Traumatic cervical discoligamentous injuries: correlation of magnetic resonance imaging and operative findings.
Retrospective review using prospectively collected data. The purpose of the study was to investigate the diagnostic properties of cervical magnetic resonance imaging (MRI) in detecting surgically verified disruptions of the anterior longitudinal ligament (ALL), intervertebral disc, and posterior longitudinal ligament (PLL). Cervical MRI findings commonly provide the basis for the decision to stabilize cervical injury operatively. The correlation of cervical MRI findings with direct visualization of the cervical discoligamentous structures during operative management is a subject of debate. The cervical spine MRI scans of patients who subsequently underwent anterior surgical stabilization after traumatic discoligamentous injury of the cervical spine were reviewed. The level and severity of ALL, disc and PLL disruption was compared with surgical findings. The sensitivity, specificity, positive and negative predictive values of MRI in the detection of surgically verified injuries were calculated. The MRI and surgical findings were compared on 31 consecutive patients, with the kappa values for ALL, intervertebral disc, and PLL disruption measuring 0.22, 0.25, and 0.31, respectively. MRI scans provided reasonable sensitivity to disc disruption (0.81) but poor sensitivity to ALL (0.48) and PLL (0.50) injury. Specificity for ALL and PLL disruption was 1.00 and 0.87, respectively, but 0.00 for disc disruption. The positive predictive value of MRI for ALL and intervertebral disc injury was 1.00 and 0.96, respectively, but 0.63 for PLL disruption. The false-negative rates for disruption of the ALL, disc and PLL were 0.52, 0.19, and 0.50, respectively. The ability of cervical MRI to detect surgically verified disruptions of the ALL, intervertebral disc, and PLL varied depending on the structure examined. MRI was sensitive but not specific for disc injury, and specific but not sensitive to ALL and PLL disruption. In this series, the comparison of cervical MRI and operative findings indicated that MRI was reliable only when positive for ALL and disc injury, and a reasonably reliable indicator of PLL status only when negative for PLL injury. Additionally, the high false-negative rates for ALL and PLL injury are concerning.


Excessive sedentary time during in-patient stroke rehabilitation.
Background and Purpose Previous research suggests that patients receiving inpatient stroke rehabilitation are sedentary although there is little data to confirm this supposition within the Canadian healthcare system. The purpose of this cross-sectional study was to observe two weeks of inpatient rehabilitation in a tertiary stroke center to determine patients' activity levels and sedentary time. Methods Heart rate (HR) and accelerometer data were measured using an Actiheart monitor for seven consecutive days, 24 h/day, on the second week and the last week of admission. Participants or their proxies completed a daily logbook. Metabolic equivalent (MET) values were calculated and time with MET < 1.5 was considered sedentary. The relationship between patient factors (disability, mood, and social support) and activity levels and sedentary time were analyzed. Results Participants (n = 19; 12 males) spent 10 h sleeping and 4 h resting each day, with 86.9% of their waking hours sedentary. They received on average 8.5 task-specific therapy sessions; substantially lower than the 15 h/week recommended in best practice guidelines. During therapy, 61.6% of physical therapy and 76.8% of occupational therapy was spent sedentary. Participants increased their HR about 15 beats from baseline during physical therapy and 8 beats during occupational therapy. There was no relationship between sedentary time or activity levels and patient factors. Discussion Despite calls for highly intensive stroke rehabilitation, there was excessive sedentary time and therapy sessions were less frequent and of lower intensity than recommended levels. Conclusions In this sample of people attending inpatient stroke rehabilitation, institutional structure of rehabilitation rather than patient-related factors contributed to sedentary time.


Widely tunable long-period waveguide grating couplers.
We demonstrate experimentally two widely tunable optical couplers formed with parallel long-period polymer waveguide gratings. One of the couplers consists of two parallel gratings and shows a peak coupling efficiency of ~34%. The resonance wavelength of the coupler can be tuned thermally with a sensitivity of 4.7 nm/ degrees C. The experimental results agree well with the coupled-mode analysis. The other coupler consists of an array of ten widely separated gratings. A peak coupling efficiency of ~11% is obtained between the two best matched gratings in the array and the resonance wavelength can be tuned thermally with a sensitivity of -3.8 nm/ degrees C. These couplers have the potential to be further developed into practical broadband add/drop multiplexers and signal dividers.


Antiangiogenic chemotherapeutic agents: characterization in comparison to their tumor growth inhibition in human renal cell carcinoma models.
The mechanism of action of anticancer chemotherapeutic agents is mainly thought to be due to a direct inhibition of tumor cell proliferation. The enhanced endothelial cell proliferation rate in tumor specimens raised the question of whether therapeutic effects of chemotherapeutic agents might be at least partially attributed to inhibition of tumor angiogenesis. In the present study, we investigated the potential effects of chemotherapeutic agents on human renal carcinoma angiogenesis with the alginate implantation model in mice. For the first time, we also compared results from the angiogenesis model with the inhibitory effects on growth of s.c. xenografts in nude mice. Vincristine and bleomycin exerted strong inhibition of tumor angiogenesis in both carcinoma lines close to the level of the standard antiangiogenic agent O-chloroacetyl-carbamyl-fumagillol (AGM-1470; T/C 22%). Adriamycin reduced angiogenesis of Caki-2 cells (T/C 33%) but had no effect on Caki-1 angiogenesis (T/C 137%). Etoposide and 5-fluorouracil reduced Caki-1 tumor angiogenesis but had no effect on Caki-2. Despite antiangiogenic effects in both carcinoma lines, vincristine, bleomycin, and AGM-1470 significantly reduced only the growth of fast-growing Caki-1 s.c. xenografts but not the slow-growing Caki-2. Antivascular effects by bleomycin and AGM-1470 were also shown by a decrease of microvessel density in nude mouse xenografts. Our findings suggest that chemotherapeutic agents may exert inhibition of tumor angiogenesis, which could be exploitable by combination therapy of fast-growing tumors. The resistance of the slow-growing Caki-2 carcinoma against acute angiogenesis inhibition indicates a need for well-tolerated angiogenesis inhibitors. Our results also suggest the use of fast-growing s.c. xenografts for demonstrating growth inhibition by antiangiogenic compounds. Further characterization of antiangiogenic compounds considered for clinical application should, however, have its focus on slow-growing tumors, which are not accessible for most therapeutic strategies.


Gestational alloimmune liver disease in cases of fetal death.
To determine whether alloimmune liver disease can be identified as a cause of fetal death. This is a retrospective examination of the autopsy tissue of 6 stillborn fetuses and 2 extreme preterm infants (gestational age, 20 to 34 weeks) drawn from families referred for suspected neonatal hemochromatosis. Thirteen appropriate nondisease controls and 8 cases of neonatal acute liver failure with known etiology were also examined. Liver sections were immunostained using anti-human C5b-9 complex. All of the study cases had died with no preceding evidence of fetal distress. Histopathology showed findings of acute liver injury, including global hepatocyte necrosis with minimal reticulum collapse and no fibrosis. Hepatocytes in cases stained strongly positively for C5b-9 complex, suggesting premortem lgG complement-mediated liver injury. Hepatocytes in acute liver failure case controls did not demonstrate a similar mechanism of liver injury. Alloimmune liver disease is sometimes associated with fetal death.


Identification of an autoinhibitory domain of p21-activated protein kinase 5.
The p21-activated protein kinases (Paks) are serine/threonine protein kinases activated by binding to Rho family small GTPases, Rac and Cdc42. Recently, Pak family members have been subdivided into two groups, I and II. Group II Paks, including Pak4, Pak5, and Pak6, does not contain the highly conserved autoinhibitory domain that is found in the group I Paks members, i.e. Pak1, Pak2, and Pak3. In the present study, we have purified the glutathione S-transferase fusion form of Pak5 and shown for the first time that Pak5 autophosphorylation can be activated by GTP bound form of Cdc42. Mutation of histidine residues 19 and 22 to leucine on the p21-binding domain of Pak5 completely abolished the binding of Cdc42 and the Cdc42-mediated autophosphorylation. On the other hand, mutation of tyrosine 40 to cysteine of Cdc42 did not knockout the binding of Pak5. Analysis of C-terminal deletion mutants has identified an autoinhibitory fragment of Pak5 that is absent from other group II Pak family members. Taken together, these results suggest that Pak5, like Pak1, contains an autoinhibitory domain and its activity is regulated by Cdc42.


The active centre of rabbit muscle triose phosphate isomerase. The site that is labelled by glycidol phosphate.
1. Glycidol (2,3-epoxypropanol) phosphate is a specific irreversible inhibitor of rabbit muscle triose phosphate isomerase (EC 18.104.22.168); the site of attachment has now been studied. 2. The labelled enzyme was digested with pepsin and a modified peptide isolated. The sequence of the peptide is: Ala-Tyr-Glu-Pro-Val-Trp. 3. It is the glutamic acid residue in this peptide that is labelled: the peptide is thus a gamma-glutamyl ester derived from glycerol phosphoric acid. The same site is labelled by a mixture of glycidol and inorganic phosphate. 4. Kinetic and stereochemical features of these reactions are discussed.


