerves (RLN) and EBSLNs who underwent monitored unilateral thyroidectomy were included. Standardized intraoperative neuromonitoring procedures were followed. RLN injuries were confirmed using stroboscopic laryngoscopy after surgery. EBSLN injuries were identified by means of observing changes in cricothyroid muscle (CTM) twitches when stimulated. Amplitude and AUW changes were assessed using statistical analysis. The correlations between AUW and amplitude were verified using the ratio of the two parameters to determine any decreases that were observed in the number of nerve injury cases. The receiver operating characteristic (ROC) curve was used to estimate the prediction of nerve injury. The overall injury rates of the RLN and EBSLN were 3.56% and 2.05%, respectively. The AUW for the RLN and EBSLN presented linear correlations with amplitude. In the RLN injury cases, no significant difference was observed between the two parameters (P>0.05). In the cases with EBSLN injuries, the AUW decreased 64.5%±14.1%, on average, which was a greater decrease compared to that observed for amplitude 49.7%±22.2% (P<0.0001). The summary of the EBSLN injury prediction included, amplitude vs. AUW, AUC: 0.918 vs. 0.994; P<0.0001, and Youden's index: 31.54% vs. 49.58%. The AUW demonstrated consistency with the change in amplitude, and the observed changes were significant. The use of the AUW allowed successful predictions for both RLN and EBSLN nerve injuries. Also, the sensitivity of AUW was greater than amplitude for predicting EBSLN injuries.


Monostotic fibrous dysplasia of the lumbar spine: case report and review of the literature.
Monostotic fibrous dysplasia of the spine is extremely rare. We present a 57-year-old man who complained of persistent low back pain with monostotic fibrous dysplasia of the lumbar spine. Computed tomography revealed a lytic expansile lesion and marginal sclerosis in the L2 posterior element, although a bone scan did not reveal increased uptake in the lesion. The patient underwent total excision of the tumor via a posterior approach. Two years later, he is asymptomatic with no recurrence of the lesion, as confirmed by imaging.


Carbon-Doping as Efficient Strategy for Improving Photocatalytic Activity of Polysilicon Supported Pd in Hydrogen Evolution from Formic Acid.
Interest in cost-effective materials pushes researchers to the inexpensive and abundant semiconductors to use photons' energy for generating electrons and holes required for photocatalytic transformations. At the same time, polysilicon is one of the economic semiconductors with a disadvantage of high bandgap which could be solved by carbon-doping. We employed this strategy to the synthesis of carbon-doped polysilicon by a new approach starting from citric acid and methyltrimethoxysilane. The nanocomposite obtained was utterly characterized, and compared with bare polysilicon; increased UV-Vis absorbance and shift to higher wavelengths were the most notable characteristics of the synthesized catalyst. The carbon-doped polysilicon was modified with Pd nanoparticles to obtain a new heterogeneous photocatalyst for the formic acid degradation. The decomposition of formic acid was photocatalyzed by the obtained nanocomposite with a hydrogen production turnover frequency of up to 690 h-1. Moreover, it was demonstrated that the catalyst is stable and recyclable.


Tongxinluo Induces nNOS Expression Through ERK Activation: Possible Contribution to the Effects of Tongxinluo to Attenuate Vasoconstriction.
Vasoconstriction and hypersensitivity to the vasoconstrictive action of serotonin occurs in the early stage of atherosclerosis. Vascular neural nitric oxide synthase (nNOS) plays an important role in the regulation of vascular tone and is vasoprotective against atherosclerosis. In this study, we intended to investigate the possible role of nNOS in mediating the effect of Chinese medicine Tongxinluo (TXL) to attenuate vasoconstriction induced by the chronic injury in the collared carotid artery. Twenty-four male Wistar Kyoto rats were assigned to 2 treatments (n = 12): vehicle and TXL (400 mg·kg·d). After 2 weeks of treatment, adventitia injury was induced by placing a silicone collar around the left carotid artery for 2 weeks. Blood flow and vascular reactivity to serotonin were determined, and carotid arteries were harvested for morphometry, RT-PCR, and Western blotting analysis. Expression of nNOS and phosphorylated ERK1/2 was also analyzed in primary cultured vascular smooth muscle cells after TXL and/or ERK kinase inhibitor treatment. Adventitia injury induced by the placement of a silicone collar around the carotid artery for 2 weeks led to chronic vasoconstriction and vascular hypersensitivity to serotonin, which was attenuated by TXL treatment. TXL improved the carotid blood flow and normalized the vascular hypersensitivity to serotonin in collared carotid arteries. The expression of nNOS and phosphorylated ERK1/2 was increased by TXL treatment in both collared carotid artery and vascular smooth muscle cells indicating a possible contribution of ERK1/2 and nNOS signaling to the beneficial effects of TXL. Moreover, we showed that the effect of TXL to increase nNOS expression was mediated by the phosphorylated ERK1/2 since the effect could be abolished by the ERK kinase inhibitor PD98059. TXL increases nNOS expression in the collared carotid artery through activation of ERK1/2 signaling, which may have contributed to the attenuation of vasoconstriction induced by the collar-induced adventitia injury.


Extraneural metastasis of a nongerminomatous germ cell tumor of the central nervous system in a pediatric patient with a ventriculoperitoneal shunt: a case report and review of the literature.
We describe the case of a 7-year-old white boy who presented with a mixed malignant germ cell tumor with predominant embryonal carcinoma component. The patient underwent right ventriculoperitoneal (VP) shunt placement for hydrocephalus at the time of diagnosis. He received multiagent chemotherapy followed by second-look surgery. Despite an initial response to chemotherapy, the patient had metastatic progression of disease within the craniospinal axis. He received craniospinal radiation and high-dose chemotherapy. Although, he had resolution of central nervous system (CNS) disease, follow-up off treatment revealed extra-abdominal metastases. This is a rare case to discuss abdominal metastasis of a CNS germ cell tumor in a patient with a VP shunt. The influence of VP shunt placement on treatment and management decisions of patients with CNS tumors will be discussed.


Haplotype analysis of the internationally distributed BRCA1 c.3331_3334delCAAG founder mutation reveals a common ancestral origin in Iberia.
The BRCA1 c.3331_3334delCAAG founder mutation has been reported in hereditary breast and ovarian cancer families from multiple Hispanic groups. We aimed to evaluate BRCA1 c.3331_3334delCAAG haplotype diversity in cases of European, African, and Latin American ancestry. BC mutation carrier cases from Colombia (n = 32), Spain (n = 13), Portugal (n = 2), Chile (n = 10), Africa (n = 1), and Brazil (n = 2) were genotyped with the genome-wide single nucleotide polymorphism (SNP) arrays to evaluate haplotype diversity around BRCA1 c.3331_3334delCAAG. Additional Portuguese (n = 13) and Brazilian (n = 18) BC mutation carriers were genotyped for 15 informative SNPs surrounding BRCA1. Data were phased using SHAPEIT2, and identical by descent regions were determined using BEAGLE and GERMLINE. DMLE+ was used to date the mutation in Colombia and Iberia. The haplotype reconstruction revealed a shared 264.4-kb region among carriers from all six countries. The estimated mutation age was ~ 100 generations in Iberia and that it was introduced to South America early during the European colonization period. Our results suggest that this mutation originated in Iberia and later introduced to Colombia and South America at the time of Spanish colonization during the early 1500s. We also found that the Colombian mutation carriers had higher European ancestry, at the BRCA1 gene harboring chromosome 17, than controls, which further supported the European origin of the mutation. Understanding founder mutations in diverse populations has implications in implementing cost-effective, ancestry-informed screening.


