[Topology of the carpal tunnel in dynamic stress of the wrist joint].
Alterations of the spatial geometry of the carpal tunnel and its contents during dynamic stress situations of the wrist are of importance in clarifying morphological causes of a carpal tunnel syndrome. In order to demonstrate the changes occurring in the form of the carpal tunnel and the location of its contents during wrist movement, casts of the carpal tunnel were produced from the hands of cadavers in flexed and extended positions. The casts were then morphometrically analyzed and the movements of the median nerve and the flexor tendons were examined radiologically. The investigation showed that a delicate equilibrium exists between the capacity of the carpal tunnel--whose hourglass shape typically changes to suit dynamic stress situations--and the volume of its contents. Spatial processes extending from the carpal tunnel wall or emanating from the structures contained within the carpal tunnel may exceed the system's ability to compensate for extreme positioning of the wrist and thus induce compression symptoms of the median nerve.


Single Nucleotide Polymorphisms in miR-122 Are Associated with the Risk of Hepatocellular Carcinoma in a Southern Chinese Population.
Single nucleotide polymorphisms (SNPs) in microRNA may affect its expression and regulation of target genes, which may consequently alter individual susceptibility to cancer. In this study we aimed to investigate associations between miR-122 polymorphisms and hepatocellular carcinoma (HCC) in a southern Chinese population. Three selected SNPs in miR-122 (rs9966765, rs1135519, and rs17669) were genotyped in 1050 HCC patients and 1079 cancer-free controls using Sequenom MassARRAY platform and the associations of the three SNPs and HCC risk were evaluated. We found that individuals with the rs1135519 CC genotypes had a significant increased risk of HCC than those with TT genotypes (adjusted OR=2.71, 95% CI=1.15-6.36, and P=0.022), while the rs9966765 CC genotypes showed a borderline significant association with increased risk of HCC when compared with the GG genotypes (adjusted OR=2.38, 95% CI=0.99-5.75, and P=0.052). There was also a significant increased risk of HCC when combining risk genotypes of these loci, i.e., rs1135519 CC and rs9966765 CC. Compared with the low-risk group (0 risk genotype), the high risk group (1-2 risk genotypes) had significantly increased risk of HCC (OR=1.61, 95% CI=1.05-2.44, and P=0.028). Further genotype-expression analysis revealed that cases carrying the CC genotype of rs1135519 had lower levels of miR-122 expression than those with the TT genotype. Our results suggest that SNP of rs1135519 modulates miR-122 expression and contributes to the genetic susceptibility of HCC, either independently or together with rs9966765 in miR-122. Further well-designed studies with lager sample sizes are needed to confirm our findings.


[Knowledge, experience and behavior at climacteric and menopause stages among family medicine female users at IMSS].
To identify knowledge, experiences and behaviors of climacteric and menopause women users of family medicine services of Instituto Mexicano del Seguro Social (IMSS). A descriptive study that included a 37 questions survey about climacteric and menopause was conducted in a national representative sample of 4162 women aged 45 to 59 years between September 2004 and January 2005. The analysis was made by using descriptive statistics and chi2. 82.9 % Of women knew about menopause or its significance; 82.1 % identified hot flushes as a climacteric symptom; 46.1 % knew about pharmacologic treatment and 25.6 % knew about postmenopausal complications such as osteoporosis. Only 26.6 % mentioned preventive measures as physical exercise or consumption of food with high calcium content. Their main information sources were media communication. Mean age at menopause was 46.8 years old; 57.7 % had symptoms at interview and 18.4 % were taking pharmacologic treatment, mainly (53.3 %) hormones. 11.1 % of treated women had had side effects. 10.7 % had received pharmacologic treatment and 39.4 % had withdrawn from medication either for medical indications or for side effects (23 %). Knowledge about climacteric was scarce and obtained from non-medical sources; use of pharmacological treatment and preventive behavior was low. We recommended reinforcing the information and education about treatment and favorable life styles by health personal.


[Effect of lamivudine and silymarin on liver fibrosis-relevant factors in HBV transgenic mice with alcohol drinking].
To observe the role of lamividine and silymarin preventing and curing liver fibrosis-relevant factors induced by alcohol drinking in hepatitis B virus (HBV) transgenic mice (Tg mice). Methods: Forty HBV-Tg BALB/C mice with 1.3 copy were randomly divided into 4 groups: a control group, a model group, a lamivudine group and a silymarin group. Tg mice in control group were treated with normal saline via intragastric administration; Tg-mice in the model group were treated with 50% alcohol (5 mL/kg) once a day via intragastric administration; while Tg-mice in lamivudine group and silymarin group were treated with alcohol (5 mL/kg) plus laminvudine (100 mg/kg) and silymarin (200 mg/kg) once a day via intragastric administration respectively. All groups were raised for 10 weeks. The levels of HBV-DNA copy number, ALT, AST in serum, the degree of inflammation, the degree of fibrosis, the mRNA expression levels of TGF-β1, Smad3, Smad7 and connective tissue growth factor (CTGF), and the protein expression levels of TGF-β1, CTGF and α-SMA in liver tissue were detected. All the images were scanned with electronic computer and the data were analyzed with SPSS13.0 software. Results: Compared with the control group, liver injury were significantly aggravated, while HBV-DNA copies, mRNA levels of TGF-β1, Smad3, Smad7 and CTGF as well as the protein levels of TGF-β1, CTGF and α-SMA were significantly increased (P<0.05). Compared with the model group, liver injury were significantly attenuated in silymarine group and lamivudine group, while mRNA levels of TGF-β1, Smad3 and CTGF as well as the protein levels of TGF-β1, CTGF and α-SMA were significantly decreased; mRNA level of Smad7 was further increased (P<0.05); the levels of ALT and AST in serum were decreased in the silymarine group (P<0.05). Conclusion: Lamivudine and silymarin relieve the histological damage in the liver of alcohol-fed Tg mice. The mechanisms for the beneficial effects of lamivudine or silymarin might be related to inhibiting the expression of TGF-β1, Smad3 and CTGF, modulating the expression of Smads and suppressing the activation of HSC.


The impact of SWI/SNF and NuRD inactivation on gene expression is tightly coupled with levels of RNA polymerase II occupancy at promoters.
SWI/SNF and NuRD are protein complexes that antagonistically regulate DNA accessibility. However, repression of their activities often leads to unanticipated changes in target gene expression (paradoxical), highlighting our incomplete understanding of their activities. Here we show that SWI/SNF and NuRD are in a tug-of-war to regulate PRC2 occupancy at lowly expressed and bivalent genes in mouse embryonic stem cells (mESCs). In contrast, at promoters of average or highly expressed genes, SWI/SNF and NuRD antagonistically modulate RNA polymerase II (Pol II) release kinetics, arguably owing to accompanying alterations in H3.3 and H2A.Z levels at promoter-flanking nucleosomes, leading to paradoxical changes in gene expression. Owing to this mechanism, the relative activities of the two remodelers potentiate gene promoters toward Pol II-dependent open or PRC2-dependent closed chromatin states. Our results highlight RNA Pol II occupancy as the key parameter in determining the direction of gene expression changes in response to SWI/SNF and NuRD inactivation at gene promoters in mESCs.


A failure of preoperative duplex imaging to diagnose a lower extremity venous aneurysm in a patient with severe chronic venous insufficiency.
We present a case of recurrent bilateral lower extremity venous stasis ulcers in association with a superficial venous aneurysm at the right saphenofemoral junction that was misdiagnosed on preoperative duplex scanning. A 53-year-old female presented to our clinic with 6-year history of bilateral lower extremity venous stasis ulcers. Her past medical history was significant for refractory venous stasis ulcers of the bilateral lower extremities present for 6 years and morbid obesity. Preoperative venous duplex demonstrated severe venous insufficiency of the superficial and deep systems, but a venous aneurysm was not appreciated. During the high ligation of the right saphenofemoral junction, a 3 × 4 × 5 cm aneurysm was encountered. Repair consisted of aneurysm resection, high ligation of the greater saphenous vein, dissociation of the great saphenous and anterior saphenous veins, and stab phlebectomy of large varicose veins of the thigh and lower leg. The patient recovered uneventfully and experienced complete healing of the venous stasis ulcer in several weeks. Superficial venous aneurysms of the lower extremity are rare and can be often missed on preoperative duplex ultrasound imaging. Large diameter measurements of the proximal greater saphenous vein and obesity increase the risk of misdiagnosing venous aneurysms with duplex imaging; therefore, clinical suspicion must remain high. These aneurysms can be associated with significant symptoms for which repair is indicated.


Prevalence and Characterization of Staphylococcus aureus Strains in the Pork Chain Supply in Chile.
The detection of methicillin-resistant Staphylococcus aureus (MRSA) and other emerging strains in meat-producing animals and retail meat has increased the risk of contamination of food. The aim of this study was to determine the prevalence and characterize S. aureus strains isolated from the pork chain supply in Chile. A total of 487 samples were collected: 332 samples from pigs at farms and slaughterhouses (nasal, n = 155; skin, n = 177); 85 samples from carcasses at slaughterhouses; and 70 meat samples at supermarkets and retail stores. The isolation of S. aureus was carried out by selective enrichment and culture media. Biochemical testing (API® Staph) and PCR (detection of the nuc and mecA genes) were used to confirm S. aureus and MRSA strains. The agglutination test was used to determine the protein PBP2'. Enterotoxins (SEA, SEB, SEC, SED) were determined by agglutination test and the se genes by PCR method. Oxacillin and cefoxitin susceptibility testing were carried out using the diffusion method. The overall prevalence of S. aureus in the pork meat supply was 33.9%. A higher prevalence was detected on carcasses (56.5%), in pigs sampled at farms (40.6%) than in pigs sampled at slaughterhouses (23.3%) and in nonpackaged retail meat (43.1%) than packaged retail meat (5.3%) (p ≤ 0.05). No significant differences (p > 0.05) were found between the prevalence in pigs (28.3%) and pork meat (32.9%) and between natural pig farming (33.3%) and conventional production (52.8%). The mecA gene and the protein PBP2' were not detected in S. aureus strains. Two S. aureus strains exhibited oxacillin and cefoxitin resistance, and one S. aureus strain was resistant to cefoxitin. One S. aureus strain isolated from a meat sample was positive for enterotoxin SEB. Although the mecA gene was not detected, oxacillin-resistant and seb-producing S. aureus strains were detected, which represent a risk in the pork chain supply.