End of life care of hospitalized patients with Parkinson disease: a retrospective analysis and brief review.
Towards the end of life (EOL), persons with parkinsonism (PwP) have complex needs and can present with unique palliative care (PC) challenges. There are no widely accepted guidelines to aid neurologists, hospitalists, or PC clinicians in managing the symptoms of PwP at EOL. We examined a population of PwP at EOL, aiming to describe trends of in-hospital management and utilization of PC services. All PwP admitted to two hospitals during 2018 (N = 727) were examined retrospectively, assessing those who died in hospital or were discharged with hospice (EOL group, N = 35) and comparing them to the main cohort. Their demographics, clinical data, engagement of multidisciplinary and palliative services, code status changes, invasive care, frequency of admissions, and medication administration were assessed. Among the EOL group, 8 expired in hospital, and 27 were discharged to hospice. Forty-six percent of EOL patients received a PC consultation during their admission. The median interval from admission to death was 37 days. Seventy-seven percent had a full code status on admission. Compared to hospice patients, those who expired in hospital had higher rates of invasive procedures and intensive care unit transfers (41% vs. 75%, in both variables), and lower rates of PC involvement (52% vs. 25%). The transition of code status change for the EOL group from Full code to Do Not Resuscitate (DNR) occurred at a median 4-5 days from admission. For patients that passed in the hospital, the median days from transition of code status to death was 0(IQR 0-1). Levodopa dose deviations were frequent in both EOL and non-EOL group, but contraindicated medications were infrequently administered (11% in EOL group vs. 9% in non-EOL group). Our data suggest a low utilization of PC services and delayed discussions of goals of care. More work is needed to raise awareness of inpatient teams managing PwP regarding the unique but common challenges facing PwP with advanced disease. A brief narrative review summarizing the suggested management of symptoms common to hospitalized PwP near EOL is provided.


Novel Insights Into Bacterial Dimethylsulfoniopropionate Catabolism in the East China Sea.
The compatible solute dimethylsulfoniopropionate (DMSP), made by many marine organisms, is one of Earth's most abundant organosulfur molecules. Many marine bacteria import DMSP and can degrade it as a source of carbon and/or sulfur via DMSP cleavage or DMSP demethylation pathways, which can generate the climate active gases dimethyl sulfide (DMS) or methanthiol (MeSH), respectively. Here we used culture-dependent and -independent methods to study bacteria catabolizing DMSP in the East China Sea (ECS). Of bacterial isolates, 42.11% showed DMSP-dependent DMS (Ddd+) activity, and 12.28% produced detectable levels of MeSH. Interestingly, although most Ddd+ isolates were Alphaproteobacteria (mainly Roseobacters), many gram-positive Actinobacteria were also shown to cleave DMSP producing DMS. The mechanism by which these Actinobacteria cleave DMSP is unknown, since no known functional ddd genes have been identified in genome sequences of Ddd+ Microbacterium and Agrococcus isolates or in any other sequenced Actinobacteria genomes. Gene probes to the DMSP demethylation gene dmdA and the DMSP lyase gene dddP demonstrated that these DMSP-degrading genes are abundant and widely distributed in ECS seawaters. dmdA was present in relatively high proportions in both surface (19.53% ± 6.70%) and bottom seawater bacteria (16.00% ± 8.73%). In contrast, dddP abundance positively correlated with chlorophyll a, and gradually decreased with the distance from land, which implies that the bacterial DMSP lyase gene dddP might be from bacterial groups that closely associate with phytoplankton. Bacterial community analysis showed positive correlations between Rhodobacteraceae abundance and concentrations of DMS and DMSP, further confirming the link between this abundant bacterial class and the environmental DMSP cycling.


The Nrf2 triterpenoid activator, CDDO-imidazolide, protects kidneys from ischemia-reperfusion injury in mice.
Acute kidney injury (AKI) caused by ischemia-reperfusion is a major clinical problem in both native and transplanted kidneys. We had previously shown that deficiency of Nrf2, a potent bZIP transcription factor that binds to the antioxidant response element, enhances susceptibility to experimental ischemic AKI. Here we further explored the role of Nrf2 in AKI by amplifying Nrf2 activation in vivo and in vitro with the synthetic triterpenoid CDDO-imidazolide. Mice treated with CDDO-imidazolide and undergoing experimental bilateral ischemic AKI had improved survival and renal function. Treated mice had improved renal histology with a decrease in tubular injury, as well as a decrease in proinflammatory cytokine and chemokine production compared with vehicle-treated mice. In an exploration of protective mechanisms, we found an upregulation of Nrf2 target antioxidant genes in CDDO-imidazolide-treated mouse kidneys. Furthermore, Nrf2-deficient mice treated with CDDO-imidazolide had no significant improvement in mortality, renal function or histology, proinflammatory cytokine gene expression, and no significant increase in antioxidant gene expression. In vitro studies demonstrated that the renal epithelial cells were likely an important target of CDDO-imidazolide. Thus, activation of Nrf2 signaling with CDDO-imidazolide confers protection from AKI, and presents a new therapeutic opportunity for this common and serious condition.


Analysis of the growth of epidural injections and costs in the Medicare population: a comparative evaluation of 1997, 2002, and 2006 data.
Interventional techniques for the treatment of spinal techniques are commonly used and are increasing exponentially. Epidural injections and facet joint interventions are the 2 most commonly utilized procedures in interventional pain management. The current literature regarding the effectiveness of epidural injections is sparse with highly variable outcomes based on the technique, outcome measures, patient selection, and methodology. Multiple reports have illustrated the exponential growth of lumbosacral injections with significant geographic variations in the administration of epidural injections in Medicare patients. However, an analysis of the growth of epidural injections and costs in the Medicare population has not been performed with recent data and has not been looked at from an interventional pain management perspective. Analysis of epidural injection growth and costs in Medicare's population 1997, 2002, and 2006. The primary purpose of this study was to evaluate the use of all types of epidural injections (i.e. caudal, interlaminar, and transforaminal in lumbar, cervical and thoracic regions), and other epidural procedures, including epidural adhesiolysis. In addition, the purpose was to identify trends in the number of procedures, reimbursement, specialty involvement, fluoroscopy use, and indications from 1997 to 2006. The Centers for Medicare and Medicaid Services (CMS) 5% national sample carrier claim record data from 1997, 2002, and 2006 was utilized. Outcome measures included Medicare beneficiaries' characteristics receiving epidural injections, epidural injections by place of service, type of specialty, reimbursement characteristics, and other variables. Epidural injections increased significantly in Medicare beneficiaries from 1997 to 2006. Patients receiving epidurals increased by 106.3%; visits per 100,000 population increased 102.7%. Hospital outpatient department (HOPD) payments increased significantly; ASC average payments decreased; overall payments increased. The increase in procedures performed by general physicians outpaced that of interventional pain management (IPM) physicians. Study limitations include no Medicare Advantage patients; potential documentation, coding, and billing errors. Epidural injections grew significantly. This growth appears to coincide with chronic low back pain growth and other treatments for low back pain. Since many procedures are performed without fluoroscopy, continued growth and inappropriate provision of services might reduce access.


Spatial and temporal dynamics of rabies virus variants in big brown bat populations across Canada: footprints of an emerging zoonosis.
Phylogenetic analysis of a collection of rabies viruses that currently circulate in Canadian big brown bats (Eptesicus fuscus) identified five distinct lineages which have emerged from a common ancestor that existed over 400 years ago. Four of these lineages are regionally restricted in their range while the fifth lineage, comprising two-thirds of all specimens, has emerged in recent times and exhibits a recent demographic expansion with rapid spread across the Canadian range of its host. Four of these viral lineages are shown to circulate in the US. To explore the role of the big brown bat host in dissemination of these viral variants, the population structure of this species was explored using both mitochondrial DNA and nuclear microsatellite markers. These data suggest the existence of three subpopulations distributed in British Columbia, mid-western Canada (Alberta and Saskatchewan) and eastern Canada (Quebec and Ontario), respectively. We suggest that these three bat subpopulations may differ by their level of female phylopatry, which in turn affects the spread of rabies viruses. We discuss how this bat population structure has affected the historical spread of rabies virus variants across the country and the potential impact of these events on public health concerns regarding rabies.


Mfsd14a (Hiat1) gene disruption causes globozoospermia and infertility in male mice.
The Mfsd14a gene, previously called Hiat1, encodes a transmembrane protein of unknown function with homology to the solute carrier protein family. To study the function of the MFSD14A protein, mutant mice (Mus musculus, strain 129S6Sv/Ev) were generated with the Mfsd14a gene disrupted with a LacZ reporter gene. Homozygous mutant mice are viable and healthy, but males are sterile due to a 100-fold reduction in the number of spermatozoa in the vas deferens. Male mice have adequate levels of testosterone and show normal copulatory behaviour. The few spermatozoa that are formed show rounded head defects similar to those found in humans with globozoospermia. Spermatogenesis proceeds normally up to the round spermatid stage, but the subsequent structural changes associated with spermiogenesis are severely disrupted with failure of acrosome formation, sperm head condensation and mitochondrial localization to the mid-piece of the sperm. Staining for β-galactosidase activity as a surrogate for Mfsd14a expression indicates expression in Sertoli cells, suggesting that MFSD14A may transport a solute from the bloodstream that is required for spermiogenesis.


Molecular cloning and characterization of a cDNA encoding a novel basic helix-loop-helix protein structurally related to Neuro-D/BHF1.
We cloned a novel basic helix-loop-helix protein, NDRF (NeuroD-related factor), cDNA. NDRF contains 383 amino acids and exhibits 53.4% and 52.2% sequence identity to NeuroD and MATH-2/NEX-1, respectively. NDRF mRNA appears in the brain of 12-day-old mouse embryos and is localized in certain regions of the adult brain, such as the hippocampus, dentate gyrus and cerebellum, Thus, the structure and expression patterns of NDRF are similar to but distinct from those of NeuroD and MATH-2/NEX-1, suggesting that NDRF may play distinct roles in neural development and plasticity as a novel member of the NeuroD family.