Conformational studies of muscarone analogues: X-ray analysis and molecular mechanics calculations.
The X-ray structure of muscarone analogues 3 and 4 was determined and compared with that of muscarone (1, iodide and picrate salts), muscarine 2, dioxolane 5, oxathiolane 6, and tetrahydrofuran 7. In order to better define the pharmacological stereoselectivity of muscarone, the conformational profiles of compounds 1, 2, 3, and 5 were analyzed using Allinger's MM2(85) program or, in the case of 4, by 1H NMR spectroscopy. The conformation of the ring in 1 proved similar to that of the other derivatives. MM2 calculations predicted a preferred gauche arrangement of the side chain for 1 and its analogues; such an arrangement was also observed in the solid state of muscarone picrate. Thus, the antiperiplanar arrangement reported for crystalline muscarone iodide appears to be due to crystallographic packing forces. As a consequence, the rationalization of the pharmacological profile of 1 based on the antiperiplanar arrangement is now highly questionable. The lack of stereoselectivity of 4 can be attributed to the absence of a stereocenter at C-2 whereas, in our opinion, there are currently no sound explanations for the low values of eudismic ratios for the muscarone enantiomers.


Cystic left ventricular mass: the utility of transthoracic echocardiography and cardiac MRI.
Accurate identification of left ventricular masses (LVM) can be challenging, and if incorrect, may have devastating consequences. While transthoracic echocardiography is often the first test to identify intracardiac masses, cardiac MRI (CMRI) allows for better anatomical definition and tissue characterisation. We present a case of a 51-year-old man who presented with 4 weeks of shortness of breath, found on echocardiogram to have severely reduced LV function and a 2.5×4.0 cm LVM with a hypolucent/cystic core. Due to the unusual appearance, CMRI was required for confirmation of an LV thrombus. This case highlights the importance of multimodality imaging in the discovery and identification of LVM.


Effects of hydrogeological properties on sea-derived benzene transport in unconfined coastal aquifers.
This paper presents numerical investigations on quantifying the hydrodynamic effects of coastal environment factors, including tidal fluctuations, beach slopes, hydraulic conductivity, and hydraulic gradients on sea-derived benzene transport in unconfined coastal aquifers. A hydrologic transport and mixed geochemical kinetic/equilibrium reactions in saturated-unsaturated media model was used to simulate the spatial and temporal behaviors of the density flow and benzene transport for various hydrogeological conditions. Simulation results indicated that the tidal fluctuations lead to upper saline plumes (USPs) near the groundwater and seawater interfaces. Such local circulation zones trapped the seaward benzene plumes and carried them down in aquifers to the depth depending on the tide amplitudes and beach slopes across the coastal lines. Comparisons based on different tidal fluctuations, beach slopes, hydraulic conductivity, and hydraulic gradient were systematically conducted and quantified. The results indicated that areas with USPs increased with the tidal amplitude and decreased with the increasing beach slope. However, the variation of hydraulic conductivity and hydraulic gradient has relatively small influence on the patterns of flow fields in the study. The increase of the USP depths was linearly correlated with the increase of the tidal amplitudes. The benzene reactive transport simulations revealed that the plume migrations are mainly controlled by the local flow dynamics and constrained in the USP circulation zones. The self-cleaning process of a coastal aquifer is time-consuming, typically requiring double the time of the contamination process that the benzene plume reach the bottom of a USP circulation zone. The presented systematic analysis can provide useful information for rapidly evaluating seaward contaminants along a coastal line with available hydrogeological properties.


Risk of contamination of lidocaine hydrochloride and phenylephrine hydrochloride topical solution: in vivo and in vitro analyses.
To investigate the risk of contamination of lidocaine hydrochloride 5 per cent weight/volume and phenylephrine hydrochloride 0.5 per cent weight/volume topical solution, both in patients (in vivo) and in the laboratory setting (in vitro). This paper reports a prospective study involving 10 samples of the lidocaine hydrochloride and phenylephrine hydrochloride topical anaesthetic spray. The samples were assessed for microbiological contamination after a single use on patients in a controlled laboratory environment. Additional samples were assessed for baseline contamination and later assessed for contamination in an in vitro setting. In the in vivo setting, 2 of the 10 samples were positive for cultures from both the pump and the bottles. However, in the in vitro setting, the pump and the contents of the bottles were contaminated after a single use when the sterile solution was sprayed from distances of 1 and 2 cm. The lidocaine hydrochloride and phenylephrine hydrochloride topical solution assembly was contaminated in both in vivo and in vitro settings after a single use.


Ciguatera fish poisoning: treatment with intravenous mannitol.
Intravenous mannitol was given to 16 patients with acute ciguatera fish poisoning requiring hospital admission. Thirteen patients (81%) presented with sensory and neuromuscular symptoms; paraesthesiae and pain and weakness in the lower limbs were predominant features. Mannitol had little effect upon gastrointestinal manifestations, but a marked reduction was observed in the expected duration of neurological symptoms. Although these results are empirical and uncontrolled, they suggest that mannitol infusion may be effective in altering the clinical course of acute ciguatera fish poisoning.


Angular-divergence calculation for Experimental Advanced Superconducting Tokamak neutral beam injection ion source based on spectroscopic measurements.
Calorimetric method has been primarily applied for several experimental campaigns to determine the angular divergence of high-current ion source for the neutral beam injection system on the Experimental Advanced Superconducting Tokamak (EAST). A Doppler shift spectroscopy has been developed to provide the secondary measurement of the angular divergence to improve the divergence measurement accuracy and for real-time and non-perturbing measurement. The modified calculation model based on the W7AS neutral beam injectors is adopted to accommodate the slot-type accelerating grids used in the EAST's ion source. Preliminary spectroscopic experimental results are presented comparable to the calorimetrically determined value of theoretical calculation.


Comparative High Voltage Impulse Measurement.
A facility has been developed for the determination of the ratio of pulse high voltage dividers over the range from 10 kV to 300 kV using comparative techniques with Kerr electro-optic voltage measurement systems and reference resistive voltage dividers. Pulse voltage ratios of test dividers can be determined with relative expanded uncertainties of 0.4 % (coverage factor k = 2 and thus a two standard deviation estimate) or less using the complementary resistive divider/Kerr cell reference systems. This paper describes the facility and specialized procedures used at NIST for the determination of test voltage divider ratios through comparative techniques. The error sources and special considerations in the construction and use of reference voltage dividers to minimize errors are discussed, and estimates of the measurement uncertainties are presented.


Tryptophan Predicts the Risk for Future Type 2 Diabetes.
Recently, 5 amino acids were identified and verified as important metabolites highly associated with type 2 diabetes (T2D) development. This report aims to assess the association of tryptophan with the development of T2D and to evaluate its performance with existing amino acid markers. A total of 213 participants selected from a ten-year longitudinal Shanghai Diabetes Study (SHDS) were examined in two ways: 1) 51 subjects who developed diabetes and 162 individuals who remained metabolically healthy in 10 years; 2) the same 51 future diabetes and 23 strictly matched ones selected from the 162 healthy individuals. Baseline fasting serum tryptophan concentrations were quantitatively measured using ultra-performance liquid chromatography triple quadruple mass spectrometry. First, serum tryptophan level was found significantly higher in future T2D and was positively and independently associated with diabetes onset risk. Patients with higher tryptophan level tended to present higher degree of insulin resistance and secretion, triglyceride and blood pressure. Second, the prediction potential of tryptophan is non-inferior to the 5 existing amino acids. The predictive performance of the combined score improved after taking tryptophan into account. Our findings unveiled the potential of tryptophan as a new marker associated with diabetes risk in Chinese populations. The addition of tryptophan provided complementary value to the existing amino acid predictors.


