The PINE study: rationale and design of a randomised comparison of epidural injection of local anaesthetics and steroids versus care-as-usual to prevent postherpetic neuralgia in the elderly [ISRCTN32866390].
BACKGROUND: Postherpetic neuralgia (PHN) is by far the most common complication of herpes zoster (HZ) and one of the most intractable pain disorders. Since PHN is seen most often in the elderly, the number of patients with this disorder is expected to increase in our ageing society. PHN may last for months to years and has a high impact on the quality of life. The results of PHN treatment are rather disappointing. Epidural injection of local anaesthetics and steroids in the acute phase of HZ is a promising therapy for the prevention of PHN. Since randomised trials on the effectiveness of this intervention are lacking, the PINE (Prevention by epidural Injection of postherpetic Neuralgia in the Elderly) study was set up. The PINE study compares the effectiveness and cost-effectiveness of a single epidural injection of local anaesthetics and steroids during the acute phase of HZ with that of care-as-usual (i.e. antivirals and analgesics) in preventing PHN in elderly patients. METHODS / DESIGN: The PINE study is an open, multicenter clinical trial in which 550 elderly (age >/= 50 yr.) patients who consult their general practitioner in the acute phase of HZ (rash < 7 days) are randomised to one of the treatment groups. The primary clinical endpoint is the presence of HZ-related pain one month after the onset of the rash. Secondary endpoints include duration and severity of pain, re-interventions aiming to treat the existing pain, side effects, quality of life, and cost-effectiveness. CONCLUSION: The PINE study is aimed to quantify the (cost-) effectiveness of a single epidural injection during the acute phase of HZ on the prevention of PHN.


Toll-like receptor 2 polymorphisms and their effect on the immune response to ESAT-6, Pam3CSK4 TLR2 agonist in pulmonary tuberculosis patients and household contacts.
Toll-like receptors (TLRs) play a pivotal role in organizing the effective immune response through inducing the pro-inflammatory cytokines for control of tuberculosis infection and TLR polymorphisms are associated with altered cytokine levels have been described. Therefore, the main aim of the present study was to confirm whether TLR2 (C2029T, G2258A) polymorphisms effects the cytokine production in PTB patients and Household contacts (HHC), healthy controls (HC). The polymorphisms were performed by amplification refractory mutation system-polymerase chain reaction (ARMS) & Restriction Fragment Length Polymorphism (RFLP) in 336 subjects. Cytokine levels were estimated in Pam3CSK4, antigen ESAT-6 stimulated culture supernatants by Enzyme-Linked Immunosorbent Assay. Under the over-dominant model GA genotype of G2258A SNP and CT genotype of the co-dominant model in C2029T SNP showed a susceptible effect in patients, whereas in HHC, CT genotype showed a protective effect. A significant decreased TNF-α, IL-12 and increased IL-1β levels were observed after Pam3CSK4, antigen ESAT-6stimulation; our results showed the following associations: TLR2 G2258A SNP of GA with decreased TNF-α; TLR2 C2029T SNP of CT, TT with decreased IL-12 and increased IL-1β levels. Regression analysis demonstrated that age, BCG, gender and T allele were significantly associated with TB. Pre-mRNA secondary structure of the A, T alleles are more stable than G, C alleles. Altogether, we suggest that cytokine levels, 2029T allele, TLR2 polymorphisms were considered as predictive markers for identification of high-risk individuals in TB.


Upper extremity musculoskeletal pain during and after rehabilitation in wheelchair-using persons with a spinal cord injury.
Prospective cohort study. To study upper extremity musculoskeletal pain during and after rehabilitation in wheelchair-using subjects with a spinal cord injury (SCI) and its relation with lesion characteristics, muscle strength and functional outcome. Eight rehabilitation centers with an SCI unit in the Netherlands. Using a questionnaire, number, frequency and seriousness of musculoskeletal pain complaints of the upper extremity were measured. A pain score for the wrist, elbow and shoulder joints was calculated by multiplying the seriousness by the frequency of pain complaints. An overall score was obtained by adding the scores of the three joints of both upper extremities. Muscle strength was determined by manual muscle testing. The motor score of the functional independence measure provided a functional outcome. All outcomes were obtained at four test occasions during and 1 year after rehabilitation. Upper extremity pain and shoulder pain decreased over time (30%) during the latter part of in-patient rehabilitation (P<0.001). Subjects with tetraplegia (TP) showed more musculoskeletal pain than subjects with paraplegia (PP) (P<0.001). Upper extremity pain and shoulder pain were significantly inversely related to functional outcome (P<0.001). Muscle strength was significantly inversely related to shoulder pain (P<0.001). Musculoskeletal pain at the beginning of rehabilitation and BMI were strong predictors for pain 1 year after in-patient rehabilitation (P<0.001). Subjects with TP are at a higher risk for upper extremity musculoskeletal pain and for shoulder pain than subjects with PP. Higher muscle strength and higher functional outcome are related to fewer upper extremity complaints.


Burden of Respiratory Viruses in Children Less Than 2 Years Old in a Community-based Longitudinal US Birth Cohort.
Respiratory viral infections are a major cause of morbidity and hospitalization in young children. Nevertheless, the population burden of respiratory viral infections, especially asymptomatic cases, is not known due to the lack of prospective community-based cohort studies with intensive monitoring. To address this gap, we enacted the PREVAIL cohort, a Centers for Disease Control and Prevention-sponsored birth cohort in Cincinnati, Ohio, where children were followed from 0 to 2 years of age. Weekly text surveys were administered to record acute respiratory illnesses (ARIs), which were defined as the presence of cough or fever (≥38°C). Weekly midturbinate nasal swabs were collected and tested using the Luminex Respiratory Pathogen Panel, which detected 16 viral pathogens. Viral infection was defined as ≥1 positive tests from the same virus or viral subtype ≤30 days of a previous positive test. Maternal report and medical chart abstractions identified healthcare utilization. From 4/2017 to 7/2020, 245 mother-infant pairs were recruited and followed. From the 13 781 nasal swabs tested, a total of 2211 viral infections were detected, of which 821 (37%) were symptomatic. Children experienced 9.4 respiratory viral infections/child-year; half were rhinovirus/enterovirus. Viral ARI incidence was 3.3 episodes/child-year. Emergency department visits or hospitalization occurred with only 15% of respiratory syncytial virus infections, 10% of influenza infections, and only 4% of all viral infections. Regardless of pathogen, most infections were asymptomatic or mild. Respiratory viral infections are common in children 0-2 years. Most viral infections are asymptomatic or non-medically attended, underscoring the importance of community-based cohort studies.


Physical activity and exercise for weight loss and maintenance in people living with obesity.
Physical activity and exercise training programs are integral part of a comprehensive obesity management approach. In persons with overweight or obesity, exercise training, specifically aerobic (i.e. endurance) training, is associated with significant additional weight loss compared to the absence of training. However the magnitude of effect remains modest amounting to only 2-3 kg additional weight loss on average. Comparable effects have been observed for total fat loss. Exercise training, specifically aerobic training, is also associated with decreased abdominal visceral fat as assessed by imaging techniques, which is likely to benefit cardiometabolic health in persons with obesity. Based on data from controlled trials with randomization after prior weight loss, the evidence for weight maintenance with exercise training is as yet not conclusive, although retrospective analyses point to the value of relatively high-volume exercise in this regard. Resistance (i.e. muscle-strengthening) training is specifically advised for lean mass preservation during weight loss. Given the relatively limited effect of exercise training on weight loss as such, the changes in physical fitness brought about by exercise training cannot be overlooked as they provide major health benefits to persons with obesity. Aerobic, as well as combined aerobic and resistance training, increase cardiorespiratory fitness (VO2max) while resistance training, but not aerobic training, improves muscle strength even in the absence of a significant change in muscle mass. Regarding the overall management strategy, adherence in the long term to new lifestyle habits remains a challenging issue to be addressed by further research.


Expression of 3-Methylcrotonyl-CoA Carboxylase in Brain Tumors and Capability to Catabolize Leucine by Human Neural Cancer Cells.
Leucine is an essential, ketogenic amino acid with proteinogenic, metabolic, and signaling roles. It is readily imported from the bloodstream into the brain parenchyma. Therefore, it could serve as a putative substrate that is complementing glucose for sustaining the metabolic needs of brain tumor cells. Here, we investigated the ability of cultured human cancer cells to metabolize leucine. Indeed, cancer cells dispose of leucine from their environment and enrich their media with the metabolite 2-oxoisocaproate. The enrichment of the culture media with a high level of leucine stimulated the production of 3-hydroxybutyrate. When 13C6-leucine was offered, it led to an increased appearance of the heavier citrate isotope with a molar mass greater by two units in the culture media. The expression of 3-methylcrotonyl-CoA carboxylase (MCC), an enzyme characteristic for the irreversible part of the leucine catabolic pathway, was detected in cultured cancer cells and human tumor samples by immunoprobing methods. Our results demonstrate that these cancer cells can catabolize leucine and furnish its carbon atoms into the tricarboxylic acid (TCA) cycle. Furthermore, the release of 3-hydroxybutyrate and citrate by cancer cells suggests their capability to exchange these metabolites with their milieu and the capability to participate in their metabolism. This indicates that leucine could be an additional substrate for cancer cell metabolism in the brain parenchyma. In this way, leucine could potentially contribute to the synthesis of metabolites such as lipids, which require the withdrawal of citrate from the TCA cycle.