Physical activity and working memory in healthy older adults: an ERP study.
This study examined the effects of physical activity on working memory in older adults using both behavioral and neuroelectric measures. Older adults were assigned to either a higher or lower physical activity group, and event-related potentials were recorded during assessments of a modified Sternberg task. The results indicated that older adults in the higher physical activity group exhibited shorter response times, independent of the working memory load. Enhanced P3 and N1 amplitudes and a decreased P3 latency were observed in the higher physical activity group. These findings suggested that physical activity facilitates working memory by allocating more attentional resources and increasing the efficiency of evaluating the stimulus during the retrieval phase as well as engaging more attentional resources for the early discriminative processes during the encoding phase of a working memory task.


Thalidomide and thalidomide transformed by pH-dependent hydrolysis or by liver enzyme treatment does Not impede the proliferation of endothelial cells.
Angiogenesis is essential for tumor growth. In the treatment of tumors with thalidomide, a rationale for its use is that it inhibits angiogenesis. To form new blood vessels, endothelial cells must proliferate. The authors were interested in describing some of the circumstances by which thalidomide may influence proliferation of endothelial cells. Human umbilical vein derived endothelial cells (HUVECs) were exposed to 4.0 or 100 microg/ml of thalidomide in dimethylsulfoxide or to 4 microg/ml of thalidomide prepared an aqueous solutions. Proliferation was determined by measuring incorporation of (3)H-thymidine. Regardless of the solvent used to dissolve thalidomide, the HUVECs treated with thalidomide were not inhibited in their ability to incorporate (3)H-thymidine.


Association Between Institutional Factors and Long-Term Survival Following Transjugular Intrahepatic Portosystemic Shunt.
Transjugular intrahepatic portosystemic shunt (TIPS) is a procedure designed to treat portal hypertension. Hospital teaching status is an institutional factor found to be predictive of outcomes following several complex procedures; however, its impact on outcomes following TIPS is unknown. The aim of this study was to determine the association between hospital teaching status and long-term survival in patients with cirrhosis receiving TIPS. We performed a retrospective population-based cohort study using linked administrative health data from Ontario, Canada. Adult patients with cirrhosis who received TIPS between January 1, 1998, and December 31, 2016, with follow-up until December 31, 2017, were included. Hospital teaching status was defined based on hospital participation in the instruction of medical students and/or resident physicians. Liver transplant-free (LTF) survival was evaluated using Kaplan-Meier analysis, and overall survival was assessed using competing risks regression analysis, which accounted for hospital clustering. A total of 857 unique patients were included (mean age 57.1 years; 69.1% male). The TIPS procedures were performed in teaching hospitals (84.3%) as well as nonteaching hospitals (15.7%). Median LTF survival was more than twice as long for procedures performed in teaching hospitals compared to nonteaching hospitals (2.2 years versus 0.9 year, respectively; P < 0.001). After adjusting for confounders and clustering, hospital teaching status was not independently associated with mortality (nonteaching subdistribution hazard ratio [sHR], 1.32; 95% confidence interval [CI], 0.97-1.81; P = 0.08); however, annual hospital procedure volume was (per unit increase sHR, 0.96; 95% CI, 0.93-0.99; P = 0.003). Conclusion: Hospital procedure volume is associated with long-term survival following TIPS. These results further support the centralization of TIPS to high-volume hospitals to improve long-term outcomes in this population.


Cell-To-Cell Communication in the Resistance Vasculature.
The arterial vasculature can be divided into large conduit arteries, intermediate contractile arteries, resistance arteries, arterioles, and capillaries. Resistance arteries and arterioles primarily function to control systemic blood pressure. The resistance arteries are composed of a layer of endothelial cells oriented parallel to the direction of blood flow, which are separated by a matrix layer termed the internal elastic lamina from several layers of smooth muscle cells oriented perpendicular to the direction of blood flow. Cells within the vessel walls communicate in a homocellular and heterocellular fashion to govern luminal diameter, arterial resistance, and blood pressure. At rest, potassium currents govern the basal state of endothelial and smooth muscle cells. Multiple stimuli can elicit rises in intracellular calcium levels in either endothelial cells or smooth muscle cells, sourced from intracellular stores such as the endoplasmic reticulum or the extracellular space. In general, activation of endothelial cells results in the production of a vasodilatory signal, usually in the form of nitric oxide or endothelial-derived hyperpolarization. Conversely, activation of smooth muscle cells results in a vasoconstriction response through smooth muscle cell contraction. © 2022 American Physiological Society. Compr Physiol 12: 1-35, 2022.


Thyroid function influences serum apolipoprotein B-48 levels in patients with thyroid disease.
Apolipoprotein B-48 (apoB-48) is a major apolipoprotein of intestine-derived chylomicrons (CM) and CM remnants (CMR). Clinically overt hypothyroidism (OH) has been associated with premature and accelerated coronary atherosclerosis. To clarify the clinical significance of apoB-48 measurement in patients with thyroid disease, we investigated the correlations between the serum apoB-48 level and thyroid hormones. From outpatients of Osaka University Hospital, patients with OH, subjects with subclinical hypothyroidism (SH) and subjects with normal thyroid function were collected and analyzed by measuring serum TSH, FT4 and FT3 levels. Serum apoB-48 levels were measured by a chemiluminescence enzyme immunoassay and the correlations with thyroid hormone levels or lipid profiles were assessed. These levels were compared among subjects with OH, SH and healthy controls. Serum apoB-48 level was correlated with TSH, total cholesterol (TC) and triglycerides (TG), but negatively with FT4 and FT3 level. LDL-C and HDL-C levels were not correlated with serum apoB-48 levels. Serum apoB-48 in patients with OH (7.4 ± 5.9 µg/mL) was significantly higher than in those with hyperthyroidism (5.1 ± 3.5 µg/mL; p<0.01) and normal subjects (4.7 ± 3.7 µg/mL; p<0.01), but decreased after levo-thyroxine replacement. ApoB-48, TG and TSH were significantly higher in SH subjects than normal subjects, suggesting that serum apoB-48 level depends on the thyroid function status, similar to TC, LDL-C and TG. Increased serum apoB-48 concentrations and CMR may contribute to the increased risk of atherosclerosis and premature coronary artery disease in the hypothyroid state.


Widespread differences in cortex DNA methylation of the "language gene" CNTNAP2 between humans and chimpanzees.
CNTNAP2, one of the largest genes in the human genome, has been linked to human-specific language abilities and neurodevelopmental disorders. Our hypothesis is that epigenetic rather than genetic changes have accelerated the evolution of the human brain. To compare the cortex DNA methylation patterns of human and chimpanzee CNTNAP2 at ultra-high resolution, we combined methylated DNA immunoprecipitation (MeDIP) with NimbleGen tiling arrays for the orthologous gene and flanking sequences. Approximately 1.59 Mb of the 2.51 Mb target region could be aligned and analyzed with a customized algorithm in both species. More than one fifth (0.34 Mb) of the analyzed sequence throughout the entire gene displayed significant methylation differences between six human and five chimpanzee cortices. One of the most striking interspecies differences with 28% methylation in human and 59% in chimpanzee cortex (by bisulfite pyrosequencing) lies in a region 300 bp upstream of human SNP rs7794745 which has been associated with autism and parent-of-origin effects. Quantitative real-time RT PCR revealed that the protein-coding splice variant CNTNAP2-201 is 1.6-fold upregulated in human cortex, compared with the chimpanzee. Transcripts CNTNAP2-001, -002, and -003 did not show skewed allelic expression, which argues against CNTNAP2 imprinting, at least in adult human brain. Collectively, our results suggest widespread cortex DNA methylation changes in CNTNAP2 since the human-chimpanzee split, supporting a role for CNTNAP2 fine-regulation in human-specific language and communication traits.


Effects of jacalin and follicle-stimulating hormone on in vitro goat primordial follicle activation, survival and gene expression.
This study aims to investigate the effects of jacalin and follicle-stimulating hormone (FSH) on activation and survival of goat primordial follicles, as well as on gene expression in cultured ovarian tissue. Ovarian fragments were cultured for 6 days in minimum essential medium (MEM) supplemented with jacalin (10, 25, 50 or 100 μg/ml - Experiment 1) or in MEM supplemented with jacalin (50 μg/ml), FSH (50 ng/ml) or both (Experiment 2). Non-cultured and cultured tissues were processed for histological and ultrastructural analysis. Cultured tissues from Experiment 2 were also stored to evaluate the expression of BMP-15, KL (Kit ligand), c-kit, GDF-9 and proliferating cell nuclear antigen (PCNA) by real-time polymerase chain reaction (PCR). The results of Experiment 1 showed that, compared with tissue that was cultured in control medium, the presence of 50 μg/ml of jacalin increased both the percentages of developing follicles and viability. In Experiment 2, after 6 days, higher percentages of normal follicles were observed in tissue cultured in presence of FSH, jacalin or both, but no synergistic interaction between FSH and jacalin was observed. These substances had no significant effect on the levels of mRNA for BMP-15 and KL, but FSH increased significantly the levels of mRNA for PCNA and c-kit. On the other hand, jacalin reduced the levels of mRNA for GDF-9. In conclusion, jacalin and FSH are able to improve primordial follicle activation and survival after 6 days of culture. Furthermore, presence of FSH increases the expression of mRNA for PCNA and c-kit, but jacalin resulted in lower GDF-9 mRNA expression.