Recent advances in craniofacial morphogenesis.
Craniofacial malformations are involved in three fourths of all congenital birth defects in humans, affecting the development of head, face, or neck. Tremendous progress in the study of craniofacial development has been made that places this field at the forefront of biomedical research. A concerted effort among evolutionary and developmental biologists, human geneticists, and tissue engineers has revealed important information on the molecular mechanisms that are crucial for the patterning and formation of craniofacial structures. Here, we highlight recent advances in our understanding of evo-devo as it relates to craniofacial morphogenesis, fate determination of cranial neural crest cells, and specific signaling pathways in regulating tissue-tissue interactions during patterning of craniofacial apparatus and the morphogenesis of tooth, mandible, and palate. Together, these findings will be beneficial for the understanding, treatment, and prevention of human congenital malformations and establish the foundation for craniofacial tissue regeneration.


Differences in knee joint degeneration between primary hip osteoarthritis and hip osteoarthritis secondary to hip developmental dysplasia: A propensity score-based analysis.
This study aimed to investigate differences in lower limb alignment and the prevalence of knee osteoarthritis (OA) among patients with primary hip osteoarthritis (PHOA) versus those with hip osteoarthritis secondary to developmental dysplasia of the hip (DDH-OA). We compared 83 patients who underwent primary total hip arthroplasty for unilateral PHOA or DDH-OA after performing propensity score matching. The prevalence of knee OA and lower limb alignment were evaluated on preoperative plain radiographs. The prevalence of knee OA on the ipsilateral side was significantly higher in the PHOA group than in the DDH-OA group (p =.019), whereas there was no difference between the groups on the contralateral side (p = .631). Lower-limb alignment was more valgus on the ipsilateral side in the DDH-OA group than the PHOA group, whereas it was not significantly different on the contralateral side between groups. The prevalence of knee OA and lower-limb malalignment on the ipsilateral side of hip OA were different for PHOA and DDH-OA patients. Shifting the mechanical axis of lower limbs might be associated with the prevalence of knee OA and lower limb malalignment in the presence of unilateral hip OA.


Treatment outcomes in 23 thoracic primitive neuroectodermal tumours: a retrospective study.
Thoracic primitive neuroectodermal tumour is an aggressive malignancy with poor survival despite multimodality treatment regimens. Early diagnosis of the tumour by histological, immunohistochemical, ultrastructural and cytogenetic techniques and early total surgical resection of the tumour with intensive chemoradiation may improve outcomes. Over 30 years, 23 patients (median age 29.5) with primitive neuroectodermal tumours (15 chest wall, 4 lung, 3 costovertebral sulcus and 1 anterior mediastinum) were diagnosed by transthoracic needle biopsy (43%) or excisional biopsy (57%). Treatment of a localized disease (Stage I and II) in 19 patients included surgery (wide excision of chest lesions in 11, 4 lung resections, excision of 3 costovertebral sulcus and 1 anterior mediastinal tumours, and resection of adjacent tissues involved by tumour en bloc) with adjuvant chemoradiation. Four metastatic chest wall tumours (Stage III) had chemotherapy and radiation alone. Tumour recurred in 5 (2 chest wall, 2 costovertebral sulcus and 1 lung) requiring further chemotherapy, radiation and completion pneumonectomy for a lung recurrence. The incidence of recurrent tumour in 7 years for Stage I was 21 vs 40% (P=0.4) for Stage II lesions and 16% after the neoadjuvant chemotherapy vs 30% (P=0.4) after adjuvant chemoradiation. Four with recurrence, except one with a chest recurrence, succumbed to second relapse (78-96 months). All four Stage III chest tumours succumbed to advanced disease (30 months). The Kaplan-Meier disease-free survival of the overall group (23 patients) was 82±2% at 5 years and 64±3% at 10 years. The 10-year disease-free survival of 19 patients with localized tumours was 76%, but was high at 90% for chest wall tumours and low 33% for costovertebral sulcus tumours (P≤0.01). The 10-year disease-free survival was 86% for Stage I vs 60% (P=0.02) for Stage II tumours; and 83% for neoadjuvant vs 76% (P=0.06) for adjuvant chemotherapy and radiation. The primitive neuroectodermal tumours are aggressive neoplasms with poor prognosis. Early diagnosis and total surgical excision of localized tumours with neoadjuvant or adjuvant chemotherapy and radiation improved disease-free survival.


[Angiographic diagnosis in liver transplantation. I: Evaluation before transplantation].
Our study covers angiographic pretransplant evaluation from 9/88-4/90. 57 out of 73 patients (78%) underwent pretransplant angiography. In all cases aortography, angiographies of the coeliac axis, the superior mesenteric artery, the splenic artery, and portograms were obtained. The arterial studies evaluated the arterial blood supply of the liver, the diameter of the common hepatic artery, aneurysms and a steal effect of the splenic artery. Portography revealed the exact venous collateralisation. Thus angiography remains a valuable procedure for pretransplant evaluation besides ultrasongraphy.


Production of cytokines in patients with primary pulmonary Mycobacterium avium-intracellulare complex disease.
To clarify the immunological state of patients with pulmonary Mycobacterium avium-intracellulare complex (MAC) disease, we compared the production of IFN-gamma, IL-10 and TNF-alpha by peripheral blood mononuclear cells (PBMC) between MAC disease patients with different levels of disease activity and healthy volunteers. The patients had no complication of systemic immunological diseases or preexisting pulmonary diseases. PBMC obtained from 46 patients and 15 healthy control volunteers were incubated with a protein antigen extracted from Mycobacterium intracellulare (PPD-B) for seven days, and IFN-gamma, IL-10 and TNF-alpha concentration in the supernatant of the cultures was measured by enzyme-linked immunosorbent assay (ELISA). We categorized the patients into 3 groups based on the findings of chest radiography or results of sputum culture for MAC: group I in a stable state of the disease activity (15 patients), group II in an unstable state (16 patients) and group III in an active state of the disease (15 patients). IFN-gamma was low in all three patient groups compared to the healthy group. There was no difference of the concentration of IFN-gamma among the three patient groups. IL-10 was high in the patient groups compared to the healthy group, and the concentration of IL-10 in the patients of groups II and III was significantly higher than in the healthy group. Although the production of TNF-alpha in group I was significantly suppressed compared to the healthy group, the production of TNF-alpha was significantly elevated in groups II and III compared to group I. There was no difference in the production of these cytokines between the patients of group III with tuberculosis-like form and with nodular-bronchietasis form. These findings suggested that the Th1-type reaction in the patients with primary pulmonary MAC disease is suppressed (lower than the healthy persons) irrespective of the disease activity state and that the Th2-type reaction is increased in parallel with disease activity.