Anticalcification effects of DS-1211 in pseudoxanthoma elasticum mouse models and the role of tissue-nonspecific alkaline phosphatase in ABCC6-deficient ectopic calcification.
Pseudoxanthoma elasticum (PXE) is a multisystem, genetic, ectopic mineralization disorder with no effective treatment. Inhibition of tissue-nonspecific alkaline phosphatase (TNAP) may prevent ectopic soft tissue calcification by increasing endogenous pyrophosphate (PPi). This study evaluated the anticalcification effects of DS-1211, an orally administered, potent, and highly selective small molecule TNAP inhibitor, in mouse models of PXE. Calcium content in vibrissae was measured in KK/HlJ and ABCC6-/- mice after DS-1211 administration for 13-14 weeks. Pharmacokinetic and pharmacodynamic effects of DS-1211 were evaluated, including plasma alkaline phosphatase (ALP) activity and biomarker changes in PPi and pyridoxal-phosphate (PLP). Anticalcification effects of DS-1211 through TNAP inhibition were further evaluated in ABCC6-/- mice with genetically reduced TNAP activity, ABCC6-/-/TNAP+/+ and ABCC6-/-/TNAP+/-. In KK/HlJ and ABCC6-/- mouse models, DS-1211 inhibited plasma ALP activity in a dose-dependent manner and prevented progression of ectopic calcification compared with vehicle-treated mice. Plasma PPi and PLP increased dose-dependently with DS-1211 in ABCC6-/- mice. Mice with ABCC6-/-/TNAP+/- phenotype had significantly less calcification and higher plasma PPi and PLP than ABCC6-/-/TNAP+/+ mice. TNAP plays an active role in pathomechanistic pathways of dysregulated calcification, demonstrated by reduced ectopic calcification in mice with lower TNAP activity. DS-1211 may be a potential therapeutic drug for PXE.


Excess of parental non-righthandedness in children with right-sided cleft lip: a preliminary report.
Parents of children with right-sided cleft lip are more likely to be non-right-handed than parents of children with left-handed or bilateral cleft lip. The implications are discussed.


Current Status and Future Direction of Immunotherapy in Urothelial Carcinoma.
Since 2016, five new programmed cell death protein 1/ligand 1 (PD-1/L1) checkpoint inhibitors have been approved for metastatic urothelial carcinoma. This review will summarize the data supporting the widespread use of these agents and highlight areas of ongoing clinical development. PD-1/L1 axis inhibition has demonstrated clear superiority to chemotherapy for the treatment of metastatic urothelial cancer in the second-line setting. A multitude of ongoing studies are investigating the feasibility and efficacy of incorporating established and novel immunotherapies into earlier lines of therapy, including non-metastatic muscle-invasive bladder cancer and even non-muscle-invasive disease. Early-phase clinical trials have begun to explore the safety and activity of novel immune-oncology combinations across a range of clinical settings. Immunotherapy has a clearly defined role in the treatment of metastatic urothelial cancer both in the platinum-refractory setting and in the first-line cisplatin-ineligible setting. Ongoing clinical trials will dictate how to best incorporate immunotherapy into earlier lines of therapy and define the safety and activity of novel immunotherapy agents and combinations.


Amyotrophic lateral sclerosis with ragged-red fibers.
Motor neuron diseases (amyotrophic lateral sclerosis [ALS] and spinal muscular atrophy [SMA]) have been rarely associated with mitochondrial respiratory chain defects. To describe a patient with typical ALS and the finding of ragged-red fibers in muscle biopsy specimens and to review the literature on respiratory chain defects in ALS and SMA. Case report and review of the literature. Collaboration between tertiary care academic hospitals. A 65-year-old man with typical ALS. The patient had 10% ragged-red fibers and 3% cytochrome-c oxidase-negative fibers in muscle biopsy specimens but no biochemical defects of respiratory chain enzymes or alterations of mitochondrial DNA (mtDNA). Amyotrophic lateral sclerosis with ragged-red fibers has been reported in 5 families and is associated with mtDNA mutations in some subjects. Spinal muscular atrophy without mutations in the survival motor neuron gene (SMN; OMIM 600354) has been associated with mtDNA depletion or with mutations in the cytochrome-c oxidase assembly gene (SCO2; OMIM 604377). Respiratory chain defects can mimic ALS or SMA and should be considered in the differential diagnosis.


Exploring the potential of halotolerant bacteria for biodegradation of polycyclic aromatic hydrocarbon.
The present study aimed to determine the degradation and transformation of three-ring PAHs phenanthrene and anthracene by Cryptococcus sp. MR22 and Halomonas sp. BR04 under halophilic conditions. The growth progress of Cryptococcus sp. MR22 and Halomonas sp. BR04 on anthracene and phenanthrene was monitored by colony-forming unit (CFU) technique. The growth of the bacteria was maintained at a maximum concentration of 200 mg/L of all tested hydrocarbon, indicating that Cryptococcus sp. MR22 and Halomonas sp. BR04 significantly perform in the removal of the PAH-contaminated medium at low concentrations. The fit model to represent the biodegradation kinetics of both PAHs was first-order rate equation The extract prepared from cells supplemented with three different substrates exhibited some enzymes such as hydroxylase, dioxygenase, laccase and peroxidase. The results suggest that both strains had an impressive ability in the degradation of aromatic and aliphatic hydrocarbon but also could tolerate in the extreme salinity condition.


Review of the fossil matamata turtles: earliest well-dated record and hypotheses on the origin of their present geographical distribution.
The matamata (Chelus fimbriatus) is a highly aquatic chelid turtle known exclusively from northern South America. Due to its extremely modified morphology, it is well circumscribed among living taxa, but that is not the case of the two extinct species ascribed to the taxon, Chelus colombianus and Chelus lewisi. These were originally described for the Miocene of Colombia and Venezuela, respectively, and are known mostly from post-cranial material. Few traits have been considered diagnostic for these fossil taxa, and their shared geographic and temporal distributions raise doubts about their distinctiveness. Here, we describe new turtle remains from the early Miocene Castillo Formation, at Cerro la Cruz, northwestern Venezuela, assigning them to C. colombianus. We also review the taxonomy and diagnostic features of the fossil species of Chelus, comparing them with the variation recognized within C. fimbriatus. All alleged differences between the fossil Chelus species were found in our sample of the extant species, and may represent intraspecific variation of a single fossil species. Further, we reviewed the fossil record of Chelus spp. and proposed a paleobiogeographic hypothesis to explain its present geographic range.


Secondary Ocular Hypertension and the Risk of Glaucoma Surgery After Dexamethasone Intravitreal Implant in Routine Clinical Practice.
To determine the rate of ocular hypertension (OHT) after dexamethasone intravitreal implant in routine clinical practice and identify patient characteristics associated with a risk for glaucoma surgery. The charts of 260 eyes from 221 patients with diabetic macular edema, retinal vein occlusion, uveitis, and macular edema secondary to various causes treated with one or more dexamethasone implants were reviewed. Intraocular pressure (IOP), medications, and glaucoma interventions were collected before and after implantation. The mean baseline IOP was 14.3 mm Hg ± 3.6 mm Hg, and after receiving dexamethasone implant(s), 26.2% and 7.7% of patients had IOP greater than 25 mm Hg and 35 mm Hg, respectively. There was evidence (P < .001) of an association between preexisting glaucoma or glaucoma suspect status (103 eyes) and need for glaucoma surgery, and 4.62% (12 eyes) required glaucoma surgery. Secondary OHT induced by the dexamethasone implant can usually be controlled by medications, but the incidence of OHT requiring glaucoma surgery was high (4.62%) in our study relative to rates previously reported in the literature. All patients, especially those with preexisting glaucoma, should be advised of the possible need for glaucoma surgery prior to undergoing treatment with the dexamethasone implant. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:680-685.].


[Surgery for colorectal cancer since the introduction of the Netherlands national screening programmeInvestigations into changes in number of resections and waiting times for surgery].
To investigate the impact of the Netherlands national colorectal cancer screening programme on the number of surgical resections for colorectal carcinoma and on waiting times for surgery. Descriptive study. Data were extracted from the Dutch Surgical Colorectal Audit. Patients with primary colorectal cancer surgery between 2011-2015 were included. The volume and median waiting times for the years 2011-2015 are described. Waiting times from first tumor positive biopsy until the operation (biopsy-operation) and first preoperative visit to the surgeon until the operation (visit-operation) are analyzed with a univariate and multivariate linear regression analysis. Separate analysis was done for visit-operation for academic and non-academic hospitals and for screening compared to non-screening patients. In 2014 there was an increase of 1469 (15%) patients compared to 2013. In 2015 this increase consisted of 1168 (11%) patients compared to 2014. In 2014 and 2015, 1359 (12%) and 3111 (26%) patients were referred to the surgeon through screening, respectively. The median waiting time of biopsy-operation significantly decreased (ß: 0.94, 95%BI) over the years 2014-2015 compared to 2011-2013. In non-academic hospitals, the waiting time visit-operation also decreased significantly (ß: 0.89, 95%BI 0.87-0.90) over the years 2014-2015 compared to 2011-2013. No difference was found in waiting times between patients referred to the surgeon through screening compared to non-screening. There is a clear increase in volume since the introduction of the colorectal cancer screening programme without an increase in waiting time until surgery.


Operative therapy for anal incontinence.
Operative therapy for fecal incontinence requires exact understanding of the anatomic and physiologic principles involved and of the potential pathophysiologic mechanisms. Many injuries of the external sphincter can be treated by direct sphincter repair. Extensive obstetric injuries with loss of the perineal body require not only reconstitution of the perineal musculature but also plastic surgical reconstruction of the perineal skin. Patients with descending perineum syndrome and resultant idiopathic fecal incontinence or rectal prolapse with associated incontinence should be treated with postanal plication of the puborectalis sling. Patients who have complex neurologic disorders or who have undergone previous unsuccessful attempts at repair of the puborectalis itself should be considered for placement of a Silastic sling. Diverting colostomy is rarely necessary; it should be performed only after thorough investigation and failure of all reasonable alternative operative procedures.


Measurement of the surface hydrophobicity of human gastrointestinal mucosa.
A technique has been developed for assessing the surface hydrophobicity of human gastrointestinal mucosa by measuring the plateau contact angle of saline drops applied to endoscopic biopsy specimens. The plateau contact angle was not affected by the mode of drying. The intraobserver and interobserver coefficient of variation was less than 5%. The gastric mucosal surface had a higher mean contact angle than the submucosal surface (69 degrees vs. 47 degrees, p less than 0.001). Glycerol drops gave lower contact angles than saline drops (55 degrees vs. 69 degrees) but gave the same derived values for surface free energy (42 vs. 41 mJ/m2). Regional values for contact angle were as follows: gastric body 70 degrees, antrum 70 degrees, duodenal bulb 62 degrees (p less than 0.01 vs. stomach), distal duodenum 50 degrees (p less than 0.001 vs. stomach and p less than 0.01 vs. bulb), and rectum 57 degrees (p less than 0.001 vs. stomach). We conclude that it is feasible to measure the surface hydrophobicity of human endoscopic biopsy specimens and that the stomach is relatively more hydrophobic than the duodenum and rectum.


Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma.
We have examined the structure and expression of the products associated with the t(2;13)(q35;q14) translocation associated with alveolar rhabdomyosarcoma. The chromosome 13 gene (FKHR) is identified as a member of the fork head domain family of transcription factors characterized by a conserved DNA binding motif. Polymerase chain reaction analysis demonstrates that a 5'PAX3-3' FKHR chimaeric transcript is expressed in all eight alveolar rhabdomyosarcomas investigated. Immunoprecipitation experiments detect the predicted fusion protein. These findings indicate that the t(2;13) generates a potentially tumorigenic fusion transcription factor consisting of intact PAX3 DNA binding domains, a truncated fork head DNA binding domain and C-terminal FKHR regions.


H7N9 influenza outbreak in China 2013: In silico analyses of conserved segments of the hemagglutinin as a basis for the selection of peptide vaccine targets.
The sudden emergence of a human infecting strain of H7N9 influenza virus in China in 2013 leading to fatalities in about 30% of the cases has caused wide concern that additional mutations in the strain leading to human to human transmission could lead to a deadly pandemic. It may happen in a short time span as the outbreak of H7N9 is more and more recurrent, which implies that H7N9 evolution is speeding up. H7N9 flu strains were not known to infect humans before this attack in China in February 2013 and it was solely an avian strain. While currently available drugs such as oseltamivir have been found to be largely effective against the H7N9, albeit with recent reported cases of development of resistance to the drug, there is a necessity to identify alternatives to combat this disease, especially if it assumes pandemic proportions. In our work, we have tried to investigate for the genetic changes in hemagglutinin (HA) protein sequence that lead to human infection by an avian infecting virus and identify possible peptide targets to design vaccines to control this upcoming risk. We identified three highly conserved regions in all H7 subtypes, of which one particular immunogenic surface exposed region was found to be well conserved in all human infecting H7N9 strains (accessed up to 27th March 2014). Compared to H7N9 avian strains, we identified two mutations in this conserved region at the receptor binding site of all post-February 2013 human-infecting H7N9China hemagglutinin protein sequences. One of the mutations is very close (3.6 Å) to the hemagglutinin sialic acid binding pocket that may lead to better binding to human host's sialic acid due to the changes in hydrophobicity of the microenvironment of the binding site. We found that the peptide region with these mutational changes that are specific for human infecting H7N9 virus possess the possibility of being used as target for a peptide vaccine.


The Study of Potentially Lignocellulolytic Actinobacteria Pseudonocardia sp. AI2.
The search for microorganisms with potential for bioconversion of lignocellulose is now of immediate interest. Industrial waste is a source of various microorganisms. This paper describes results of the research of potentially lignocellulolytic actinobacteria isolated from activated sludge of the wastewater treatment plant of a pulp and paper mill located in Komi Republic (Russia). One strain of actinobacteria, AI2, was found to be sufficiently active in terms of degradation of lignocellulose-containing materials. Testing of the AI2 isolate demonstrated its ability to synthesize cellulase, dehydrogenase and protease to various extents. The AI2 strain was found capable of biosynthesizing cellulase to 5.5 U/ml. In case of solid-phase fermentation using treated softwood and hardwood sawdust, the content of main components changed most significantly in aspen sawdust: from initial concentration of 20.4% down to 15.6% for lignin, and from 50.6% down to 31.8% for cellulose. In case of liquid-phase fermentation, the content of lignin components decreased significantly in the treated aqueous medium that contained lignosulfonates: from initial concentration of 3.6 g down to 2.1g. Taxonomic study of the AI2 strain of actinobacteria confirmed that it belongs to the rare Pseudonocardia genus of actinomycetes. Based on the results of 16S rRNA sequencing, the AI2 strain is most similar to the species Pseudonocardia carboxydivorans.


Current Practices, Challenges, and Recommendations in Enteral Nutrition After Necrotizing Enterocolitis.
Necrotizing enterocolitis (NEC) is a neonatal disease with high mortality and morbidity. There is a lack of evidence-based recommendations on nutritional rehabilitation following NEC, and much of the current practice is guided by institutional policies and expert opinions. After a diagnosis of NEC, infants are exposed to an extended period of bowel rest and a prolonged course of antibiotics. Recognizing the patient characteristics that predict nutritional tolerance, early initiation of enteral nutrition, minimizing periods of bowel rest and antibiotic exposure, and standardization of dietary practices are the mainstay of post-NEC nutrition.


High pressure infrared spectroscopy of lipid bilayers: new tests for interdigitation.
High-pressure infrared spectroscopy is used to compare the barotropic behaviour of various interdigitated lipid bilayer systems (1,2-di-O-hexadecyl-sn-glycero-3-phosphocholine, 1,3-dipalmitoyl-sn-glycero-2-phosphocholine and 1-palmitoyl-sn-glycero-3-phosphocholine) with non-interdigitated bilayers of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine. In the pressure range between 0 and 20 kbar, we have monitored the pressure dependence of the relative peak height intensity ratio of the chain methylene scissoring band, delta CH2, and its correlation field component band, delta'CH2. We demonstrate that this parameter, in conjunction with a visual inspection of the pressure-induced correlation field splittings of the methylene scissoring and rocking mode bands, can provide reliable indications of chain interdigitation.


A revised model of the molecular structure of the acetylcholine receptor at the neuromuscular junction.
The recently reported amino acid sequence of the alpha subunit of Electrophorus indicates that a previous hypothesis presented of the molecular structure of the acetylcholine receptor at the neuromuscular junction based on the sequence of the alpha subunit of Torpedo is improbable: an "essential" glu (13) of Torpedo is replaced by ser (13) which cannot subsume the function for glu (13) postulated in the hypothesis. This paper presents a new hypothesis which is applicable to both Electrophorus and Torpedo. A mode of rigorously testing the hypothesis provided by the irreversible blocker, lophotoxin, is described.


A new strategy for distinguishing menstrual blood from peripheral blood by the miR-451a/miR-21-5p ratio.
Distinction between menstrual blood and peripheral blood is vital for forensic casework, as it could provide strong evidence to figure out the nature of some criminal cases. However, to date no single blood-specific gene, including the most variable microRNAs (miRNAs) could work well in identification of blood source. In this study, we developed a new strategy for identification of human blood samples by using the copy number ratios of miR-451a to miR-21-5p based on 133 samples, including 56 menstrual blood and 47 peripheral blood, as well as 30 non-blood samples of saliva (10), semen (10) and vaginal secretion (10). The cut-off value and efficacy of the identification strategy were determined through receiver operating characteristic (ROC) analysis. Our results showed that when the miR-451a/miR-21-5p ratio below 0.929, the sample should be non-blood. In contrast, when the miR-451a/miR-21-5p ratio above 0.929 and below 10.201, the sample should be menstrual blood; and when this ratio above 10.201, the sample should be peripheral blood. External validation using 86 samples (62 menstrual blood and 24 peripheral blood samples) fully supported this strategy with the 100% sensitivity and 100% specificity. We confirmed that this result accuracy was not affected by various potential confounding factors of samples and different experimental platforms. We showed that 0.2 ng of total RNA from menstrual blood and peripheral blood was sufficient for qPCR quantification. In conclusion, our results provide an accurate reference to distinguish menstrual blood from peripheral blood for forensic authentication.


Using ChromEvol to Determine the Mode of Chromosomal Evolution.
The ChromEvol software was the first to implement a likelihood-based approach, using probabilistic models that depict the pattern of chromosome number change along a specified phylogeny. The initial models have been completed and expanded during the last years. New parameters that model polyploid chromosome evolution have been implemented in ChromEvol v.2. In recent years, new and more complex models have been developed. The BiChrom model is able to implement two distinct chromosome models for the two possible trait states of a binary character of interest. ChromoSSE jointly implements chromosome evolution, speciation, and extinction. In the near future, we will be able to study chromosome evolution with increasingly complex models.


Sound complexity and 'speechness' effects on pre-attentive auditory discrimination in children.
The evidence in adults suggests that at a cortical level simple and complex sounds are processed by partly divergent subsystems. In children, central processing of sounds differing in complexity has not been investigated. Therefore, the present study examined preconscious discrimination of the differences in sound frequency and duration as a function of sound complexity in 8-10-year-old children. A mismatch negativity (MMN) component of auditory event-related potentials was elicited in a paradigm where 'deviant' (rare) stimuli were either shorter in duration or higher in frequency than the 'standard' (repetitive) sounds. Vowels and vowel-matched complex and simple tones were presented in separate sequences. The stimulus complexity effects were sizable and appeared as larger areas and shorter and more consistent latencies of the MMNs, elicited by more complex stimuli. In addition, the vowel frequency MMN showed left hemisphere preponderance compared to the complex tone frequency MMN. No such effect was found for the duration decrement MMNs. In addition, the complex tone duration decrement MMN was distributed posteriorly to either the vowel or sinusoidal tone MMNs. A late discriminative negativity, LDN, did not show consistent effects of sound complexity. In conclusion, acoustically rich sound content facilitates auditory sensory discrimination in 8-10-year-old children. The sound 'speechness' effects were not as robust though present. Unlike adults, children demonstrated high intersubject variability in discriminating spectrally poor, but not rich, sounds. The discrimination of the sound duration appears to differ from that of the sound frequency in nature and, consequently, in the neural substrates.