Factors associated with maintenance of long-term plasma human immunodeficiency virus RNA suppression.
To analyze factors associated with long-term (>or=2 years) suppression of virus load (VL), we performed a nested case-control analysis of 1235 Human Immunodeficiency Virus Outpatient Study cohort participants who were well characterized by multiple VL and CD4(+) cell count determinations. Of these patients, 286 (23.1%) had maintained undetectable VLs (i.e., <400 copies/mm(3) or <50 copies/mm(3)) for >or=2 years. Being treatment naive at the start of antiretroviral therapy was associated with a greater likelihood of achieving long-term suppression of VL (odds ratio [OR], 1.5; 95% confidence interval, 1.0-2.0; P=.028). In multivariate models, abacavir, indinavir, efavirenz, and drug combinations that included both lamivudine and indinavir were the most effective treatments for achieving long-term suppression of VL (adjusted OR for each, >3.6; P value for each, <.01). Long-term suppression of VL is more likely in treatment-naive than in treatment-experienced patients, but there were several drugs--abacavir, efavirenz, indinavir, and drug combinations including lamivudine and indinavir--that appeared to be effective, whether they were part of a first or subsequent drug regimen.


Quantitative analysis of molecular partition towards lipid membranes using surface plasmon resonance.
Understanding the interplay between molecules and lipid membranes is fundamental when studying cellular and biotechnological phenomena. Partition between aqueous media and lipid membranes is key to the mechanism of action of many biomolecules and drugs. Quantifying membrane partition, through adequate and robust parameters, is thus essential. Surface Plasmon Resonance (SPR) is a powerful technique for studying 1:1 stoichiometric interactions but has limited application to lipid membrane partition data. We have developed and applied a novel mathematical model for SPR data treatment that enables determination of kinetic and equilibrium partition constants. The method uses two complementary fitting models for association and dissociation sensorgram data. The SPR partition data obtained for the antibody fragment F63, the HIV fusion inhibitor enfuvirtide, and the endogenous drug kyotorphin towards POPC membranes were compared against data from independent techniques. The comprehensive kinetic and partition models were applied to the membrane interaction data of HRC4, a measles virus entry inhibitor peptide, revealing its increased affinity for, and retention in, cholesterol-rich membranes. Overall, our work extends the application of SPR beyond the realm of 1:1 stoichiometric ligand-receptor binding into a new and immense field of applications: the interaction of solutes such as biomolecules and drugs with lipids.


[Effect of bacteriophage on the serum level of iron and copper in pregnant women with pyelonephritis].
Eighty-nine pregnant women, including 62 pregnant females with pyelonephritis, were examined. After bacteriophage treatment for pyelonephritis, there was an increase in the content of iron, a decrease in the level of soluble transferrin receptor without iron therapy, suggesting iron redistribution in pregnant woman. The blood levels of copper, ceruloplasmin, and transferrin in pregnant women with pyelonephritis point to antioxidative defense activation in both healthy pregnant women and pregnant females with pyelonephritis. The serum concentration of ceruloplasmin is of importance for prognosis and evaluation of ceruloplasmin in pregnant women. The higher content of ceruloplasmin in pregnancy is indicative of the involvement of protective mechanisms from autoaggression.


Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters.
Defects in colonic epithelial barrier defenses are associated with ulcerative colitis (UC). The proteins that regulate bacterial clearance in the colonic epithelium have not been completely identified. The Drosophila chromosome-associated protein D3 (dCAP-D3) regulates responses to bacterial infection. We examined whether CAP-D3 promotes bacterial clearance in human colonic epithelium. Clearance of Salmonella or adherent-invasive Escherichia coli LF82 was assessed by gentamycin protection assays in HT-29 and Caco-2 cells expressing small hairpin RNAs against CAP-D3. We used immunoblot assays to measure levels of CAP-D3 in colonic epithelial cells from patients with UC and healthy individuals (controls). RNA sequencing identified genes activated by CAP-D3. We analyzed the roles of CAP-D3 target genes in bacterial clearance using gentamycin protection and immunofluorescence assays and studies with pharmacologic inhibitors. CAP-D3 expression was reduced in colonic epithelial cells from patients with active UC. Reduced CAP-D3 expression decreased autophagy and impaired intracellular bacterial clearance by HT-29 and Caco-2 colonic epithelial cells. Lower levels of CAP-D3 increased transcription of genes encoding SLC7A5 and SLC3A2, the products of which heterodimerize to form an amino acid transporter in HT-29 cells after bacterial infection; levels of SLC7A5-SLC3A2 were increased in tissues from patients with UC compared with controls. Reduced CAP-D3 in HT-29 cells resulted in earlier recruitment of SLC7A5 to Salmonella-containing vacuoles, increased activity of mTORC1, and increased survival of bacteria. Inhibition of SLC7A5-SLC3A2 or mTORC1 activity rescued the bacterial clearance defects of CAP-D3-deficient cells. CAP-D3 down-regulates transcription of genes that encode amino acid transporters (SLC7A5 and SLC3A2) to promote bacterial autophagy by colon epithelial cells. Levels of CAP-D3 protein are reduced in patients with active UC; strategies to increase its levels might restore mucosal homeostasis to patients with active UC.


Psycho-cognitive behavioral problems in sleep disordered children.
Sleep disturbances are common in childhood and adolescence. Sleep problems in early infants tend to be persistent and prominent in preschool and school-aged children. Chronic sleep disorders, especially in young children may lead to neurobehavioral problems and psycho-cognitive impairment. Sleep difficulties may be the result of underlying medical conditions, (breathing disorders) or psychological problems. Research studies have shown the association between sleep disorders and day time cognitive impairment, behavioral problems, poor school performance and inattention in children. Appropriate diagnosis and early management of sleep disorders in children lead to improvement of neurocognitive function and behavioral problems in these children.


Hydrolysis of milk lactose by immobilized beta-galactosidase-hen egg white powder.
Immobilized beta-galactosidase was obtained by crosslinking the enzyme with hen egg white using 2% glutaraldehyde. The gel obtained could be lyophilized to give a dry enzyme powder. The pH optimum of both the soluble and immobilized enzyme was found to be 6.8. The immobilized enzyme showed a higher K(m) for the substrates. The extent of enzyme inhibition by galactose was reduced upon immobilization. The stability towards inactivation by heat, urea, gamma irradiation, and protease treatment were enhanced. The bound enzyme as tested in a batch reactor could be used repeatedly for the hydrolysis of milk lactose. The possible application of this system for small-scale domestic use has been suggested.


One Versus 2 Venous Anastomoses in Free Flap Surgery: A Systematic Review and Meta-Analysis.
The necessity of a second venous anastomosis in free flap surgery is controversial. The purpose of this systematic review is to determine whether venous flap failure and reoperation rates are lower when 2 venous anastomoses are performed. The secondary objective is to determine whether venous flap failure and reoperation rates are lower when the 2 veins are from 2 different drainage systems. A comprehensive search of the literature identified relevant studies. Investigators independently extracted data on rates of flap failure and reoperation secondary to venous congestion. A meta-analysis was performed; odds ratios (ORs) were pooled using a random-effects model and 95% confidence intervals (CIs). Of 18 190 studies identified, 15 were included for analysis. The mean sample size was 287 patients (minimum = 102, maximum = 564). No statistically significant difference in venous flap failure was found when comparing 1 versus 2 venous anastomoses (OR: 1.35; 95% CI: 0.46-3.93). A significant decrease in reoperation rate due to venous congestion was shown (OR: 3.03; 95% CI: 1.64-5.58). The results favor using 2 veins from 2 different systems over veins from the same system (OR: 0.16; 95% CI: 0.02-1.27). There is low-quality evidence suggesting that the use of 2 venous anastomoses will lower the rate of reoperation due to venous congestion. There are insufficient data published to meaningfully compare outcomes of flaps with 2 venous anastomoses from different systems to flaps with anastomoses from the same system.


How to tame an endogenous retrovirus: HERVH and the evolution of human pluripotency.
HERVH is one of the most successful endogenous retrovirus in the human genome. Relative to other endogenous retroviruses, slower degradation of HERVH internal sequences indicates their potential relevance for the host. HERVH is transcriptionally active during human preimplantation embryogenesis. In this review, we focus on the role of HERVH in regulating human pluripotency. The HERVH-mediated pluripotency network has been evolved recently in primates. Nevertheless, it became an essential feature of human pluripotency. We discuss how HERVH modulates the human pluripotency network by providing alternative transcription factor binding sites, functioning as a long-range enhancer, and as being a major source for pluripotency specific long non-coding RNAs and chimeric transcripts.


[Epidural anesthesia in a child with femoral fracture and congenital pain insensitivity].
An 8-year-old boy with congenital insensitivity to pain underwent open reduction of a fractured femur with osteosynthesis under epidural block, without complications and with intraoperative hemodynamic stability. The postoperative course was favorable with minimal analgesia. Congenital insensitivity to pain is a rare hereditary condition characterized by abnormal response to painful stimuli and associated with orthopedic complications requiring surgery. Anesthesia is essential because, even though pain is absent, autonomic dysfunction and catecholamine metabolism alterations are present. An epidural block can be recommended for patients with congenital insensitivity to pain who must undergo surgery.


Two TGA Transcription Factor Members from Hyper-Susceptible Soybean Exhibiting Significant Basal Resistance to Soybean mosaic virus.
TGA transcription factors (TFs) exhibit basal resistance in Arabidopsis, but susceptibility to a pathogen attack in tomatoes; however, their roles in soybean (Glycine max) to Soybean mosaic virus (SMV) are unknown. In this study, 27 TGA genes were isolated from a SMV hyper-susceptible soybean NN1138-2, designated GmTGA1~GmTGA27, which were clustered into seven phylogenetic groups. The expression profiles of GmTGAs showed that the highly expressed genes were mainly in Groups I, II, and VII under non-induction conditions, while out of the 27 GmTGAs, 19 responded to SMV-induction. Interestingly, in further transient N. benthamiana-SMV pathosystem assay, all the 19 GmTGAs overexpressed did not promote SMV infection in inoculated leaves, but they exhibited basal resistance except one without function. Among the 18 functional ones, GmTGA8 and GmTGA19, with similar motif distribution, nuclear localization sequence and interaction proteins, showed a rapid response to SMV infection and performed better than the others in inhibiting SMV multiplication. This finding suggested that GmTGA TFs may support basal resistance to SMV even from a hyper-susceptible source. What the mechanism of the genes (GmTGA8, GmTGA19, etc.) with basal resistance to SMV is and what their potential for the future improvement of resistance to SMV in soybeans is, are to be explored.