Femtogram-scale photothermal spectroscopy of explosive molecules on nanostrings.
We demonstrate detection of femtogram-scale quantities of the explosive molecule 1,3,5-trinitroperhydro-1,3,5-triazine (RDX) via combined nanomechanical photothermal spectroscopy and mass desorption. Photothermal spectroscopy provides a spectroscopic fingerprint of the molecule, which is unavailable using mass adsorption/desorption alone. Our measurement, based on thermomechanical measurement of silicon nitride nanostrings, represents the highest mass resolution ever demonstrated via nanomechanical photothermal spectroscopy. This detection scheme is quick, label-free, and is compatible with parallelized molecular analysis of multicomponent targets.


Human hair melanins: what we have learned and have not learned from mouse coat color pigmentation.
Hair pigmentation is one of the most conspicuous phenotypes in humans. Melanocytes produce two distinct types of melanin pigment: brown to black, indolic eumelanin and yellow to reddish brown, sulfur-containing pheomelanin. Biochemically, the precursor tyrosine and the key enzyme tyrosinase and the tyrosinase-related proteins are involved in eumelanogenesis, while only the additional presence of cysteine is necessary for pheomelanogenesis. Other important proteins involved in melanogenesis include P protein, MATP protein, α-MSH, agouti signaling protein (ASIP), MC1R (the receptor for MSH and ASIP), and SLC7A11, a cystine transporter. Many studies have examined the effects of loss-of-function mutations of those proteins on mouse coat color pigmentation. In contrast, much less is known regarding the effects of mutations of the corresponding proteins on human hair pigmentation except for MC1R polymorphisms that lead to pheomelanogenesis. This perspective will discuss what we have/have not learned from mouse coat color pigmentation, with special emphasis on the significant roles of pH and the level of cysteine in melanosomes in controlling melanogenesis. Based on these data, a hypothesis is proposed to explain the diversity of human hair pigmentation.


Health behaviors in elderly people. A 5-year follow-up of 75-year-old people living in three Nordic localities. Smoking, physical activity, alcohol consumption, and healthy eating, and attitudes to their importance.
Few studies about health behavior among elderly persons in the Nordic countries are available, and our knowledge about longitudinal changes is especially limited. The purpose of this study was to assess the prevalence of selected health behaviors as reported at age 75 years in Finland, Sweden and Denmark together with answers regarding attitudes to such habits, and study longitudinal changes between 75 and 80 years. The study population included 499 men and 704 women born in 1914/15 and examined in 1989/90 in Jyväskylä (Finland), Göteborg (Sweden), and Glostrup (Denmark). Survivors were re-examined in 1994/95. A self-administered validated questionnaire developed from the Danish Nationwide Health Surveys was given to the participants during a home visit and checked when the subjects came to the laboratory examination. The Danes had the highest proportion of smokers and persons with daily alcoholic beverage consumption and the smallest proportion of healthy eaters, but the Swedes had the most sedentary life-style. Women had the healthiest life-style. Between ages 75 and 80 years, the proportion of participants who tried to improve their health decreased, but there was no change in believing the importance of one's own effort in maintaining health. The free-time physical activity decreased, but there was no change in the attitude towards physical activity. There were major cross-national differences among the three Nordic localities, but the health behaviors were rather stable, though the proportion of participants who tried to improve their health decreased. Not more than 60 to 70% of the subjects believed that their own efforts are important to health.


Pressure-Induced Collapse of Magnetic Order in Jarosite.
We report a pressure-induced phase transition in the frustrated kagomé material jarosite at ∼45 GPa, which leads to the disappearance of magnetic order. Using a suite of experimental techniques, we characterize the structural, electronic, and magnetic changes in jarosite through this phase transition. Synchrotron powder x-ray diffraction and Fourier transform infrared spectroscopy experiments, analyzed in aggregate with the results from density functional theory calculations, indicate that the material changes from a R3[over ¯]m structure to a structure with a R3[over ¯]c space group. The resulting phase features a rare twisted kagomé lattice in which the integrity of the equilateral Fe^{3+} triangles persists. Based on symmetry arguments we hypothesize that the resulting structural changes alter the magnetic interactions to favor a possible quantum paramagnetic phase at high pressure.


Auditory cortical response patterns to multiple rhythms of AM sound.
Multiple amplitude modulation (AM) of a tone results in a time series with a complex structure of envelope fluctuations. In this study the cortical responses elicited by such an auditory stimulus were investigated. It was hypothesized that the auditory cortex responds simultaneously with different patterns of activity corresponding to the different rhythm of periodical stimulus fluctuations. The relations of these response patterns to either steady-state responses (SSR) in the 40 Hz range or the transient slow auditory evoked responses were investigated. Auditory evoked magnetic fields were recorded from the left temporal cortex of nine healthy humans in response to 250 Hz tones that were amplitude modulated with the sum of two sinusoids of 38 and 40 Hz. The stimulus was presented continuously to the subject's right ear at the intensity of 70 dB sensation level. In addition, the responses to 250 Hz tone-burst stimuli with duration of 20, 50, 100, and 200 msec, respectively, were recorded. The tone-bursts were presented at an inter-stimulus interval (ISI) of 0.5 sec, which was equivalent to the slowest rhythm of the multiple-AM stimulus. Magnetic source analysis was applied to all elicited waveforms. From all subjects SSR at 38 and 40 Hz were clearly recognizable and were superimposed by a periodical response pattern corresponding to 2 Hz stimulus envelope fluctuations. A positive peak with latency of 70 msec was the mostly pronounced response to tone-burst stimulation at the ISI of 0.5 sec and resembles the low-frequency response pattern to the AM stimulus. The N1-P2 complex showed an almost complete suppression at 0.5 sec ISI. In contrast, it was the most prominent evoked response activity when using a longer ISI of 3 sec. Source locations in overlapping areas were estimated for the SSR in the 40 Hz range, the prominent peak of low-frequency response to the AM stimulus, and the P1 peak at tone-burst stimulation, respectively. These were separated from the N1 source location by about 0.5 cm in anterior and 0.5 cm in medial direction. As a result of multiple AM the stimulus signal envelope fluctuates with frequencies of 2 Hz and around 40 Hz. The auditory cortex responds to this stimulus with different response patterns. Both modulation signals at 38 and 40 Hz were almost linearly represented as steady-state responses. The evoked response patterns to stimulus fluctuations at low-frequency rhythm resemble the slow cortical auditory evoked responses. The 2 Hz stimulus rhythm is perceived as loudness fluctuation, and 40 Hz modulation is perceived as a rough sound. It is assumed that the different cortical representations correspond to both types of perception of the complex AM sound.


The impact of diabetic neuropathy on the distal versus proximal comparison of weakness in lower and upper limb muscles of patients with type 2 diabetes mellitus: a cross-sectional study.
This study aimed to determine the impact of diabetic neuropathy (dNP) on the distal versus proximal comparison of weakness in lower and upper limb muscles of patients with type 2 Diabetes Mellitus (T2DM). 19 healthy male controls without neuropathy (HC) and 35 male T2DM patients, without dNP (n=8), with sensory dNP (n=13) or with sensorimotor dNP (dNPsm; n=14), were enrolled in this study. Maximal isometric (IM) and isokinetic (IK) muscle strength and IK muscle endurance of the dominant knee, ankle and elbow, and maximal IM handgrip strength were measured by means of dynamometry. Ankle muscle endurance was lower compared to the knee, independently of dNP (p<0.001). Maximal IK ankle muscle strength was also lower compared to the knee, albeit only in dNPsm (p=0.003). No differences were found between maximal IM handgrip and elbow strength. Our results suggest an impact of T2DM -with or without dNP- on lower limb muscle strength more distally than proximally, while this was not observed in the upper limb. The gradient of dNP seemed to be a determining factor for the maximal muscle strength, and not for muscle endurance, in the lower limb.