Research update on serotonin function in bulimia nervosa and anorexia nervosa.
The extent to which dysregulation of serotonin function in the central nervous system may contribute to core symptoms in patients with bulimia nervosa and anorexia nervosa is currently an area of intensive psychobiological investigation. Preclinical and clinical studies have demonstrated the involvement of the neurotransmitter serotonin in the regulation of food intake, suggesting that impaired serotonin-mediated satiety signals could contribute to patterns of recurrent binge eating. Other symptom patterns in patients with eating disorders, including mood dysregulation, impulsivity, and obsessionality, as well as therapeutic response to serotonergic agents, suggest involvement of serotonergic pathways. With a primary focus on serotonin function, this article reviews clinical studies of neuroendocrine and behavioral response to pharmacological challenges, levels of neurotransmitter metabolite in cerebrospinal fluid, and platelet studies. Controlled clinical trials involving pharmacological treatment with serotonergic medications are summarized. Considerations for future research are discussed.


Binding of UNC-18 to the N-terminus of syntaxin is essential for neurotransmission in Caenorhabditis elegans.
SNAREs (soluble N-ethylmaleimide-sensitive fusion protein-attachment protein receptors) are widely accepted to drive all intracellular membrane fusion events. SM (Sec1/Munc18-like) proteins bind to SNAREs and this interaction may underlie their ubiquitous requirement for efficient membrane fusion. SM proteins bind to SNAREs in at least three modes: (i) to a closed conformation of syntaxin; (ii) to the syntaxin N-terminus; and (iii) to the assembled SNARE complex. Munc18-1 exhibits all three binding modes and recent in vitro reconstitution assays suggest that its interaction with the syntaxin N-terminus is essential for neuronal SNARE complex binding and efficient membrane fusion. To investigate the physiological relevance of these binding modes, we studied the UNC-18/UNC-64 SM/SNARE pair, which is essential for neuronal exocytosis in Caenorhabditis elegans. Mutations in the N-terminus of UNC-64 strongly inhibited binding to UNC-18, as did mutations targeting closed conformation binding. Complementary mutations in UNC-18 designed to selectively impair binding to either closed syntaxin or its N-terminus produced a similarly strong inhibition of UNC-64 binding. Therefore high-affinity UNC18/UNC-64 interaction in vitro involves both binding modes. To determine the physiological relevance of each mode, unc-18-null mutant worms were transformed with wild-type or mutant unc-18 constructs. The UNC-18(R39C) construct, that is defective in closed syntaxin binding, fully rescued the locomotion defects of the unc-18 mutant. In contrast, the UNC-18(F113R) construct, that is defective in binding to the N-terminus of UNC-64, provided no rescue. These results suggest that binding of UNC-18 to closed syntaxin is dispensable for membrane fusion, whereas interaction with the syntaxin N-terminus is essential for neuronal exocytosis in vivo.


Dynamic Cardiomyoplasty.
On January 8, 1985, Carpentier and his cardiovascular surgery group at the Broussais Hospital were the first to replace diseased human myocardium with a stimulated latissimus dorsi muscle flap. A few months later, Magovern and co-workers at Allegheny General Hospital in Pittsburgh were the first to repair a large left ventricular aneurysm with a latissimus dorsi cardiomyoplasty. Over the past six years, approximately 120 patients have undergone the operation throughout the world.


Putrid pulmonary abscess and empyema with inappropriate secretion of antidiuretic hormone.
The syndrome of inappropriate secretion of antidiuretic hormone has been associated with many pulmonary inflammatory diseases. The origin of the hormone in these cases is the neurohypophysis, although the afferent stimulus has not been adequately characterized. A previously unreported association of this syndrome with putrid pulmonary abscess and empyema is documented.


Excretion of the N(2)-glucuronide conjugate of 2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in urine and its relationship to CYP1A2 and NAT2 activity levels in humans.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic aromatic amine formed in meat products during cooking. The genotoxity of PhIP requires an initial cytochrome P450-mediated N-oxidation followed by N-O-esterification catalyzed generally by N-acetyltransferases and sulfotransferases. This study examined the urinary excretion of N(2)-(beta-1-glucos-iduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine-the major human urinary N-oxidation metabolite of PhIP-and determined its relationship to individual activity levels of cytochrome P4501A2 (CYP1A2) and N-acetyltransferase (NAT2). The subjects (33 males and 33 females) in the dietary study were phenotyped for their CYP1A2 and NAT2 activity prior to consumption of meat-based diet, and urine collections were obtained 0-12 and 12-24 h after ingestion of the meal. Acidic hydrolysis of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine and its d(3)-analog to form their respective deaminated products 2-hydroxy-1-methyl-6-phenylimidazo[4,5-b]pyridine (2-OH-PhIP) was used in the assay. The products after derivatization were analyzed by capillary gas chromatography-negative ion chemical ionization mass spectrometry with selective ion monitoring. The amount of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine measured as the acid hydrolysis product 2-OH-PhIP in the 0-12 h urine was 20.2 +/- 8.0% (mean +/- SD) of the ingested dose; the median was 18.8% and the range varied from 5.4 to 39.6% within the group. In a subset (n = 18) of samples from individual urine collected from the 12-24 h period, an average value of 4.4 +/- 2.5% (+/- SD) of the dose was recovered. The excretion of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine in the 0-12 h urine was significantly related to the quantity of PhIP ingested for all subjects (r = 0.52, P <0.0001). Linear regression analysis of the relationship between the excretion level of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine, adjusted for meat intake and CYP1A2 activity in the combined group of males and females showed a low association (r = 0.25, P = 0.05). There was no association between the amount of N(2)-(beta-1-glucosiduronyl)-2-hydroxyamino-1-methyl-6-phenylimid-azo[4,5-b]pyridine in urine and NAT2 activity levels of the subjects nor with the age of the subjects. N(2)-(beta-1-glucosi-duronyl)-2-hydroxyamino-1-methyl-6-phenylimidazo[4,5-b]pyridine comprised a significant proportion of the ingested dose in some individuals; however, considerable variation was found within the group. The results indicate that interindividual differences in the rates of N-oxidation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, as well as phase II glucuronidation reactions regulate the formation of this metabolite in humans.


NATURAL HYBRIDIZATION BETWEEN THE SYMPATRIC HAWAIIAN SPECIES DROSOPHILA SILVESTRIS AND DROSOPHILA HETERONEURA.
Two newly formed, morphologically distinct species of Drosophila from the island of Hawaii have been found to form fertile hybrids in two areas of sympatry. Both F1 and backcross hybrids have been recognized in nature; in one case, the hybridization events extended over three years. Original hybridizations involved one or more D. silvestris females mating with D. heteroneura males. Female F1 hybrids from this cross have participated in backcrosses to D. silvestris. In any one locality, less than 2% hybrids have been found in nature. A hybrid swarm was not formed; selection appears to favor a strict maintenence of morphologies characteristic of the separate species. This result is attributed to pervasive sexual selection, which serves to preserve the syndromes of sexual characteristics that arose during past allopatric divergence. Populations of D. silvestris both within and outside the present range of D. heteroneura often display heritable variation in color patterns involving the abdomen, pleurae, legs, and wings. Genes effecting variation in these characters may be derived from genes involved in a past introgression from D. heteroneura. Independent evidence for past hybridization between these species comes from study of mitochondrial DNA. Although the inferred direction of the cross is the opposite of that observed in the recent case described here, both reciprocal crosses have been obtained experimentally in the laboratory. Accordingly, we suggest that these species may have been open to hybridization since their first sympatic encounters following their inception in allopatry. That they remain as strictly recognizable morphological entities is due both to their current partial allopatry and to the action of sexual selection in maintaining two separate major modes of efficient reproduction. There is no reason to invoke specific reinforcing selection that has imposed reproductive isolation.


A review of invasive and non-invasive sensory feedback in upper limb prostheses.
The constant challenge to restore sensory feedback in prosthetic hands has provided several research solutions, but virtually none has reached clinical fruition. A prosthetic hand with sensory feedback that closely imitates an intact hand and provides a natural feeling may induce the prosthetic hand to be included in the body image and also reinforces the control of the prosthesis. Areas covered: This review presents non-invasive sensory feedback systems such as mechanotactile, vibrotactile, electrotactile and combinational systems which combine the modalities; multi-haptic feedback. Invasive sensory feedback has been tried less, because of the inherent risk, but it has successfully shown to restore some afferent channels. In this review, invasive methods are also discussed, both extraneural and intraneural electrodes, such as cuff electrodes and transverse intrafascicular multichannel electrodes. The focus of the review is on non-invasive methods of providing sensory feedback to upper-limb amputees. Expert commentary: Invoking embodiment has shown to be of importance for the control of prosthesis and acceptance by the prosthetic wearers. It is a challenge to provide conscious feedback to cover the lost sensibility of a hand, not be overwhelming and confusing for the user, and to integrate technology within the constraint of a wearable prosthesis.


Changes in grassland soil types lead to different characteristics of bacterial and fungal communities in Northwest Liaoning, China.
Soil microbial communities are critical in regulating grassland biogeochemical cycles and ecosystem functions, but the mechanisms of how environmental factors affect changes in the structural composition and diversity of soil microbial communities in different grassland soil types is not fully understood in northwest Liaoning, China. We investigated the characteristics and drivers of bacterial and fungal communities in 4 grassland soil types with 11 sites across this region using high-throughput Illumina sequencing. Actinobacteria and Ascomycota were the dominant phyla of bacterial and fungal communities, respectively, but their relative abundances were not significantly different among different grassland soil types. The abundance, number of OTUs, number of species and diversity of both bacterial and fungal communities in warm and temperate ecotone soil were the highest, while the warm-temperate shrub soil had the lowest microbial diversity. Besides, environmental factors were not significantly correlated with soil bacterial Alpha diversity index. However, there was a highly significant negative correlation between soil pH and Shannon index of fungal communities, and a highly significant positive correlation between plant cover and Chao1 index as well as Observed species of fungal communities. Analysis of similarities showed that the structural composition of microbial communities differed significantly among different grassland soil types. Meanwhile, the microbial community structure of temperate steppe-sandy soil was significantly different from that of other grassland soil types. Redundancy analysis revealed that soil total nitrogen content, pH and conductivity were important influencing factors causing changes in soil bacterial communities, while soil organic carbon, total nitrogen content and conductivity mainly drove the differentiation of soil fungal communities. In addition, the degree of connection in the soil bacterial network of grassland was much higher than that in the fungal network and soil bacterial and fungal communities were inconsistently limited by environmental factors. Our results showed that the microbial community structure, composition and diversity of different grassland soil types in northwest Liaoning differed significantly and were significantly influenced by environmental factors. Microbial community structure and the observation of soil total nitrogen and organic carbon content can predict the health changes of grassland ecosystems to a certain extent.


