Men and women adopt similar walking mechanics and muscle activation patterns during load carriage.
Although numerous studies have investigated the effects of load carriage on gait mechanics, most have been conducted on active military men. It remains unknown whether men and women adapt differently to carrying load. The purpose of this study was to compare the effects of load carriage on gait mechanics, muscle activation patterns, and metabolic cost between men and women walking at their preferred, unloaded walking speed. We measured whole body motion, ground reaction forces, muscle activity, and metabolic cost from 17 men and 12 women. Subjects completed four walking trials on an instrumented treadmill, each five minutes in duration, while carrying no load or an additional 10%, 20%, or 30% of body weight. Women were shorter (p<0.01), had lower body mass (p=0.01), and had lower fat-free mass (p=0.02) compared to men. No significant differences between men and women were observed for any measured gait parameter or muscle activation pattern. As load increased, so did net metabolic cost, the duration of stance phase, peak stance phase hip, knee, and ankle flexion angles, and all peak joint extension moments. The increase in the peak vertical ground reaction force was less than the carried load (e.g. ground force increased approximately 6% with each 10% increase in load). Integrated muscle activity of the soleus, medial gastrocnemius, lateral hamstrings, vastus medialis, vastus lateralis, and rectus femoris increased with load. We conclude that, despite differences in anthropometry, men and women adopt similar gait adaptations when carrying load, adjusted as a percentage of body weight.


Impaired neural differentiation of MPS IIIA patient induced pluripotent stem cell-derived neural progenitor cells.
Mucopolysaccharidosis type IIIA (MPS IIIA) is characterised by a progressive neurological decline leading to early death. It is caused by bi-allelic loss-of-function mutations in SGSH encoding sulphamidase, a lysosomal enzyme required for heparan sulphate glycosaminoglycan (HS GAG) degradation, that results in the progressive build-up of HS GAGs in multiple tissues most notably the central nervous system (CNS). Skin fibroblasts from two MPS IIIA patients who presented with an intermediate and a severe clinical phenotype, respectively, were reprogrammed into induced pluripotent stem cells (iPSCs). The intermediate MPS IIIA iPSCs were then differentiated into neural progenitor cells (NPCs) and subsequently neurons. The patient derived fibroblasts, iPSCs, NPCs and neurons all displayed hallmark biochemical characteristics of MPS IIIA including reduced sulphamidase activity and increased accumulation of an MPS IIIA HS GAG biomarker. Proliferation of MPS IIIA iPSC-derived NPCs was reduced compared to control, but could be partially rescued by reintroducing functional sulphamidase enzyme, or by doubling the concentration of the mitogen fibroblast growth factor 2 (FGF2). Whilst both control heparin, and MPS IIIA HS GAGs had a similar binding affinity for FGF2, only the latter inhibited FGF signalling, suggesting accumulated MPS IIIA HS GAGs disrupt the FGF2:FGF2 receptor:HS signalling complex. Neuronal differentiation of MPS IIIA iPSC-derived NPCs was associated with a reduction in the expression of neuronal cell marker genes βIII-TUBULIN, NF-H and NSE, revealing reduced neurogenesis compared to control. A similar result was achieved by adding MPS IIIA HS GAGs to the culture medium during neuronal differentiation of control iPSC-derived NPCs. This study demonstrates the generation of MPS IIIA iPSCs, and NPCs, the latter of which display reduced proliferation and neurogenic capacity. Reduced NPC proliferation can be explained by a model in which soluble MPS IIIA HS GAGs compete with cell surface HS for FGF2 binding. The mechanism driving reduced neurogenesis remains to be determined but appears downstream of MPS IIIA HS GAG accumulation.


Orientation anisotropies in macaque visual areas.
In mammals, a larger number of neurons in V1 are devoted to cardinal (horizontal and vertical) orientations than to oblique orientations. However, electrophysiological results from the macaque monkey visual cortex are controversial. Both isotropic and anisotropic orientation distributions have been reported. It is also unclear whether different visual areas along the visual hierarchy have different orientation anisotropies. We analyzed orientation maps in a large set of intrinsic signal optical imaging data and found that both V1 and V4 exhibited significant orientation anisotropies. However, their overrepresented orientations were very different: in V1, both cardinal and radial orientations were overrepresented, while in V4, only cardinal bias was presented. These findings suggest that different cortical areas have evolved to emphasize different features that are suitable for their functional purposes, a factor that needs to be considered when efforts are made to explain the relationships between the visual environment and the cortical representation and between the cortical representation and visual perception.


A porcine reproductive and respiratory syndrome virus (PRRSV)-specific IgM as a novel adjuvant for an inactivated PRRSV vaccine improves protection efficiency and enhances cell-mediated immunity against heterologous PRRSV challenge.
Current strategies for porcine reproductive and respiratory syndrome (PRRS) control are inadequate and mainly restricted to immunization using different PRRS virus (PPRSV) vaccines. Although there are no safety concerns, the poor performance of inactivated PRRSV vaccines has restricted their practical application. In this research, we employed the novel PRRSV-specific IgM monoclonal antibody (Mab)-PR5nf1 as a vaccine adjuvant for the formulation of a cocktail composed of inactivated PRRSV (KIV) and Mab-PR5nf1 along with a normal adjuvant to enhance PRRSV-KIV vaccine-mediated protection and further compared it with a normal KIV vaccine and modified live virus vaccine (MLV). After challenge with highly pathogenic (HP)-PRRSV, our results suggested that the overall survival rate (OSR) and cell-mediated immunity (CMI), as determined by serum IFN-γ quantification and IFN-γ ELISpot assay, were significantly improved by adding PRRSV-specific IgM to the PRRSV-KIV vaccine. It was also notable that both the OSR and CMI in the Mab-PR5nf1-adjuvanted KIV group were even higher than those in the MLV group, whereas the CMI response is normally poorly evoked by KIV vaccines or subunit vaccines. Compared with those in piglets immunized with the normal KIV vaccine, viral shedding and serum neutralizing antibody levels were also improved, and reduced viral shedding appeared to be a result of enhanced CMI caused by the inclusion of IgM as an adjuvant. In conclusion, our data provide not only a new formula for the development of an effective PRRSV-KIV vaccine for practical use but also a novel method for improving antigen-specific CMI induction by inactivated vaccines and subunit vaccines.


Corrigendum: Development and validation of a model for predicting the risk of brain arteriovenous malformation rupture based on three-dimensional morphological features.
[This corrects the article DOI: 10.3389/fneur.2022.979014.].


Simultaneous detection of the antioxidant and pro-oxidant activity of dietary polyphenolics in a peroxidase system.
The ability to reduce the peroxidase (myeloglobin/H2O2)-generated ABTS*+ [2,2'-azinobis-(3-ethylbenzthiazoline-6-sulfonic acid) radical cation] has been used to rank the antioxidant activity of various agents including dietary flavonoids and chalcones. Surprisingly, we found that in the presence of catalytic concentrations of the phenol B-ring containing flavonoids, apigenin, naringenin and the chalcone phloretin, the formation of the ABTS*+ was initially increased. The enhanced formation of the ABTS*+ was attributed to the peroxidase/H2O2 mediated generation of polyphenolic phenoxyl radicals that were able to co-oxidize ABTS. The relative ABTS*+ generating ability of these dietary polyphenolics correlated with their ability to co-oxidize NADH to the NAD* radical with the resultant generation of superoxide. This pro-oxidant activity was not observed for either luteolin or eriodyctiol, which are B-ring catecholic analogues of apigenin and naringenin, respectively, suggesting that these antioxidants are incapable of the transition metal-independent generation of reactive oxygen species. This pro-oxidant activity of the polyphenolics therefore needs to be taken into account when quantifying antioxidant activity.


Epidermal growth factor stimulates a protein tyrosine kinase which is separable from the epidermal growth factor receptor.
The intrinsic protein tyrosine kinase activity of the epidermal growth factor (EGF) receptor is necessary for ligand-induced signaling. To determine whether cellular protein tyrosine kinases are substrates for EGF-activated receptors, phosphotyrosine-containing proteins were isolated from EGF-treated cells and assayed for tyrosine kinase activity using peptide substrates. A tyrosine kinase activity that is distinct from the EGF receptor was adsorbed to monoclonal anti-phosphotyrosine antibody columns and eluted with phenyl phosphate. Near-maximal tyrosine phosphorylation of this kinase occurred within 1 min of cell stimulation with an ED50 for EGF of 2.5 nM. The kinase was deactivated by incubation with purified CD45 tyrosine phosphatase in vitro, but activity could be restored by incubation with purified EGF receptor and Mn2+ ATP. These results suggest a cascade of tyrosine kinase signaling analogous to well characterized serine/threonine kinase cascades.


[Marble bone disease: The role of SPECT/CT hybrid imaging].
Osteopetrosis is an autosomal metabolic bone disease characterized by a decrease in bone resorption. It can be dominant or recessive. The patient often has increased bone fragility with fractures, which are usually the first sign of disease. Symptoms are variable, ranging from mild hematological disorders to severe neurological complications that can be life threatening. This work reports on the contribution of single-photon emission computed tomography (SPECT)/CT in the diagnosis and management of osteoarticular complications of marble bone disease, based on a clinical case. A 2-year-old child, born after a consanguineous marriage, was hospitalized because of mucocutaneous pallor, splenomegaly, failure to thrive, and altered psychomotor development. Radiographic examination showed signs of osteopetrosis. SPECT/CT revealed a double fracture of the right coracoid process and the 10th right rib. Fractures are a common complication of osteopetrosis. They are spontaneous or associated with minor trauma. SPECT/CT is important in the evaluation of the extension of bone lesions, and it confirms the diagnosis of osteomyelitis or fracture when radiological images are atypical or clinical expression is unusual.


Control of pancreas and liver gene expression by HNF transcription factors.
The transcriptional regulatory networks that specify and maintain human tissue diversity are largely uncharted. To gain insight into this circuitry, we used chromatin immunoprecipitation combined with promoter microarrays to identify systematically the genes occupied by the transcriptional regulators HNF1alpha, HNF4alpha, and HNF6, together with RNA polymerase II, in human liver and pancreatic islets. We identified tissue-specific regulatory circuits formed by HNF1alpha, HNF4alpha, and HNF6 with other transcription factors, revealing how these factors function as master regulators of hepatocyte and islet transcription. Our results suggest how misregulation of HNF4alpha can contribute to type 2 diabetes.