Use of a hypervariable minisatellite DNA probe (33.15) for evaluating engraftment two or more years after bone marrow transplantation for aplastic anaemia.
We have studied long-term engraftment in 24 multiply transfused patients transplanted for severe aplastic anaemia (SAA) 2-7 years previously from HLA identical sibling donors. All 24 patients had engrafted initially; nine (38%) developed grade II-IV a-GVHD, but only 5 (21%) developed chronic GVHD, which was mild, localized and transient. In 22 cases DNA 'fingerprint' analysis using a hypervariable minisatellite DNA probe (33.15) confirmed the donor/recipient origin of patient peripheral blood (PB) nucleated cells. Red cell antigens and PB lymphocyte chromosomes were also analysed in informative cases. In 19 patients (79%) PB cells were of donor origin confirming sustained engraftment, whereas five (21%) had PB cells of recipient origin. In four of these five cases complete autologous reconstitution was demonstrated. In one case DNA fingerprinting revealed mixed haemopoietic chimaerism. In three of the four cases of autologous reconstitution there had been a previous episode of late graft failure. The low incidence of chronic GVHD in the study group was not explained by autologous reconstitution or mixed chimaerism. We conclude that the hypervariable minisatellite probes are valuable in the study of engraftment after BMT, especially when patient and donor are HLA identical, of the same sex, and have the same ABO-Rh blood type. Pre-transplant specimens from the patient are not necessary for interpretation of the results provided that DNA from the donor is available.


SGLT2 Protein Expression Is Increased in Human Diabetic Nephropathy: SGLT2 PROTEIN INHIBITION DECREASES RENAL LIPID ACCUMULATION, INFLAMMATION, AND THE DEVELOPMENT OF NEPHROPATHY IN DIABETIC MICE.
There is very limited human renal sodium gradient-dependent glucose transporter protein (SGLT2) mRNA and protein expression data reported in the literature. The first aim of this study was to determine SGLT2 mRNA and protein levels in human and animal models of diabetic nephropathy. We have found that the expression of SGLT2 mRNA and protein is increased in renal biopsies from human subjects with diabetic nephropathy. This is in contrast to db-db mice that had no changes in renal SGLT2 protein expression. Furthermore, the effect of SGLT2 inhibition on renal lipid content and inflammation is not known. The second aim of this study was to determine the potential mechanisms of beneficial effects of SGLT2 inhibition in the progression of diabetic renal disease. We treated db/db mice with a selective SGLT2 inhibitor JNJ 39933673. We found that SGLT2 inhibition caused marked decreases in systolic blood pressure, kidney weight/body weight ratio, urinary albumin, and urinary thiobarbituric acid-reacting substances. SGLT2 inhibition prevented renal lipid accumulation via inhibition of carbohydrate-responsive element-binding protein-β, pyruvate kinase L, SCD-1, and DGAT1, key transcriptional factors and enzymes that mediate fatty acid and triglyceride synthesis. SGLT2 inhibition also prevented inflammation via inhibition of CD68 macrophage accumulation and expression of p65, TLR4, MCP-1, and osteopontin. These effects were associated with reduced mesangial expansion, accumulation of the extracellular matrix proteins fibronectin and type IV collagen, and loss of podocyte markers WT1 and synaptopodin, as determined by immunofluorescence microscopy. In summary, our study showed that SGLT2 inhibition modulates renal lipid metabolism and inflammation and prevents the development of nephropathy in db/db mice.


An empirical test of Woody and Bowers's dissociated-control theory of hypnosis.
Woody and Bowers's dissociated-control theory predicts impaired performance on tasks indexing frontally mediated supervisory attentional functions during hypnosis, especially for high susceptibles. This prediction is tested using Stroop task behavioral performance to measure aspects of anterior-mediated supervisory attentional function. All measures of anterior-mediated attentional functions significantly declined during hypnosis. Interactions be-tween susceptibility and hypnosis condition showed specific changes among hypnotized high susceptibles. Total Stroop errors (failures of attentional suppression) were significantly higher in hypnosis for high, but not low, susceptibles. Tellegen's experiential mental set was highest for hypnotized highs. Use of rehearsal strategy (instrumental set) decreased significantly in hypnosis but more so for highs than lows. Results suggest that "absorption" in hypnosis may be a consequence of dissociated anterior attentional control. It is proposed that dissociated control emerges from the functional disconnection of left dorsolateral prefrontal cortex and anterior cingulate cortex.


Individuals with stroke reporting unmet need for occupational therapy following discharge from hospital.
ABSTRACT The purpose of this study was to identify the characteristics and needs of individuals with stroke who report an unmet need for occupational therapy following discharge from hospital. Needs were assessed using a semi-structured interview and a survey in a sample of 209 adults hospitalized with a stroke. Participants were divided into three groups-those needing occupational therapy; those receiving occupational therapy, and those neither needing nor receiving occupational therapy. Thirteen percent (n = 28) reported an unmet need for occupational therapy and were more dependent in activities of daily living (ADL) before and after their stroke and had lower acute functional independence measure (FIM) scores than the comparison groups (p < .05). Participants with unmet needs for occupational therapy were more likely to report unmet needs related to upper extremity function, basic and instrumental ADL, leisure, assistive devices, and the resumption of social roles.


Custom Knee Device for Knee Contractures After Internal Femoral Lengthening.
The development of knee flexion contractures is among the most common problems and complications associated with lengthening the femur with an internal device or external fixator. Conservative treatment strategies include physical therapy, serial casting, and low-load prolonged stretching with commercially available splinting systems. The authors developed an individually molded, low-cost custom knee device with polyester synthetic conformable casting material to treat knee flexion contractures. The goal of this study was to evaluate the results of treatment with a custom knee device and specialized physical therapy in patients who had knee flexion contracture during femoral lengthening with an intramedullary lengthening femoral nail. This retrospective study included 23 patients (27 limbs) who underwent femoral lengthening with an internal device for the treatment of limb length discrepancy. All patients had a knee flexion contracture raging from 10° to 90° during the lengthening process and were treated with a custom knee device and specialized physical therapy. The average flexion contracture before treatment was 36°. The mean amount of lengthening was 5.4 cm. After an average of 3.8 weeks of use of the custom knee device, only 2 of 27 limbs (7.5%) had not achieved complete resolution of the flexion contracture. The average final extension was 1.4°. Only 7 of 27 limbs (26%) required additional soft tissue release. The custom knee device is an inexpensive and effective method for treating knee flexion contracture after lengthening with an internal device.