Individual, social and environmental factors influencing dietary behaviour in shift workers with type 2 diabetes working in UK healthcare: A cross-sectional survey.
The present study aimed to understand the individual, social and environmental factors influencing dietary behaviour in shift workers with type 2 diabetes (T2D) working in UK healthcare settings. A cross-sectional study was conducted using data collected from an anonymous online survey. Participant agreement was measured using five-point Likert scale (strongly disagree to strongly agree) against 38 belief statements informed by the Theoretical Domains Framework (TDF) of behaviour change. From the complete responses (n = 119), 65% worked shifts without nights, 27% worked mixed shift rota including nights and 8% worked only night shifts. The statements ranked with the highest agreements were in the TDF domains: Environment Context/Resources (ECR) - mainly identified as a barrier to healthy eating, Behaviour Regulation (BR) and intention (IN) - identified as enablers to healthy eating. For the belief statement 'the available options for purchasing food are too expensive' (ECR), 80% of night workers and 75% non-night workers agreed/strongly agreed. Taking their own food to work to prevent making unhealthy food choices (BR) had agreement/strong agreement in 73% of non-night and 70% night workers; 74% non-night workers and 80% of night workers agreed/strongly agreed with the statement 'I would like to eat healthily at work' (IN). Mixed shift workers agreed that following dietary advice was easier when working a non-night compared to a night shift (p = 0.002). Access and affordability of food were identified as important determinants of dietary behaviour during shifts. The findings support interventions targeting the food environment for shift workers with T2D.


Crystal structure of a family 4 uracil-DNA glycosylase from Thermus thermophilus HB8.
Uracil-DNA glycosylase (UDG; EC 3.2.2.-) removes uracil from DNA to initiate DNA base excision repair. Since hydrolytic deamination of cytosine to uracil is one of the most frequent DNA-damaging events in all cells, UDG is an essential enzyme for maintaining the integrity of genomic information. For the first time, we report the crystal structure of a family 4 UDG from Thermus thermophilus HB8 (TthUDG) complexed with uracil, solved at 1.5 angstroms resolution. As opposed to UDG enzymes in its other families, TthUDG possesses a [4Fe-4S] cluster. This iron-sulfur cluster, which is distant from the active site, interacts with loop structures and has been suggested to be unessential to the activity but necessary for stabilizing the loop structures. In addition to the iron-sulfur cluster, salt-bridges and ion pairs on the molecular surface and the presence of proline on loops and turns is thought to contribute to the enzyme's thermostability. Despite very low levels of sequence identity with Escherichia coli and human UDGs (family 1) and E.coli G:T/U mismatch-specific DNA glycosylase (MUG) (family 2), the topology and order of secondary structures of TthUDG are similar to those of these distant relatives. Furthermore, the coordinates of the core structure formed by beta-strands are almost the same. Positive charge is distributed over the active-site groove, where TthUDG would bind DNA strands, as do UDG enzymes in other families. TthUDG recognizes uracil specifically in the same manner as does human UDG (family 1), rather than guanine in the complementary strand DNA, as does E.coli MUG (family 2). These results suggest that the mechanism by which family 4 UDGs remove uracils from DNA is similar to that of family 1 enzymes.


How do cytokines say hello to the brain? Neural versus humoral mediation.
Infection and inflammation are accompanied by fever, neuroendocrine activation and alterations in behaviour and mood. It is commonly accepted that these non specific symptoms are mediated by blood-borne mediators acting on the brain. These mediators include proinflammatory cytokines such as IL-1, IL-6 and TNF. In this paper, we present new evidence indicating that this view is inadequate and that the proinflammatory cytokines which are released at the periphery by activated accessory immune cells act on the brain via a neural pathway involving activation of peripheral sensory nerves.


Incidental appendicectomy in pancreas transplantation: A single-center study.
Appendicitis in pancreatic transplant recipients can be challenging to diagnose and manage. Incidental appendicectomy (IA) during pancreas transplantation obviates the risk of appendicitis but potentially at the cost of increased operating time or early post-operative complications. This study reviewed the value of IA at a single center. This was a retrospective study of patients who underwent a pancreas transplant in our unit from January 1st, 2012 to December 31st, 2020, with end of follow-up on May 21st, 2023; recipients were grouped by whether or not an IA was performed during pancreas transplantation. Donor, recipient, operative, and graft outcomes were compared between the two groups. Post-transplant complications related to appendiceal pathology (or IA) were recorded and classified. Two hundred forty-three patients underwent a pancreas transplant; 227 (93%) patients had an appendix in situ at transplantation, and of these 53 (23%) underwent an IA and 174 (77%) did not. There were no statistically significant differences in operative time (p = .06) or hospital stay (p = .50) between the two groups. In the IA cohort, there were no Clavien-Dindo Grade III-V complications relating to the appendicectomy. In those that did not undergo an IA, two patients (1%) subsequently required appendicectomy due to appendicitis. Comparison of pancreatic graft survival showed no statistically significant difference between the groups (p = .44). This study suggests that IA is effective at reducing risks of post-transplant appendiceal complications without significantly prolonging inpatient stay or impairing graft survival. These data support the consideration of undertaking an IA for all patients undergoing a pancreas transplant.


Urgent Revascularization of the Left Proximal Circumflex Following Cessation of Cangrelor Within Six Hours of Procedure.
Patients undergoing procedures are often transitioned off anticoagulants using anti-platelet agents with short half-lives as a "bridge." We present the case of a patient with a history of in-stent thromboses who experienced a thrombotic event following a literature-guided bridging protocol. This case is one of the first to show that stopping cangrelor within six hours led to a need for urgent revascularization and suggests that the timing for discontinuing bridging agents should be customized based on the patient's history of increased blood clotting.


Swift heavy ion irradiation induced enhancement in the antioxidant activity and biocompatibility of polyaniline nanofibers.
Polyaniline (PAni) nanofibers doped with HCl and CSA have been irradiated with 90 MeV O(7+) ions with fluence of 3 x 10(10), 3 x 10(11) and 1 x 10(12) ions cm(-2). TEM micrographs show a decrease in the fiber diameter with increasing irradiation fluence, which has been explained on the basis of the Coulomb explosion model. XRD analysis reveals a decrease in the crystalline domain length and an increase in the strain. The increase in d-spacing for the (100) reflection with increasing irradiation fluence is ascribed to the increase in the tilt angle of the polymer chain, which is also evident from micro-Raman spectra. UV-vis spectra of the PAni nanofibers exhibit blue-shift in the absorption bands attributed to pi-pi* band transitions indicating a reduction in particle size after SHI irradiation; as also observed in TEM micrographs. Micro-Raman spectra also reveal a transition from the benzenoid to quinoid structures in the PAni chain as the fluence is increased. Although the quinoid unit has no hydrogen for DPPH scavenging, the antioxidant activity of PAni nanofibers is found to increase with increasing fluence. This has been attributed to the availability of more reaction sites as a result of fragmentation of the PAni nanofibers which compensates for the benzenoid to quinoid transition after irradiation. The biocompatibility of the PAni nanofibers is also found to increase with increasing irradiation fluence, indicating the possibility of employing swift heavy ion irradiation as an effective technique in order to modify conducting polymer nanostructures for biomedical applications.


The functional anatomy of frontal lobe neglect in the monkey: behavioral and quantitative 2-deoxyglucose studies.
A syndrome of hemisensory neglect follows damage to frontal association areas in monkeys and humans. To study the syndrome we removed frontal association cortex from the right hemisphere of macaque monkeys. After operation, behavioral testing showed conditional deficits in visual, somatosensory, and motor responses contralateral to the lesion. Brains of animals were studied with [14C]2-deoxyglucose autoradiography to evaluate functional neuroanatomical changes. Ipsilateral striatal and selected thalamic and midbrain nuclei exhibited depression of glucose utilization (10 to 60%). No consistent glucose utilization changes appeared in cortex or in primary motor or sensory pathways. Brains from unoperated control animals did not exhibit these changes, nor did brains from operated animals with behavioral recovery from neglect. We conclude that the symptoms of frontal lobe neglect in the monkey are the result of dysfunction within a widely distributed system of subcortical centers. The distribution of the dysfunction provides an explanation for some of the clinical features of neglect.


Vaccine package inserts and prescribing habits of obstetricians-gynecologists for maternal vaccination.
Despite ample evidence of the safety and efficacy of the influenza vaccine and the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine during pregnancy, two-thirds of pregnant women do not receive these vaccines. Providers have a significant role in increasing prenatal vaccine uptake. It is important to understand how different sources of vaccine prescribing information, such as Food and Drug Administration package inserts, influence provider recommendations. We aimed to examine the role of vaccine package inserts in provider recommendations and perceptions of safety and effectiveness of vaccines during pregnancy. A cross-sectional survey was mailed to a random, weighted sample of American College of Obstetricians and Gynecologists Fellows living in the United States in March 2019. Providers were asked about their attitudes toward package inserts, and to evaluate sample package insert statements following two different labeling rules. Their evaluations of each rule were then compared. Of the 321 respondents, the majority (90%, 288/321) recommended and/or administered maternal vaccinations. Few respondents (7.8%, 25/321) read package inserts for information regarding vaccination. Respondents were less likely to recommend sample vaccines with Pregnancy and Lactation Labeling Rule-complying inserts (46.1%, 148/321) than vaccines with Pregnancy Category inserts (87.5%, 282/321). Although most providers did not actively utilize vaccine package inserts to inform recommendations, the previous Pregnancy Categories rule was preferred compared to the Pregnancy and Lactation Labeling Rule. Collaborative efforts to update inserts with current clinical practices for pregnancy would be valuable in reducing apprehensiveness around package inserts to generate safer and more cogent recommendations for pregnant women.


Outpatient treatment for liposarcoma of the spermatic cord.
Liposarcoma of the spermatic cord is a very rare neoplastic disease. In effect little more than two hundred cases are described in literature. Natural history of this tumour is characterized by high local recurrence rate although hematogenic and lymphatic spread is usually a late event and involves high-grade tumours. The clinical diagnosis of spermatic cord liposarcoma can be difficult particularly for non expert surgeons, and is often mistaken for different diagnoses. Radical orchiectomy with high cord ligation is the treatment of choice to prevent local recurrence. Otherwise than commonly advised, the treatment is suitable to be performed under local anaesthesia and the patient easily and safely discharged few hours after surgery.