Versatile aliphatic polyester biosynthesis system for producing random and block copolymers composed of 2-, 3-, 4-, 5-, and 6-hydroxyalkanoates using the sequence-regulating polyhydroxyalkanoate synthase PhaCAR.
Polyhydroxyalkanoates (PHAs) are microbial polyesters synthesized by PHA synthases. Naturally occurring PHA copolymers possess a random monomer sequence. The development of PhaCAR, a unique sequence-regulating PHA synthase, has enabled the spontaneous biosynthesis of PHA block copolymers. PhaCAR synthesizes both a block copolymer poly(2-hydroxybutyrate)-b-poly(3-hydroxybutyrate) [P(2HB)-b-P(3HB)], and a random copolymer, poly(3HB-co-3-hydroxyhexanoate), indicating that the combination of monomers determines the monomer sequence. Therefore, in this study, we explored the substrate scope of PhaCAR and the monomer sequences of the resulting copolymers to identify the determinants of the monomer sequence. PhaCAR is a class I PHA synthase that is thought to incorporate long-main-chain hydroxyalkanoates (LMC HAs, > C3 in the main [backbone] chain). Thus, the LMC monomers, 4-hydroxy-2-methylbutyrate (4H2MB), 5-hydroxyvalerate (5HV), and 6-hydroxyhexanoate (6HHx), as well as 2HB, 3HB, and 3-hydroxypropionate (3HP) were tested. Recombinant Escherichia coli harboring PhaCAR, CoA transferase and CoA ligase genes was used for PHA production. The medium contained the monomer precursors, 2HB, 3HB, 3HP, 4H2MB, 5HV, and 6HHx, either individually or in combination. As a result, homopolymers were obtained only for 3HB and 3HP. Moreover, 3HB and 3HP were randomly copolymerized by PhaCAR. 3HB-based binary copolymers P(3HB-co-LMC HA)s containing up to 2.9 mol% 4H2MB, 4.8 mol% 5HV, or 1.8 mol% 6HHx were produced. Differential scanning calorimetry analysis of the copolymers indicated that P(3HB-co-LMC HA)s had a random sequence. In contrast, combining 3HP and 2HB induced the synthesis of P(3HP)-b-P(2HB). Similarly, P(2HB) segment-containing block copolymers P(3HB-co-LMC HA)-b-P(2HB)s were synthesized. Binary copolymers of LMC HAs and 2HB were not obtained, indicating that the 3HB or 3HP unit is essential to the polymer synthesis. PhaCAR possesses a wide substrate scope towards 2-, 3-, 4-, 5-, and 6-hydroxyalkanoates. 3HB or 3HP units are essential for polymer synthesis using PhaCAR. The presence of a 2HB monomer is key to synthesizing block copolymers, such as P(3HP)-b-P(2HB) and P(3HB-co-LMC HA)-b-P(2HB)s. The copolymers that did not contain 2HB units had a random sequence. This study's results provide insights into the mechanism of sequence regulation by PhaCAR and pave the way for designing PHA block copolymers.


Monitoring the PACS implementation process in a large university hospital--discrepancies between radiologists and physicians.
Successfully introducing a new technology in a health-care setting is not a walk in the park. Many barriers need to be overcome, not only technical and financial but also human barriers. In this study, we focus on the human barriers to health-care information systems' implementation. We monitored the acceptance of a Picture Archiving and Communication System (PACS) by radiologists and hospital physicians in a large Belgian university hospital. Hereto, questionnaires were taken pre-implementation (T1) and 1 year after the radiology department stopped printing film (T2). The framework we used to perform the study was the Unified Theory of Acceptance and Use of Technology. Main findings were that both groups were positive toward PACS prior to the introduction and that each group was even more positive at T2 with extensive PACS experience. In general, the ratings of the radiologists were higher than those of the physicians, as the radiologists experienced more of the benefits of PACS and had to use PACS throughout the day. Two factors were salient for predicting users' intention to use PACS: the usefulness of PACS (performance expectancy) and the availability of support of any kind (facilitating conditions). The results show that our approach was successful. Both radiologists and physicians give evidence of an excellent level of user acceptance. We can conclude that the implementation of PACS into our hospital has succeeded.


Epigenetic Regulation of Human Neural Stem Cell Differentiation.
Emerging evidence has demonstrated that epigenetic programs influence many aspects of neural stem cell (NSC) behavior, including proliferation and differentiation. It is becoming apparent that epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNA expression, are spatiotemporally regulated and that these intracellular programs, in concert with extracellular signals, ensure appropriate gene activation. Here we summarize recent advances in understanding of the epigenetic regulation of human NSCs directly isolated from the brain or produced from pluripotent stem cells (embryonic and induced pluripotent stem cells, respectively).


Changing epidemiology of hepatocellular carcinoma in South America: A report from the South American liver research network.
Most epidemiological data on hepatocellular carcinoma (HCC) originate from resource-rich countries. We have previously described the epidemiology of HCC in South America through the South American Liver Research Network. Here, we provide an update on the changing epidemiology of HCC in the continent seven years since that report. We evaluated all cases of HCC diagnosed between 2019 to 2021 in centers from six countries in South America. A templated, retrospective chart review of patient characteristics at the time of HCC diagnosis, including basic demographic, clinical and laboratory data, was completed. Diagnosis of HCC was made radiologically or histologically for all cases via institutional standards. Centers contributed to a total of 339 HCC cases. Peru accounted for 37% (n=125) of patients; Brazil 16% (n=57); Chile 15% (n=51); Colombia 14% (n=48); Argentina 9% (n=29); and Ecuador 9% (n=29). The median age at HCC diagnosis was 67 years (IQR 59-73) and 61% were male. The most common risk factor was nonalcoholic fatty liver disease (NAFLD, 37%), followed by hepatitis C (17%), alcohol use disorder (11%) and hepatitis B (12%). The majority of HCCs occurred in the setting of cirrhosis (80%). HBV-related HCC occurred at a younger age compared to other causes, with a median age of 46 years (IQR 36-64). We report dramatic changes in the epidemiology of HCC in South America over the last decade, with a substantial increase in NAFLD-related HCC. HBV-related HCC still occurs at a much younger age when compared to other causes.


A bibliometric review on the top 20 cited articles in the Jackson heart study.
Cardiovascular diseases are higher in African American population, and in the past three decades, less decline in mortality was observed in African Americans compared with white Americans American health disparities resulted in establishing one of the largest single-site investigations to examine causes of cardiovascular diseases in African American population, namely the Jackson Heart Study (JHS). In January 2020, we used the jacksonheartstudy.org website to obtain the list of publications produced by the JHS from 1999 to 2018. The citation's frequency was obtained for 455 articles using the search engine "google.com". The top 20 cited articles were characterized based on the first author's name, the month and year of publication, and the journal's name and its impact factor. The frequency of citations for the 20 most-cited articles in the Jackson heart study ranged from 282 to 5545. The average number of citations was 1045.60. The top 20 articles were represented in 8 different peer-reviewed journals. The top 20 cited articles in the JHS were in the genetics field and were all observational in type. Future direction of the JHS should be directed toward well established interventional studies.


Prognostic biomarkers for the response to the radiosensitizer nimorazole combined with RCTx: a pre-clinical trial in HNSCC xenografts.
Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use. Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined. Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC. Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.


Credibility and the 'professionalized' lay expert: reflections on the dilemmas and opportunities of public involvement in health research.
Contemporary health policy in England places increasing emphasis on patient and public involvement (PPI) in health and health research. With regard to the latter, it has been suggested that PPI brings 'different' perspectives to research decision-making spaces, based on what has been referred to as 'experiential expertise'. This article presents findings from a qualitative study of PPI in cancer research settings in England. We argue that participants highlighted specific forms of expertise in their accounts about involvement, above and beyond experiential expertise, which they felt legitimated their claims to be credible participants within cancer research settings. We report here on the various strategies by which participants sought to accomplish this and highlight, in particular, a concomitant process of 'professionalization' of some within our group of participants. We discuss the significance of these findings in the context of recent debates around the status of experiential expertise.


Postmenopausal effects of intrastriatal estrogen on catalepsy and pallidal electroencephalogram in an animal model of Parkinson's disease.
The main objective was to test the preventive and treatment effects of central injection of estrogen (ES) on muscular rigidity and pallidal EEG in menopausal rats' model of Parkinson's disease (PD). We hypothesized that intrastriatal pretreatment and post-lesion treatment by estrogen improve the pallidal local EEG and muscular stiffness in animal model of menopause with PD. Forty-eight female Wistar rats (300-350 g) were ovariectomized (OVX) and divided into two main groups: Non-pretreated subgroups; sham (S), lesioned (L), post-lesion treated (LT) and pretreated subgroups; pretreated (Pt), pretreated and then lesioned (PtL), pretreated and post-lesion treated (PtLT). Pallidal local EEG was recorded by a bipolar recording electrode and muscle stiffness was scored by Dekundy's test in freely moving rats. Muscle stiffness and pallidal local EEG were indicated as main outcome measures. In pretreated group the local pallidal EEG was decreased in sham-operated rats compared with non-pretreated group (P<0.01), and SNc lesioning decreased EEG in the non-pretreated (P<0.01), while it increased the EEG in the pretreated group (P<0.01). In both groups administration of ES restore the EEG to the respective sham-operated group (P<0.01). Regarding muscle stiffness, it increased after SNc lesioning in both pretreated and non-pretreated groups and ES administration decreased the rigidity significantly (P<0.05, P<0.001 respectively). However, the lesion-induced rigidity in pretreated groups was significantly less than non-pretreated groups (P<0.05). Because of its modulatory effect estrogen may protect dopaminergic neurons from injury and may interfere with the uptake of 6-hydroxydopamine (6-OHDA) into the nigral dopaminergic neurons or alter dopamine release and uptake in remaining neurons.


The effects of D-pencillamine and levamisole on leucocyte chemotaxis in the rat.
The administration of D-penicillamine (25 mg/kg) or levamisole (5 mg/kg) had no effect on leucocyte emigration into the exudates formed in inert sponges implanted in normal rats. 2 In rats, previously sensitized to Bordetella pertussis and implanted with sponges containing pertussis vaccine, an increased leucocyte migration into the exudates occurred; this was significantly enhanced by the administration of the drugs. 3 Neither drug in vitro affected the chemotaxis of rat polymorphonuclear leucocytes although random migration was significantly increased by levamisole (2 microgram to 1 mg/ml). Neither drug affected the chemotaxis of rat mononuclear cells although levamisole (25 microgram/ml) significantly increased that of human monocytes. 4 It is concluded that both drugs produce similar effects in an animal model of delayed hypersensitivity and that their clinical antirheumatic actions may have common elements.


3D bioprinted silk fibroin hydrogels for tissue engineering.
The development of biocompatible and precisely printable bioink addresses the growing demand for three-dimensional (3D) bioprinting applications in the field of tissue engineering. We developed a methacrylated photocurable silk fibroin (SF) bioink for digital light processing 3D bioprinting to generate structures with high mechanical stability and biocompatibility for tissue engineering applications. Procedure 1 describes the synthesis of photocurable methacrylated SF bioink, which takes 2 weeks to complete. Digital light processing is used to fabricate 3D hydrogels using the bioink (1.5 h), which are characterized in terms of methacrylation, printability, mechanical and rheological properties, and biocompatibility. The physicochemical properties of the bioink can be modulated by varying photopolymerization conditions such as the degree of methacrylation, light intensity, and concentration of the photoinitiator and bioink. The versatile bioink can be used broadly in a range of applications, including nerve tissue engineering through co-polymerization of the bioink with graphene oxide, and for wound healing as a sealant. Procedure 2 outlines how to apply 3D-printed SF hydrogels embedded with chondrocytes and turbinate-derived mesenchymal stem cells in one specific in vivo application, trachea tissue engineering, which takes 2-9 weeks.