Simvastatin decreases hyperbaric oxygen-induced acute lung injury by upregulating eNOS.
Statins, which are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase competitive inhibitors, not only lower blood cholesterol but also exert pleiotropic and beneficial effects in various diseases. However, the effects of statins on acute lung injury (ALI) induced by hyperbaric oxygen (HBO) have not been investigated. The present study is the first to investigate the effects of simvastatin in ALI induced by HBO in 8- to 9-wk-old C57BL/6 mice exposed to 0.23 MPa [=2.3 atmosphere absolute (ATA)] hyperoxia (≥95% O2) for 6 h. Mice were either given simvastatin (20 mg·kg·-1·day-1) in saline or a saline vehicle for 3 days before oxygen exposure. Lung tissue, serum, and bronchoalveolar lavage fluid (BALF) were collected for analysis of proapoptotic proteins, low-density lipoprotein cholesterol (LDL-C) levels, and lung inflammation. Simvastatin treatment significantly reduced lung permeability, serum LDL-C levels, tissue apoptosis, and inflammation. However, simvastatin treatment had no effect on antioxidant enzyme activity, nicotinamide adenine dinucleotide phosphate oxidase 4 (NADPH4) expression, and Akt phosphorylation levels. Furthermore, we investigated the role of endothelial nitric oxide synthase (eNOS) in simvastatin protection through inhibiting eNOS activity with NG-nitro-l-arginine methyl ester (l-NAME; 20 mg/kg). Results showed that the beneficial effects of simvastatin on ALI induced by HBO (antiinflammatory, antiapoptotic, lipid lowering, and reduction in lung permeability) were reversed. These results showed that simvastatin curbs HBO-induced lung edema, permeability, inflammation, and apoptosis via upregulating eNOS expression and that simvastatin could be an effective therapy to treat prolonged HBO exposure.


Pressor sensitivities to vasopressin, angiotensin II, or methoxamine in diabetic rats.
We investigated the pressor sensitivities to vasopressin, angiotensin II, and methoxamine of intact and ganglion-blocked rats that had been treated 21 days earlier with streptozotocin or saline. No differences in blood pressure or heart rate responses to vasopressin or angiotensin II were found between the intact groups when these peptides were administered intravenously in equimolar doses. After ganglion blockade a significant enhancement in pressor responsiveness to both vasopressin and angiotensin II was observed in the control groups, but in the streptozotocin-treated animals no enhancement in pressor sensitivity to vasopressin was found. Furthermore, although a significant augmentation of the responses to angiotensin II was observed, it was smaller than that seen in the ganglion-blocked control group. Neither group showed enhanced pressor responsiveness to methoxamine. These results indicate that the previously observed diminished contributions from endogenous vasopressin and the renin-angiotensin system to blood pressure recovery following ganglion blockade in streptozotocin-treated rats may have been due, at least in part, to diminished pressor responsiveness.


Age-specific differences in outcomes after out-of-hospital cardiac arrests.
We assessed out-of-hospital cardiac arrests (OHCAs) for various pediatric age groups. This prospective, population-based, observational study included all emergency medical service-treated OHCAs in Osaka, Japan, between 1999 and 2006 (excluding 2004). Patients were grouped as adults (>17 years), infants (<1 year), younger children (1-4 years), older children (5-12 years), and adolescents (13-17 years). The primary outcome measure was 1-month survival with favorable neurologic outcome. Of 950 pediatric OHCAs, resuscitations were attempted for 875 patients (92%; 347 infants, 203 younger children, 135 older children, and 190 adolescents). The overall incidence of nontraumatic pediatric OHCAs was 7.3 cases per 100 000 person-years, compared with 64.7 cases per 100 000 person-years for adults and 65.5 cases per 100 000 person-years for infants. Most infant OHCAs occurred in homes (93%) and were not witnessed (90%). Adolescent OHCAs often occurred outside the home (45%), were witnessed by bystanders (37%), and had shockable rhythms (18%). One-month survival was more common after nontraumatic pediatric OHCAs than adult OHCAs (8% [56 of 740 patients] vs 5% [1677 of 33 091 patients]; adjusted odds ratio: 2.26 [95% confidence interval: 1.63-3.13]). One-month survival with favorable neurologic outcome was more common among children than adults (3% [21 of 740 patients] vs 2% [648 of 33 091 patients]; adjusted odds ratio: 2.46 [95% confidence interval: 1.45-4.18]). Rates of 1-month survival with favorable neurologic outcome were 1% for infants, 2% for younger children, 2% for older children, and 11% for adolescents. Survival and favorable neurologic outcome at 1 month were more common after pediatric OHCAs than adult OHCAs.


The role of primordial emotions in the evolutionary origin of consciousness.
Primordial emotions are the subjective element of the instincts which are the genetically programmed behaviour patterns which contrive homeostasis. They include thirst, hunger for air, hunger for food, pain and hunger for specific minerals etc. There are two constituents of a primordial emotion--the specific sensation which when severe may be imperious, and the compelling intention for gratification by a consummatory act. They may dominate the stream of consciousness, and can have plenipotentiary power over behaviour. It is hypothesized that early in animal evolution complex reflex mechanisms in the basal brain subserving homeostatic responses, in concert with elements of the reticular activating system subserving arousal, melded functionally with regions embodied in the progressive rostral development of the telencephalon. This included the emergent limbic and paralimbic areas, and the insula. This phylogenetically ancient organization subserved the origin of consciousness as the primordial emotion, which signalled that the organisms existence was immediately threatened. Neuroimaging confirms major activations in regions of the basal brain during primordial emotions in humans. The behaviour of decorticate humans and animals is discussed in relation to the possible existence of primitive awareness. Neuroimaging of the primordial emotions reveals that rapid gratification of intention by a consummatory act such as ingestion causes precipitate decline of both the initiating sensation and the intention. There is contemporaneous rapid disappearance of particular regions of brain activation which suggests they may be part of the jointly sufficient and severally necessary activations and deactivations which correlate with consciousness [Crick, F. & Koch, C. (2003). A framework for consciousness. NatureNeuroscience,6, 119-126].


Oculo-Visual Findings among Industrial Mine Workers at Goldfields Ghana Limited, Tarkwa.
The focus of this study was to evaluate the visual status of mine workers who were directly involved in mining and/or are exposed to the mining environment. A hospital based cross-sectional study was conducted. Four hundred and six (406) workers were conveniently sampled for the study. Information on their socio-demographic data was also collected. In addition, all participants underwent ophthalmic examination. The mean age of the workers was 41.1 years. Visual impairment was found in 114 (28.1%) of the study population of which refractive error (56.8%) was the major cause. Presbyopia was also observed in 45.5% of the workers with only 30.3% of them wearing near correction. The prevalence of eye diseases were pterygium/pingueculae (25.8%), conjunctivitis (26.8%), suspected glaucoma (15.3%), and cataract (7.4%). Visual impairment and eye diseases were found among the miners.


A novel deletion in the GTPase domain of OPA1 causes defects in mitochondrial morphology and distribution, but not in function.
Autosomal dominant optic atrophy (ADOA), the commonest cause of inherited optic atrophy, is caused by mutations in the ubiquitously expressed gene optic atrophy 1 (OPA1), involved in fusion and biogenesis of the inner membrane of mitochondria. Bioenergetic failure, mitochondrial network abnormalities and increased apoptosis have all been proposed as possible causal factors. However, their relative contribution to pathogenesis as well as the prominent susceptibility of the retinal ganglion cell (RGC) in this disease remains uncertain. Here we identify a novel deletion of OPA1 gene in the GTPase domain in three patients affected by ADOA. Muscle biopsy of the patients showed neurogenic atrophy and abnormal morphology and distribution of mitochondria. Confocal microscopy revealed increased mitochondrial fragmentation in fibroblasts as well as in myotubes, where mitochondria were also unevenly distributed, with clustered organelles alternating with areas where mitochondria were sparse. These abnormalities were not associated with altered bioenergetics or increased susceptibility to pro-apoptotic stimuli. Therefore, changes in mitochondrial shape and distribution can be independent of other reported effects of OPA1 mutations, and therefore may be the primary cause of the disease. The arrangement of mitochondria in RGCs, which degenerate in ADOA, may be exquisitely sensitive to disturbance, and this may lead to bioenergetic crisis and/or induction of apoptosis. Our results highlight the importance of mitochondrial dynamics in the disease per se, and point to the loss of the fine positioning of mitochondria in the axons of RGCs as a possible explanation for their predominant degeneration in ADOA.