Incidence and predictors of respiratory adverse events in children undergoing procedural sedation with intramuscular ketamine in a paediatric emergency department.
Although ketamine is one of the commonest medications used in procedural sedation of children, to our knowledge, there is currently no published report on predictors of respiratory adverse events during ketamine sedation in Asian children. We aimed to determine the incidence of and factors associated with respiratory adverse events in children undergoing procedural sedation with intramuscular (IM) ketamine in a paediatric emergency department (ED) in Singapore. A retrospective analysis was conducted of all children who underwent procedural sedation with IM ketamine in the paediatric ED between 1 April 2013 and 31 October 2017. Demographics and epidemiological data, including any adverse events and interventions, were extracted electronically from the prospective paediatric sedation database. The site of procedure was determined through reviewing medical records. Descriptive statistics were used for incidence and baseline characteristics. Univariate and multivariate logistic regression analyses were performed to determine significant predictors. Among 5,476 children, 102 (1.9%) developed respiratory adverse events. None required intubation or cardiopulmonary resuscitation. Only one required bag-valve-mask ventilation. The incidence rate was higher in children aged less than three years, at 3.6% compared to 1.0% in older children (odds ratio [OR] 3.524, 95% confidence interval [CI] 2.354-5.276; p < 0.001). Higher initial ketamine dose (adjusted OR 2.061, 95% CI 1.371-3.100; p = 0.001) and the type of procedure (adjusted OR 0.190 (95% CI 0.038-0.953; p = 0.044) were significant independent predictors. The overall incidence of respiratory adverse events was 1.9%. Age, initial dose of IM ketamine and type of procedure were significant predictors.


Co-induction of anaesthesia with 0.75 mg kg propofol followed by sevoflurane: a randomized trial in the elderly with cardiovascular risk factors.
The induction of general anaesthesia is associated with the greatest cardiovascular changes in elderly patients. Induction can be performed either intravenously or with gaseous induction. Sevoflurane has advantages over propofol for induction of anaesthesia in the elderly, since the lower reduction in mean arterial pressure with sevoflurane is both statistically and clinically significant. This prospective randomized controlled trial investigated the cardiovascular benefits of co-induction of anaesthesia with 0.75 mg kg(-1) propofol and 8% sevoflurane, when compared with 8% sevoflurane alone in patients requiring surgery for fractured neck of femur. In total, 38 patients aged 75 or over were allocated into the two groups, receiving either 0.75 mg kg(-1) of propofol followed by 8% sevoflurane or 8% sevoflurane alone. Vital signs were recorded until successful insertion of a laryngeal mask. Induction times, induction events and patient satisfaction scores were also recorded. Results showed that there were no differences in the cardiovascular parameters between the two groups. Induction times were faster in the propofol and sevoflurane group (62 vs. 81 s; P = 0.028). The postoperative questionnaire showed that the majority of patients in both groups were satisfied with the induction process. We concluded that 0.75 mg kg(-1) of propofol followed by sevoflurane induction is an acceptable alternative to sevoflurane induction. It is associated with similar haemodynamic variables, faster induction times and is very well tolerated.


Approximate Sensory Data Collection: A Survey.
With the rapid development of the Internet of Things (IoTs), wireless sensor networks (WSNs) and related techniques, the amount of sensory data manifests an explosive growth. In some applications of IoTs and WSNs, the size of sensory data has already exceeded several petabytes annually, which brings too many troubles and challenges for the data collection, which is a primary operation in IoTs and WSNs. Since the exact data collection is not affordable for many WSN and IoT systems due to the limitations on bandwidth and energy, many approximate data collection algorithms have been proposed in the last decade. This survey reviews the state of the art of approximatedatacollectionalgorithms. Weclassifythemintothreecategories: themodel-basedones, the compressive sensing based ones, and the query-driven ones. For each category of algorithms, the advantages and disadvantages are elaborated, some challenges and unsolved problems are pointed out, and the research prospects are forecasted.


A constructive replication of the association between the oxytocin receptor genotype and parenting.
Behavioral genetic studies have robustly indicated that parenting behaviors are heritable-that is, individual differences in parenting are at least partially a function of genetic differences between persons. Few studies, however, have sought to identify the specific genetic variants that are associated with individual differences in parenting. Genes that influence the oxytocin system are of particular interest, given the growing body of evidence that points to the role of oxytocin for social behaviors, including parenting. The current study conducted examinations of associations between a variant in the oxytocin receptor gene (OXTR rs53576) and parental warmth, control, and negativity in a sample of 1,000 twin children and their parents (N = 500 families) from the Michigan State University Twin Registry to constructively replicate and extend prior work (Bakermans-Kranenburg & van IJzendoorn, 2008; Michalska et al., 2014). Analyses were conducted both at the level of the child and the level of the parent, allowing us to examine both child-driven (via evocative gene-environment correlation) and parent-driven genetic effects on parenting. Mothers' OXTR genotype predicted her warmth toward her children, even after controlling for child genotype. This association was not found for fathers. These findings add to the growing body of evidence linking oxytocin functioning to parental behavior and also highlight potential etiological differences in parenting across mothers and fathers.


Intramuscular nerve distribution pattern of ankle invertor muscles in human cadaver using sihler stain.
We sought to the ideal sites for botulinum toxin injection by examining the intramuscular nerve patterns of the ankle invertors. A modified Sihler method was performed on the flexor hallucis longus, tibialis posterior, and flexor digitorum longus muscles (10 specimens each). The muscle origins, nerve entry points, and intramuscular arborization areas were measured as a percentage of the total distance from the most prominent point of the lateral malleolus (0%) to the fibular head (100%). Intramuscular arborization patterns were observed at 20-50% for the flexor hallucis longus, 70-80% for the tibialis posterior, and 30-40% for the flexor digitorum longus. These findings suggest that treatment of muscle spasticity of the ankle invertors involves botulinum toxin injections in specific areas. These areas, corresponding to the areas of maximum arborization, are recommended as the most effective and safest points for injection.


Long-Term Risk of Hip Fracture After Ischemic Stroke.
Data are lacking on the long-term risk of hip fracture among patients with ischemic stroke. A better understanding of the contemporary incidence of hip fracture after ischemic stroke could benefit patient care by promoting strategies to prevent this disabling complication in stroke survivors. We performed a retrospective cohort study using inpatient and outpatient claims between 2008 and 2015 from a nationally representative 5% sample of Medicare beneficiaries. We included patients ≥66 years of age who were hospitalized with acute ischemic stroke, defined through a validated diagnostic code algorithm. We excluded patients who had a prior or concurrent hip fracture diagnosis at the time of ischemic stroke. The primary outcome was hip fracture requiring hospitalization. Survival statistics were used to calculate crude incidence rates, and the Kaplan-Meier method was used to calculate cumulative rates. Among the 1 772 550 beneficiaries in our sample, 60 099 were diagnosed with an acute ischemic stroke without prior or concomitant hip fracture. During 4.5 (±2.2) years of follow-up, the incidence of hip fracture was 1.6 (95% confidence interval [CI]: 1.5-1.6) per 100 person-years in patients with acute ischemic stroke versus 0.6 (95% CI: 0.6-0.6) per 100 person-years in patients without acute ischemic stroke. The cumulative 5-year rate of hip fracture was 7.6% (95% CI: 7.2%-8.0%) among patients with acute ischemic stroke versus 2.8% (95% CI: 2.8%-2.9%) among the remaining Medicare beneficiaries. We found that among elderly Medicare beneficiaries with acute ischemic stroke, nearly 1 in 12 developed a hip fracture over the next 5 years.


Measurement of sub-picoampere direct currents with uncertainties below ten attoamperes.
A new type of the ultrastable low-noise current amplifier (ULCA) is presented. It involves thick-film resistors to achieve a high feedback resistance of 185 GΩ at the input amplifier. An improved noise level of 0.4 fA/Hz with a 1/f corner of about 30 μHz and an effective input bias current well below 100 aA are demonstrated. For small direct currents, measurement uncertainties below 10 aA are achievable even without current reversal or on/off switching. Above about 1 pA, the stability of the ULCA's resistor network limits the relative measurement uncertainty to about 10 parts per million. The new setup is used to characterize and optimize the noise in the wiring installed on a dilution refrigerator for current measurements on single-electron transport pumps. In a test configuration connected to the wiring in a pulse tube refrigerator, a total noise floor of 0.44 fA/Hz was achieved including the contributions of amplifier and cryogenic wiring.


The distinctive features of acute monocytic leukemia.
Acute monocytic leukemia is an uncommon form of acute leukemia. Distinctive clinical features include gingival hypertrophy, lymphoadenopathy, coagulation disorders, and lysozymuria. Blast cell morphology and cytochemistry are diagnostic. Receptors for the Fc fragment of IgG have been demonstrated on the basis of a few cases. The drug VP 16-213 has been shown to be very effective in treatment of untreated and previously treated patients.


Short communication: Effect of maternal heat stress in late gestation on blood hormones and metabolites of newborn calves.
Maternal heat stress alters immune function of the offspring, as well as metabolism and future lactational performance, but its effect on the hormonal and metabolic responses of the neonate immediately after birth is still not clear. The objective of this study was to investigate the blood profiles of hormones and metabolites of calves born to cows that were cooled (CL) or heat-stressed (HS) during the dry period. Within 2 h after birth, but before colostrum feeding, blood samples were collected from calves [18 bulls (HS: n=10; CL: n=8) and 20 heifers (HS: n=10; CL: n=10)] born to CL or HS dry cows, and hematocrit and plasma concentrations of total protein, prolactin, insulin-like growth factor-I, insulin, glucose, nonesterified fatty acid, and β-hydroxybutyrate were measured. Compared with CL, HS calves had lower hematocrit and tended to have lower plasma concentrations of insulin, prolactin, and insulin-like growth factor-I. However, maternal heat stress had no effect on plasma levels of total protein, glucose, fatty acid, and β-hydroxybutyrate immediately after birth. These results suggest that maternal heat stress desensitizes a calf's stress response and alters the fetal development by reducing the secretion of insulin-like growth factor-I, prolactin, and insulin.