"V-Plasty" technique using dual synthetic vascular grafts to reconstruct outflow channel in living donor liver transplantation.
The reconstruction of outflow is a crucial step in living donor liver transplantation. This study describes a suitable technique that uses synthetic vascular conduits in presence of multiple draining veins of right lobe of liver and the outcome of the recipients to evaluate safety of using multiple synthetic grafts. From March 2011 to September 2014, 325 patients underwent right lobe living donor liver transplantation. Expanded polytetra-fluoroethylene (ePTFE) grafts were used in total 155 of the liver allografts. Among these, 16 liver grafts required dual ePTFE grafts to reconstruct the outflow due to presence of multiple hepatic veins. The mean diameters for venous branches of segment 5 (V5) and 8 (V8) were 5 mm (range, 4-8 mm) and 7 mm (range, 5-9 mm). The mean diameter of inferior right hepatic veins was 8 mm (7-10 mm). All the recipients who received the right liver with dual ePTFE grafts showed satisfactory inflow and outflow immediately after reconstruction as measured by Doppler flowmetry. Postoperative ultrasonographic studies showed no disturbances in outflow. Protocol dynamic computed tomography performed in the second postoperative month showed 100% patency rates of the artificial grafts. At median follow-up of 24 months graft survival was achieved in 88%, whereas the patency rates of the ePTFE grafts were 100%. The use of "V-Plasty" technique using dual artificial vascular grafts is a safe and feasible technique in the presence of various allograft venous anomalies & ensures a single venous channel for outflow reconstruction. Our study also suggests that ePTFE graft may be a useful interposition material without serious complications.


[Additive, heterosis and maternal effects in various methods of crossing in swine breeding].
The effects of genes with various cross methods in swine breeding have been revealed. Additive and maternal effects are determined on the basis of a great number of fattening and meat qualities. Thus, it is advisable to use the absorptive crossing.


Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation.
Ivacaftor (VX-770) is a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator that was approved in the United States for the treatment of cystic fibrosis (CF) in patients ≥ 6 years of age who have a G551D mutation; however, the most prevalent disease-causing CFTR mutation, F508del, causes a different functional defect. The objectives of this study were to evaluate the safety of ivacaftor in a larger population and for a longer time period than tested previously and to assess the efficacy of ivacaftor in subjects with CF who are homozygous for F508del-CFTR. This was a phase 2 study with a 16-week randomized (4:1), double-blind, placebo-controlled period (part A) and an open-label extension (part B) for subjects who met prespecified criteria. Part A: The safety profile of ivacaftor was comparable to that of the placebo. The overall adverse event frequency was similar in the ivacaftor (87.5%) and placebo (89.3%) groups through 16 weeks. The difference in the change of FEV₁ % predicted from baseline through week 16 (primary end point) between the ivacaftor and placebo groups was 1.7% (P = .15). Sweat chloride, a biomarker of CFTR activity, showed a small reduction in the ivacaftor vs placebo groups of -2.9 mmol/L (P = .04) from baseline through week 16. Part B: No new safety signals were identified. The changes in FEV₁ or sweat chloride in part A were not sustained with ivacaftor treatment from week 16 to week 40. These results expand the safety information for ivacaftor and support its continued evaluation. Lack of a clinical effect suggests that a CFTR potentiator alone is not an effective therapeutic approach for patients who have CF and are homozygous for F508del-CFTR. ClinicalTrials.gov; No.: NCT00953706; URL: www.clinicaltrials.gov.


Remote perconditioning reduces myocardial injury in adult valve replacement: a randomized controlled trial.
Remote perconditioning has been proved to reduce myocardial infarction and improve ventricular function in vivo. This study aims to determine the protection of remote perconditioning against cardiac reperfusion injury in patients undergoing valve replacement. Eighty-one patients admitted for selective valve replacement were divided into three groups randomly. Control patients (con. n = 27) underwent sham placement of the tourniquet around the right thigh without inflation; the remote preconditioning group (pre. n = 26) received three cycles of 4/4 min right lower limb ischemia and reperfusion after induction of anesthesia, the limb ischemia was induced by the tourniquet inflated to 600 mmHg; the remote perconditioning group (per. n = 28) received the same stimulus immediately after aortic cross-clamping. Venous blood samples were obtained preoperatively, 5 min before declamping, 30 min, 4, 12, and 72 h after declamping for detecting troponin I (cTnI) concentration. The clinical data of inotrope requirement, drainage, ventilation. and intensive care time were routinely recorded. The remote perconditioning group had significantly lower release of cTnI 5 min before declamping (con. versus pre. versus per., 0.15 ± 0.10 versus 0.13 ± 0.08 versus 0.10 ± 0.04 ng/mL, P = 0.050) and 30 min after declamping (con. versus pre. versus per., 0.40 ± 0.24 versus 0.41 ± 0.40 versus 0.24 ± 0.13 ng/mL, P = 0.043). Less incidence of defibrillation were observed in the remote perconditioning groups. Remote perconditioning, which is induced by transient lower limb ischemia after aortic cross-clamping, reduces myocardial injury over cardioplegia in adults undergoing selective valve replacement.


Variation in the α2A-adrenergic receptor gene and risk of gestational diabetes.
Sympathetic activation suppresses insulin secretion via pancreatic ADRA2A. Because sympathetic activity and insulin demand increase during pregnancy, we tested the hypothesis that ADRA2A variants are associated with gestational diabetes (GDM). Among Caucasian pregnant women without pre-existing diabetes, we genotyped 458 who had GDM and 1537 without GDM for seven ADRA2A variants. rs1800038 (OR: 2.34; p = 0.020) and rs3750625 (OR: 1.56; p = 0.010) increased the risk of GDM, and rs11195418 decreased it (OR: 0.62; p = 0.025). The associations remained significant after adjustment for maternal age, maternal BMI, parity and a genetic risk score that included variants previously associated with Type 2 diabetes mellitus and GDM. ADRA2A genetic variation contributes independently to the risk of GDM in Caucasian women.


Systemic inflammation modulates the ability of serum ferritin to predict all-cause and cardiovascular mortality in peritoneal dialysis patients.
This study aimed to ascertain whether the correlation of high serum ferritin with mortality is affected by systemic inflammation and to investigate the optimal serum ferritin level for predicting death when inflammation is considered in peritoneal dialysis (PD) patients. We classified 221 patients into four groups according to serum ferritin concentration (100 μg/L) and high-sensitivity CRP (hs-CRP) level (3 mg/L), and followed them regularly from the date of catheterization to Dec 31, 2016, at Sun Yat-Sen Memorial Hospital, China. Clinical and biochemical data were collected at baseline, and clinical outcomes such as all-cause and cardiovascular mortality were assessed. During a median follow-up of 35 months (3 ~ 109 months), 50 (22.6%) deaths occurred. Cardiovascular disease (46.0%) was the most common cause of death, followed by infection (10.0%). The Kaplan-Meier survival analysis and log-rank test revealed significantly worse survival accumulation among PD patients with higher serum ferritin (≥100 μg/L) under elevated hsCRP levels (> 3 mg/L) (P = 0.022). A multivariate Cox regression analysis revealed that an increased serum ferritin level was independently associated with a higher risk of all-cause and cardiovascular mortality in PD patients (HR = 3.114, P = 0.021; and HR = 9.382, P = 0.032) with hsCRP above 3 mg/L after adjusting for relevant confounding factors. Higher serum ferritin levels were associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing PD only in the presence of elevated hsCRP levels. The correlation of serum ferritin with poor outcome should take into consideration systemic inflammation.


Spontaneous erosion of a lost intra-abdominal gallstone through the back eight months following laparoscopic cholecystectomy.
Gallbladder perforation during laparoscopic cholecystectomy with spillage of bile and gallstones occurs in up to 40% of patients. Several reports have recently been published describing complications related to these lost gallstones. The purpose of this study was to determine the incidence of this complication in our patients. A prospectively maintained database of 856 laparoscopic cholecystectomies performed between 1989 and 1996 by a single surgeon was analyzed. The number of perforations resulting in loss of stones in the abdominal cavity was 16% (165 patients). Of these 165 patients, only a single patient could be identified as having a long-term complication. Intra-abdominal lost gallstones can produce complications secondary to migration and erosion. It is prudent to make a concerted effort to remove spilled gallstones by every possible means but conversion to laparotomy is not justifiable.


Cervical and lumbar routes for metrizamide cervical examination.
The C1-C2 lateral spinal puncture for metrizamide injection is compared to decubitus lumbar puncture for cervical myelography. By lumbar route, the contrast medium was taken into the cervical region with the patient prone. The instances when the lumbar route could not be used include cervical spinal trauma, spinal deformity, and lumbar epidural infection. Routine metrizamide cervical myelography by the C1-C2 route has better film quality and probably fewer short-term adverse reactions than use of the lumbar route of injection.


Identification of keratins and analysis of their expression in carp and goldfish: comparison with the zebrafish and trout keratin catalog.
With more than 50 genes in human, keratins make up a large gene family, but the evolutionary pressure leading to their diversity remains largely unclear. Nevertheless, this diversity offers a means to examine the evolutionary relationships among organisms that express keratins. Here, we report the analysis of keratins expressed in two cyprinid fishes, goldfish and carp, by two-dimensional polyacrylamide gel electrophoresis, complementary keratin blot binding assay, and immunoblotting. We further explore the expression of keratins by immunofluorescence microscopy. Comparison is made with the keratin expression and catalogs of zebrafish and rainbow trout. The keratins among these fishes exhibit a similar range of molecular weights and isoelectric points, with a similar overall pattern on two-dimensional gels. In addition, immunofluorescence microscopy studies of goldfish and carp tissues have revealed the expression of keratins in both epithelial and mesenchymally derived tissues, as reported previously for zebrafish and trout. We conclude that keratin expression is qualitatively similar among these fishes, with goldfish and carp patterns being more similar to each other than to zebrafish, and the cyprinid fishes being more similar to each other than to the salmonid trout. Because of the detected similarity of keratin expression among the cyprinid fishes, we propose that, for certain experiments, they are interchangeable. Although the zebrafish distinguishes itself as being a developmental and genetic/genomic model organism, we have found that the goldfish, in particular, is a more suitable model for both biochemical and histological studies of the cytoskeleton, especially since goldfish cytoskeletal preparations seem to be more resistant to degradation than those from carp or zebrafish.