Diabetes-Associated Susceptibility to Tuberculosis: Contribution of Hyperglycemia vs. Dyslipidemia.
Diabetes is a major risk factor for tuberculosis (TB). Diabetes increases the risk of the progression from latent tuberculosis infection (LTBI) to active pulmonary TB and TB patients with diabetes are at greater risk of more severe disease and adverse TB treatment outcomes compared to TB patients without co-morbidities. Diabetes is a complex disease, characterised not only by hyperglycemia but also by various forms of dyslipidemia. However, the relative contribution of these underlying metabolic factors to increased susceptibility to TB are poorly understood. This review summarises our current knowledge on the epidemiology and clinical manifestation of TB and diabetes comorbidity. We subsequently dissect the relative contributions of body mass index, hyperglycemia, elevated cholesterol and triglycerides on TB disease severity and treatment outcomes. Lastly, we discuss the impact of selected glucose and cholesterol-lowering treatments frequently used in the management of diabetes on TB treatment outcomes.


Cell Surfaces in Plant-Microorganism Interactions: I. A Structural Investigation of Cell Wall Hydroxyproline-rich Glycoproteins Which Accumulate in Fungus-infected Plants.
Infection of muskmelon Cucumis melo seedlings by the fungus Colletotrichum lagenarium causes a 10-fold increase in the amount of cell wall hydroxyproline-rich glycoprotein. Evidence for this increase was provided by studying two specific markers of this glycoprotein, namely hydroxyproline and glycosylated serine. The lability of the O-glycosidic linkage of wall-bound glycosylated serine in the presence of hydrazine, was used to determine the amount of serine which is glycosylated.A large increase in the hydroxyproline content of infected plants is shown, but the ratios of glycosylated serine to hydroxyproline are similar in healthy and infected plants. As far as these markers are concerned, the hydroxyproline-rich glycoproteins secreted into the wall as a result of the disease are similar to those of healthy plants. In addition, the extent of glycosylation of the wall serine, in both healthy and infected plants, decreases as the plant ages.Serine- and hydroxyproline-rich (glyco)peptides were also isolated after trypsinolysis of the wall. These (glyco)peptides include the galactosyl-containing pentapeptide, serine-hydroxyproline(4). This pentapeptide is characteristic of cell wall protein.


Decarboxylating and nondecarboxylating glutaryl-coenzyme A dehydrogenases in the aromatic metabolism of obligately anaerobic bacteria.
In anaerobic bacteria using aromatic growth substrates, glutaryl-coenzyme A (CoA) dehydrogenases (GDHs) are involved in the catabolism of the central intermediate benzoyl-CoA to three acetyl-CoAs and CO(2). In this work, we studied GDHs from the strictly anaerobic, aromatic compound-degrading organisms Geobacter metallireducens (GDH(Geo)) (Fe[III] reducing) and Desulfococcus multivorans (GDH(Des)) (sulfate reducing). GDH(Geo) was purified from cells grown on benzoate and after the heterologous expression of the benzoate-induced bamM gene. The gene coding for GDH(Des) was identified after screening of a cosmid gene library. Reverse transcription-PCR revealed that its expression was induced by benzoate; the product was heterologously expressed and isolated. Both wild-type and recombinant GDH(Geo) catalyzed the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA at similar rates. In contrast, recombinant GDH(Des) catalyzed only the dehydrogenation to glutaconyl-CoA. The latter compound was decarboxylated subsequently to crotonyl-CoA by the addition of membrane extracts from cells grown on benzoate in the presence of 20 mM NaCl. All GDH enzymes were purified as homotetramers of a 43- to 44-kDa subunit and contained 0.6 to 0.7 flavin adenine dinucleotides (FADs)/monomer. The kinetic properties for glutaryl-CoA conversion were as follows: for GDH(Geo), the K(m) was 30 +/- 2 microM and the V(max) was 3.2 +/- 0.2 micromol min(-1) mg(-1), and for GDH(Des), the K(m) was 52 +/- 5 microM and the V(max) was 11 +/- 1 micromol min(-1) mg(-1). GDH(Des) but not GDH(Geo) was inhibited by glutaconyl-CoA. Highly conserved amino acid residues that were proposed to be specifically involved in the decarboxylation of the intermediate glutaconyl-CoA were identified in GDH(Geo) but are missing in GDH(Des). The differential use of energy-yielding/energy-demanding enzymatic processes in anaerobic bacteria that degrade aromatic compounds is discussed in view of phylogenetic relationships and constraints of overall energy metabolism.


Chronic cerebral hypoperfusion and blood-brain barrier disruption in uninjured brain areas of rhesus monkeys subjected to transient ischemic stroke.
Blood-brain barrier (BBB) disruption is a pivotal pathophysiological process in ischemic stroke. Although temporal changes in BBB permeability during the acute phase have been widely studied, little is known about the chronic phase of cerebrovascular changes that may have a large impact on the long-term outcome. Therefore, this study was aimed to measure cerebral vascular abnormalities using CT perfusion in nine rhesus monkeys subjected to transient middle cerebral artery occlusion (tMCAO) for ≥1 year (MCAO-1Y+). The level of cerebral perfusion demonstrated by mean transit time was significantly higher in the ipsilateral caudate nucleus, white matter, thalamus, hippocampus, and contralateral thalamus in MCAO-1Y+ compared with the other nine age-matched control monkeys. The increase in BBB permeability measured through the permeability surface was found in the same ten regions of interest ipsilaterally and contralaterally. We also found decreased levels of Aβ 42/40 ratio in the cerebrospinal fluid (CSF), suggesting a potential link between post-MCAO cognitive decline and Aβ metabolism. Overall, we demonstrated significant cerebral hypoperfusion, BBB disruption, and CSF Aβ decrease during the rehabilitation stage of ischemic stroke in a non-human primate model. Future studies are needed to elucidate the cause-effect relationship between cerebrovascular disruptions and long-term neurological deficits.


A rare autism-associated MINT2/APBA2 mutation disrupts neurexin trafficking and synaptic function.
MINT2/APBA2 is a synaptic adaptor protein involved in excitatory synaptic transmission. Several nonsynonymous coding variants in MINT2 have been identified in autism spectrum disorders (ASDs); however, these rare variants have not been examined functionally and the pathogenic mechanisms are unknown. Here, we examined the synaptic effects of rat Mint2 N723S mutation (equivalent to autism-linked human MINT2 N722S mutation) which targets a conserved asparagine residue in the second PDZ domain of Mint2 that binds to neurexin-1α (Nrxn1α), a presynaptic cell-adhesion protein implicated in ASDs. We show the N723S mutation impairs Nrxn1α stabilization and trafficking to the membrane while binding to Nrxn1α remains unaffected. Using time-lapse imaging in primary mouse neurons, we found that the N723S mutant had more immobile puncta at neuronal processes compared to Mint2 wild type. We therefore, reasoned that the N723S mutant may alter the co-transport of Nrxn1α at axonal processes to presynaptic terminals. Indeed, we found the N723S mutation affected Nrxn1α localization at presynaptic terminals which correlated with a decrease in Nrxn-mediated synaptogenesis and miniature event frequency in excitatory synapses. Together, our data reveal Mint2 N723S leads to neuronal dysfunction, in part due to alterations in Nrxn1α surface trafficking and synaptic function of Mint2.