Distribution of selenium in egg white and yolk after feeding natural and synthetic selenium compounds.
Practical diets containing various selenium levels, with and without selenite supplementation, were fed to hens. Eggs were then collected over a 14-day period to determine how quickly changes in dietary selenium affected egg white and yolk selenium. Changes in egg white selenium content were rapid and essentially completed seven days after changing the selenium content of a practical diet. Changes in egg yolk were not yet completed by 14 days. When selenium from practical feedstuffs was fed, the selenium content of dried egg white was about equal to or greater than the selenium content of dried egg yolk. When selenite was fed, the selenium content of dried yolk was higher. Feeding selenomethionine resulted in more selenium in egg white than in egg yolk. Feeding selenocystine resulted in more selenium in egg yolk than egg white, a pattern similar to that from feeding selenite. The data suggest that selenocystine is not incorporated into protein but is metabolized to an inorganic selenium compound.


Student academic performance factors affecting matching into first-choice residency and competitive specialties.
Although specific specialties and residency programs have investigated student performance factors affecting matching, there is a paucity of information from medical schools. Furthermore, factors contributing to matching into first-choice residency have not been examined. This study aimed to identify academic performance factors affecting matching into first-choice residency and highly competitive specialties. The authors conducted a study of 1726 graduates from their institution from 2010 to 2017 and assessed pre-/post-admission academic variables associated with matching into first choice and highly competitive specialties. 53.9% of graduates matched into their first choice. This was associated with passing COMLEX Level 2 CE (p = 0.01), PE (p = 0.02) on first attempt, and higher COMLEX Level 2 CE and USMLE 2 CK scores (p < 0.001 and 0.002; 14.1 and 3.9-point difference in mean scores respectively). Pre-clinical GPA (p = 0.002) and highest MCAT score (p = 0.02) were associated, however differences in means were < 1 point for both. Factors associated with matching into first choice included: MCAT (OR 0.95, 95% CI = (0.92, 0.98)), Level 2 CE score (OR = 1.01, 95% CI = (1.01, 1.02)) and passing Level 2 PE (OR = 3.68, 95% CI = (1.2, 11.28)). 12% of graduates matched into high- and 63% into low-competitiveness specialties. Matching into highly competitive specialties was associated with passing COMLEX Level 1 (p < 0.001), Level 2 CE (p < 0.001), USMLE Step 1 (p < 0.001) and Step 2 CK (p = 0.03) on first attempt. Mean scores of students matching into high- versus low-competitiveness specialties differed as follows: COMLEX Level 1 62.7 points, Level 2 CE 50.5 points, USMLE Step 1 13.6 points, Step 2 CK 7 points (all p < 0.001), as did pre-clinical GPA (2.4 points, p < 0.001). Level 1 score was the strongest predictor for matching into highly competitive specialties (OR = 1.04, 95% CI = (1.02, 1.05)). Licensing exam performance is important for matching into first-choice residency and into highly competitive specialties. Differences in exam scores were more pronounced for matching into highly competitive specialties than into first choice, with a larger difference in mean scores between students matching into specialties of high versus low competitiveness, than between students matching into their first- versus non first-choice residency. These results may help faculty prepare students and inform curriculum design to improve matching.


Appraisal of endocrine function of segmental autotransplanted pancreas in dogs.
There is increasing interest in pancreatic transplantation for patients with diabetes. In experimental models, endocrine function is usually monitored by determination of insulin and glucose levels in plasma. In this study following a segmental pancreatic autotransplant to the iliac fossa in dogs, a combined analysis of three pancreatic islet hormones, insulin, pancreatic polypeptide (PP) and glucagon was undertaken by radioimmunoassay of plasma. These were measured under basal conditions and following provocation with a standard meal, arginine, secretin and bombesin infusions. Immunohistochemical and electron microscopic examination of transplanted tissue was also performed. Circulating insulin and glucose levels in the surviving dogs with transplants reflected normoglycaemia with a normal tolerance to iv glucose and immunohistochemical detection of endocrine cells producing insulin, PP and glucagon. Secretory granules were found in A and B cells by electron microscopy. The normal circulating glucagon immunoreactivity could have originated in gastric antral A cells as well as in pancreatic tissue. It was not possible, however, to stimulate the autotransplanted pancreas to release detectable PP into the circulation.


Reliability of Early Ambulation after Intradural Spine Surgery : Risk Factors and a Preventive Method for Cerebrospinal Fluid Leak Related Complications.
Cerebrospinal fluid leakage related complications (CLC) occasionally occur after intradural spinal surgery. We sought to investigate the effectiveness of early ambulation after intradural spinal surgery and analyze the risk factors for CLC. For this retrospective cohort study, we enrolled 314 patients who underwent intradural spinal surgery at a single institution. The early group contained 79 patients who started ambulation after 1 day of bedrest without position restrictions, while the late group consisted of 235 patients who started ambulation after at least 3 days of bed rest and were limited to the prone position after surgery. In the early group, Prolene 6-0 was used as the dura suture material, while black silk 5-0 was used as the dura suture material in the late group. The overall incidence rate of CLC was 10.8%. Significant differences between the early and late groups were identified in the rate of CLC (2.5% vs. 13.6%), surgical repair required (1.3% vs. 7.7%), and length of hospital stay (2.99 vs. 9.29 days) (p<0.05). Logistic regression analysis revealed that CLC was associated with practices specific to the late group (p=0.011) and the revision surgery (p=0.022). Using Prolene 6-0 as a dura suture material for intradural spinal surgery resulted in lower CLC rates compared to black silk 5-0 sutures despite a shorter bed rest period. Our findings revealed that suture - needle ratio related to dura defect was the most critical factor for CLC. One-day ambulation after primary dura closure using Prolene 6-0 sutures appears to be a cost-effective and safe strategy for intradural spinal surgery.


Dose Finding of Lenvatinib in Subjects With Advanced Hepatocellular Carcinoma Based on Population Pharmacokinetic and Exposure-Response Analyses.
Hepatocellular carcinoma (HCC) accounts for up to 90% of primary liver cancer occurrences worldwide. Lenvatinib, a multikinase inhibitor, was approved in radioiodine-refractory differentiated thyroid cancer. In this phase 2 study (study 202), we aimed to identify the lenvatinib optimal dose for subjects with advanced HCC Child-Pugh class A. Pooled data from phase 1 studies in healthy adults and in subjects with mixed tumor types, and from study 202 in subjects with HCC, were analyzed using a population pharmacokinetic approach. The relationship between treatment-emergent adverse events leading to withdrawal or dose reduction during cycle 1 and lenvatinib exposure was explored by logistic regression analysis. A receiver operating characteristics analysis was used to investigate the best cutoff values of lenvatinib exposure and body weight to identify a high-risk group for early dose modification. The final pharmacokinetic model included body-weight effects on apparent clearance and volume. The relationship between the lenvatinib area under the plasma concentration-time curve (AUC) at steady state and body weight demonstrated an increase in AUC as body weight decreased in subjects with HCC. An exposure-response relationship was observed, with higher lenvatinib AUC and lower body weight resulting in earlier drug withdrawal or dose reduction. The best cutoff values for body weight and lenvatinib AUC were 57.8 kg and 2430 ng·h/mL, respectively, to predict the group at high risk for early drug withdrawal or dose reduction. We therefore recommend 12-mg and 8-mg starting doses for subjects ≥60 kg and <60 kg, respectively, in subjects with HCC Child-Pugh class A.


Proton pump inhibitor-refractory gastroesophageal reflux disease: current diagnosis and management.
Proton pump inhibitor (PPI) therapy is the mainstay of treatment for gastroesophageal reflux disease (GERD). However, up to 30% of patients with reflux symptoms report inadequate symptom control with PPI therapy. PPI-refractory GERD should be suspected when troublesome reflux symptoms persist after 4-week standard dosage and 8-week high-dosage PPI therapy. Impedance-pH monitoring represents the gold standard for investigating the mechanism(s) of PPI refractoriness and for distinguishing patients with reflux-related from those with reflux-unrelated PPI-refractory syndromes. New impedance parameters, namely the postreflux swallow-induced peristaltic wave (PSPW) index and mean nocturnal baseline impedance (MNBI), have significantly increased the diagnostic yield of impedance-pH monitoring. Currently, laparoscopic fundoplication in experienced hands represents a treatment modality of documented efficacy in patients with PPI-refractory GERD.


Transplantation of immortalized mesencephalic progenitors (CSM14.1 cells) into the neonatal parkinsonian rat caudate putamen.
The present study analyzed whether grafts of the mesencephalic progenitor cell line CSM14.1 into the neonatal rat caudate putamen (CPu) differentiate into neurons and whether this is accompanied by a functional improvement in 6-hydroxydopamine (6-OHDA)-lesioned animals. As in previous studies, a neuronal differentiation of CSM14.1 cells transplanted into the CPu of adult animals could not be observed, so we here used neonatal rats, because graft location and host age seemingly are crucial parameters for neural transplant differentiation and integration. Rats bilaterally lesioned at postnatal day 1 by intraventricular 6-OHDA-injections 2 days later received 100,000 CSM14.1 cells prelabelled with the fluorescent dye PKH26 into the right CPu. Five weeks after grafting, the cylinder test was performed, and the data compared with data from age-matched intact controls and bilaterally lesioned-only animals. Brain slices immunostained for tyrosine hydroxylase (TH) were quantified by optical densitometry. We observed a significant preference of left forelimb use exclusively in transplanted animals. In these rats, TH-containing perikarya were found in the grafted CPu, presumedly leading to the significant increase of TH-immunoreactive fibers in this region. Moreover, confocal laser microscopy revealed a differentiation of transplanted PKH26-labelled CSM14.1 cells into neuronal nuclei antigen or TH-immunoreactive cells. Thus, CSM14.1 cells differentiate into TH-containing neurons, which most probably contribute to the preferred forelimb use, indicating a functional integration of CSM14.1 cells into the host basal ganglia loops during early postnatal development. These findings that are in contrast to observations in adult rats suggest instructive cues for neuronal differentiation and integration given by the neonatal microenvironment.


Interpretation of polymorphic DNA patterns in the human alpha-amylase multigene family.
Previous molecular studies have clearly shown that the human amylase locus has a very complicated structure. Multiple salivary and pancreatic amylase genes are present on haplotypes with variable numbers of genes. To study the population heterogeneity, human genomic DNA from family members and random individuals was digested with a number of different restriction enzymes and hybridized with probes representing various parts of the human pancreatic amylase cDNA. The complex patterns obtained were, in most cases, compatible with predictions from the restriction enzyme maps of cloned human amylase genes. With some enzymes deviations from the predicted intensities of the bands associated with the pancreatic amylase gene AMY2A were observed. These findings can be explained by unequal homologous crossovers between AMY2A and AMY1A, resulting in haplotypes with one gene less or one gene more than the haplotypes described thus far. Moreover, a very complicated TaqI polymorphism was found that can be explained by homologous crossovers between different salivary amylase genes. Because some salivary amylase genes have an inverted orientation with respect to the others, these data provide evidence for the occurrence of intrachromosomal, homologous crossovers, as proposed by us previously (P. C. Groot et al., 1990, Genomics 8: 97-105).