[Prevalence and Co-prevalence of Complex Regional Pain Syndrome (CRPS) and Carpal Tunnel Syndrome (CTS) in Hand Rehabilitation].
In the current literature, there are reports of associations between complex regional pain syndromes (CRPS) and carpal tunnel syndromes (CTS). The aim of this study was to determine the prevalence of both disease patterns in hand rehabilitation patients and to investigate whether there is a correlation between CTS and CRPS. Furthermore, differences in the healing process of patients with and without additional CTS, and the effectiveness of the rehabilitative therapy for both diseases, were investigated. The computerised medical records of 791 patients in the years 2009-2015 who had been in hand rehabilitation were retrospectively analysed. At the beginning and end of rehabilitation, measurements were made of pain by visual analogue scales (VAS, 0-10), grip strength and finger mobility (mean distance from finger pulp to palmar D2-D5). The clinical course was statistically analysed. CRPS diagnosis was confirmed clinically by a pain therapist, CTS diagnosis was confirmed by neurological and neurophysiological examination. Surgical therapy was performed despite CRPS diagnosis. The prevalence of CRPS was 161/1000 and of CTS 62/1000; the co-prevalence of the 2 diagnoses was 24/1000 (p<0.0001). In the CRPS group, after a mean of 8 (1-21) weeks of rehabilitative therapy, mean pain was reduced from 5 (1-10) to 3 (0-9), grip strength improved from 10 (0-39)kg to 18.5 (2.5-45.5)kg and finger mobility increased from 2.9 (0-7.6)cm to 1.8 (0-7.8)cm. In the CRPS+CTS group, after a mean of 6.8 (3-23) weeks of rehabilitative therapy, mean pain was reduced from 5 (0-8) to 2.6 (0-5), grip strength improved from 9.7 (2.4-25.5)kg to 17.4 (0.9-47.4)kg and finger mobility increased from 2.7 (0-5.3)cm to 1.7 (0-5.3)cm. Improvement over the period of rehabilitation was significant in both groups, though the period of therapy was significantly shorter in the CRPS+CTS group. CRPS and CTS are often associated. Rehabilitative therapy was effective for CRPS- and CRPS+CTS patients.


Management of epilepsy and pregnancy: an obstetrical perspective.
Women with epilepsy who take antiseizure medicines have successful and unremarkable pregnancies the majority of the time. Achieving seizure freedom is important for successful pregnancies, and it is also highly predictive of seizure freedom during pregnancy. From data derived from the general population, vitamin supplementation is important to prevent birth defects, and women with epilepsy of child-bearing potential should be encouraged to take folic acid supplements daily. Pregnant women with epilepsy should have their pregnancies screened for neural tube defects with a maternal serum alpha-feto-protein level at 15-16 weeks of gestational age and an anatomical survey by ultrasound at 18-22 weeks of gestation. Pregnant women with epilepsy do face a higher risk of both non-proteinuric hypertension and induction of labor than do then general population, as well as an approximately twofold risk of cesarean section. However, the indication for cesarean section is unclear and appears not to be related to fetal distress and may in part be influenced by caution at the time of delivery for such patients. Collaboration between the patient, neurologist, and obstetrician is important for managing this dynamic and complex clinical situation.


Morbidity and mortality associated with intraoperative radiotherapy.
From May 1984 through July 1988, 67 patients have been treated with intraoperative radiation therapy (IORT) at LDS Hospital. We conducted a detailed evaluation of the morbidity and mortality related to our intraoperative experience. Major complications were classified as those requiring reoperation or resulting in death. Minor complications included all others that could not be attributed to tumor growth or recurrence. Of twelve major complications, three resulted in death. Nonfatal complications included anastomotic leak (5), wound dehiscence (1), gastric outlet obstruction (1), and bowel obstruction (1). When compared with historical controls undergoing comparable surgery at this institution prior to the availability of IORT, complication rates were similar. We feel in our institution, intraoperative radiotherapy has not added to morbidity of aggressive abdominal surgery.


Risk factors for blunt cerebrovascular injury in the pediatric patient: A systematic review.
While blunt cerebrovascular injury (BCVI) is a rare complication of blunt trauma, it is associated with significant morbidity and mortality. In the pediatric population, unique anatomy and development require screening criteria that accurately diagnose these injuries while limiting unwarranted radiation. We searched Medline OVID, EMBASE, and Cochrane Library databases for studies that investigated the risk factors of BCVI in individuals younger than 18 years of age. We adhered to the Preferred Reporting Items in Systematic Reviews and Meta-Analyses (PRISMA) guidelines and assessed the quality of each study using the Newcastle-Ottawa Scale. We compared key characteristics of the papers, including incidence of BCVI, incidence of risk factors, and statistical significance of risk factors. Of 1304 studies, 16 met the inclusion criteria. Of these, 15 were retrospective cohort studies and one was a retrospective case control study. Most of the studies included all pediatric blunt trauma admissions, but four only included those which underwent imaging, one only included those with cervical seatbelt sign, and one excluded those who did not survive 24-h post-admission. The ages included as pediatric varied between papers. Papers examined different risk factors and reported differing statistical significances. Though no single risk factor was found to be statistically significant in every study, cervical spine and skull fractures were found to be significant by most. Maxillofacial fractures, depressed GCS score, and stroke were found to be statistically significant by multiple studies. Twelve studies examined cervical soft tissue injury, and none found it to be statistically significant. The risk factors most found to be statistically significant for BCVI were cervical spine fracture (10/16 studies), skull fracture (9/16), maxillofacial fractures (7/16), depressed GCS score (5/16), and stroke (5/16). There is a need for prospective studies on this topic. Level III, Systematic Review.


Selectivity evaluation of core-shell sislica columns for reversed-phase liquid chromatography using the solvation parameter model.
For the selectivity evaluation of core-shell silica, siloxane-bonded reversed-phase columns by the solvation parameter model a minimal set of thirty-five calibration compounds were identified for applications with mobile phases containing from 20-70 % (v/v) methanol- or acetonitrile-water. The Kennard-Stone uniform mapping algorithm was employed to select the calibration compounds from a larger database of compounds with known retention properties used previously for column selectivity evaluation. The number and identity of the calibration compounds was optimized by considering the statistical quality of the calibration models, the absolute value for the standard deviation of the individual system constants, and the closeness of the estimated system constants for the calibration models to the values for the full data set on seven core-shell columns with different morphology for mobile phases containing 50 % (v/v) methanol- or acetonitrile-water. The predictive capability of the calibration models was evaluated for an external test set for 50 % (v/v) methanol-water for the same columns with a typical root mean square error of prediction (log k) of 0.028 for the thirty-five calibration compounds (n = 35) models. For all columns and mobile phase compositions the calibration models with n = 35 had a range for the coefficient of determination from 0.999 to 0.970 with < 5 % smaller than 0.99 (84 models) and a standard error of the estimate from 0.011 to 0.057 with 75 % < 0.030. System constants determined at 10 % (v/v) increments of organic solvent were utilized for the construction of system maps and correlation diagrams on Kinetex columns with octadecylsiloxane-bonded (C18 and EVO C18), diisobutyloctadecylsiloxane-bonded (XB-C18) octylsiloxane-bonded (C8), biphenylsiloxane-bonded (Biphenyl), phenylhexylsiloxane-bonded (Phenyl-Hexyl) and pentafluorophenylpropylsiloxane-bonded (F5) silica stationary phases for 20-70 % (v/v) methanol- and acetonitrile-water mobile phases. System maps for the Kinetex Phenyl-Hexyl column and correlation diagrams for columns of similar selectivity (Kinetex C8 and Phenyl-Hexyl) and dissimilar selectivity (Kinetex EVO C18 and Biphenyl) is used to illustrate the general approach to selectivity evaluation.


Psychological and dietary treatments of binge eating disorder: conceptual implications.
The authors review the available literature on psychological and dietary treatment approaches for binge eating disorder (BED). Studies were grouped according to psychological versus dietary approaches to BED. Studies were reviewed in terms of general implications, but particular emphasis was placed on drop-out rates, abstinence from binge eating, and weight loss. Drop-out rates from psychological or dietary approaches to treatment averaged 20% and the presence of binge eating did not confer a greater risk of drop-out among obese individuals. Both psychological and dietary approaches to treatment produced abstinence rates from binge eating of approximately 50% at the 12-month follow-up. Both psychological and dietary approaches show modest efficacy of short-term weight loss, but these effects are generally not sustained in long-term follow-up assessments. Psychological and dietary approaches to BED treatment show reasonable efficacy in binge eating reduction, but limited efficacy in weight loss. These findings are discussed in terms of the validity of the BED construct and the need for more psychopathology studies of BED.


Te Ira Tangata: a Zelen randomised controlled trial of a culturally informed treatment compared to treatment as usual in Māori who present to hospital after self-harm.
Indigenous people have high rates of suicide and self-harm compared to other population groups. The aim of this trial was to see if a package of interventions delivered in a culturally appropriate way improved outcomes at one year in Maori who presented with intentional self-harm to emergency departments. Participants were Maori who presented with intentional self-harm to emergency departments in New Zealand. The study design was a double consent Zelen randomised controlled trial. The intervention included regular postcards, problem solving therapy, patient support, risk management, improved access to primary care and cultural assessment in addition to usual care. The control group received usual care. The main outcome measure was the self-rated change in scores on the Beck Hopelessness Scale at one year. 182 people were randomized to the intervention group 95 of whom consented to take part in the study. 183 people were randomized to the control group 72 of whom consented to take part in the study. For those who consented comparing the intervention group with the control group there was a statistically significant greater change in hopelessness scores at 3 months (difference -1.7 95 % CI -3.4 to -0.01, p = 0.05) but not at one year (difference -1.6 95 % CI -3.4 to 0.3, p = 0.11). Maori who consented and received the intervention were also significantly less likely to present to hospital for non-self-harm reasons in the year after the index episode (44.2 vs. 61.1 %, p = 0.03). Those participants randomised to the intervention were less likely to re-present with self-harm at 3 months (10.4 vs. 18 %, p = 0.04) but not at 12 months compared to the control group. In Maori who presented to hospital with intentional self-harm a culturally informed intervention had an effect on hopelessness and re-presentation with self-harm in the short term but not at 12 months. There was a significant decrease in hospital presentations for non-self harm over the next year. Australian and New Zealand Clinical Trials Registry ACTRN12609000952246.


Diffuse arachnoiditis following epidural analgesia.
Four cases of spinal arachnoiditis are reported, which occurred as a delayed complication of epidural anaesthesia. Different causes are considered: the most convincing hypothesis is that there was a subarachnoid hyperergic reaction to the drugs injected during epidural anaesthesia.