Extrastriate cortex and medial temporal lobe regions respond differentially to visual feature overlap within preferred stimulus category.
It has been proposed that domain-specific regions in extrastriate cortex, parahippocampal cortex and the medial temporal lobe (MTL, particularly the hippocampus, HC, and perirhinal cortex, PrC) may respond differently to the degree of feature complexity present in sets of visual stimuli, with the latter two regions tuned to represent the differences among stimuli with a high degree of visual overlap or featural ambiguity (Graham, Barense, & Lee, 2010; Cowell, Bussey, & Saksida, 2010a). To test this prediction, healthy participants viewed blocks containing visually similar or visually different exemplars from four stimulus categories (scenes, faces, inanimate objects and animate objects). Independent functional regions of interest were identified in extrastriate and MTL regions that were preferentially responsive to one or more of these visual categories, and the main experimental data interrogated for any evidence of an interaction between visual category and degree of feature overlap. In PrC and posterior HC (PostHC) viewing sets of stimuli with a large number of overlapping features resulted in greater activity than blocks containing items that were more visually distinct. The opposite pattern was found in fusiform face area (FFA), parahippocampal place area (PPA) and lateral occipital complex (LOC). The increased response in the HC and PrC to high visual similarity was seen only for visual categories that effectively activate these regions (PrC-faces and objects; PostHC-scenes). This study confirms that regions throughout the visual ventral stream, parahippocampal cortex and MTL are engaged differentially by visual complexity, consistent with recent lesion experiments in which MTL damage affects discrimination and learning of, as well as recognition memory for, exemplars with a high degree of visual feature overlap.


Mu-conotoxins share a common binding site with tetrodotoxin/saxitoxin on eel electroplax Na channels.
The binding characteristics of conotoxin GIIIA purified from the venom of a marine snail, Conus geographus, with regard to electroplax membranes from Electrophorus electricus were studied using a radiolabeled monopropionyl derivative of the toxin (3H-Pr-CGIIIA). 3H-Pr-CGIIIA bound specifically to a single class of saturable binding sites in electroplax membranes with a dissociation constant of 1.1 +/- 0.2 nM and a maximal binding capacity of 11 +/- 2 pmol/mg of protein. The latter value was similar to the number of specific binding sites (10 +/- 2 pmol/mg of protein) for 3H-lysine-tetrodotoxin (3H-Lys-TTX). Monopropionyl CGIIIA and CGIIIA had similar inhibitory effects on the binding of 3H-Lys-TTX (1 nM) to electroplax membranes with IC50 values of 3.5 and 0.9 nM, respectively. The association and dissociation of 3H-Pr-CGIIIA and electroplax membranes were much slower than those of 3H-Lys-TTX and the membranes. Mu-Conotoxins (CGIIIA and CGIIIB) and guanidinium toxins (TTX and saxitoxin) inhibited 3H-Pr-CGIIIA (1 nM) binding to electroplax membranes with IC50 values of 0.6, 1.1, 7.1, and 2.2 nM, respectively. However, several other kinds of neurotoxins and local anesthetics known to interact with Na channels did not affect 3H-Pr-CGIIIA binding. These findings indicate that mu-conotoxins must be classified in the same group of Na channel inhibitors as guanidinium toxins, since they competed with guanidinium toxins for binding sites on the Na channel. The peptide mu-conotoxins should be useful in studies on the functional and structural domains of Na channel proteins.


Chromatin Proteomics to Study Epigenetics - Challenges and Opportunities.
Regulation of gene expression is essential for the functioning of all eukaryotic organisms. Understanding gene expression regulation requires determining which proteins interact with regulatory elements in chromatin. MS-based analysis of chromatin has emerged as a powerful tool to identify proteins associated with gene regulation, as it allows studying protein function and protein complex formation in their in vivo chromatin-bound context. Total chromatin isolated from cells can be directly analyzed using MS or further fractionated into transcriptionally active and inactive chromatin prior to MS-based analysis. Newly formed chromatin that is assembled during DNA replication can also be specifically isolated and analyzed. Furthermore, capturing specific chromatin domains facilitates the identification of previously unknown transcription factors interacting with these domains. Finally, in recent years, advances have been made toward identifying proteins that interact with a single genomic locus of interest. In this review, we highlight the power of chromatin proteomics approaches and how these provide complementary alternatives compared with conventional affinity purification methods. Furthermore, we discuss the biochemical challenges that should be addressed to consolidate and expand the role of chromatin proteomics as a key technology in the context of gene expression regulation and epigenetics research in health and disease.


Competing risks of death in women treated with adjuvant aromatase inhibitors for early breast cancer on NCIC CTG MA.27.
Baseline patient and tumor characteristics differentially affected type of death in the MA.17 placebo-controlled letrozole trial where cardiovascular death was not separately identified. The MA.27 trial allowed competing risks analysis of breast cancer (BC), cardiovascular, and other type (OT) of death. MA.27 was a phase III adjuvant breast cancer trial of exemestane versus anastrozole. Effects of baseline patient and tumor characteristics were tested for whether factors were associated with (1) all cause mortality and (2) cause-specific mortality. We also fit step-wise forward cause-specific-adjusted models. 7576 women (median age 64 years; 5417 (72 %) < 70 years and 2159 (28 %) ≥ 70 years) were enrolled and followed for median 4.1 years. The 432 deaths comprised 187 (43 %) BC, 66 (15 %) cardiovascular, and 179 (41 %) OT. Five baseline factors were differentially associated with type of death. Older patients had greater BC (p = 0.03), cardiovascular (p < 0.001), and other types (p < 0.001) of mortality. Patients with pre-existing cardiovascular history had worse cardiovascular mortality (p < 0.001); those with worse ECOG performance status had worse OT mortality (p < 0.001). Patients with T1 tumors (p < 0.001) and progesterone receptor positive had less BC mortality (p < 0.001). Fewer BC deaths occurred with node-negative disease (p < 0.001), estrogen receptor-positive tumors (p = 0.001), and without adjuvant chemotherapy (p = 0.005); worse cardiovascular mortality (p = 0.01), with trastuzumab; worse OT mortality, for non-whites (p = 0.03) and without adjuvant radiotherapy (p = 0.003). Overall, 57 % of deaths in MA.27 AI-treated patients were non-breast cancer related. Baseline patient and tumor characteristics differentially affected type of death with women 70 or older experiencing more non-breast cancer death.


Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders.
Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAFV600E+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND.


Monoclonal antibodies evaluated for use in a screening assay for conjugates of human serum albumin and pyridoxal 5'-phosphate.
This enzyme immunoassay (EIA) was developed to measure pyridoxal 5'-phosphate bound to albumin (PLP-HSA) in human serum. The monoclonal antibody titer was 1:2000 and a sequential saturation analysis curve, prepared with samples containing from 10 to 1000 nmol/L, showed a 50% inhibition of antibody at 50 nmol of the conjugate per liter. The lower limit of detection for PLP-HSA was 10 nmol/L, a sensitivity 1000-fold greater than that for any potential interferent. When serum samples gave negative results in the assay, we compared the antigenicity of the principal sites for PLP binding on HSA. It was apparent that the preferred physiological site was not antigenic; however, three additional sites for PLP binding on HSA elicited comparable antibody avidity. This EIA is potentially quite sensitive and specific for PLP-HSA, but considerable additional effort is required to convert serum PLP to an HSA-bound form detectable in the assay, which limits its application as a screening method.


Development of a semi-quantitative plate-based alpha-galactosidase gene reporter for Schizosaccharomyces pombe and its use to isolate a constitutively active Mam2.
To extend the tools available for biochemical and genetical analysis in the fission yeast Schizosaccharomyces pombe we have investigated the development of gene reporter systems using the secreted alpha-galactosidase encoded by the Sz. pombe ORF SPAC869.07c (CAB60017), which we propose naming Mel1p to reflect its structural and functional similarity to MEL1p in Saccharomyces cerevisiae. The alpha-galactosidase activity can be monitored in liquid assays and converted the colourless substrate 5-bromo-4-chloro-3-indolyl-alpha-D-galactopyranoside (X-alpha-gal) into an insoluble blue product that was suitable for semi quantitative plate-based assays; colonies expressing the highest levels of alpha-galactosidase developed the most intense blue colour. Unlike assays based on beta-galactosidase, the Sz. pombe colonies develop the blue colouration under normal growth conditions, avoiding the need to replicate colonies to fresh plates for analysis. It is therefore suitable for screening large numbers of colonies. To illustrate the use of mel1 as a reporter we linked expression to the sxa2 gene promoter to provide a convenient readout for signalling through the pheromone response pathway. The sxa2 > mel1 strain identified constitutively active Mam2 pheromone receptors from a randomly mutagenised library. There was an approximate correlation between the intensity of the blue colour developed by each mutant colony and its level of constitutive activity and we identified a subset of mutants with low constitutive activity that could not have been isolated by a previous screen using nutritional selection. The mel1 alpha-galactosidase activity identified and characterised in this study can be easily adapted to provide a gene reporter for many biological processes and is a new addition to the research tools available in Sz. pombe.