Risk factors contributing to the development of neutropenia in patients receiving oral trifluridine-tipiracil (TAS-102) chemotherapy for advanced/recurrent colorectal cancer.
Elucidating the factors influencing severe neutropenia could aid in earlier management of neutropenia during oral trifluridine-tipiracil (TAS-102) chemotherapy in advanced and recurrent colorectal cancer (CRC). This study was conducted to assess the risk of TAS-102-induced grade 3 or more neutropenia. Between August 2014 and July 2017, 60 patients underwent oral TAS-102 monotherapy at Ogaki Municipal Hospital, Japan. The patients were divided into two groups based on the development of grade 3 or more neutropenia (9 patients) or not (51 patients). Risk factors for grade 3 or more neutropenia were examined by univariate and multivariate analyses. Creatinine clearance rate (CrCl) before TAS-102 administration significantly correlated with the incidence of Grade 3 or more neutropenia after TAS-102 administration (odds ratio 6.5, 95% confidence interval 1.14-30.00; p = 0.02). Multivariate analysis revealed that a CrCl of lower than 57.1 mL/min before TAS-102 administration (odds ratio 54.06, 95% confidence interval 2.14-1364.2; p = 0.02) was an independent risk factor significantly contributing to the development of grade 3 or more neutropenia, induced by TAS-102. CrCl < 57.1 mL/min in patients with advanced and recurrent CRC who underwent TAS-102 chemotherapy was associated with grade 3 or more neutropenia.


Evaluation of the effect of the interleukin-25 serum concentration on the intensity of the symptoms of atopic dermatitis and epidermal barrier.
Interleukin 25 (IL-25) is a cytokine with proinflammatory and anti-inflammatory effects, and its biological function of reciprocal epidermal hyperplasia and of inhibiting the filaggrin synthesis points to an essential role connecting the inflammatory process with damage to the epidermal barrier in the course of atopic dermatitis (AD). To assess the IL-25 in serum concentration in AD patients and to analyse its possible correlation with the disease intensity and selected epidermal barrier parameters such as transepidermal water loss (TEWL). The study involved 43 patients with AD and 22 healthy volunteers. The IL-25 concentration was measured using the ELISA method. The intensity of disease symptoms was investigated using W-AZS and EASI indicators. The epidermal barrier was evaluated using a Tewameter TM300 and Corneometer CM825. The concentration of IL-25 in serum was higher in the study group than in the control group. IL-25 serum concentration correlates with W-AZS/EASI in patients with a severe and moderate course of AD. The concentration of IL-25 affects the TEWL within the affected, evaluated skin surface. An elevated IL-25 concentration in serum is characteristic for patients with moderate and severe AD intensity. The IL-25 concentration in serum correlates with TEWL and with the moisture level in the affected area. However, further studies are necessary to determine the role played by IL-25 in the course of the disease and how it affects the functional parameters of the epidermal barrier.


Enhanced reactivity of Alz-50 antibody in brains of sudden infant death syndrome victims versus brains with lethal hypoxic/ischemic injury. Diagnostic significance after application of the ImmunoMax technique on routine paraffin material.
Alz-50 antibody is immunoreactive with brain tissue of subjects with Alzheimer's disease and can also be demonstrated by immunocytochemistry in neurons of vibratome-prepared brain tissue of victims of sudden infant death syndrome (SIDS). The application of a slightly modified ImmunoMax method enabled us to demonstrate Alz-50 immunoreactivity in paraffin-embedded material. The Alz-50 epitope was detected in the hippocampus region and in nuclei of the medulla oblongata at the level of the inferior olivary protuberance in three diagnostic groups: victims of SIDS (n = 10), infants dying of subacute hypoxia/ischemia with subsequent (re-)perfusion (n = 9), and infants dying of acute ischemia without (re-) perfusion (n = 7). Quantitative evaluation of the hippocampal cortex and the nucleus olivaris inferior disclosed a significantly (P < 0.05) higher percentage of Alz-50-reactive neurons in SIDS cases than in the control groups (hippocampal cortex and the nucleus olivaris; SIDS victims: median = 100%; subacute hypoxia/ischemia: median = 33.6-81%; acute ischemia: median = 89.2-99%). Semiquantitative analysis revealed an equally pronounced preponderance of Alz-50-reactive neurons in SIDS victims versus the control groups. This greater expression in SIDS victims may be due to an ongoing hypoxia/ischemia during agony, but the present paucity of knowledge prohibits definitive elucidation. Nevertheless, the method described here appears to offer the realistic possibility of distinguishing SIDS cases from cases of sudden death in infants due to other causes, i.e., it offers for the first time a positive criterion for the diagnosis of SIDS.


Combinations of immunotherapy and radiation in cancer therapy.
The immune system has the ability to recognize and specifically reject tumors, and tumors only become clinically apparent once they have evaded immune destruction by creating an immunosuppressive tumor microenvironment. Radiotherapy (RT) can cause immunogenic tumor cell death resulting in cross-priming of tumor-specific T-cells, acting as an in situ tumor vaccine; however, RT alone rarely induces effective anti-tumor immunity resulting in systemic tumor rejection. Immunotherapy can complement RT to help overcome tumor-induced immune suppression, as demonstrated in pre-clinical tumor models. Here, we provide the rationale for combinations of different immunotherapies and RT, and review the pre-clinical and emerging clinical evidence for these combinations in the treatment of cancer.


Multimodal analgesia in children.
Acute and chronic pain management in children is increasingly characterized by either a multimodal or a preventive analgesia approach, in which smaller doses of opioid and nonopioid analgesics, such as nonsteroidal anti-inflammatory drugs, local anaesthetics, N-methyl-D-aspartate antagonists, alpha(2)-adrenergic agonists, and voltage-gated calcium channel alpha-2 delta-proteins, are combined alone and in combination with opioids to maximize pain control and minimize drug-induced adverse side effects. A multimodal approach uses nonpharmacological complementary and alternative medicine therapies too. These include distraction, guided imagery, hypnosis, relaxation techniques, biofeedback, transcutaneous electrical nerve stimulation, and acupuncture. Using the neurophysiology of pain as a blueprint, the molecular targets and strategies used in multimodal pain management are described. Finally, weight-based dosage guidelines for commonly used opioid and nonopioid analgesics are provided to facilitate therapy.


Map-based analysis of genetic loci on chromosome 2D that affect glume tenacity and threshability, components of the free-threshing habit in common wheat (Triticum aestivum L.).
During the domestication of bread wheat (Triticum aestivum L.), evolutionary modifications that took place in seed dispersal mechanisms enhanced its suitability for agricultural production. One of these modifications involved the evolution of the free-threshing or hulless characteristic. In this study, we studied quantitative trait loci (QTL) affecting components of the free-threshing habit (threshability and glume tenacity) on chromosome 2D in a recombinant inbred line (RIL) population developed by the International Triticeae Mapping Initiative (ITMI) as well as the tenacious glumes 1 (Tg1) gene in F(2) progeny (CS/CS2D F(2)) of a cross between Chinese Spring and the 2D2 substitution line [Chinese Spring (Ae. tauschii 2D)]. In the ITMI population, two QTL affected threshability (QFt.orst-2D.1 and QFt.orst-2D.2) and their location coincided with QTL affecting glume tenacity (QGt.orst-2D.1 and QGt.orst-2D.2). In the CS/CS2D F(2) population, the location of QTL that affected glume tenacity (QGt.orst-2D.1), the size of a glume base scar after detachment (QGba.orst-2D), and Tg1 (12-cM interval between Xwmc112 and Xbarc168) also coincided. Map comparisons suggest that QFt-orst-2D.1, QGt.orst-2D.1, and QGba.orst-2D correspond to Tg1 whereas QFt.orst-2D.2 and QGt.orst-2D.2 appear to represent separate loci. The observation of coincident QTL for threshability and glume tenacity suggests that threshability is a function of glume adherence. In addition, the observation of the coincident locations of Tg1 and QTL for the force required to detach a glume and the size of a glume base scar after detachment suggests that Tg1's effect on both glume tenacity and threshability resides on its ability to alter the level of physical attachment of glumes to the rachilla of a spikelet.


Dissociation of RecA filaments from duplex DNA by the RuvA and RuvB DNA repair proteins.
The RuvA and RuvB proteins of Escherichia coli act late in recombination and DNA repair to catalyze the branch migration of Holliday junctions made by RecA. In this paper, we show that addition of RuvAB to supercoiled DNA that is bound by RecA leads to the rapid dissociation of the RecA nucleoprotein filament, as determined by a topological assay that measures DNA underwinding and a restriction endonuclease protection assay. Disruption of the RecA filament requires RuvA, RuvB, and hydrolysis of ATP. These findings suggest several important roles for the RuvAB helicase during genetic recombination and DNA repair: (i) displacement of RecA filaments from double-stranded DNA, (ii) interruption of RecA-mediated strand exchange, (iii) RuvAB-catalyzed branch migration, and (iv) recycling of RecA protein.


Evaluation and synthesis of health effects studies of communities surrounding arsenic producing industries.
Epidemiological studies designed to detect lung cancer risk and other health effects in communities surrounding arsenic-producing copper smelters were reviewed. The studies were about evenly divided in finding deleterious and 'beneficial' effects of arsenic. All of the studies had insufficient statistical power to detect the small increases in risk that may occur. Even the most powerful studies were not designed to detect relative risks less than about 1.2 and the majority of the studies had little power to detect risks under 2.0. Confidence intervals for the relative risks from these studies were not very useful in putting an upper bound on adverse effects of arsenic. Sources of bias and other difficulties with community health studies are also discussed. We argue that these studies may be a good and economical first investigation but, due to a lack of power, null findings do not rule out the possibility of excess risks that may be significant from a public health viewpoint.