Environmental Risks for Inflammatory Myopathies.
This is an up-to-date review on external environmental factors for adult-onset idiopathic inflammatory myopathies (IIMs). Environmental factors with suggestive evidence including ultraviolet radiation, smoking, infectious agents (viruses in particular), pollutants, medications (ie, statin) and vitamin D deficiency are discussed. We also discuss the potential implications of environmental factors in IIM development, identify current challenges, and provide insight into future investigations.


A method of image registration for three-dimensional reconstruction of microscopic structures using an IBAS 2000 image analysis system.
Registration of histological tissue sections is a longstanding problem in three-dimensional reconstruction. Our solution is to insert rigid straight narrow birefringent structures namely cactus spines as artificial registration points (ARPs) into the tissue block before embedding in wax or resin. The microscopic image of the tissue section with ARPs in situ is presented to an IBAS 2000 Image Analyser and digitised. Registration is performed in two stages using the ARP nearest to the area to be reconstructed as the principle reference point for alignment. The automatic stage is then used to align the structure under reconstruction. These reconstructions are more accurate than those produced without the use of ARPs.


The human corticocortical vestibular network.
Little is known about the cortical organization of human vestibular information processing. Instead of a dedicated primary vestibular cortex, a distributed network of regions across the cortex respond to vestibular input. The aim of this study is to characterize the human corticocortical vestibular network and compare it to established results in non-human primates. We collected high-resolution multi-shell diffusion-weighted (DWI) and state-of-the-art resting-state functional MR images of 29 right-handed normal subjects. Ten cortical vestibular regions per hemisphere were predefined from previous vestibular stimulation studies and applied as regions of interest. Four different structural corticocortical vestibular networks accounting for relevant constraints were investigated. The analyses included the investigation of common network measures and hemispheric differences for functional and structural connectivity patterns alike. In addition, the results of the structural vestibular network were compared to findings previously reported in non-human primates with respect to tracer injections (Guldin and Grusser, 1998). All structural networks independent of the applied constraints showed a recurring subdivision into identical three submodules. The structural human network was characterized by a predominantly intrahemispheric connectivity, whereas the functional pattern highlighted a strong connectivity for all homotopic nodes. A significant laterality preference towards the right hemisphere can be observed throughout the analyses: (1) with larger nodes, (2) stronger connectivity values structurally and functionally, and (3) a higher functional relevance. Similar connectivity patterns to non-human primate data were found in sensory and higher association cortices rather than premotor and motor areas. Our analysis delineated a remarkably stable organization of cortical vestibular connectivity. Differences found between primate species may be attributed to phylogeny as well as methodological differences. With our work we solidified evidence for lateralization within the corticocortical vestibular network. Our results might explain why cortical lesions in humans do not lead to persistent vestibular symptoms. Redundant structural routing throughout the network and a high-degree functional connectivity may buffer the network and reestablish network integrity quickly in case of injury.


FAM5C is a soluble osteoblast differentiation factor linking muscle to bone.
Muscle mass is related to higher bone mass and a reduction in fracture risk. However, the interactions between muscle tissues and bone metabolism are incompletely understood and there might be some humoral factors that are produced in muscle tissues and exhibit bone anabolic activity. We therefore investigated the role of FAM5C in osteoblast differentiation and the interactions between muscle and bone. A reduction of endogenous FAM5C by siRNA reduced the levels of osterix, alkaline phosphatase (ALP) and osteocalcin (OCN) mRNA as well as the levels of type 1 collagen and β-catenin in mouse osteoblastic MC3T3-E1 cells and mouse calvarial osteoblasts, although FAM5C overexpression significantly antagonized the levels of osterix, ALP and OCN mRNA induced by bone morphogenetic protein-2 in C2C12 cells. The conditioned medium from FAM5C-overexpressed and -suppressed C2C12 cells increased and decreased the levels of osterix, ALP and OCN mRNA in MC3T3-E1 cells, respectively. In conclusion, the present study is the first to show that FAM5C enhances osteoblast differentiation in differentiated osteoblasts, and that the effects of the conditioned medium from FAM5C-modulated myoblastic cells were positively correlated with the effects of FAM5C on osteoblast phenotype in osteoblasts. FAM5C might be an important humoral bone anabolic factor produced from muscle cells.


Cost-effectiveness analysis of sacral nerve stimulation as treatment for severe irritable bowel syndrome.
Early results from sacral nerve stimulation (SNS) for severe irritable bowel syndrome (IBS) are promising but estimates of cost-effectiveness are lacking. Our object was to perform a cost-effectiveness analysis for SNS as an alternative to no treatment of IBS. This retrospective analysis was based on the results from a randomized controlled crossover study with a cost-utility analysis performed on patient-level data and modelling of censored data over a projected period of time of up to 20 years. The analysis was conducted on an intention-to-treat approach. For estimation of the uncertainty of the incremental cost-effectiveness ratio a bias corrected bootstrap analysis was performed. Cost-effectiveness was not reached for 4 years after permanent implantation (£31 270 per quality-adjusted life years), which was the upper limit for patient follow-up, but our data imply a cost-effectiveness from a 7-year perspective onwards. The study indicates the SNS treatment for IBS is cost effective from a 7-year perspective onwards.


The validity of the patient health Questionnaire-9 to screen for depression in patients with type-2 diabetes mellitus in non-communicable diseases clinics in Malawi.
Depression is a global problem, affecting populations worldwide, but is too often under-diagnosed. The identification of depression among patients with diabetes is important because depression is prevalent in this group and can complicate diabetes management. The aim of the study was to determine the sensitivity and specificity of the PHQ-9 in the detection of depression among patients with type-2 diabetes mellitus attending non-communicable diseases (NCD) clinics in Malawi. We conducted a validation study of the Patient Health Questionnaire (PHQ-9) among 323 patients with type-2 diabetes mellitus who attended two NCD clinics in one of the 28 districts of Malawi. The participants were screened consecutively using the nine-item PHQ-9 in Chichewa by a research assistant and completed a diagnostic interview using the Structured Clinical Interview for DSM-IV (SCID) for depression with a mental health clinician. We evaluated both content validity based on expert judgement and criterion validity of the Patient Health Questionnaire (PHQ-9) based on performance against the SCID. The PHQ-9 cutpoint that maximized sensitivity plus specificity was selected to report test characteristics. Using the SCID for depression, the prevalence of minor or major depression was 41% (133/323). The internal consistency estimate for the PHQ-9 was 0.83, with an area under the receiver operator curve (AUC) of 0.93 (95% CI, [0.91-0.96]). Using the optimal cut-point of ≥9, the PHQ-9 had a sensitivity of 64% and a specificity of 94% in detecting both minor and major depression, with likelihood ratio-positive = 10.1 and likelihood ratio negative =0.4 as well as overall correct classification (OCC) rate of 81%. This is the first validation study of the PHQ-9 in NCD clinics in Malawi. Depression was highly prevalent in this sample. The PHQ-9 demonstrated reasonable accuracy in identifying cases of depression and is a useful screening tool in this setting. Health care workers in NCD clinics can use the PHQ-9 to identify depression among their patients with those having a positive screen followed up by additional diagnostic assessment to confirm diagnosis. PACTR201807135104799 . Retrospectively registered on 12 July 2018.


Desmoid tumors of the abdominal wall: A case report.
BACKGROUND: Desmoid tumors are slow growing deep fibromatoses with aggressive infiltration of adjacent tissue but without any metastatic potential. CASE PRESENTATION: We report on two female patients with desmoid tumor of the abdominal wall who underwent primary resection. Both patients had a history of an earlier abdominal surgery. Preoperative evaluation included abdominal ultrasound, magnetic resonance imaging and computed tomography. The histology in both cases revealed a desmoid tumor. CONCLUSION: Complete surgical resection is the first line management of this tumor entity.


Ultrastructural observations on the effects of different substrates on ischaemic contracture in global subtotal ischaemia in the rat heart.
Ultrastructural morphology was examined in myocardia perfused with different substrates, following the hypothesis that ultrastructural changes or differences would indicate the mechanism of early ischaemic contracture. Substrates used were glucose, acetate and no substrate (substrate-free). Isolated rat hearts were subjected to global low flow ischaemia followed by perfusion fixation at either no contracture, early contracture (5%) or full contracture (100%). Total tissue adenosine triphosphate (ATP) levels were analysed from myocardia of each group. Glucose perfused myocardia did not develop contracture for at least 30 minutes and maintained ultrastructural and ATP normality. Substrate-free and acetate perfused myocardia developed contracture after 10-12 minutes of ischaemia at which time myofibrillar morphology was altered within small sparse foci of developing mild oedema with contracture and hyperextension of myofibrils. ATP levels were normal. At full ischaemic contracture, both substrate-free and acetate perfused myocardia showed severe mitochondrial damage, oedema, myofibrillar contracture and hyperextension with accompanying distortion and swelling of the sarcoplasmic reticulum.


Comparison of two microenvironments and nurse caregiving on thermal stability of ELBW infants.
This study tested a novel bioinstrumented radiant warmer (RW), designed to provide a reduced-intervention nursing caregiving environment (RINCE) on the ambient and body surface temperature stability of extremely low birth-weight (ELBW) infants (< 1,000 g) during caregiver disruptions. The RINCE was compared with a control bed consisting of a standard RW, modified with a Plexiglas hood (Rohm and Haas, Philadelphia, PA) and an external humidity source. The sample consisted of 10 extremely low birth-weight infants. The mean gestational age was 25.7 weeks (+/- 1.4 weeks). Birth weight ranged from 570 to 880 g: mean birth weight was 730 g (+/- 95.14 g). The mean Scores for Neonatal Acute Physiology was 21.4 (+/- 6). This clinical study used a small n sample, crossover time-series design. Infants were randomized to treatment order (control bed v RINCE) on the first day of life. A washout period between microenvironments was observed, and then each infant was placed into the other condition. Each infant was studied for 5 hours in each treatment condition (control bed v RINCE). Abdominal skin temperatures, heel temperatures, ambient temperatures, and relative humidity (RH) were recorded by a computerized data acquisition system every 60 seconds for hours 12 to 24 of life. Caregiver interventions, microenvironment disruptions, or both were manually coded in the data set. The mean number of minutes abdominal temperatures were less than 36.5 degrees C was not significantly different in either microenvironment (P = 0.48). The mean number of minutes that heel temperatures were less than 35.2 degrees C and central-peripheral differences were greater than 2 degrees C was significantly less in the RINCE (P < 0.04 and P < 0.0001, respectively). Although the number and duration of caregiving disruptions (P = 0.71), number of procedures (P = 0.30), and the duration of interventions (P = 0.56) were not significantly different in either environment, the ambient air temperature (P < 0.001) and RH (P < 0.001) were significantly less variable in the RINCE during and after caregiving disruptions. This study identified the extreme inter-dependence of the ELBW infant's temperature and the ambient environment. The RINCE significantly improved ambient temperature variability, RH variability, and the infant's peripheral and delta temperature (delta T) stability, particularly during and after caregiver disruptions.