Contextualized Knowledge Reduces Misconceived COVID-19 Health Decisions.
How do we resolve conflicting ideas about how to protect our health during a pandemic? Prior knowledge influences our decisions, potentially creating implicit cognitive conflict with new, correct information. COVID-19 provides a natural condition for investigating how an individual's health-specific knowledge (e.g., understanding mask efficacy) and their personal context (e.g., outbreak proximity) influence their protective health behavior endorsement, as information about the virus, its spread, and lethality has changed over time. Using a dual-process-model framework, we investigated the role cognitive conflict has on health decision-making. We used a computer mouse-tracking paradigm alongside geographical information systems (GIS) as a proxy for context. The results support a contextualized-deficit-model framework in which relevant knowledge and context-based factors help individuals override cognitive conflict to make more preventative health decisions. Findings from this study may provide evidence for a more effective way for experts to combat non-adherence due to conflicting health information.


The ChatGPT (Generative Artificial Intelligence) Revolution Has Made Artificial Intelligence Approachable for Medical Professionals.
In November 2022, OpenAI publicly launched its large language model (LLM), ChatGPT, and reached the milestone of having over 100 million users in only 2 months. LLMs have been shown to be useful in a myriad of health care-related tasks and processes. In this paper, I argue that attention to, public access to, and debate about LLMs have initiated a wave of products and services using generative artificial intelligence (AI), which had previously found it hard to attract physicians. This paper describes what AI tools have become available since the beginning of the ChatGPT revolution and contemplates how it they might change physicians' perceptions about this breakthrough technology.


Endohedral Gd-Containing Fullerenol: Toxicity, Antioxidant Activity, and Regulation of Reactive Oxygen Species in Cellular and Enzymatic Systems.
The Gd-containing metallofullerene derivatives are perspective magnetic resonance imaging contrast agents. We studied the bioeffects of a water-soluble fullerene derivative, gadolinium-endohedral fullerenol, with 40−42 oxygen groups (Gd@Fln). Bioluminescent cellular and enzymatic assays were applied to monitor toxicity and antioxidant activity of Gd@Fln in model solutions; bioluminescence was applied as a signaling physiological parameter. The Gd@Fln inhibited bioluminescence at high concentrations (>2·10−1 gL−1), revealing lower toxicity as compared to the previously studied fullerenols. Efficient activation of bioluminescence (up to almost 100%) and consumption of reactive oxygen species (ROS) in bacterial suspension were observed under low-concentration exposure to Gd@Fln (10−3−2·10−1 gL−1). Antioxidant capability of Gd@Fln was studied under conditions of model oxidative stress (i.e., solutions of model organic and inorganic oxidizers); antioxidant coefficients of Gd@Fln were determined at different concentrations and times of exposure. Contents of ROS were evaluated and correlations with toxicity/antioxidant coefficients were determined. The bioeffects of Gd@Fln were explained by hydrophobic interactions, electron affinity, and disturbing of ROS balance in the bioluminescence systems. The results contribute to understanding the molecular mechanism of "hormetic" cellular responses. Advantages of the bioluminescence assays to compare bioeffects of fullerenols based on their structural characteristics were demonstrated.


Design and analysis of multiple-choice feeding-preference experiments.
A serious omission in ecological methodology is the absence of a rigorous statistical procedure to analyse multiple-choice feeding-preference experiments. A sample of 21 studies in the littoral marine context shows that results from such experiments are used to study a variety of conceptual issues, ranging from nutritional biology to ecosystem dynamics. A majority of such studies have been incorrectly analysed. The analytical problem has two facets: (1) lack of independence in the simultaneous offer of food types and (2) the existence of autogenic changes particular to each food type. Problem (2) requires the use of control arenas without the consumer. A recent advance allows the rigorous analysis of experiments with two food types offered simultaneously. Here I propose a method for the multiple-choice case. For the first problem I suggest the use of multivariate statistical analysis, providing both a parametric and a nonparametric procedure. The second problem is solved using basic statistical theory. I analyse data from an experiment with the sea urchin Tetrapygus niger feeding on three species of algae: Ulva nematoidea, Gymnogongrus furcellatus, and Macrocystis pyrifera. The parametric and nonparametric procedures yielded similar results, and showed that when offered the three species of algae T. niger does not feed at random but shows a preference for U. nematoidea. The method requires that the number of replicates in the treatment and control arenas be the same, and greater than the number of food types. The method is useful for other kinds of multiple-choice experiments.


Microfragmented Adipose Tissue Versus Platelet-Rich Plasma for the Treatment of Knee Osteoarthritis: A Prospective Randomized Controlled Trial at 2-Year Follow-up.
Intra-articular microfragmented adipose tissue (MF-AT) injections have been proposed for the treatment of knee osteoarthritis (OA). To compare a single injection of MF-AT or platelet-rich plasma (PRP) in terms of clinical outcomes and OA progression. Randomized controlled trial; Level of evidence, 1. A total of 118 patients with symptomatic knee OA were randomized to receive a single intra-articular injection of MF-AT or PRP. Patients were evaluated before the injection and at 1, 3, 6, 12, and 24 months with the International Knee Documentation Committee (IKDC) subjective score, Knee injury and Osteoarthritis Outcome Score (KOOS) subscales, EuroQol visual analogue scale (EQ-VAS), EuroQol 5 dimensions (EQ-5D), and visual analogue scale (VAS) for pain. Primary outcomes were the IKDC subjective score and the KOOS pain subscore at 6 months. Knees were evaluated at baseline and at 6, 12, and 24 months with radiography and high-resolution magnetic resonance imaging (MRI) using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Both MF-AT and PRP provided a statistically and clinically significant improvement up to 24 months. The improvement in the IKDC subjective score from baseline to 6 months was similar in both MF-AT (41.1 ± 16.3 to 57.3 ± 18.8) and PRP (44.8 ± 17.3 to 58.4 ± 18.1) groups (P < .0005). The improvement in the KOOS pain subscore from baseline to 6 months was similar in both the MF-AT (58.4 ± 15.9 to 75.8 ± 17.4) and PRP (63.5 ± 17.8 to 75.5 ± 16.1) groups (P < .0005). Overall, no differences were found between the MF-AT and PRP groups in terms of clinical outcomes, adverse events (18.9% and 10.9%, respectively), and failures (15.1% and 25.5%, respectively). Radiographic and MRI findings did not show changes after the injection. As a secondary outcome, more patients in the MF-AT group with moderate/severe OA reached the minimal clinically important difference for the IKDC score at 6 months compared with the PRP group (75.0% vs 34.6%, respectively; P = .005). A single intra-articular injection of MF-AT was not superior to PRP, with comparable low numbers of failures and adverse events and without disease progression. No differences were found in clinical and imaging results between the 2 biological approaches.


Deciphering the pathways that protect from IL-13-mediated potentiation of oxidative stress-induced dopaminergic nerve cell death.
The majority of Parkinson's disease (PD) cases are sporadic with only about 10% of PD patients having a family history of the disease suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Both oxidative stress and neuroinflammation are thought to contribute to PD. Previously, we showed that the activation of interleukin 13 receptor alpha 1 (IL-13Rα1) increases the sensitivity of dopaminergic neurons to oxidative damage both in cultured cells and in animals. In this study, we investigated the pathways involved in the IL-13-mediated potentiation of oxidative stress-induced dopaminergic cell death using a combination of cell survival assays and Western blotting with appropriate antibodies. In addition, siRNA was used to examine the role of 4E-BP1 in this cell toxicity paradigm. We show that activation of both the Jak-Stat and PI3 kinase-mTOR pathways play key roles in the promotion of cell death by IL-13 in the presence of mild oxidative stress. The Jak 1/2 inhibitor ruxolitinib, the mTOR inhibitor rapamycin and the PI3 kinase inhibitor LY294002 all prevented the potentiation of cell death by IL-13. Moreover, 4E-BP1, a target of mTOR, appeared to mediate the protective effects of rapamycin. Together, these results indicate that multiple signaling pathways downstream of IL-13Rα1 activation play a role in the toxic effects of IL-13 in dopaminergic neurons in the presence of mild oxidative stress and suggest that any of these pathways might provide potential targets for the treatment of PD.


In vitro selection of Staphylococcus aureus mutants resistant to tigecycline with intermediate susceptibility to vancomycin.
Tigecycline (TIG) is an antibiotic belonging to the glycylcyclines class and appears to be a good choice to fight infections caused by Staphylococcus aureus. To date, TIG exhibits good activity against this microorganism. The aim of this work was to obtain in vitro mutants of S. aureus resistant to TIG and evaluate possible changes in their susceptibility patterns to other antibiotics. Two mutants of S. aureus resistant to TIG (MIC = 16 µg/mL) were selected in vitro from clinical isolates of methicillin-resistant S. aureus. In both mutants, corresponding to different lineage (ST5 and ST239), an increase of efflux activity against TIG was detected. One mutant also showed a reduced susceptibility to vancomycin, corresponding to the VISA phenotype (MIC = 4 µg/mL), with a loss of functionality of the agr locus. The emergence of the VISA phenotype was accompanied by an increase in oxacillin and cefoxitin MICs. This study demonstrates that, under selective pressure, the increase of efflux activity in S. aureus is one of the mechanisms that may be involved in the emergence of tigecycline resistance. The emergence of this phenotype may eventually be associated to changes in susceptibility to other antibiotics such oxacillin and vancomycin.