The role of the basal ganglia and cerebellum in language processing.
The roles of the cerebellum and basal ganglia have typically been confined in the literature to motor planning and control. However, mounting evidence suggests that these structures are involved in more cognitive domains such as language processing. In the current study, we looked at effective connectivity (the influence that one brain region has on another) of the cerebellum and basal ganglia with regions thought to be involved in phonological processing, i.e. left inferior frontal gyrus and left lateral temporal cortex. We analyzed functional magnetic resonance imaging data (fMRI) obtained during a rhyming judgment task in adults using dynamic causal modeling (DCM). The results showed that the cerebellum has reciprocal connections with both left inferior frontal gyrus and left lateral temporal cortex, whereas the putamen has unidirectional connections into these two brain regions. Furthermore, the connections between cerebellum and these phonological processing areas were stronger than the connections between putamen and these areas. This pattern of results suggests that the putamen and cerebellum may have distinct roles in language processing. Based on research in the motor planning and control literature, we argue that the putamen engages in cortical initiation while the cerebellum amplifies and refines this signal to facilitate correct decision making.


[Inguinal mycetoma caused by A. pelletieri. Apropos of a case].
This work is a report of a new case of A. pelletieri inguinal mycetoma probably of primary localization. This ganglionary localization may be responsible for therapeutic failures and a regular survey is needed after a partial surgical cure was done.


Prevalence of Intimate Partner Violence and Associated Factors.
The aim of the present cross-sectional study was to investigate the prevalence of intimate partner physical violence among depressive Turkish women, as well as the association of intimate partner physical violence with attachment patterns, childhood traumas, and socio-demographic factors. The study included 100 women diagnosed with depressive disorder and 30 healthy women. The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders-IV axis I disorders, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, Adult Attachment Style Questionnaire (AASQ), and Childhood Trauma Questionnaire (CTQ) were used for clinical assessment. It was found that 64% of the women diagnosed with depression were suffering from intimate partner physical violence. In these women, the severity of depression and anxiety symptoms was higher, suicidal ideation and suicide attempts were more common, and the diagnosis of double depression was more prevalent. These women also achieved higher scores in the avoidant and ambivalent subscales of AASQ and higher total scores and higher scores in the physical abuse subscale of CTQ. The partner's and the woman's experiences of physical violence in their families during their childhood predicted intimate partner physical violence for women suffering from depression. The investigation of domestic violence contributes to the treatment of depression and also to the recognition and prevention of domestic violence that has profound effects on successive generations.


INHIBITION OF EVOKED POTENTIALS BY STRIATAL STIMULATION AND ITS BLOCKAGE BY STRYCHNINE.
Brief stimulation of the basal ganglia in cats deeply anesthetized with chloralose produces a selective, prolonged inhibition of multisensory peripherally evoked potentials at different levels of the neuraxis without altering activity in primary sensory pathways. The inhibition is blocked by small amounts of strychnine, administered intravenously.


Antiinfection immunity and autoimmunity.
This review summarizes findings that indicate that immune reactions of T and B cells depend on thresholds of the binding avidity of the receptor, on antigen amounts, on the time period during which antigen is available in secondary lymphatic tissues, as well as on the detection methods used. Usually immunologically ignored, strictly extralymphatic host cells or their antigens may be released by infection or immunopathology to reach lymphatic organs and induce autoimmune diseases. If we know the infection, we call the disease immunopathologically mediated; if we do not recognize or know it, we call the disease autoimmune.


[The use of the latex agglutination test for the rapid diagnosis of salmonellosis in children].
From 237 children hospitalized in the enteric department of an infectious clinic 381 fecal samples were obtained and examined (after 24-hour pre-cultivation in selenite enrichment medium) in the latex agglutination test. The results thus obtained were compared with the data of the bacteriological study of these samples. For the first time the diagnostic value of the latex agglutination test (LAT) both for the early and retrospective diagnosis of Salmonella mono- and combined infections was established. The possibility of using LAT for augmenting the laboratory determination of salmonellosis, on the average, 2.1-fold in cases of acute enteric infections, including 3.3-fold in mild and non-manifest forms of such infections and 6.2-fold in clinical variants of the disease with lesions of the proximal sections of the gastrointestinal tract, was demonstrated.


Electrochemical determination of oxidative damaged DNA with high sensitivity and stability using a nanocarbon film.
We describe the electrochemical determination of oxidative damaged DNA by using a nanocarbon film electrode combined with a high performance liquid chromatography (HPLC) system. The nanocarbon film was formed by employing the electron cyclotron resonance sputtering method, and has a nano-crystalline sp(2) and sp(3) mixed bond structure with an atomically flat surface. This film electrode provided the high electrode activity and stability needed to quantitatively detect oxidative damaged DNA, 8-hydroxy-2'-deoxyguanosine (8-OHdG), by direct electrochemical oxidation. The coefficient of variation (C.V.) value of 1 µM 8-OHdG at our film electrode was 0.75% (n = 12), which constitutes superior reproducibility to that of a conventional glassy carbon (GC) electrode (9.28%, n = 12) in flow-injection analysis. This was because the nanocarbon film suppressed fouling for the oxidized product of 8-OHdG owing to its hydrophilically ultraflat and chemically stable surface. We also investigated the performance of HPLC with an electrochemical detection (HPLC-ECD) system using our nanocarbon film electrode. The detection limit for 8-OHdG at the nanocarbon film electrode was 3 nM, which was superior to the detection limit of the GC electrode (7.2 nM). Furthermore, this electrode was more suitable for use in a urinary 8-OHdG experiment than the GC electrode. The concentration of urinary 8-OHdG in the urinary sample was 8.30 nM. These results indicate that this HPLC-ECD system with our nanocarbon film electrode enables us to realize an accurate, sensitive, reproducible and easy to use analysis technique.


A comparative analysis of isotonic versus hypertonic solution volume replacement in septic rats.
Sepsis severity and mortality risk require aggressive therapy which includes hemodynamic support. The best fluid for volume replacement, however, is controversial. This study aimed to compare 0.9% isotonic saline solution versus 7.5% hypertonic saline solution as volume replacement fluid in sepsis induced by cecum ligation plus puncture rats. This experimental trial included 30 rats divided into three groups: Control group (CG, n = 10), isotonic (ISG, n = 10) and hypertonic solution (HSG, n = 10). Fifteen hours after cecum ligation and puncture, all animals underwent respiratory rate, mean arterial pressure, renal and hepatic blood flow and weight evaluation, plus blood collection for TNF-α measurement. The ISG and HSG treatment groups received volume replacement 60 minutes before the procedure with either 0.9% or 7.5% saline solution, respectively. Two animals died. Significant differences were found for the animals' mean weight after 15 hours (p=0.018), particularly relevant when ISG and HSG are compared (p=0.003). Renal blood flow was also significantly different for the CG versus HSG (p=0.002) and CG versus ISG (p=0.008), but not significantly different for ISG versus HSG. No mean arterial pressure improvement was found for HSG (0.054). Other variables were not significant. Although no mean blood pressure, hepatic flow or TNF-α improvements were detected, the rats with sepsis 15 hours after cecum ligation and puncture showed significantly increased renal blood flow which was 0.9% isotonic saline solution or of 7.5% hypertonic solution use independent.


The impossibility of informed consent?
The problematic nature of informed consent to medical treatment and research, and its relation to autonomy, trust and clinical practice, has been addressed on many occasions and from a variety of ethical perspectives in the pages of the Journal of Medical Ethics. This paper gives an account of how discussion of these issues has developed and changed, by describing a number of significant contributions to these debates which provide examples of 'doing good medical ethics' over the 40 years of the Journal's publication.


Gene transfer in swine embryos by injection of cells infected with retrovirus vectors.
Key components for gene transfer to swine embryos using an avian retrovirus are described. A replication-defective reticuloendotheliosis (REV) viral vector can infect and be expressed in pig embryo fibroblasts (PEF). Infection with a replication-competent vector (REV-A) indicates a presumptive block to viral replication in PEF. Swine embryos obtained at the morula stage can be cultured in vitro to the blastocyst stage, injected with retrovirus helper cells or quail embryo fibroblasts producing REV, and transferred to recipient swine with survival to at least 6 wk of gestation.


Pathogenesis of paradoxical hypertension after coarctation resection.
The pathogenesis of paradoxical hypertension after resection of coarctation of the aorta was investigated by comparing the course of seven children undergoing repair of coarctation with five acyanotic children undergoing elective cardiovascular surgery. During the first 24 hours after surgery, all coarctation patients demonstrated a rise in systolic blood pressure (35 +/- 15.5 mm Hg; P less than 0.001), a significant depression in cold pressor test response, and only a slight elevation in plasma renin activity. In the next 24-72 hours, coarctation patients developed a rise in diastolic blood pressure (26.8 +/- 10.6 mm Hg; P less than 0.001), plasma renin activity (22.9 +/- 10.2/ml/hr; P less than 0.001) and fluid retention. By contrast, control patients had no significant postoperative changes. Abdominal pain occurred in five coarctation patients during the period of maximal plasma renin activity. The data suggest that the sympathetic nervous system may be responsible for the initial phase of hypertension after coarctation resection and that the renin angiotension system plays a major role in the second phase of hypertension and in the pathogenesis of mesenteric arteritis.


Hydrogen Treatment for Superparamagnetic VO2 Nanowires with Large Room-Temperature Magnetoresistance.
One-dimensional (1D) transition metal oxide (TMO) nanostructures are actively pursued in spintronic devices owing to their nontrivial d electron magnetism and confined electron transport pathways. However, for TMOs, the realization of 1D structures with long-range magnetic order to achieve a sensitive magnetoelectric response near room temperature has been a longstanding challenge. Herein, we exploit a chemical hydric effect to regulate the spin structure of 1D V-V atomic chains in monoclinic VO2 nanowires. Hydrogen treatment introduced V(3+) (3d(2) ) ions into the 1D zigzag V-V chains, triggering the formation of ferromagnetically coupled V(3+) -V(4+) dimers to produce 1D superparamagnetic chains and achieve large room-temperature negative magnetoresistance (-23.9 %, 300 K, 0.5 T). This approach offers new opportunities to regulate the spin structure of 1D nanostructures to control the intrinsic magnetoelectric properties of spintronic materials.