Prostacyclin and right ventricular function in patients with pulmonary hypertension associated with ARDS.
Eight patients who developed pulmonary artery hypertension during the adult respiratory distress syndrome (ARDS) were treated with an infusion of prostacyclin (PGI2, 12.5-35.0 ng.kg-1.min-1) for 45 min. We examined whether reducing the right ventricular (RV) outflow pressures by PGI2 infusion would increase the right ventricular ejection fraction (RVEF) measured by thermodilution. PGI2 reduced the pulmonary artery pressure (PAP) from 35.6 to 29.1 mmHg (p less than 0.01). The cardiac index (CI) increased from 4.2 to 5.81.min-1.m-2 (p less than 0.01) partly due to an increased stroke volume. The decreased PAP together with the increased CI resulted in a fall of the calculated pulmonary vascular resistance index (PVRI, from 5.1 to 2.5 mmHg.min.m2.1-1, p less than 0.01). In the patients with subnormal baseline RVEF the increased stroke volume was associated with an increased RVEF (from 47.6% to 51.8%, p less than 0.05) suggesting improved RV function. This result was underscored by a significant relationship between the changes in PVRI and RVEF (r = 0.789, delta % RVEF = 2.11.delta PVRI-1.45). Despite an increased venous admixture from 27.8% to 36.9% (p less than 0.05) the arterial PO2 remained constant resulting in an increased oxygen delivery from 657 to 894 ml.min-1.m-2 (p less than 0.01). We conclude that short term infusions of PGI2 increased CI concomitant to improved RV function parameters when baseline RVEF was depressed. Since improved oxygen availability should be a major goal in the management of patients with ARDS PGI2 may be useful to lower pulmonary artery pressure in ARDS.


Oxaliplatin versus Mitomycin C following complete cytoreduction for colorectal peritoneal metastases: a comparative study.
Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases (CRPM) a favorable long-term survival. While cytoreductive techniques are standardized, there remains great variability in HIPEC drugs with mitomycin C or oxaliplatin use based largely on institute preference. In this study, we compared outcomes based on mitomycin C or oxaliplatin use after complete cytoreduction. This is a retrospective analysis over a 7-year period of all patients undergoing complete cytoreduction with HIPEC. Seventy-eight patients underwent complete cytoreduction with HIPEC during this time. Forty-six patients received oxaliplatin as HIPEC, and 32 received mitomycin C. There was no difference in patient characteristics, resections, or major morbidity between the two groups. Superficial wound infections were higher in the mitomycin C group (37.5% v 15.2%, p = 0.02). Median overall and disease-free survival for the entire cohort was 40 and 14 months, respectively. There was no difference in overall survival or disease-free survival between the two HIPEC groups (HR 0.50, 95% CI 0.11-2.28). Complete cytoreduction and HIPEC can offer selected patients a favorable survival. The choice of mitomycin C or oxaliplatin for HIPEC had no influence on survival. Prospective studies are needed to explore this important issue.


Decreased cognitive functioning in patients with advanced oral squamous cell carcinoma.
Cognitive impairment causes a delay in diagnosis and treatment of the various cancer entities, resulting in reduced surgical outcomes and patient survival. However, no investigations have been carried out as to whether an association exists between cognitive functioning and tumour size in patients with oral squamous cell carcinoma (OSCC). In this study, 46 patients with OSCC were evaluated by using a screening test for dementia, consisting of a combination of the mini-mental state examination and the clock test (81% sensitivity and 90% specificity). Test scores were correlated with tumour size according to the TNM staging system, which was categorized as being either limited (T1, T2; n=24) or advanced (T3, T4; n=22). No difference in age (P=0.172), sex (P=0.330), the percentage of drinkers (P=0.090) or the percentage of smokers (P=0.484) was evident between the groups. Patients with advanced tumour size scored significantly lower (median 5.5 of 9 possible points) when compared with those having tumours of a limited size (median 9 of 9 possible points; P=0.005). The median score of patients with T3/T4 tumours suggested the need for comprehensive neuropsychological evaluations for dementia. In conclusion, this study has demonstrated the correlation of reduced cognitive functioning in patients with advanced OSCC. As a consequence, instructions for the identification of early signs and of symptoms of oral cancer are strongly recommended for relatives and nursing staff of patients with cognitive impairment. Such patients might need immediate treatment for oral cancer but might not be able to understand the significance of their symptoms and therefore present late, often too late.


Trastuzumab, leuprorelin, letrozole, and palbociclib as first-line therapy in HER2-positive and hormone receptor-positive metastatic breast cancer: A case report.
Cyclin-dependent kinase 4/6 inhibitors are promising candidates for patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, current international guidelines recommend endocrine therapy alone or with HER2-targeted therapy to treat HER2-positive and hormone receptor (HR)-positive metastatic breast cancer in patients who cannot tolerate first-line chemotherapy. Moreover, data on the effectiveness and safety of cyclin-dependent kinase 4/6 inhibitors combined with trastuzumab and endocrine therapy as a first-line treatment for HER2-positive and HR-positive metastatic breast cancer are limited. A 50-year-old premenopausal woman was with epigastric pain for more than 20 days. Ten years ago, she was diagnosed with left breast cancer and underwent surgical treatment, chemotherapy, and endocrine therapy. After relevant examination, the patient was diagnosed with liver, lung, and left cervical lymph node metastatic HER2-positive and HR-positive carcinoma from the left breast after systemic therapy. The laboratory investigations showed that the patient's liver function was seriously damaged due to the liver metastases, and the patient was assessed as unable to tolerate chemotherapy. She was treated with trastuzumab, leuprorelin, letrozole, and piperacillin combined with percutaneous transhepatic cholangic drainage. The patient's symptoms were relieved, her liver function returned to normal, and the tumor showed partial response. Neutropenia (Grade 3) and thrombocytopenia (Grade 2) occurred during treatment but improved after symptomatic treatment. To date, the progression-free survival of the patient is over 14 months. We believe that trastuzumab, leuprorelin, letrozole, and palbociclib is a feasible and effective treatment for HER2-positive and HR-positive metastatic breast cancer in premenopausal patients who cannot tolerate first-line chemotherapy.


Lymphoid enhancer factor/T cell factor expression in colorectal cancer.
Genetic inactivation of key components of the Wnt signal transduction system is a frequent event in colorectal cancer. These genetic mutations lead to stabilization of beta-catenin, a cytoplasmic-nuclear shuttling protein with a potent transcription activation domain. Stabilization and subsequent nuclear localization of beta-catenin produces aberrant, Wnt-independent signals to target genes, an activity tightly linked to the genesis of colon cancers. In the nucleus, the transcription factor family of LEF/TCF proteins transmits Wnt signals by binding to beta-catenin and recruiting it to target genes for activation. Such activities are carried out by full-length LEF/TCFs that are thought to be mostly interchangeable and redundant. However, truncated forms of LEF-1 and TCF-1 that do not bind to beta-catenin function as dominant negatives and an alternatively spliced TCF isoform with a unique activation function has recently been discovered. The dominant negative forms block Wnt signals because they occupy Wnt target genes and limit beta-catenin access; the alternatively spliced TCF isoform activates certain Wnt target promoters whereas other TCF isoforms and LEF-1 do not. A study of LEF/TCF expression and activity in normal intestine and colon carcinomas suggests that the relative amounts of LEF/TCF isoforms may change as tumors progress and this may influence the strength and specificity of Wnt signals in the nucleus. While the underlying mechanism for a change in the LEF/TCF isoform expression is not yet known, recent evidence implicates the Wnt signaling pathway itself as a potential modulator.


Central venous catheter infection with Bacillus pumilus in an immunocompetent child: a case report.
Bacillus organisms are common laboratory contaminants. The majority of Bacillus bacteraemias are transient and not clinically significant. Clinically significant infection due to Bacillus species is rare and mostly due to Bacillus cereus infections in immuno-compromised hosts. We report a case of central venous catheter infection with Bacillus pumilus in an immunocompetent child with tufting enteropathy on long-term parenteral nutrition (PN). There were three episodes of central venous catheter infection with Bacillus pumilus in three months. Despite adequate and appropriate use of intravenous antibiotics, the infection failed to clear resulting in the need for removal of the catheter for complete cure. Bacillus species can cause clinically significant central venous catheter infection, even in an immunocompetent host. Despite adequate antibiotic treatment, the central venous catheter may need removal for complete cure.


Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.


Trends in serious quit attempts in the United States, 2009-14.
Quitting smoking is the most potent way to reduce the health risks associated with smoking cigarettes, and public health objectives in the United States include dramatic increases in the proportion of smokers making a serious quit attempt each year. The US Centers for Disease Control and Prevention (CDC) has, since 2000, set as its Healthy People 2020 objective to encourage 80% of smokers to make a serious quit attempt per year. This study assessed the trend in quit attempts from 2009 to 2014. We examined the percentage of US smokers making a serious quit attempt each year from 2009 to 2014 from the repeating cross-sectional National Health Interview Survey (NHIS). United States. The number of qualifying respondents per year ranged from 5748 in 2010 to 7219 in 2012, with a total of 40 362 respondents included in the analysis. Respondents were deemed to have made a serious quit attempt if they were either current smokers who reported that they stopped smoking for more than 1 day in the past 12 months because they were trying to quit smoking, or reported being former smokers (smoked 100+ cigarettes life-time, but now not smoking) who quit in the past year. Analyses of trends from 2009 to 2014 showed an overall linear increase in quit attempts [odds ratio (OR) = 1.02, 95% confidence interval (CI) = 1.01-1.04, P = 0.0075], but also a quadratic trend (OR = 1.01, 95% CI = 1.00-1.02, P = 0.0189). The proportion of US smokers making a serious quit attempt has increased since 2009, due to an upward trend since 2011. The 2014 serious quit attempt rate was 55.0%. These rates are still below the Healthy People 2020 objective of 80% of smokers making a serious quit attempt per year.