Characterization of Ad5 E3-14.7K, an adenoviral inhibitor of apoptosis: structure, oligomeric state, and metal binding.
The adenovirus E3-14.7K protein, expressed early in the life cycle of human adenoviruses to protect the virus from the antiviral response of host cells, inhibits cell death mediated by TNF-alpha and FasL receptors. To better understand its role in cell death inhibition, we have sought to characterize the biophysical properties of the protein from adenovirus serotype 5 (Ad5 E3-14.7K, or simply 14.7K) through a variety of approaches. To obtain sufficient quantities of recombinantly expressed protein for biophysical characterization, we explored the use of various expression constructs and chaperones; fusion to MBP was by far the most effective at generating soluble protein. Using limited proteolysis, mass spectrometry, and protein-protein interaction assays, we demonstrate that the C-terminal two-thirds of the protein, predicted to be composed of five beta-strands and one alpha-helix, is highly structured and binds its putative cellular receptors. Furthermore, using atomic absorption and ultraviolet/visible spectroscopies, we have studied the metal binding properties of the protein, providing insight into the observation that cysteine/serine mutants of 14.7K lack in vivo antiapoptotic activity. Lastly, results from size exclusion chromatography, dynamic light scattering, sucrose gradient sedimentation, chemical crosslinking, and electron microscopy experiments revealed that 14.7K exists in a stable high-order oligomeric state (nonamer) in solution.


Adequate endocrine and cardiovascular response to social stress in survivors of childhood acute lymphoblastic leukemia.
Survivors of childhood ALL have been demonstrated to have increased morning cortisol levels compared to healthy controls. Information regarding the response of the HPA axis and the sympathetic nervous system to stress in childhood ALL survivors is not available. The present study aimed at assessing the endocrine and cardiovascular stress response in childhood ALL survivors and healthy controls by evaluating perceived stress on visual analog scales, by determining saliva cortisol, blood pressure and heart rate in response to the Trier Social Stress Test for Children (TSST-C). Fifty survivors who had completed their treatment for childhood ALL 57 (IQR 47.0-72.3) months before and 50 healthy age and sex matched controls were included. Exposure to the TSST-C induced a significant response of perceived stress, saliva cortisol and cardiovascular outcome variables in the total study group. These responses did not significantly differ between survivors of childhood ALL and healthy controls. We conclude that the endocrine and cardiovascular response to social stress are intact in survivors of childhood ALL.


Gender differences in susceptibility to kainic acid-induced neurodegeneration in aged C57BL/6 mice.
Some epidemiological studies concerning gender differences in Alzheimer's disease (AD) support the higher prevalence and incidence of AD in women, while most studies using animal models of aging have included only male subjects. It is still uncommon for aged males and females to be compared in the same study. In the present study, we investigated how age and gender influence the excitotoxic neurodegeneration by treating C57BL/6 mice (aged females and males as well as adult females and males) with kainic acid (KA) intranasally. Clinical signs, behavioural changes, pathological changes and astrocyte proliferation were tested; and the levels of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) were measured after KA treatment. The results showed that aged female mice were more sensitive to KA-induced excitotoxicity as demonstrated by severer seizure activity, increased locomotion and rearing in open-field test, prominent hippocampal neuronal damage, enhanced astrocyte proliferation compared with aged males, adult females and adult male mice. In addition, higher BDNF level in hippocampus of aged female mice was observed. These results denote the disparity of aging and gender in KA-induced hippocampal neurodegeneration and aged female mice are more sensitive to the excitotoxicity.


FBXO22 promotes the development of hepatocellular carcinoma by regulating the ubiquitination and degradation of p21.
Deregulation of ubiquitin ligases is related to the malignant progression of human cancers. F-box only protein 22 (FBXO22), an F-box E3 ligase, is a member of the F-box protein family. However, the biological function of FBXO22 in HCC and the underlying molecular mechanisms are still unclear. In this study, we explored the role of FBXO22 in HCC and its mechanism of promoting tumor development. We examined the expression of FBXO22 in normal liver cell lines, HCC cell lines, HCC tissue microarrays and fresh specimens. The correlation between FBXO22 and clinical features was analyzed in a retrospective study of 110 pairs of HCC tissue microarrays. Univariate and multivariate survival analyses were used to explore the prognostic value of FBXO22 in HCC. At the same time, the correlation between the FBXO22 and p21 was also studied in HCC samples. Knock-down and overexpression experiments, CHX and Mg132 intervention experiments, ubiquitination experiments, rescue experiments and nude mouse xenograft models were used to determine the potential mechanism by which FBXO22 promotes tumorigenesis in vitro and in vivo. The expression of FBXO22 in HCC tissues was significantly higher than in normal liver tissues. The overall survival rate and disease-free survival time of patients with high expression of FBXO22 were significantly shorter than those of patients with low expression of FBXO22. The high expression of FBXO22 in HCC tissues were significantly correlated with serum AFP (p = 0. 003, Pearson's chi-squared test), tumor size (p = 0. 019, Pearson's chi-squared test) and vascular invasion (p = 0. 031, Pearson's chi-squared test). Especially, Multivariate analysis showed that tumor size and the expression of FBXO22 were independent prognostic indicator of OS (95% CI: 1.077-5.157, P<0.05). Correlation analysis also showed that FBXO22 was negatively correlated with p21 in tissue microarrays (r = - 0.3788, P<0.001, Pearson correlation) and fresh specimens (r = - 0.4037, P<0.01, Pearson correlation). Moreover, both in vitro and in vivo experiments showed that knocking down FBXO22 expression could inhibit cell proliferation, while overexpression of FBXO22 promoted tumor formation. Furthermore, we identified that FBXO22 interacts with p21 by regulating protein stability and by influencing the ubiquitination process. A knockdown of FBXO22 decreased the ubiquitylation of p21, while overexpression enhanced it. This study uncovered a new mechanism by which FBXO22 functions as an oncogene in HCC pathogenesis and progression by mediating the ubiquitination and degradation of p21. It was also found that tumor size and the expression of FBXO22 were independent prognostic indicator of OS and the expression of FBXO22 and p21 was negatively correlated in clinical samples. Our findings present a new perspective for understanding the development of HCC, which may provide a new target for the treatment and management of this challenging cancer.


Agreement of mothers' and teachers' hyperactivity ratings with scores on drug-sensitive psychological tests.
Hyperactivity ratings were obtained from parents and teachers for 45 hyperactive, children. The children were also given several psychological tests. Teachers' ratings, but not parents' ratings were negatively correlated with performance on the psychological tests that require sustained attention and on which performance is improved by stimulant drugs. This pattern of correlations was interpreted as evidence that teachers, but not parents, have an opportunity to observe children performing daily tasks that require sustained attention.


A successful model to learn and implement ultrasound-guided venous catheterization in apheresis.
Apheresis treatments can be performed with peripheral venous catheters (PVC), although central venous catheters (CVC) are inserted when PVCs fail or patient with history of difficult vascular access prior to the apheresis. Ultrasound guidance for PVC has shown promising results in other settings. To investigate if ultrasound guidance for PVC could be implemented among apheresis nurses. Second, how implementation of ultrasound guidance affected the number of CVCs used for apheresis per patient. Apheresis nurses completed a systematic training program for ultrasound-guided vascular access. All independent catheterizations were registered during the implementation stage. The number of CVCs in the pre- and postimplementation stages of the ultrasound guidance was compared. Six nurses completed the training program within a median of 48 days (range 38-83 days). In 77 patients, 485 independent ultrasound-guided PVC placements were performed during the implementation stage. All apheresis treatments (485/485) were accomplished using PVCs without requiring CVC as rescue. During the preimplementation stage, 125 of 273 (45.8%) procedures required a CVC for completion of apheresis procedures; during the postimplementation stage only 30 of 227 (13.2%) procedures required a CVC (p < 0.001). In the postimplementation stage, no CVCs were placed as rescue caused by failed PVCs but were only placed for patients where the ultrasound machine was unavailable. It indicates an effective success rate of 100% for ultrasound-guided PVC use. This study showed that ultrasound guidance could be implemented among apheresis nurses as a routine tool eliminating the need of CVC as a rescue.


Deconstructing the role of the ECM microenvironment on drug efficacy targeting MAPK signaling in a pre-clinical platform for cutaneous melanoma.
Therapeutics targeting the BRAF kinase in cutaneous melanoma have significantly improved patient survival. However, durable responses in the face of metastatic disease are rarely realized where the problem of brain metastases is generally growing in magnitude. Tumor and stromal cells dynamically remodel the extracellular matrix (ECM) during the establishment of a metastatic lesion. We reasoned that ECM composition strongly determines drug efficacy on cell motility, adhesion and viability rendering one drug more potent and another less so. To test this hypothesis, we constructed platforms recreating the ECM composition due to the stroma and tumor cells, mimicking the brain's perivascular niche and hyaluronic acid (HA) rich parenchyma. Using human melanoma cell lines, we observed that cell adhesion was minimally affected by BRAF inhibition but ablated by ERK inhibition. Cell motility was impaired for both drugs. We determined that the composition and architecture of the ECM niche modulated drug efficacy. In one series, potency of BRAF inhibition was blunted in 3D Fibronectin-HA hydrogels whereas Laminin-HA hydrogels protected against ERK inhibition. In the other series, Laminin blunted drug efficacy, despite both series sharing the same BRAF mutation. These data reinforce the importance of contextual drug assessment in designing future therapeutics.


Androgen-dependent loss of muscle BDNF mRNA in two mouse models of SBMA.
Transgenic expression of neurotrophic factors in skeletal muscle has been found to protect mice from neuromuscular disease, including spinal bulbar muscular atrophy (SBMA), triggering renewed interest in neurotrophic factors as therapeutic agents for treating neuromuscular disease. Because SBMA is an androgen-dependent disease, and brain-derived neurotrophic factor (BDNF) mediates effects of androgens on neuromuscular systems, we asked whether BDNF expression is impaired in two different transgenic (Tg) mouse models of SBMA, the so called "97Q" and "myogenic" SBMA models. The 97Q model globally overexpresses a full length human AR with 97 glutamine repeats whereas the myogenic model of SBMA overexpresses a wild-type rat androgen receptor (AR) only in skeletal muscle fibers. Using quantitative PCR, we find that muscle BDNF mRNA declines in an androgen-dependent manner in both models, paralleling changes in motor function, with robust deficits (6-8 fold) in both fast and slow twitch muscles of impaired Tg males. Castration rescues or reverses disease-related deficits in muscle BDNF mRNA in both models, paralleling its effect on motor function. Moreover, when disease is acutely induced in Tg females, both motor function and muscle BDNF mRNA expression plummet, with the deficit in muscle BDNF emerging before overt motor dysfunction. That androgen-dependent motor dysfunction is tightly associated with a robust and early down-regulation of muscle BDNF mRNA suggests that BDNF delivered to skeletal muscle may have therapeutic value for SBMA.