Iron deficiency anemia from diagnosis to treatment in children.
Iron deficiency is the most common nutritional deficiency worldwide and an important public health problem especially in developing countries. Since the most important indicator of iron deficieny is anemia, the terms "iron deficiency" and "iron deficiency anemia" are often used interchangeably. However, iron deficiency may develop in the absence of anemia and the tissues may be affected from this condition. The most common causes of iron deficiency in children include insufficient intake together with rapid growth, low birth weight and gastrointestinal losses related to excessive intake of cow's milk. If insufficient intake can be excluded and there is insufficient response to oral iron treatment in patients with iron deficiency especially in older children, blood loss should be considered as the underlying cause. The main principles in management of iron deficiency anemia include investigation and elimination of the cause leading to iron deficiency, replacement of deficiency, improvement of nutrition and education of the patient and family. In this article, the practical approaches in the diagnosis and treatment of iron deficiency and the experience of our center have been reviewed.


σ or π? Bonding interactions in a series of rhenium metallotetrylenes.
Salt metathesis reactions between a low-valent rhenium(i) complex, Na[Re(η5-Cp)(BDI)] (BDI = N,N'-bis(2,6-diisopropylphenyl)-3,5-dimethyl-β-diketiminate), and a series of amidinate-supported tetrylenes of the form ECl[PhC(NtBu)2] (E = Si, Ge, Sn) led to rhenium metallotetrylenes Re(E[PhC(NtBu)2])(η5-Cp)(BDI) (E = Si (1a), Ge (2), Sn (4)) with varying extents of Re-E multiple bonding. Whereas the rhenium-stannylene 4 adopts a σ-metallotetrylene arrangement featuring a Re-E single bond, the rhenium-silylene (1a) and -germylene (2) both engage in π-interactions to form short Re-E multiple bonds. Temperature was found to play a crucial role in reactions between Na[Re(η5-Cp)(BDI)] and SiCl[PhC(NtBu)2], as manipulation of reaction conditions led to isolation of an unusual rhenium-silane, (BDI)Re(μ-η5:η1-C5H4)(SiH[PhC(NtBu)2]) (1b) and a dinitrogen bridged rhenium-silylene, (η5-Cp)(BDI)Re(μ-N2)Si[PhC(NtBu)2] (1c), in addition to 1a. Finally, the reaction of Na[Re(η5-Cp)(BDI)] with GeCl2·dioxane led to a rare μ2-tetrelido complex, μ2-Ge[Re(η5-Cp)(BDI)]2 (3). Bonding interactions within these complexes are discussed through the lens of various spectroscopic, structural, and computational investigations.


Identification and analysis of a gene encoding L-2,4-diaminobutyrate:2-ketoglutarate 4-aminotransferase involved in the 1,3-diaminopropane production pathway in Acinetobacter baumannii.
The ca. 2.2-kbp region upstream of the ddc gene encoding L-2,4-diaminobutyrate decarboxylase in Acinetobacter baumannii was sequenced and found to contain another open reading frame of 1,338 nucleotides encoding a protein with a deduced molecular mass of 47,423 Da. Analysis of the homologies observed from the deduced amino acid sequence indicated that the gene product is an enzyme belonging to subgroup II of the aminotransferases. This was first verified when examination of the crude extracts from Escherichia coli transformants led to detection of a novel aminotransferase activity catalyzing the following reversible reactions: L-2,4-diaminobutyric acid + 2-ketoglutaric acid<-->L-glutamic acid + L-aspartic beta-semialdehyde. Further confirmation was obtained when the gene was overexpressed in E. coli and the corresponding protein was purified to homogeneity. It catalyzed the same reactions and its N-terminal amino acid sequence was consistent with that deduced from the nucleotide sequence. Therefore, the gene and its product were named dat and L-2,4-diaminobutyrate:2-ketoglutarate 4-aminotransferase (DABA AT), respectively. Feeding experiments of A. baumannii with L-[U-14C]aspartic acid resulted in the incorporation of the label into 1,3-diaminopropane. Apparent homologs of dat and DABA AT were detected in other Acinetobacter species by PCR amplification and Western blotting. These results indicate that the dat gene (as well as the ddc gene) participates in the synthesis of 1,3-diaminopropane, the only diamine found in this genus. However, the biological role, if one exists, of 1,3-diaminopropane synthesis is unknown.


Can life history trade-offs explain the evolution of short stature in human pygmies? A response to Migliano et al. (2007).
Walker et al. ["Growth rates and life histories in twenty-two small-scale societies," Am. J. Hum. Biol. 18:295-311 (2006)] used life history theory to develop an innovative explanation for human diversity in stature. Short stature could have been selected for in some human populations as a result of the advantage of an earlier growth cessation and earlier reproduction in a context of high mortality. Migliano et al. ["Life history trade-offs explain the evolution of human pygmies," Proc. Natl. Acad. Sci. USA 104:20,216-20,219 (2007)] recently published an important article that tested this hypothesis to explain short stature in human pygmy populations. However innovative this work may be, we believe that some of the data and results presented are controversial if not questionable. As problematic points we note (1) the use of an arbitrary threshold of height (155 cm) to categorize populations into pygmies and nonpygmies; (2) the use of demographic data from Philippine pygmy groups that have experienced dramatic cultural and environmental changes in the last 20 years, and (3) the use of demographic data concerning African pygmy groups because good systematic data on these groups are not available. Finally, we report here mathematical errors and loopholes in the optimization model developed by Migliano and colleagues. In this paper we suggest alternative trade-offs that can be used to explain Migliano's results on more reliable bases.


Mixed blocked/event-related designs separate transient and sustained activity in fMRI.
Recent functional magnetic resonance imaging (fMRI) studies using mixed blocked/event-related designs have shown activity consistent with separable sustained task-related processes and transient trial-related processes. In the mixed design, control blocks are intermixed with task blocks, during which trials are presented at varying intervals. Two studies were conducted to assess the ability of this design to detect and dissociate sustained task-related from transient trial-related activity. Analyses on both simulated and empirical data were performed by using the general linear model with a shape assumed for sustained effects, but not transient effects. In the first study, simulated data were produced with sustained time courses, transient time courses, and the sum of both together. Analyses of these data showed appropriate parsing of sustained and transient activity in all three cases. For the empirical fMRI experiment, counterphase-flickering checkerboard stimuli were constructed to produce sustained, transient, and combined sustained and transient responses in visual cortex. As with the simulation, appropriate parsing of sustained and transient activity was seen in all three cases; i.e., sustained stimuli produced sustained time courses and transient stimuli produced transient time courses. Combined stimuli produced both transient and sustained time courses. Critically, transient stimuli alone did not produce spurious positive sustained responses; sustained stimuli alone produced negligible spurious transient time courses. The results of these two studies along with supplemental simulations provide strong evidence that mixed designs are an effective tool for separating transient, trial-related activity from sustained activity in fMRI experiments. Mixed designs can allow researchers a means to examine brain activity associated with sustained processes, potentially related to task-level control signals.


Excitation-contraction coupling mechanisms in airway smooth muscle: new targets in drug design.
Homeostatic regulation of Ca2+ levels within airway smooth muscle cells, and the consequences of changes in intracellular Ca2+ levels are reviewed, and a number of mechanisms are identified as targets for drug action. In the prophylaxis of asthma--by preventing the induction of contraction--the opportunities relate to receptor antagonism, the inhibition of Ca2+ influx, the inhibition of intracellular Ca2+ release, calmodulin antagonism, and the antagonism of contractile proteins. In the symptomatic relief of asthma--by reversal of established contractile responses--the opportunities relate to the inhibition of Ca2+ influx, the inhibition of inositol trisphosphate metabolism, the inhibition of protein kinase C, and the augmentation of Ca2+ removal mechanisms.


Cationic Biopolymeric Scaffold of Chelating Nanohydroxyapatite Self-Regulates Intraoral Microenvironment for Periodontal Bone Regeneration.
Periodontal bone defect is a common but longstanding healthcare issue since traditional bone grafts have limited functionalities in regulating complex intraoral microenvironments. Here, a porous cationic biopolymeric scaffold (CSC-g-nHAp) with microenvironment self-regulating ability was synthesized by chitosan-catechol chelating the Ca2+ of nanohydroxyapatite and bonding type I collagen. Chitosan-catechol's inherent antibacterial and antioxidant abilities endowed this scaffold with desirable abilities to eliminate periodontal pathogen infection and maintain homeostatic balances between free radical generation and elimination. Meanwhile, this scaffold promoted rat bone marrow stromal cells' osteogenic differentiation and achieved significant ectopic mineralization after 4 weeks of subcutaneous implantation in nude mice. Moreover, after 8 weeks of implantation in the rat critical-sized periodontal bone defect model, CSC-g-nHAp conferred 5.5-fold greater alveolar bone regeneration than the untreated group. This cationic biopolymeric scaffold could regulate the local microenvironment through the synergistic effects of its antibacterial, antioxidant, and osteoconductive activities to promote solid periodontal bone regeneration.


Simultaneous determination of mifepristone and monodemethyl-mifepristone in human plasma by liquid chromatography-tandem mass spectrometry method using levonorgestrel as an internal standard: application to a pharmacokinetic study.
A rapid and sensitive liquid chromatography/tandem mass spectrometry (LC-MS/MS) method was developed and validated to simultaneously determine mifepristone and monodemethyl-mifepristone in human plasma using levonorgestrel as the internal standard (IS). After solid-phase extraction of the plasma samples, mifepristone, monodemethyl-mifepristone and the IS were subjected to LC-MS/MS analysis using electro-spray ionization (ESI) in the multiple reaction monitoring (MRM) mode. Chromatographic separation was performed on an XTERRA MS C(18) column (150 x 2.1 mm i.d., 5 microm). The method had a chromatographic run time of 4.5 min and linear calibration curves over the concentration ranges of 5-2000 ng/mL for mifepristone and monodemethyl-mifepristone. The recoveries of the method were found to be 94.5-103.7% for mifepristone and 70.7-77.3% for monodemethyl-mifepristone. The method had a lower limit of quantification (LLOQ) of 5.0 ng/mL and a lower limit of detection (LOD) of 1.0 ng/mL for both mifepristone and monodemethyl-mifepristone. The intra- and inter-batch precision was less than 15% for all quality control samples at concentrations of 10, 100 and 1000 ng/mL. These results indicate that the method was efficient with a short run time (4.5 min) and acceptable accuracy, precision and sensitivity. The validated LC-MS/MS method was successfully used in a pharmacokinetic study in healthy female volunteers after oral administration of 25 mg mifepristone tablet.