Kinetics of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Avidity Maturation and Association with Disease Severity.
The kinetics of IgG avidity maturation during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was studied. The IgG avidity assay, using a novel label-free immunoassay technology, revealed a strong correlation between IgG avidity and days since symptom onset. Peak readings were significantly higher in severe than mild disease cases.


A tale of two GTPases in cotranslational protein targeting.
Guanosine triphosphatases (GTPases) comprise a superfamily of proteins that provide molecular switches to regulate numerous cellular processes. The "GTPase switch" paradigm, in which a GTPase acts as a bimodal switch that is turned "on" and "off" by external regulatory factors, has been used to interpret the regulatory mechanism of many GTPases. Recent work on a pair of GTPases in the signal recognition particle (SRP) pathway has revealed a distinct mode of GTPase regulation. Instead of the classical GTPase switch, the two GTPases in the SRP and SRP receptor undergo a series of conformational changes during their dimerization and reciprocal activation. Each conformational rearrangement provides a point at which these GTPases can communicate with and respond to their upstream and downstream biological cues, thus ensuring the spatial and temporal precision of all the molecular events in the SRP pathway. We suggest that the SRP and SRP receptor represent an emerging class of "multistate" regulatory GTPases uniquely suited to provide exquisite control over complex cellular pathways that require multiple molecular events to occur in a highly coordinated fashion.


Accelerating the Implementation of Evidence-Based Practice in Physical Medicine and Rehabilitation.
Over the past 3 decades, a substantial number of studies were published with the purpose of improving the effectiveness and efficiency of rehabilitation clinical practice. Clinicians and researchers face considerable challenges in successfully implementing these research findings into routine clinical practice. Knowledge translation includes the synthesis, dissemination, exchange, and ethically sound application of knowledge to improve health, provide more effective health services and products, and strengthen the health care system. An aim of knowledge translation research is to identify strategies to accelerate implementation of evidence into practice. A recent citation analysis on a commonly used knowledge translation framework, the Knowledge-to-Action Framework, identified implementation activities performed in physical medicine and rehabilitation. Although this citation analysis describes activities performed and outcomes assessed while conducting knowledge translation projects, successful knowledge translation also requires a robust social and physical infrastructure. In this commentary, we offer several observations that appear related to the increased likelihood of implementation success. Funders, higher education institutions, health care payers, and health care organizations contribute to successful implementation and must embrace their roles in implementation. Administrators, clinicians, and consumers of physical medicine and rehabilitation also have essential roles in knowledge translation.


Results of laser in situ keratomileusis performed using solid-state laser technology.
To evaluate and report the visual, refractive, and aberrometry outcomes of laser in situ keratomileusis (LASIK) to correct low to moderate myopia using a commercial solid-state laser. Oftalmar, Medimar International Hospital, Alicante, Spain. Prospective case series. This study evaluated consecutive eyes with low to moderate myopia that had LASIK performed using a Pulzar Z1 solid-state laser. Visual, refractive, and aberrometry changes as well as potential complications were evaluated. The study enrolled 60 eyes (34 patients). The mean follow-up was 8.5 months (range 6 to 13 months). There was a significant improvement in logMAR uncorrected distance visual acuity (UDVA) postoperatively (P<.01). No significant change was detected in logMAR corrected distance visual acuity (CDVA) (P=.21). The postoperative logMAR UDVA was 0.1 (approximately 20/25) or better in 57 eyes (95.00%). The mean overall efficacy index was 0.99 and the mean safety index, 1.02. Postoperatively, 1 eye (1.67%) lost lines (1 line) of CDVA. The postoperative spherical equivalent was within ± 0.50 diopter in 58 eyes (96.67%). There was a small, but statistically significant increase in the primary coma root mean square (0.17 μm) and in the magnitude of primary spherical aberration (0.09 μm). No severe complications occurred. Laser in situ keratomileusis using the solid-state laser provided predictable correction of low to moderate myopia, minimizing the induction of higher-order aberrations and preserving CDVA. No author has a financial or proprietary interest in any material or method mentioned.


Modulation of polymorphonuclear leukocyte responsiveness by copper (II)2 (niflumate)4.
Antiinflammatory activities and modulations of PMNL responses produced by treatment with tetrakis-mu-2-[3-(trifluoromethyl)-phenyl]aminonicotinatodicopper (II) [Cu(II)2(niflumate)4] and niflumic acid were studied in isologous serum-induced rat pleurisy. Doses of 10 or 30 mg/kg (35 or 106 mumol/kg) of niflumic acid or Cu(II)2(niflumate)4 (8 or 23 mumol/kg) caused significant (p < 0.01) reductions in pleural exudate and number of polymorphonuclear leukocytes (PMNLs) in the exudate. While both doses of Cu(II)2(niflumate)4 produced significant dose-related reductions in both parameters, only the higher dose of niflumic acid produced a significant dose-related reduction in both parameters. Boyden chamber measurements of N-formyl-methionyl-leucyl-phenylalanine (f-MLP) chemotaxis by PMNLs incubated with 10 or 30 micrograms/ml niflumic acid (35 or 106 nmol/ml) or Cu(II)2(niflumate)4 (8 or 23 nmol/ml) were significantly (p < 0.01 to p < 0.001) decreased in dose-related fashions. Chemotaxis of PMNLs from pleuritic rats treated orally with 10 or 30 mg/kg niflumic acid or Cu(II)2(niflumate)4 was significantly (p < 0.001) inhibited by the larger dose of niflumic acid and both doses of Cu(II)2(niflumate)4. Opsonized zymosan (OZ)-stimulated chemiluminescence (CL) of PMNLs from pleuritic rats treated orally with these same doses of niflumic acid or Cu(II)2(niflumate)4 was only significantly (p < 0.05 or p < 0.01 respectively) decreased by the larger doses. Superoxide (O2-) production by these cells was significantly decreased by the larger dose of niflumic acid (p < 0.05) while both doses of Cu(II)2(niflumate)4 produced significant (p < 0.05 to p < 0.01) decreases.(ABSTRACT TRUNCATED AT 250 WORDS)


Duodenal Adenocarcinoma Mimicking Metastasis of Prostate Cancer on 18F-Prostate-Specific Membrane Antigen-1007 PET/CT.
A 76-year-old man with dyspnea (initial prostate-specific antigen [PSA]: 216 ng/mL) underwent F-FDG PET/CT, with uptake in the prostate, lymph nodes, fifth thoracic vertebra (T5), and cricoid cartilage. A biopsy revealed prostate adenocarcinoma (Gleason score 4 + 5, cT4 N1 M1). On initiation of combined androgen blockade therapy, PSA value decreased. However, 4 years later, in a castration-resistant state (PSA 2.14 ng/mL), CT and bone scintigraphy revealed a duodenal tumor and T5 metastasis. F-prostate-specific membrane antigen-1007 PET/CT showed uptake in the already known T5 metastasis (SUVmax, 33.55) and even in the duodenal tumor (16.55). The latter was histologically diagnosed as duodenal adenocarcinoma.


Mitochondrial DNA 5178 C/A polymorphism modulates the effects of coffee consumption on elevated levels of serum liver enzymes in male Japanese health check-up examinees: an exploratory cross-sectional study.
Longevity-associated mitochondrial DNA 5178 cytosine/adenine (Mt5178 C/A) polymorphism modulates the effects of coffee consumption on the risk of hypertension, dyslipidemia, and abnormal glucose tolerance. The objective of this study was to investigate whether Mt5178 C/A polymorphism modifies the effects of coffee consumption on abnormally elevated levels of serum liver enzymes in male Japanese health check-up examinees. A total of 421 male subjects (mean age ± SD, 54.1 ± 7.7 years) were selected from among individuals visiting the hospital for regular medical check-ups. After Mt5178 C/A genotyping, a cross-sectional study assessing the joint effects of Mt5178 C/A polymorphism and coffee consumption on elevated levels of serum aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), and serum gamma-glutamyl transpeptidase (GGT) was then conducted. For men with Mt5178C, after adjustment for age, body mass index, alcohol consumption, habitual smoking, green tea consumption, antihypertensive treatment, and antidiabetic treatment, elevated levels of serum AST, as defined as ≥30 U/L; those of serum ALT, as defined as ≥25 U/L; or those of serum GGT, as defined as ≥60 or >51 U/L, may depend on coffee consumption (P for trend = 0.013, P for trend <0.001, P for trend = 0.002, and P for trend <0.001, respectively). On the other hand, no significant joint effects of Mt5178A genotype and coffee consumption on elevated levels of serum liver enzymes were observed. The present results suggest that Mt5178 C/A polymorphism modifies the effects of coffee consumption on abnormally elevated levels of serum liver enzymes in male Japanese health check-up examinees.


Elevated serum soluble Fas ligand in natural killer cell proliferative disorders.
We evaluated the serum level of soluble Fas ligand (sFasL) in patients with natural killer lymphocyte proliferative disorders (NK- LPD). The serum sFasL level was elevated in neoplastic groups of aggressive NK leukaemia, indolent NK leukaemia and NK lymphoma, all of which contained clonal EBV-DNA. In NK leukaemia the serum sFasL level was significantly higher than that found in others. However, it was not elevated in the patients with reactive NK-LPD and in one patient with NK leukaemia in remission. These findings indicate that the serum sFasL level is a useful indicator in evaluating disease activity.


Ophthalmoplegic "migraine" or recurrent ophthalmoplegic cranial neuropathy: new cases and a systematic review.
Ophthalmoplegic migraine is a poorly understood neurologic syndrome characterized by recurrent bouts of head pain and ophthalmoplegia. By reviewing cases presenting to our centers in whom the phenotype has been carefully dissected, and systematically reviewing all published cases of ophthalmoplegic migraine in the magnetic resonance imaging (MRI) era, this review sets out to clearly define the syndrome and discuss possible etiologies. We found that in up to one-third of patients, the headache was not migrainous or associated with migrainous symptoms. In three-quarters of the cases involving the third nerve, there was focal nerve thickening and contrast enhancement on MRI. Observational data suggest systemic corticosteroids may be beneficial acutely. The etiology remains unclear, but may involve recurrent bouts of demyelination of the oculomotor nerve. "Ophthalmoplegic migraine" is a misnomer in that it is probably not a variant of migraine but rather a recurrent cranial neuralgia. A more appropriate name might be "ophthalmoplegic cranial neuropathy."