Wasteful carotenoid coloration and its effects on territorial behavior in a cichlid fish.
The famously diverse body coloration of cichlid fish serves communicative functions in mating and social interactions including competition for resources. Here, we examined the effects of a color pattern trait-the width of a yellow bar on a black body-on territorial competition in males and females of a color variant ("Ikola") of the Lake Tanganyika cichlid Tropheus. First, measuring integumentary carotenoid concentrations in the yellow and black body regions, we established that wider yellow bars require more carotenoids allocated to body coloration. However, we also detected high carotenoid concentrations in the black body regions (> 100 µg/g fresh skin), raising questions about the function of non-displayed integumentary carotenoids. Behavioral experiments showed that fish with wider bars were quicker to explore an unfamiliar area of the tank. In experiments including presentations of fish dummies, the bar width of 'territorial' dummies had no effect on the latency time which test fish took to intrude into the dummies' territories. However, male test fish performed fewer aggressive acts against wide-barred than against narrow-barred dummy competitors. Our results suggest that intimidation by wide bars as well as correlations between bar width and explorative behavior may contribute to mediating success in territorial Tropheus "Ikola".


Designing an intervention program over the effects of Pilates on pregnancy outcomes among the pregnant women: A protocol study.
Pregnancy is a pleasure for most women, it is often considered as a stressful period with physiological, anatomical, biochemical, and psychological changes. Pilates exercise improved quality of life in women. Therefore, the present study targeted at designing an intervention program over the effects of Pilates on pregnancy outcomes among the pregnant women. In this protocol, a clinical intervention will be designed in three phases. In the first phase of the study, a researcher-made checklist will be used to evaluate the pregnancy and neonatal outcomes based on the literature review. In the second phase, an intervention program of Pilates exercise will be conducted according to different studies and viewpoints of a panel of reproductive health and physical activity specialists. The exercises will include two sessions of 30 minutes per week for 12 weeks conducted under the supervision of a qualified trainer. The third phase of the intervention will include the pre-test and post-test using a standard questionnaire and a researcher-made checklist for the two intervention groups and one control group. The present study provides useful data regarding the design of a Pilates exercise intervention program for pregnant women with the aim of influencing pregnancy and neonatal outcomes, reducing depression, low back pain and improving maternal mental health. It can also reduce their medical and treatment costs. The strategies of this program could be important and cost effective, and therefore we hope that the success of such a program is a step forward in improving reproductive health status.


Aromatic amino acid biosynthesis in Alcaligenes eutrophus H16. I. Properties and regulation of 3-deoxy-d-arabino heptulosonate 7-phosphate synthase.
Properties and regulation of 3-deoxy-D-arabino-heptulosonate 7-phosphate synthase (DAHP-synthase), EC126.96.36.199, from Alcaligenes eutrophus H16 were investigated. DAHP synthase was unstable during manipulations such as dialysis, dilution, ammonium sulfate fractionation, chromatography on DEAE-cellulose or Sephadex G-200. For kinetic measurements Sephadex G-25 treated crude extracts were used. The enzyme was not affected by thiol reagents, EDTA or divalent metal ions. The activation energy, deltaH, amounted to 16100 cal/mole. Between pH 7.2 and pH 8.2 there was little change of enzyme activity. The Km-values for the two substrates were found to be 0.043 mM phosphoenolpyruvate and 0.055 mM erythrose-4-phosphate. DAHP-synthase was inhibited by 0.5 mM phenylalanine for 60% and by 0.5 mM tyrosine for 20%. In the presence of both amino acids cumulative inhibition occurred amounting to about 70%. No other amino acid exerted inhibitory effects. A repression of DAHP-synthase by the aromatic amino acids was not observed. Some other strains of hydrogen bacteria were included in this study. The DAHP synthase from strain 12/60/X and Corynebacterium autotrophicum 7C was unregulated. The enzyme from strain 33/X was subject to retro-tyrosine inhibition and from strain 3/2, H1 and H20 were subject to cumulative inhibition.


Intraventricular meningioma of the fourth ventricle.
A rare case of meningioma of the fourth ventricle is reported. A review of the literature revealed only 24 reported cases of this type of tumor.


Individual preferences, government policy, and COVID-19: A game-theoretic epidemiological analysis.
The ongoing COVID-19 pandemic imposes serious short-term and long-term health costs on populations. Restrictive government policy measures decrease the risks of infection, but produce similarly serious social, mental health, and economic problems. Citizens have varying preferences about the desirability of restrictive policies, and governments are thus forced to navigate this tension in making pandemic policy. This paper analyses the situation facing government using a game-theoretic epidemiological model. We classify individuals into health-centered individuals and freedom-centered individuals to capture the heterogeneous preferences of citizens. We first use the extended Susceptible-Exposed-Asymptomatic-Infectious-Recovered (SEAIR) model (adding individual preferences) and the signaling game model (adding government) to analyze the strategic situation against the backdrop of a realistic model of COVID-19 infection. We find the following: 1. There exists two pooling equilibria. When health-centered and freedom-centered individuals send anti-epidemic signals, the government will adopt strict restrictive policies under budget surplus or balance. When health-centered and freedom-centered individuals send freedom signals, the government chooses not to implement restrictive policies. 2. When governments choose not to impose restrictions, the extinction of an epidemic depends on whether it has a high infection transmission rate; when the government chooses to implement non-pharmacological interventions (NPIs), whether an epidemic will disappear depends on how strict the government's restrictions are. Based on the existing literature, we add individual preferences and put the government into the game as a player. Our research extends the current form of combining epidemiology and game theory. By using both we get a more realistic understanding of the spread of the virus and combine that with a richer understanding of the strategic social dynamics enabled by game theoretic analysis. Our findings have important implications for public management and government decision-making in the context of COVID-19 and for potential future public health emergencies.


Impact of safety warnings on antipsychotic prescriptions in dementia: nothing has changed but the years and the substances.
Dementia patients suffering from behavioral and psychological symptoms (BPSD) are often treated with antipsychotics. Trial results document an increased risk for serious adverse events and mortality in dementia patients taking these agents. Furthermore, the efficacy of treating BPSD with antipsychotics seems to be only modest. Using data of a German statutory health insurance company, we examined prescription trends of antipsychotics in prevalent dementia patients in the context of official warnings. The study period is 2004-2009. We studied trends in demographics, age and sex, as well as need of care and the intake of typical and atypical antipsychotics. Seeking for linear trends adjusted for age, sex and level of care between 2004 and 2009, we obtained p-values from a multivariate logistic regression. Prescription volumes were calculated by number of packages as well as defined daily doses (DDDs) using multiple linear regressions for trends in prescriptions amount. We included 3460-8042 patients per year (mean age 80 years). The prescription prevalence of antipsychotics decreased from 35.5% in 2004 to 32.5% in 2009 (multivariate analysis for linear trend: p=0.1645). Overall prescriptions for typical antipsychotics decreased (from 27.2% in 2004 to 23.0% in 2009, p<0.0001) and prescriptions for atypical antipsychotics increased from 17.1% to 18.9% (p<0.0001). The mean DDD per treated patient increased from 80.5 to 91.2 (2004-2009; p=0.0047). Our findings imply that warnings of international drug authorities and manufacturers against adverse drug events in dementia patients receiving antipsychotics did not impact overall prescription behavior.


Gastric banding induces negative bone remodelling in the absence of secondary hyperparathyroidism: potential role of serum C telopeptides for follow-up.
Data about the consequences of laparoscopic adjustable gastric banding (LAGB) on phospho-calcic and bone metabolism remain scarce. We studied a group of 37 obese premenopausal women (age: 24-52 y; mean BMI = 43.7 kg/m2) who underwent LAGB. Serum calcium, phosphate, alkaline phosphatase, parathormone (PTH), vitamin D3, serum C-telopeptides, IGFBP-3 and IGF-1 were measured at baseline, 6, 12, 18 and 24 months after surgery. Body composition, bone mineral content (BMC) and density (BMD) were measured using dual-X-ray absorptiometry (DXA) at baseline, 6, 12 and 24 months after surgery. There was no clinically significant decrease of calcemia; PTH remained stable. Serum telopeptides increased by 100% (P < 0.001) and serum IGFBP-3 decreased by 16% (P < 0.001) during the first 6 months, and then stabilized, whereas IGF-1 remained stable over the 2 y. BMC and BMD decreased, especially at the femoral neck; this decrease was significantly correlated with the decrease of waist and hip circumference. We concluded that there was no evidence of secondary hyperparathyroidism 24 months after LAGB. The observed bone resorption could be linked to the decrease of IGFBP-3, although this decrease could be attributable to other confounding factors. Serum telopeptides seem to be a reliable marker of bone metabolism after gastric banding. DXA must be interpreted cautiously during major weight loss, because of the artefacts caused by the important variation of fat tissue after LAGB.


Enhancing Prosthetic Control through High-Fidelity Myoelectric Mapping with Molecular Anchoring Technology.
Myoelectric control utilizes electrical signals generated from the voluntary contraction of remaining muscles in an amputee's stump to operate a prosthesis. Precise and agile control requires low-level myoelectric signals (below 10% of maximum voluntary contraction, MVC) from weak muscle contractions such as phantom finger or wrist movements, but imbalanced calcium concentration in atrophic skin can distort the signals. This is due to poor ionic-electronic coupling between skin and electrode, which often causes excessive muscle contraction, fatigue, and discomfort during delicate tasks. To overcome this challenge, a new strategy called molecular anchoring is developed to drive hydrophobic molecular effectively interact with and embed into stratum corneum for high coupling regions between ionic fluxes and electronic currents. The use of hydrophobic poly(N-vinyl caprolactam) gel has resulted in an interface impedance of 20 kΩ, which is 1/100 of a commercial acrylic-based electrode, allowing the detection of ultralow myoelectric signals (≈1.5% MVC) that approach human limits. With this molecular anchoring technology, amputees operate a prosthesis with greater dexterity, as phantom finger and wrist movements are predicted with 97.6% accuracy. This strategy provides the potential for a comfortable human-machine interface when amputees accomplish day-to-day tasks through precise and dexterous myoelectric control.