Targeting epigenetic mechanisms: potential of natural products in cancer chemoprevention.
The term epigenetics is defined as heritable changes in gene expression patterns that occur without changes in DNA sequence. Epigenetic changes according to this definition are achieved by methylation of cytosine bases in the DNA and by histone modifications, such as acetylation, methylation or phosphorylation. These modifications play an important role in regulating gene expression and the existence of an epigenetic code which maintains these modifications even upon cell division has been underlined by many investigations. Targeting the enzymes which catalyze DNA methylation or histone modifications may be a possibility not only for cancer therapy but also for chemoprevention since disruption of epigenetic balance is known to cause diseases such as cancer. In this review, we want to present the key epigenetic targets. We highlight natural products that modulate these epigenetic mechanisms and show their potential for cancer chemoprevention.


Disability, absence and the health reform era.
The total cost of employee absence for many employers is high, and the correlation between employee health and disability is clear. This article reviews several challenges employers face in managing employee health and absence in a well-integrated manner. Although such an undertaking is not easy, the additional cost national health care reform may bring makes the interrelationship between employer profitability and employee absence, health and disability more crucial than ever for employers to recognize and manage.


Pharmacological analysis of the positive inotropic effect of endothelin-1 in guinea pig left atria.
Endothelin-1 (ET-1) increased the force of contraction and stimulated phosphoinositide hydrolysis in guinea pig left atria. ET-1 at 20 nM produced a dual-component positive inotropic effect composed of an initial increasing phase (early component) and a second and late developing, greater positive inotropic phase (late component). The late component was preferentially and markedly inhibited by nifedipine and the protein kinase C inhibitors H-7 and staurosporine. In guinea pig left atria, the activation of protein kinase C might contribute to the establishment of the positive inotropic effect of ET-1 mediated by modulation of voltage-dependent Ca2+ channels.


Weighing behavior and symptom distress of clinic patients with CHF.
Congestive heart failure (CHF) is a prevalent disease that causes patients troubling symptoms, which can be difficult for clinicians to manage. A descriptive pilot study examining the weighing behaviors of patients with CHF and their symptom distress was conducted, and the findings have implications for future research and patient management.


Electromagnetic boundary and its realization with anisotropic metamaterial.
A set of boundary conditions requiring vanishing of the normal components of the D and B vectors at the boundary surface is introduced and labeled as that of DB boundary. Basic properties of the DB boundary are studied in this paper. Reflection of an arbitrary plane wave, incident with a complex propagation vector, is analyzed for the planar DB boundary. It is shown that waves polarized transverse electric (TE) and transverse magnetic (TM) with respect to the normal of the boundary are reflected as from respective perfect electric conductor and perfect magnetic conductor planes. The basic problem of current source above the planar DB boundary is solved by applying TE and TM decomposition for the source. Realization of the DB boundary in terms of an interface of uniaxially anisotropic metamaterial half-space with zero axial medium parameters is considered. It is also shown that such a medium with small axial parameters acts as a spatial filter for waves incident at the interface which could be used for narrowing the beam of a directive antenna. Application of DB boundary as an isotropic soft surface with low interaction between antenna apertures also appears possible.


Unmanipulated haploidentical peripheral blood stem cell transplantation for patients with Philadelphia-negative acute lymphoblastic leukaemia in first complete remission.
Haploidentical peripheral blood stem cell transplantation (Haplo-PBSCT) is a promising treatment option for patients with Ph-negative acute lymphoblastic leukemia (ALL). In this study, we retrospectively analyzed data from Ph-negative ALL patients who underwent haplo-PBSCT during their first complete remission (CR1), and compared the long-term outcomes between the standard-risk and high-risk patients. The 3-year probability of relapse was 7.6% and 16.7% for the standard- and high-risk group (p = .274). The 3-year probability of disease-free survival (DFS) and overall survival (OS) for the standard-risk versus high-risk groups were 84.6% versus 50% (p = .0063) and 92.3% versus 61.1% (p = .046), respectively. Univariate analysis showed that a diagnosis of high risk with fusion/mutation genes were associated with worse outcomes, which was confirmed by multivariate analysis (p = .016). In summary, haplo-PBSCT may be a promising alternative for patients with Ph-negative ALL in CR1, although the fusion/mutation genes in high-risk patients may relatively impair the long-term efficacy compared with standard-risk patients.


Ultramafic geoecosystems as a natural source of Ni, Cr, and Co to the environment: A review.
Ultramafic soils are in equal parts fascinating and dangerous. Developed on rocks derived predominately from the Earth's mantle and metamorphosed at the ocean floors, ultramafic soils form in the places where tectonic forces brought these rocks from mantle depths to the surface. As it is common in nature, both ultramafic rocks and soils are site-specific, and vary in character and composition; however, they have one thing in common, they are enriched in certain elements and three metals in particular form an "ultramafic" triad: Ni, Cr, and Co. These three metals are far from being human-friendly and strict legislative limits are established for maximum allowable concentrations of these metals in soils, but mostly in the case when the metals are of anthropogenic origin. However, ultramafic soils are a natural phenomenon where increased metal content is not the result of pollution, but rather referred as a peculiar geochemical background, therefore there is no reason for their remediation. At the same time, it is not that easy to actually find an ultramafic soil that does not overstep the limits (for the sake of this paper we use median world Regulatory Guidance Values - RGVs). Often, mobile Ni and Co concentrations are above the guidelines when doing tests to estimate the bioavailable fraction (EDTA and DTPA), and high concentrations of Ni are also commonly present in excluder plants (also edible ones). Also waters in ultramafic areas often exceed Ni and Cr(VI) limits. It is therefore expected that the ultramafic metals are present in the food chain and they might constitute a potential health risk. Thus, there is a need for additional research focused on assessment of the potential health consequences of chronic high exposure on naturally occurring Ni, Cr, and Co.


Innovative uses of near-infrared spectroscopy in food processing.
Near-infrared spectroscopy (NIRS) has experienced widespread use as an analytical tool in the last 3 decades. Researchers today are exploring ways of applying NIRS that expand beyond compositional analyses into process control. Processes such as meat tenderness evaluation, curd cutting, and dough mixing have traditionally been controlled by highly skilled master craftsmen; new NIRS research applications are demonstrating that these complex processes can be monitored and controlled in situ to produce consistent, high quality end products with online NIRS technology. Additionally, researchers also now have the potential ability to develop new nondestructive spectroscopic techniques to probe the underlying molecular evolution of these products during processing.


Best practices: surveillance and management of diabetes in a CMHC population.
To improve detection and management of diabetes at a community mental health center, a cross-sectional study of the prevalence and management of type 2 diabetes mellitus was conducted among patients receiving maintenance antipsychotic medication (N=494). Diabetes was more than two-and-a-half times as prevalent among participants (17.4%) as in the general population. Fourteen percent of patients classified as diabetic had previously undiagnosed disease, compared with national sample rates of over 30%. Impaired fasting glucose was found for 26% of the sample. Glucose dysregulation was common. The known poor cardiovascular profile of persons with serious mental illness, reflected in the high rates of tobacco use and obesity in the sample, requires contextualizing efforts to screen and monitor for diabetes within overall efforts to monitor cardiovascular health.