Isolation of intramitochondrial bodies in bovine adrenocortical cells by density gradient centrifugation.
Two method for isolating the intramitochondrial bodies from bovine adrenocortical cells are proposed. Electron microscopic examination shows that discontinuous sucrose density gradient centrifugation can separate the fraction rich in intramitochondrial bodies, but some indistinguishable fragments remain among them. Continuous sucrose density gradient centrifugation is probably superior to the former method in obtaining a highly purified fraction of the bodies. The amido black positive granules, presumed to be intramitochondrial bodies, are collected in the fractions of the sucrose density of around 1.27 (1.23--1.30), which lack cytochrome c oxidase activity.


Solitary benign schwannoma of the brachial plexus.
A solitary benign schwannoma of the brachial plexus unassociated with von Recklinghausen's disease is presented. The initial presentation is usually that of a painless, supraclavicular mass, but this patient had a tingling sensation in the right forearm. Local excision was performed. The literature is reviewed.


Pharmacokinetic and pharmacodynamic aspects of salmeterol therapy.
Salmeterol xinafoate is a highly selective beta2-adrenoceptor for the maintenance treatment of asthma in adults and children. To review the pharmacokinetics, clinical pharmacology, and therapeutic properties of a recently introduced, long acting antiasthmatic drug. Recent English-language publications were selected using Medline as database. Salmeterol's pharmacokinetics, clinical pharmacology, and therapeutic properties are reviewed and aspects related to salmeterol's unusual duration of action, its high potency, beta2-selectivity, possible antiinflammatory actions, its interaction with other drugs, low systemic adverse effects, dosage, and administration are also discussed. Salmeterol is a safe long-acting beta2-agonist very useful for maintenance treatment of asthma.


Estimating the health economic impact of the universal varicella vaccination in Argentina from 2015 to 2019.
Since the introduction of Universal Varicella Vaccination (UVV) in the Argentinean National Immunization Program in 2015, a significant decline in the incidence of varicella has been reported. This study aimed to estimate the economic impact of single-dose UVV in Argentina from 2015 to 2019. The economic impact was assessed based on the observed incidence of varicella in the post-UVV period and the number of cases avoided, obtained from a previously published study that used an Autoregressive Integrated Moving Average (ARIMA) model. The weighted average cost per case was calculated using local studies. The post-UVV cost reductions were calculated by multiplying the number of cases avoided from 2015 -2019 by the weighted average cost per case. Data were summarized yearly and by peak (September-November) periods for the target (1-4 years) and overall populations. We estimated avoided costs of United States dollars (USD) $65 million in the target population and $112 million in the overall population over 4 years following UVV introduction. We observed a trend toward greater reductions in costs over time, with substantial differences observed in peak periods. We estimated that the single-dose UVV program considerably reduced the economic burden of varicella in Argentina by avoiding direct and indirect costs associated with varicella management.


HLA typing demands for peptide-based anti-cancer vaccine.
Immunological treatment of cancer has made some very promising advances during the last years. Anti-cancer vaccination using peptides or peptide-pulsed dendritic cells and adoptive transfer of in vitro generated, epitope-specific T cells depend on a well-fitting interaction of HLA molecule and epitope. Accurate HLA-typing is a key factor for successful anti-cancer vaccination. No comprehensive data and no suggestion exist on the HLA-typing in this setting. We performed a systematic review of PubMed analyzing HLA-typing data in cancer vaccination trials over the last 4 years (2004-2007). Then, using the SYFPEITHI database, we calculated the peptide binding prediction of the eight most often used HLA-A*0201 binding epitopes. Finally, high-resolution typing [by sequence-specific primers (SSP)] data of a HLA-A*02 or HLA-A*24 positive population in Berlin, Germany, were analyzed. Forty-five cancer vaccination trials with 764 patients were included. Eighteen studies were performed in the USA, 13 in Europe, 12 in Asia (mainly Japan), and two in Australia. Most common diseases targeted were melanoma, prostate cancer, colorectal cancer, renal cell cancer, and breast cancer. The trials tested protocols using peptide plus adjuvants without DC or protocols using peptide-pulsed DC. In 38 trials (84%) HLA-A2 positive patients were vaccinated, in 11 studies (24%) HLA-A24 positive patients were vaccinated. Nineteen studies with 291 patients (38%) presented the HLA type as four-digit code (high-resolution), 26 studies with 473 patients (62%) presented the HLA-type in a low-resolution code. The method of HLA determination was given in six out of 45 trials (13%). Using the SYFPEITHI database we calculated the peptide binding prediction of the eight most often used HLA-A*0201 binding tumor antigen-derived epitopes for binding to HLA-A*0203. While the epitopes had a binding score of 17-28 for HLA-A*0201, the score for binding to HLA-A*0203 was zero in seven out of eight tested peptides. Only for one peptide the score was eight. Finally, we analyzed high-resolution data of HLA-A*02 and HLA-A*24 positive patients in Berlin, Germany. We found the HLA-A*0201 allele and HLA-A*2402 allele in 95%, respectively. HLA-A*0201 and HLA-A*2402 are most commonly used for peptide based vaccine in cancer. Data on HLA-typing given in the included cancer vaccine manuscripts are fractional. Only 13% report the method of HLA typing and most HLA types are given as low-resolution code. Looking at the binding of specific peptides to both the alleles, it is important to perform high-resolution typing. Further suggestions for immunogenetic laboratories and clinical tumor immunologists regarding HLA-typing for cancer vaccine trials and adoptive T cell transfer approaches are discussed.


Meeting report: fungal its workshop (october 2012).
This report summarizes a meeting held in Boulder, CO USA (19-20 October 2012) on fungal community analyses using ultra-high-throughput sequencing of the internal transcribed spacer (ITS) region of the nuclear ribosomal RNA (rRNA) genes. The meeting was organized as a two-day workshop, with the primary goal of supporting collaboration among researchers for improving fungal ITS sequence resources and developing recommendations for standard ITS primers for the research community.


Protein overproduction alters exosome secretion in Chinese hamster ovary cells.
Despite the abundance of available cell lines, nearly 70% of all recombinant therapeutic proteins today are produced in Chinese hamster ovary (CHO) cells. The impact of protein overproduction on the secretion of exosomes by CHO cells has been investigated here. Increased secretion of extracellular vesicles (EVs) by protein overexpressing CHO cells was demonstrated with protein content assay, nanoparticle tracking analysis, and capillary electrophoresis. Our results revealed that a protein overproduction might induce EVs secretion, which might be accompanied by the sequestration and loading of overexpressed proteins into the exosomes. These findings are of vital importance for the manufacturing of therapeutics in CHO expression systems due to the risk of product loss during downstream processing of culture medium as well as the application of exosomes as nanocarriers of therapeutic proteins. The study indicates also the importance of culturing process control.


Efficacy of laparoscopic mesenteric/retroperitoneal lymph node biopsy.
Lymphadenopathy-identified incidentally during computed tomography (CT) mandates a tissue diagnosis. When percutaneous techniques are not possible, surgical tissue diagnosis becomes necessary. Laparotomy is the current gold standard; however a laparoscopic approach offers many potential benefits. This institutional review board (IRB)-approved study evaluated all patients undergoing laparoscopic retroperitoneal lymph node biopsy from 2001 to 2007 at the Cleveland Clinic. Patient records were retrospectively reviewed for age, sex, pathologic diagnosis, conversion to laparotomy, and perioperative complications. A total of 30 cases were reviewed. In this group, 67% were males and 33% were female; mean age was 48 years. Ten patients underwent mesenteric lymph node sampling and 20 (67%) underwent retroperitoneal tumor resection. There were four (17%) conversions and no complications. Lymphoma was the most common pathologic finding. Laparoscopic lymph node biopsy is a safe effective alternative to open surgical biopsy.


Aging-induced decrease in dopaminergic-stimulated phosphoinositide metabolism in rat brain.
Accumulation of [3H]inositol phosphate and [3H]inositol labeling of phosphoinositides were evaluated in brain slices of 3-, 6-, 12-, and 24-month-old Fischer-344 rats. The dopamine agonist, SKF38393, stimulated significantly lower accumulations of inositol trisphosphate, inositol bisphosphate, and inositol monophosphate in the striatum, hippocampus, and frontal cortex of 24-month-old rats compared with the 6-month-old animals. No differences, however, were observed between the 3, 6, and 12-month-old groups. Furthermore there were marked decrements of 41% to 58% in the labeling of phosphoinositides in the different brain regions of the aged animals. Dose-response studies in forebrain slices of the 6-month-old and 24-month-old animals showed aging-related decrements of 53% (p less than 0.001) and 48% (p less than 0.001) in the maximal SKF38393-stimulated labeling of phosphoinositides and accumulation of inositol phosphates, respectively. These data suggest that aging of the rat brain is associated with alterations in the basal turnover of the inositol cycle and in the sensitivity of the transduction pathway to dopamine receptor stimulation.


Endoscopic Tendon Release for Iliopsoas Impingement After Total Hip Arthroplasty-Excellent Clinical Outcomes and Low Failure Rates at Short-Term Follow-Up.
To investigate the clinical effectiveness of endoscopic iliopsoas tendon release (IPR) at the lesser trochanter (LT) in patients with iliopsoas impingement (IPI) after total hip arthroplasty (THA). Between November 2017 and March 2021, a consecutive series of 36 patients were treated with endoscopic IPR for diagnosed IPI. Patients included had acetabular cup position confirmed by functional imaging (OPS, Corin, Pymble, NSW), typical clinical symptoms of IPI, and a positive response to diagnostic injection. Clinical assessment included validated patient-reported outcome measures (PROMs) along with hip flexion strength and active range of motion at different time marks up to 2-year follow-up, as well as surgical complications. Overall, 36 consecutive patients (11 males) with a mean age of 62 ± 12 years were included. All patients had failed nonoperative management. Dynamic computed tomography assessment was available in 89% of the patients, edge loading was reported in 10%, and variable cup overhang was reported in 50%. Clinically, PROMs were significantly improved at every time mark when compared with preoperative values (P < .001), showing the biggest improvement within the first 4 weeks after surgery. At the 6-month follow-up, peak isometric hip flexion strength on the operated side was 20% lower than the contralateral side (P < .001). Failure rate of the procedure was 2.8% (1 case). Linear regression showed no association between cup overhang and clinical outcomes. Endoscopic IPR at the LT is a safe and reproducible technique associated with significant and immediate improvement in pain, functional outcomes, and high patient satisfaction. With minimal short-term weakness, no complications, and only a single revision, even in cases with cup malposition and/or edge loading, we believe that endoscopic IPR can be considered as one of the first-line operative options in patients with symptomatic IPI, irrespective of component position. Level IV, case series.


Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group.
Methylmalonic acidaemia (MMA) is a genetic disorder caused by defects in methylmalonyl-CoA mutase or in any of the different proteins involved in the synthesis of adenosylcobalamin. The aim of this work was to examine the biochemical and clinical phenotype of 32 MMA patients according to their genotype, and to study the mutant mRNA stability by real-time PCR analysis. Using cellular and biochemical methods, we classified our patient cohort as having the MMA forms mut (n = 19), cblA (n = 9) and cblB (n = 4). All the mut (0) and some of the cblB patients had the most severe clinical and biochemical manifestations, displaying non-inducible propionate incorporation in the presence of hydroxocobalamin (OHCbl) in vitro and high plasma odd-numbered long-chain fatty acid (OLCFA) concentrations under dietary therapy. In contrast, mut (-) and cblA patients exhibited a milder phenotype with propionate incorporation enhanced by OHCbl and normal OLCFA levels under dietary therapy. No missense mutations identified in the MUT gene, including mut (0) and mut (-) changes, affected mRNA stability. A new sequence variation (c.562G>C) in the MMAA gene was identified. Most of the cblA patients carried premature termination codons (PTC) in both alleles. Interestingly, the transcripts containing the PTC mutations were insensitive to nonsense-mediated decay (NMD).


Increased oxidative stress, the renin-angiotensin system, and sympathetic overactivation induce hypertension in kidney androgen-regulated protein transgenic mice.
Gender differences in the incidence and severity of hypertension have suggested the involvement of a sex-dependent mechanism. Transgenic (Tg) mice overexpressing kidney androgen-regulated protein (KAP) specifically in kidney showed hypertension associated with oxidative stress. Reactive oxygen species (ROS) are strongly implicated in the pathological signaling leading to hypertension in a framework that includes renin-angiotensin system (RAS) activation, increased sympathetic activity, and cardiac remodeling. In this report, we observed that plasma levels of angiotensin II and catecholamines were increased in KAP Tg mice, compared with wild-type animals. Systemic administration of Tempol, a membrane-permeative superoxide dismutase mimetic, reduced arterial pressure as well as urinary excretion of oxidative stress markers and reduced both angiotensin II and norepinephrine plasma levels in KAP Tg mice. Intracerebroventricular administration of Tempol also reduced arterial pressure in Tg mice. Moreover, administration of apocynin and DPI, inhibitors of NADPH oxidase, a major source of ROS, also reduced arterial pressure and both angiotensin II and norepinephrine plasma levels in Tg mice. Thus, we analyzed the involvement of the RAS and sympathetic nervous system in KAP Tg mouse hypertension. Both captopril and losartan reduced arterial blood pressure in Tg mice, as also occurred after β-adrenergic blockade with atenolol. Also, intracerebroventricular losartan administration reduced arterial pressure in KAP Tg mice. Our data demonstrate that hypertension in male KAP Tg mice is based on increased oxidative stress, increased sympathetic activity, and RAS activation. Moreover, our results suggest a role for increased oxidative stress in the CNS as a major cause of hypertension in these animals.


Influence of rs1042713 and rs1042714 polymorphisms of β2-adrenergic receptor gene with erythrocyte cAMP in sickle cell disease patients from Odisha State, India.
The vaso-occlusive crisis (VOCs) in sickle cell disease (SCD) is often associated with stress. Epinephrine released during stress acts via beta 2-adrenergic receptors (β2-AR or ADRB2) to stimulate the synthesis of cyclic adenosine monophosphate (cAMP) in the red blood cells (RBCs). Higher cAMP levels promote adhesion of sickled RBCs to vascular endothelium, a major contributor for VOCs. Several single-nucleotide polymorphisms (SNPs) of the β2-AR gene have been reported; two of them at codon 16 (rs1042713) and codon 27 (rs1042714) have been extensively studied for their clinical relevance. Therefore, we assessed the influence of polymorphism at these two sites of the β2-AR gene on the RBC cAMP concentrations with and without epinephrine stimulation in SCD subjects. We determined the frequency distribution of different genotypes of codon 16 and codon 27 of the β2-AR gene using the Sanger sequencing method in the SCD subjects. We measured the RBC-cAMP levels at baseline and after stimulation with epinephrine, to ascertain the influence of different genotypes in determining cAMP levels. There was no difference in the socio-demographic and hematological indicators in different genotypes of both codon 16 and 27. In the sham-treated erythrocytes, the cAMP levels were significantly different with three genotypes of codon 16 (F = 3.39, P = 0.036; one way ANOVA) but not with different genotypes of codon 27. A significant increase in cAMP levels was noticed with epinephrine treatment in all genotypes of codons 16 and 27 (P = 0.001; Wilcoxon signed-rank test). However, the extent of increase in the epinephrine-treated cAMP values from the sham-treated (baseline) cAMP values was significantly different between the three genotypes of codon 16 (H = 8.74; P = 0.012; Kruskal-Wallis test) but not in codon 27 genotypes. Polymorphism in codon 16 (rs1042713) of the β2-AR gene influences cAMP concentrations in the RBC both before and after epinephrine treatment. Higher cAMP levels may lead to increased adhesion of sickle cell RBCs to vascular endothelium and may increase the frequency of VOCs.


Influence of the biophysical and biochemical environment on the kinetics of pore formation by Cry toxins.
The effect of Bacillus thuringiensis toxins on the permeability of the luminal membrane of Manduca sexta midgut columnar epithelial cells is strongly influenced by several biophysical and biochemical factors, including pH, ionic strength, and divalent cations, suggesting an important role for electrostatic interactions. The influence of these factors can differ greatly, however, depending on the toxin being studied, even for closely related toxins such as Cry1Ac and Cry1Ca. In the present study, the possibility of using temperature changes as a tool for controlling the rate and extent of pore formation in midgut brush border membrane vesicles was evaluated. Lowering temperature gradually decreased the rate of pore formation, but had little effect on the permeability of vesicles previously incubated with toxin at room temperature. The formation of new pores, following incubation of the vesicles with toxin, could thus be almost abolished by rapidly cooling the vesicles to 2 degrees C. Using this approach, changes in the rate of pore formation could be more easily distinguished from alterations in the properties of the pores formed, thus allowing a more detailed analysis of the kinetics and mechanism of pore formation.


Mist and water condensation inside incubators reduce the efficacy of phototherapy.
To measure the irradiance in humidified incubator under three different overhead phototherapy devices. The effective irradiance of three phototherapy devices was assessed by taking a series of irradiance measurements in the illuminated field. Measurements were made with a fixed bandwidth broadband radiometer (380-530 nm). The distance between the light source and the radiometer was 35 cm for the daylight fluorescent lamp, 40 cm for the light emitting diode (LED) and 50 cm for the halogen phototherapy. A double-wall incubator was kept at 36°C and set at three different levels of humidity (60-70%, 80% and equal or above 90%). The irradiance under the overhead daylight fluorescent lamp phototherapy did not change with the increasing humidity. However, above 90% humidity, when water vapour inside the incubator was so saturated to the point of totally condensing in the incubator walls, the measured irradiance decreased 15% of the initial values with the blue LED phototherapy and 45% with the halogen spotlight phototherapy. Highly humidified incubators are frequently used to treat very low birthweight infants. Health professionals should be aware that mist and water condensation inside an incubator may significantly reduce the efficacy of treatment.


Acute macular neuroretinopathy as a manifestation of coronavirus disease 2019: A case report.
The current findings is important in raising clinicians' awareness of the possibility of coincident acute macular neuroretinopathy (AMN) and COVID-19 as a potential cause of retinal vascular damage and ischemia.


Protect right: right ventricular failure prevention strategy for left ventricular assist device implantation.
Right ventricular failure imparts poor prognosis following left ventricular assist device implantation. We present a strategy for the primary prevention of right ventricular failure after left ventricular assist device implantation in a high-risk patient.


Beta-lactoglobulin-nutrition allergen and nanotransporter of different nature ligands therapy with therapeutic action.
β-lactoglobulin is one of the nutrition allergens present in the milk of many mammals, with the exception of human. This protein belongs to the family of lipocalins, consisting of nine antiparallel β-strands (β-A to β-I) and one α-helix. This structure allows it to serve as a nanotransporter of various nature ligands in a pH dependent manner, which allows us to confidently consider it as a reliable carrier of drugs directly into the intestine, bypassing the destructive acidic environment of the stomach. Based on the latest data, this review describes the currently known methods of reducing the allergenicity of beta-lactoglobulin, as well as the mechanisms and methods of forming complexes of this protein with ligands, which emphasizes its importance and versatility and explains the growing interest in studying its properties in recent decades, and also opens up prospects for its practical application in medicine and pharmaceuticals.


Functional characteristics of buffy-coat PLTs photochemically treated with amotosalen-HCl for pathogen inactivation.
One blood system for PLTs (INTERCEPT, Baxter Transfusion Therapies) is based on photochemical treatment (PCT) with small molecules that target cross-link nucleic acids (Helinx technology, Cerus Corp.) with amotosalen-HCl (S-59) and UVA light (320-400 nm) to inactivate pathogens and WBCs. A two-arm in vitro study was conducted to compare pooled buffy-coat-derived PLT concentrates (PCs) treated with the INTERCEPT blood system, resuspended in PLT additive solution (PAS) III (InterSol, Baxter Transfusion Therapies), and stored for up to 7 days (test units, n = 20) with unpaired, nontreated PCs, resuspended in PAS II (T-Sol, Baxter Transfusion Therapies), and prepared at the same center in the same manner (control units, n = 18). PLT dose (x 1011/unit +/- SD) on Day 1 immediately following PCT was 3.0 +/- 0.4 for test units and 3.2 +/- 0.4 for control units. After 7 days of storage, the pH of all test units was maintained above 6.8. No marked trend was observed in the hypotonic shock response (HSR). Values among study groups were similar at the end of observation period: 68 +/- 11 percent for control unites versus 67 +/- 8 percent for test units (p > 0.05). Aggregation response to ristocetin was slightly lower in test units: at Day 7, 65 +/- 10 percent versus 76 +/- 6 percent (p < 0.05). Significantly higher (p < 0.001) glucose consumption, lactate production, and CD62P expression were observed in test units. Compared to nontreated PLTs, the PCT process was associated with a variety of differences of in vitro analyses. Although significant, these changes were relatively small in most cases. Characteristics correlated with survival in vivo such as HSR and swirling were comparable between both study groups, indicating that the viability of the majority of cells appears to have persisted throughout 7 days of storage. The impact of this finding, however, remains to be investigated in clinical trials performed with 7-day stored PLTs.