Quantitative assessment of the influence of glutathione S-transferase T1 null variant on gastric cancer risk.
Glutathione S-transferase T1 (GSTT1) catalyzes reactions between glutathione and lipophilic compounds with electrophilic centers, leading to neutralization of toxic compounds, xenobiotics, and products of oxidative stress. In the past decade, a number of case-control studies have been carried out to investigate the relationship between the GSTT1 null polymorphism and gastric cancer (GC), but the results have been inconclusive. To investigate this inconsistency, we performed a meta-analysis of 46 studies involving a total of 9012 GC cases and 14,215 controls for null variant of the GSTT1 gene to evaluate the effect of GSTT1 on genetic susceptibility for GC. Potential sources of heterogeneity including ethnicity, source of control, and sample size were also assessed. Overall, significantly increased GC risk was associated with GSTT1 null polymorphism with OR of 1.20 (95% CI, 1.10-1.32; P < 0.05). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians and Indians, while no significant associations were found among Caucasian, and Middle Eastern and African populations. By pooling data from 19 studies that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for GC (OR = 2.04, 95% CI, 1.49-2.64; P < 0.05) was detected for individuals with dual deletion in both genes compared with positive genotypes. In addition, we found that cigarette smoking and alcohol drinking may modified the association of GSTT1 null genotypes with the risk of GC. In conclusion, this meta-analysis suggests that GSTT1 null polymorphism is associated with elevated GC risk, but these associations vary in different ethnic populations.


Antiobesity designed multiple ligands: Synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents.
Searching for new antiobesity agents, a new series of fatty acid amide derivatives of 1,5-diarylpyrazole have been synthesized as dual peroxisome proliferator activated receptor alpha (PPARalpha)/cannabinoid receptor ligands. The compounds have been evaluated in vivo and in vitro as PPARalpha activators and as cannabinoids in two tests of the mouse tetrad. In vivo, food intake studies have been performed with all the compounds. No significant cannabinoid activity has been found but some compounds behaved as potent PPARalpha activators. Several compounds showed anorexigenic properties reducing food intake in rats.


Calcium in myocardial tissue and isolated mitochondria from a teleost.
A method is presented for isolating cardiac mitochondria from bony-fish. Calcium levels in ventricular whole tissue and isolated mitochondria of Gadus virens L. are determined by atomic absorption flame spectroscopy, and were found to be about 8 and 16 nmolCa/mg prot., respectively. In conclusion, the calcium concentration within the myocardial mitochondria in this species may be nearly three times higher than at the outside, and probably these structures serve as a "calcium sink". The results are compared with those previously reported for mammals.


MR spectroscopy of the brain in Leigh syndrome.
Brain magnetic resonance spectroscopy in two patients with Leigh syndrome revealed the presence of lactate in gray and white matter brain tissue and relatively high choline levels in the white matter. The latter observation, most probably related to an ongoing demyelination process, underlines specific involvement of white matter metabolism in Leigh syndrome even in cases without involvement of the white matter as visualized on MRI. Magnetic resonance spectroscopy might thus be of help in differentiating Leigh syndrome from a range of other mitochondrial diseases, such as ophthalmoplegia and Kearns-Sayre syndrome, showing lack of lactate in brain tissues appearing normal on MRI.


[Choice of optimal margins in prostate conformal radiotherapy].
The planning CT allows the delineation of the prostate (clinical target volume, CTV) but with an imprecision at the apex and the inability to visualize the intraprostatic cancer. MRI enables accurate visualization of the prostate outlines and in some extent the intraprostatic tumour (gross tumour volume [GTV]). The integration of MRI data within the CT remains still complex. Analysis of prostatectomy specimen has guided the definition of a CTV beyond the capsule, depending on pretreatment factors. In practice, the CTV can be defined as follows: prostate-only, for good prognosis tumours; prostate (+0 to 5mm margins, excluding the rectum) and seminal vesicles (possibly limited to 2 cm of their proximal region) for intermediate-risk tumours; prostate (+5mm margins) and seminal vesicles for high-risk tumours. The planning target volume (PTV) should be between 5mm and 10mm depending on the space directions, in the absence of image-guidance (IGRT). It could be reduced to 5mm in case of IGRT. In the adjuvant setting after prostatectomy, the definition of the CTV should follow the recommendations from cooperative groups. It takes into account both the analysis of pattern of local recurrence after prostatectomy, but also the specific histological analysis of the surgical specimen of the patient. The corresponding PTV margin is 6 to 8mm.


ABO-incompatible liver transplantation in acute liver failure: a single Portuguese center study.
ABO-incompatible liver transplantation (ABOi LT) is considered to be a rescue option in emergency transplantation. Herein, we have reported our experience with ABOi LT including long-term survival and major complications in these situations. ABOi LT was performed in cases of severe hepatic failure with imminent death. The standard immunosuppression consisted of basiliximab, corticosteroids, tacrolimus, and mycophenolate mofetil. Pretransplantation patients with anti-ABO titers above 16 underwent plasmapheresis. If the titer was above 128, intravenous immunoglobulin (IVIG) was added at the end of plasmapheresis. The therapeutic approach was based on the clinical situation, hepatic function, and titer evolution. A rapid increase in titer required five consecutive plasmapheresis sessions followed by administration of IVIG, and at the end of the fifth session, rituximab. From January 2009 to July 2012, 10 patients, including 4 men and 6 women of mean age 47.8 years (range, 29 to 64 years), underwent ABOi LT. At a mean follow-up of 19.6 months (range, 2 days to 39 months), 5 patients are alive including 4 with their original grafts. One patient was retransplanted at 9 months. Major complications were infections, which were responsible for 3 deaths due to multiorgan septic failure (2 during the first month); rejection episodes (4 biopsy-proven of humoral rejections in 3 patients and 1 cellular rejection) and biliary. The use of ABOi LT as a life-saving procedure is justifiable in emergencies when no other donor is available. With careful recipient selection close monitoring of hemagglutinins and specific immunosuppression we have obtained acceptable outcomes.


Glycoxidative profile of cancer patient serum: A clinical result to associate glycation to cancer.
The influence of advanced glycation end products (AGEs) in the biological processes contribute to the life-changing complications such as progression of cancer, diabetes and other chronic disorders. The receptor of AGEs while interacting with its ligands causes a never-ending irregularity in the cell-signaling communication. Hence, AGEs are considered as an important link between progression and contribution to cancer. This study focuses on the presence and/or absence of oxidative and glycative stress in the serum samples of various cancer patients. During analysis of the early and intermediate glycation product in cancer patient's sera, our result indicates an increasing trend of both the adducts as compared to normal healthy subjects. Similarly, one of the AGEs i.e., carboxymethyllysine was found to be enhanced in cancer sera as compared to NHS. The binding characteristics of circulating auto-antibodies in cancer patient's sera against human serum albumin (HSA)-AGEs were assessed through ELISA and furthermore, the maximum percent inhibition against HSA-AGEs was observed as 57-63%, 46-62% and 42-64% in prostate cancer, lung cancer and head and neck cancer. Hence, our result successfully assisted the presence of AGEs in all the cancer patient's sera though it is not clear which specific cancer is more potent to AGEs.


The carcinoembryonic antigen (CEA) contains multiple immunoglobulin-like domains.
The amino acid sequences of human carcinoembryonic antigen deduced from the cDNA sequences have been analysed. This antigen contains seven extracellular domains (previously recognized three highly repetitive domains are further divided into A and B subdomains each) which are strikingly homologous to each other and to immunoglobulin variable regions, poly-Ig receptor and Thy 1.1. The N-terminal domain lacks immunoglobulin-like fold but the other six domains have, suggesting that the CEA belongs to immunoglobulin superfamily.


Biomechanical Changes on the Typical Sites of Pressure Ulcers in the Process of Turning Over from Supine Position: Theoretical Analysis, Simulation, and Experiment.
Pressure ulcers are mainly caused by prolonged pressure on local tissues. The current method of preventing pressure ulcers is mainly to change the patient's position by turning, so it is significant to study the biomechanics of the typical site of pressure ulcers. Based on anatomical theory, a three-dimensional model of the shoulder and hip was established, and the theoretical contact pressure between the body and the bed was calculated by force analysis. Then, finite element models of typical parts of pressure ulcers were established, and the maximum stresses under different boundary conditions were obtained by finite element analysis. Finally, a human body turning experiment was conducted using a pressure distribution sensor, and the pressure distribution clouds and maximum contact pressure curves under different turning angles were obtained. The results show that the extreme point of maximum stress occurs at [Formula: see text], producing a stress concentration phenomenon; the peak stresses at the shoulder and hip are more balanced in the angular threshold range of [Formula: see text] to [Formula: see text], the stresses are more dispersed, and there exists an angular threshold for optimal integrated pressure, which can improve the efficiency of the use of assisted turning equipment. The relevant results help to explain the causes of pressure ulcer disease and can provide clinical references to improve the effectiveness of care.


A time-saving method for recording chemosensory event-related potentials.
The objective of this study was to reduce the recording duration of chemosensory event-related potentials (CSERP) and thereby to make the method more suitable for routine clinical use. Measurements were performed in the Department of Otorhinolaryngology of the university hospital of Cologne. Two protocols with different sequences [inter-stimulus intervals (ISI)-standard sequence: 30 s; PRS-15: pseudo-randomized sequence, mean ISI of 15 s] were applied to 40 volunteers to record CSERPs. To compare CSERP recordings under optimal and adverse test conditions, 20 younger/normosmic adults and 20 older/hyposmic participants were included in this study. Olfactory function was gauged using the "Sniffin'Sticks" test. For CSERP recordings, phenylethyl alcohol, hydrogen sulfide and carbon dioxide were used for olfactory or trigeminal stimulation, respectively. Both ISI protocols allowed recording CSERPs under optimal and adverse test conditions and distinguishing both groups by latencies (p ≤ 0.015). The time requirement for the recording of CSERPs with the PRS-15 sequence was less than 30 min. The pseudo-randomized sequence allowed the recording of diagnostically conclusive CSERPs in both groups and saved approximately 40% of the measuring time. This seems to be especially useful in cases where a yes/no answer (e.g., medical reports, exclusion of anosmia) is required. Shortening the time requirement significantly allows applying CSERPs to larger populations of patients with olfactory impairment.