Outcomes of Clostridium difficile-infected patients managed in a common isolation unit compared with isolation in their bed of diagnosis.
Cohorting Clostridium difficile infection (CDI) patients is a strategy which has not been thoroughly evaluated. We compared clinical characteristics and outcomes of CDI patients treated in a common isolation unit (CIU) versus those treated in their bed of diagnosis. Patients treated in the CIU showed lower mortality rates and antibiotic usage; however, a higher recurrence rate was reported.


MMPI-2 short form proposal: CAUTION.
The Minnesota Multiphasic Personality Inventory-2 (MMPI-2) is widely used in neuropsychology, though its length (567 items) is sometimes prohibitive. This study investigated some psychometric characteristics of the 180-item version of the MMPI-2 () in order to delineate its strengths, limitations, and appropriate scope of clinical application. Limited reliability and poor predictive accuracy were recently reported for many of the MMPI-2 short-form scales in a study that used 205 brain-injured patients. In the present investigation, we used a psychiatric sample (N=186) with normal neurological findings to examine short-form accuracy in predicting basic scale scores, profile code types, identifying high-point scales, and classifying scores as pathological (T>/=65) or normal-range. The results suggest that, even as applied to neurologically normal individuals, the proposed short form of the MMPI-2 is unreliable for predicting clinical code types, identifying the high-point scale, or predicting the scores on most of the basic scales. In contrast, this short form can be used to predict whether the full-scale scores fall within the pathological range (T>/=65). These findings suggest that clinicians might be able to salvage a small amount of information from the shortened (180-item) version of the MMPI-2 when MMPI-2 protocols are incomplete. However, clinicians should not use a standard interpretive approach with this test, and routine clinical application is unwarranted. Future evaluations of short-form validity should provide a more detailed examination of individual protocols, including an analysis of the frequency of accurate prediction of full-form scores.


A Diagnostic Marker to Discriminate Childhood Apraxia of Speech From Speech Delay: I. Development and Description of the Pause Marker.
The goal of this article (PM I) is to describe the rationale for and development of the Pause Marker (PM), a single-sign diagnostic marker proposed to discriminate early or persistent childhood apraxia of speech from speech delay. The authors describe and prioritize 7 criteria with which to evaluate the research and clinical utility of a diagnostic marker for childhood apraxia of speech, including evaluation of the present proposal. An overview is given of the Speech Disorders Classification System, including extensions completed in the same approximately 3-year period in which the PM was developed. The finalized Speech Disorders Classification System includes a nosology and cross-classification procedures for childhood and persistent speech disorders and motor speech disorders (Shriberg, Strand, & Mabie, 2017). A PM is developed that provides procedural and scoring information, and citations to papers and technical reports that include audio exemplars of the PM and reference data used to standardize PM scores are provided. The PM described here is an acoustic-aided perceptual sign that quantifies one aspect of speech precision in the linguistic domain of phrasing. This diagnostic marker can be used to discriminate early or persistent childhood apraxia of speech from speech delay.


[Psychological guidance of children during dental care].
Due to the high incidence of caries, affections of the marginal periodontium and occlusal anomalies, the regular preventive and therapeutical care of the children is imperative. For this reason, the motivation of the children toward treatment is of paramount importance. Suggestions are given for long-term and short-term psychopreventive influencing and the management of children of poor co-operativeness.


The Use of a Surgical Spoon in the Removal of Substernal Goiter.
Goiter with substernal extension is common, with a reported incidence of up to 20% in patients undergoing thyroidectomy. It has been shown that the vast majority of substernal goiters can be removed through a cervical incision. However, if this is not possible, a sternotomy is usually required, which could add significant morbidity to an otherwise routine operation. During substernal mobilization, the surgeon's finger is typically placed under the strap muscles and against the thyroid capsule, hooking around the inferior aspect of the gland to facilitate separation of the gland from its mediastinal attachments. In cases where the length required for successful substernal mobilization is beyond the reach of a surgeon's fingers, the use of an alternative strategy may be required. A surgical spoon is a blunt, curved instrument that can allow safe substernal mobilization while providing the added length needed when digital mobilization is inadequate. Here, we describe the use of a surgical spoon for the safe and successful removal of a goiter with substernal extension unable to be removed with digital manipulation.


IFN-γ stimulated dental follicle mesenchymal stem cells regulate activated lymphocyte response in rheumatoid arthritis patients in vitro.
Multipotent mesenchymal stem cells (MSCs) have been investigated in autoimmune diseases such as rheumatoid arthritis (RA) due to their immunomodulatory and regenerative properties. In this study, their immunosuppressive effects on peripheral blood mononuclear cells (PBMC) of RA patients were studied. Dental follicle stem cells (DFSCs) were isolated from follicle tissue in the orofacial region. Characterization and multipotency analyses were performed. Lymphocytes were isolated from peripheral venous blood of RA patients (n = 5) and healthy individuals (n = 5). DFSCs were preincubated with IFN-γ for 48 h. PBMCs of RA patients and healthy individuals were separately cultured with or without DFSCs for 72 h. After culture period, lymphocyte proliferation and viability, the frequency of CD4+ CD25+FoxP3+ T regulatory cells, IL-10 and TNF-α levels in the culture supernatants were measured via flow cytometry. Our results demonstrated that DFSCs suppressed proliferation of T lymphocytes by increasing the number of FoxP3 expressing CD4+CD25+ T regulatory cells and suppressed lymphocyte apoptosis in RA patients. Also, DFSCs reduced TNF-α cytokine secretion and upregulated IL-10 secreting cells. Such cells could potentially be a source for future immunomodulatory treatments of RA patients.


Is it all about Depression? Determinants of Burnout among Employees Referred for Inpatient Treatment of Job-Related Stress Disorders.
Objectives: There is an ongoing debate as to whether job burnout and depression are overlapping concepts or differ from each other, although this has not been scrutinized in inpatients. To further elucidate the robustness of this relationship, we used three different measurements of depression. We further examined the influence of psychological distress, perceived stress and sleep quality in the link between depressive symptoms and burnout. Methods: We investigated 723 consecutive inpatients, aged 23 to 82 years, 51.2 % women, referred to a hospital specialized in the treatment of job stress-related disorders. Patients completed the Maslach Burnout Inventory, the Beck Depression Inventory, the Hospital Anxiety and Depression Scale, the Brief Symptom Inventory, the Perceived Stress Scale, and the Pittsburgh Sleep Quality Index. Results: We found significant correlations between burnout total scores as well as subscales (emotional exhaustion, depersonalization, lack of accomplishment) and depressive symptoms, virtually independent of the applied depression measure. The shared variance ranged between 1.1 % and 19.4 %. Greater levels of burnout were directly associated with cognitiveaffective symptoms and, although to a lesser extent, also with somatic-affective symptoms of depression. In the multivariable analysis, significantly more total burnout symptoms were revealed in more depressed and younger patients, in men than women, and in employees with greater levels of psychological distress and perceived stress, respectively. Conclusions: The findings suggest that although burnout and depression do not represent the same psychopathology, there is considerable overlap between the two constructs; the extent of this overlap may vary depending upon the applied depression measure.


A newborn with duodenal atresia and a gastric perforation.
Congenital duodenal atresia complicated by gastric perforation (GP) is a very rare and a very mortal condition. Only three newborns could be cured in the reported 13 cases. We report a successfully treated newborn with this complicated disease. A 2-day-old male was hospitalized with prediagnosis of duodenal obstruction. Twelve hours later, significant abdominal distention occurred promptly. At laparotomy, GP and preampullary duodenal atresia were detected. Gastrorrhaphy and duodenoduodenostomy were performed in the same operation. The patient was discharged on the 15th postoperative day. This complicated disease can be treated by early diagnosis and surgical intervention. We choose one-stage operation because of the clean peritoneal cavity. However, generalized peritonitis may require two-stage operation in delayed cases.


The home literacy environment and Latino head start children's emergent literacy skills.
This study examined children's early literacy skills in both English and Spanish at entry to preschool to investigate the pattern of association among these skills and their families' home language and literacy practices. The participants were 392 primarily Latino immigrant (85%) families and their children. Mothers completed questionnaires about their families and their home literacy environment (HLE), and children's emergent literacy skills were measured in English and Spanish at the outset of the preschool year. Project assistants interviewed mothers in their homes and tallied the presence of literacy-related materials. Results of structural equation modeling showed that the 3 preliteracy skills were significantly associated within and across English and Spanish, suggesting the possible transfer of these early preliteracy skills across languages. For the English language HLE, parents' literacy-related behaviors, sibling-child reading, and families' literacy resources were all associated with children's English oral language skills, and their English print knowledge was associated with their home resources. For the Spanish language HLE, only parents' literacy-related behaviors were related to children's Spanish oral language and print knowledge skills. There were no significant cross-linguistic relations between any aspect of the English HLE and children's Spanish preliteracy skills, whereas parents' literacy-related behaviors in Spanish were negatively associated with children's English oral language and phonological awareness skills. Given the importance of oral language and vocabulary in promoting children's literacy, these results indicate that parents can support this skill in both languages, but their relative impact seems to be within rather across language.