Characterization of functional relationships of R-loops with gene transcription and epigenetic modifications in rice.
We conducted genome-wide identification of R-loops followed by integrative analyses of R-loops with relation to gene expression and epigenetic signatures in the rice genome. We found that the correlation between gene expression levels and profiled R-loop peak levels was dependent on the positions of R-loops within gene structures (hereafter named "genic position"). Both antisense only (ASO)-R-loops and sense/antisense (S/AS)-R-loops sharply peaked around transcription start sites (TSSs), and these peak levels corresponded positively with transcript levels of overlapping genes. In contrast, sense only (SO)-R-loops were generally spread over the coding regions, and their peak levels corresponded inversely to transcript levels of overlapping genes. In addition, integrative analyses of R-loop data with existing RNA-seq, chromatin immunoprecipitation sequencing (ChIP-seq), DNase I hypersensitive sites sequencing (DNase-seq), and whole-genome bisulfite sequencing (WGBS or BS-seq) data revealed interrelationships and intricate connections among R-loops, gene expression, and epigenetic signatures. Experimental validation provided evidence that the demethylation of both DNA and histone marks can influence R-loop peak levels on a genome-wide scale. This is the first study in plants that reveals novel functional aspects of R-loops, their interrelations with epigenetic methylation, and roles in transcriptional regulation.


[Neuro-immuno-cutaneous system (NICS)].
The concept of neuro-immuno-cutaneous system (NICS) means narrow interrelations between nervous system, immunity and skin. Indeed, there are numerous cellular contacts between nerve fibers, cutaneous cells and immune cells; cutaneous cells can synthesize neuromediators and they express receptors to these molecules; neuromediators are able to modulate functions of cutaneous and/or immune cells. Using confocal or electron microscopy, connexions between nerve fibers and cutaneous cells have been observed. In the skin, nerve fibers may secrete neuromediators: substance P, vaso-active intestinal peptide (VIP), somatostatin, calcitonin-gene related peptide (CGRP), gastrin-releasing peptide (GRP), neuropeptide Y, peptide histidine-isoleucine (PHI), neurotensin, neurokinins A et B, bradykinin, acetylcholine, catecholamines, endorphins and enkephalins. Neurohormones such as prolactin, melano-stimulating hormone (MSH) or adreno-corticotrophic hormone (ACTH) are also expressed in the skin. Neuromediators and neurohormones are also secreted by cutaneous cells and these cells express receptors. Functions of epidermal or dermal cells are modulated by these substances. Immune cells transiently present in the skin (macrophages, lymphocytes...) are modulated by neuromediators through receptors. In the course of skin diseases, especially inflammatory diseases, the NICS is destabilized. Psoriasis and atopic dermatitis are good examples. This phenomenon might be due to inflammation but is also responsible for induction and maintenance of the inflammation.


Inducible production of alcohol oxidase and catalase in a pectin medium by Thermoascus aurantiacus IFO 31693.
Thermoascus aurantiacus showed the best growth on medium containing pectin as a carbon source. The enzyme involved in the production of catalase in the fungus was alcohol oxidase. Formaldehyde dehydrogenase and formate dehydrogenase, in addition to alcohol oxidase and catalase, were detected in the cells grown on pectin. Alcohol oxidase was alkali resistant (pH 7 to 11), and was comparatively heat stable (55 degrees C).


Cavernous malformation of the optic nerve mimicking optic neuritis.
A 30-year-old woman developed acute visual loss and optic disc elevation in the left eye after breastfeeding her second son. The initial diagnosis was optic neuritis. However, MRI showed a lesion in left intraorbital and intracanalicular optic nerve and several cerebral lesions with imaging features of cerebral cavernous malformations (CCMs). Genetic testing was positive for abnormalities known to predispose to CCMs in the patient and her father, who also showed MRI evidence of CCMs. During a 44-month follow-up period in which no intervention took place, the patient's vision in the affected eye fluctuated but eventually became extinguished. Serial MRIs did not always show lesion changes that explained the visual deterioration. In familial CCM, pregnancy might be a "second hit" to genetically predisposed tissue.


Meta-analysis of blood indices and production physiology of broiler chickens on dietary fermented cassava intervention.
The effects of dietary fermented cassava on the blood constituents and production parameters of broiler chickens have been reported with variable outcomes. Therefore, this investigation aimed to explore the impacts of dietary fermented cassava on growth traits, blood constituents, visceral organ, and carcass characteristics of broiler chickens. Four databases were searched for studies that assessed responses of broiler chickens dietary fermented cassava. Eleven articles were used for the investigation, and data generated were analysed using OpenMEE software. A random effects model was used, and effect sizes were presented as standardised mean difference (SMD) at a 95 % confidence interval (CI). Sources of heterogeneity were evaluated using the following modifiers: broiler strain used, cassava form, feeding duration, type of microbes used for the fermentation, and inclusion level of cassava. Results indicate that fermented cassava-based diets increased feed intake (SMD = 0.38; 95 % CI: 0.11, 0.65; P = 0.006), feed conversion ratio (SMD = 1.26; 95 % CI: 0.91, 1.61; P < 0.001), white blood cells (SMD = 1.26; 95 % CI: 0.54, 1.98; P < 0.001), total serum protein (SMD = 1.23; 95 % CI: 0.41, 2.05; P = 0.003), serum cholesterol (SMD = 0.43; 95 % CI: 0.01, 0.85; P = 0.050), serum creatinine (SMD = 2.53; 95 % CI: 0.53, 4.53; P = 0.013), and serum uric acid (SMD = 4.33; 95 % CI: 6.25, 2.41; P < 0.001), but lowered average daily gain and carcass yield, taking heterogeneity into account. Results reveal that studied modifiers were responsible for the inconsistent results among authors. In conclusion, dietary fermented cassava negatively influenced carcass yield, growth performance, and aspects of blood indices of broiler chickens, but did not affect abdominal fat content, visceral organ weights, and cut-part weights. However, more innovative research is needed to improve the feeding quality of cassava using other biotechnological tools in order to maximise its potential as an energy source in broiler chickens.


Guidance in social and ethical issues related to clinical, diagnostic care and novel therapies for hereditary neuromuscular rare diseases: "translating" the translational.
Drug trials in children engage with many ethical issues, from drug-related safety concerns to communication with patients and parents, and recruitment and informed consent procedures. This paper addresses the field of neuromuscular disorders where the possibility of genetic, mutation-specific treatments, has added new complexity. Not only must trial design address issues of equity of access, but researchers must also think through the implications of adopting a personalised medicine approach, which requires a precise molecular diagnosis, in addition to other implications of developing orphan drugs. It is against this background of change and complexity that the Project Ethics Council (PEC) was established within the TREAT-NMD EU Network of Excellence. The PEC is a high level advisory group that draws upon the expertise of its interdisciplinary membership which includes clinicians, lawyers, scientists, parents, representatives of patient organisations, social scientists and ethicists. In this paper we describe the establishment and terms of reference of the PEC, give an indication of the range and depth of its work and provide some analysis of the kinds of complex questions encountered. The paper describes how the PEC has responded to substantive ethical issues raised within the TREAT-NMD consortium and how it has provided a wider resource for any concerned parent, patient, or clinician to ask a question of ethical concern. Issues raised range from science related ethical issues, issues related to hereditary neuromuscular diseases and the new therapeutic approaches and questions concerning patients rights in the context of patient registries and bio-banks. We conclude by recommending the PEC as a model for similar research contexts in rare diseases.


CO2- and anaerobiosis-induced changes in physiology and gene expression of different Listeria monocytogenes strains.
Although carbon dioxide (CO(2)) is known to inhibit growth of most bacteria, very little is known about the cellular response. The food-borne pathogen Listeria monocytogenes is characterized by its ability to grow in high CO(2) concentrations at refrigeration temperatures. We examined the listerial responses of different strains to growth in air, 100% N(2), and 100% CO(2). The CO(2)-induced changes in membrane lipid fatty acid composition and expression of selected genes were strain dependent. The acid-tolerant L. monocytogenes LO28 responded in the same manner to CO(2) as to other anaerobic, slightly acidic environments (100% N(2), pH 5.7). An increase in the expression of the genes encoding glutamate decarboxylase (essential for survival in strong acid) as well as an increased amount of branched-chain fatty acids in the membrane was observed in both atmospheres. In contrast, the acid-sensitive L. monocytogenes strain EGD responded differently to CO(2) and N(2) at the same pH. In a separate experiment with L. monocytogenes 412, an increased isocitrate dehydrogenase activity level was observed for cells grown in CO(2)-containing atmospheres. Together, our findings demonstrate that the CO(2)-response is a partly strain-dependent complex mechanism. The possible links between the CO(2)-dependent changes in isocitrate dehydrogenase activity, glutamate metabolism and branched fatty acid biosynthesis are discussed.


Key prognostic factors for EGFR-mutated non-adenocarcinoma lung cancer patients in the Japanese Joint Committee of Lung Cancer Registry Database.
The efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) for EGFR-mutated non-adenocarcinoma (ADC) non-small cell lung cancer patients is not well established. Herein, we investigated key prognostic factors influencing the efficacy of EGFR-TKIs in these patients. A total of 12,320 lung cancer patients pathologically diagnosed in 2012 at teaching hospitals in Japan were retrospectively selected. The follow-up survey was closed in 2016. EGFR-mutated non-ADC patients were more prone to malignant pleural effusion (MPE) and distant metastasis than ADC patients (P = 0.071 and 0.022, respectively). EGFR-mutated ADC patients were likely to have a longer median overall survival (OS) than non-ADC patients [hazard ratio (HR) 1.3 (95 % CI, 0.97-1.8, P = 0.072)-29.5 months (95 % CI, 27.9-31.1 months) versus 19.5 months (95 % CI, 10.8-28.2 months) (P = 0.068)]. There was no significant difference in median OS between EGFR-positive ADC and non-ADC patients receiving treatment with first-generation EGFR-TKI. Among EGFR-positive non-ADC patients, the median OS was significantly longer for patients receiving EGFR-TKI treatment than for those who did not [HR 4.5 (95 % CI, 2.1-9.8, P < 0.001)-25.5 months (95 % CI, 8.1-42.9 months) versus 7.5 months (95 % CI, 3.4-11.6 months) (P < 0.001)]. While there was no significant difference in the median OS for ADC patients with either 19 del or L858R mutations, the median OS was significantly longer for EGFR-mutated non-ADC patients with 19 del than for those with L858R mutation (HR 3.2 [95 % CI, 1.5-6.9, P = 0.004]; it was not reached for 19 del and was 15.5 months for L858R [95 % CI, 6.6-24.4 months], P = 0.002). EGFR-mutated non-ADC patients were more prone to MPE and distant metastasis. Both ADC and EGFR del19-positive non-ADC patients can benefit from EGFR-TKI treatment, whereas EGFR L858R-positive non-ADC patients might require different therapeutic options.