Actions of insulin-potentiating peptides on glycogen synthesis.
The action of urinary and synthetic AcG (acceleratory factor from growth hormone) peptides was studied in vitro and in vivo. Both peptides were inactive alone and active only in the presence of insulin to enhance glucose uptake, glycogen synthesis, and glycogen synthase conversion to the active I form in vitro and in vivo. Responses were dependent on both peptide and insulin concentrations in a dose-dependent manner. No response was obtained with glucose alone, but the presence of glucose did enhance the response of insulin alone or insulin in the presence of peptide. It is concluded that both AcG peptides enhance either the effective concentration or the activity of insulin at its site of action.


Exploiting the Catalytic Ability of Polydopamine-Remodeling Gold Nanoparticles toward the Naked-Eye Detection of Cancer Cells at a Single-Cell Level.
In this study, a catalytic polydopamine-remodeling gold nanoparticle sensitized with an antinucleolin AS1411 probe (pAu nanoprobe) is synthesized, where the surface of the gold nanoparticles (AuNPs) is modified with a spontaneous self-polymerization of a polydopamine coating that imparts the probe functionalization ability and antispecific protein binding while the intrinsic catalytic property of the AuNPs is preserved. The functionalized AS1411 probe exerts specific recognition with nucleolin protein that is found to be overexpressed on the surface of breast cancer cells (MDA-MB-231). Scanning electron microscopy (SEM) confirms that the specific binding of the pAu nanoprobe occurs at the cancer cell surface. Taking advantage of the catalytic ability of the pAu nanoprobe in reducing blue-colored methylene blue (MB) to colorless leuco-MB, a colorimetric biosensing platform is established based on the accessible catalytic active sites on the pAu nanoprobe toward MB. The specific binding inhibits the pAu nanoprobe from efficiently catalyzing the reduction of MB, resulting in a "turn-off" catalytic biosensing platform. The catalytic conversion of MB is inversely proportional to the concentration of the nucleolin protein and the cancer cells, yielding a detection limit of 15 pM of the nucleolin protein and two cancer cells. The presence of five orders of magnitude higher concentration of bovine serum albumin hardly affects the catalytic ability of the pAu nanoprobe, that is, 88% catalytic ability is still preserved, which validates the specificity of the proposed pAu nanoprobe. In particular, a distinct color contrast creates a significant signal-to-noise ratio so as to enable single-cell level detection of two cancer cells by naked-eye judgment. Moreover, the undiluted, real human serum samples spiked with the cancer cells were examined with an impressive recovery of 94 ± 0.3%, which holds great promise in cancer cell screening.


Anaesthetic management during repair of tracheo-oesophageal fistula.
A flexible fibreoptic laryngoscope was used to facilitate the passage of a long polyvinyl chloride tracheal tube into the left main bronchus during repair of a tracheo-oesophageal fistula situated near the carina in a patient in whom intubation with a double-lumen endobronchial tube was difficult. Close monitoring of neuromuscular transmission using a peripheral nerve stimulator also contributed to the successful anaesthetic management of this patient.


An SSVEP-based brain-computer interface for the control of functional electrical stimulation.
A brain-computer interface (BCI) based on steady-state visual-evoked potentials (SSVEPs) is combined with a functional electrical stimulation (FES) system to allow the user to control stimulation settings and parameters. The system requires four flickering lights of distinct frequencies that are used to form a menu-based interface, enabling the user to interact with the FES system. The approach was evaluated in 12 neurologically intact subjects to change the parameters and operating mode of an abdominal stimulation system for respiratory assistance. No major influence of the FES on the raw EEG signal could be observed. In tests with a self-paced task, a mean accuracy of more than 90% was achieved, with detection times of approximately 7.7 s and an average information transfer rate of 12.5 bits/min. There was no significant dependency of the accuracy or time of detection on the FES stimulation intensity. The results indicate that the system could be used to control FES-based neuroprostheses with a high degree of accuracy and robustness.


Parsimony or poor luck: Concurrent Birt-Hogg- Dubé Syndrome and sarcoidosis.
While sarcoidosis is notorious for myriad manifestations including cystic lung changes, we present a case with both Birt-Hogg-Dubé syndrome (BHD) and pulmonary sarcoidosis. BHD is a rare, autosomal dominant genetic disorder characterized by numerous thin-walled, irregular cysts, but lung function is typically normal otherwise. We present a case with confirmed BHD syndrome and concurrent granulomatous lung disease consistent with sarcoidosis. (Sarcoidosis Vasc Diffuse Lung Dis 2017; 34: 194-196).


The expression of SEL1L and TAN-1 in normal and neoplastic cells.
We have previously reported on the isolation and chromosomal mapping of a novel human gene (SEL1L), which shows sequence similarity to sel-1, an extragenic suppressor of C. elegans. sel-1 functions as a negative regulator of lin-12 activity, the latter being implicated in the control of diverse cellular differentiation events. In the present study we compare the expression patterns of SEL1L and TAN-1, the human ortholog of lin-12 in normal and neoplastic cells. We found that, whereas both genes are expressed in fetal tissues at similar levels, they are differentially expressed in normal adult and neoplastic cells. In normal adult cells SEL1L is generally present at very low levels; only in the cells of the pancreas does it show maximum expression. By contrast, SEL1L is generally well represented in most neoplastic cells but not in those of pancreatic and gastric carcinomas, where transcription is either downregulated or completely repressed. TAN-1 on the other hand is well represented in almost all normal and neoplastic cells, with very few exceptions. Our observations suggest that SEL1L is presumably implicated in pancreatic and gastric carcinogenesis and that, along with TAN-1, it is very important for normal cell function. Alterations in the expression of SEL1L may be used as a prognostic marker for gastric and pancreatic cancers.


[Trastuzumab combined with chemotherapy in patients with HER2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma].
To evaluate the efficacy and safety of trastuzumab combined with chemotherapy in the treatment for HER-2-positive chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma. Twenty consecutive cases of chemo-refractory advanced gastric or gastro-esophageal junction adenocarcinoma treated in Peking University Cancer Hospital between 2009 June and 2013 August were included in this study. The patients with adenocarcinoma were previously confirmed and were eligible if their tumor showed overexpression of HER-2+++ by immunohistochemistry or HER-2 gene amplification-positive by FISH, and if they failed to at least one previous chemotherapy. Response and toxicities were evaluated with RECIST 1.0 and CTC AE 3.0 criteria. The twenty patients received trastuzumab plus second- or later-line chemotherapy, consisting of nine platinum with fluoropyrimidines, five paclitaxel with fluoropyrimidines, three fluoropyrimidines monotherapy, two irinotecan monotherapy, and one docetaxel monotherapy. In these 20 cases, 3 PR (15.0%) and 10 SD (50.0%) were achieved, with a disease control rate of 65.0%. The median PFS was 6.1 months (95%CI 3.0-9.2) and median OS was 11.1 months (95%CI 8.4-13.7). The median cycle number of Trastuzumab administration was 6.5. The patients treated with Trastuzumab ≥ 6 times had a median OS of 13.8 months, significantly longer than that of 9.5 months in the patients treated <6 times (P < 0.001). The patients treated with Trastuzumab ≥ 6 times had a median PFS of 7.8 months, significantly longer than that of 3.7 months in patients treated <6 times (P = 0.029). Among the 20 cases, loss of appetite (13 cases of grade 1-2), neutropenia (12 cases of grade 1-2 and 3 cases of grade 3-4) and fatigue (9 cases of grade 1-2 and 3 cases of grade 3-4) were the most frequent adverse events. No cardiac events including asymptomatic decreases in LVEF ≥ 10% and no treatment-related death were recorded. Combination of trastuzumab with chemotherapy is effective and safe in patients with HER2-positive advanced chemo-refractory gastric or gastro-esophageal junction adenocarninoma. However, prospective studies are warranted to further confirm its efficacy and safety.


Vigorous physical activity among tweens, VERB Summer Scorecard program, Lexington, Kentucky, 2004-2007.
Empirical examinations of the efficacy of community-based programs to increase and sustain physical activity among youth are lacking. This study describes changes in vigorous physical activity during a 3-year period among children aged 9 to 13 years (tweens) in Lexington, Kentucky, following introduction of the VERB Summer Scorecard (VSS) intervention. A community coalition, guided by a marketing plan that addressed motivators for tweens to participate in physical activity, designed and implemented VSS. Youth used a scorecard to monitor their physical activity, which was verified by adults. There were 3,428 students surveyed in 2004; 1,976 in 2006; and 2,051 in 2007 (mean age for 2004, 2006, and 2007, 12 y). For each year, we performed Χ(2) tests and computed summary statistics for age, sex, and grade. Chi-square tests and cumulative logit models were used to analyze physical activity trends among VSS participants, VSS nonparticipants, and a reference group. The proportion of youth who reported frequent vigorous physical activity increased from 32% in 2004 to 42% in 2007. The proportion of VSS participants with moderate or high levels of vigorous physical activity increased by approximately 17 percentage points, more than twice the proportion of nonparticipants. Interventions such as VSS may empower communities to take action to encourage greater physical activity among youth.


Actin cytoskeleton remodeling at the cancer cell side of the immunological synapse: good, bad, or both?
Cytotoxic lymphocytes (CLs), specifically cytotoxic T lymphocytes and natural killer cells, are indispensable guardians of the immune system and orchestrate the recognition and elimination of cancer cells. Upon encountering a cancer cell, CLs establish a specialized cellular junction, known as the immunological synapse that stands as a pivotal determinant for effective cell killing. Extensive research has focused on the presynaptic side of the immunological synapse and elucidated the multiple functions of the CL actin cytoskeleton in synapse formation, organization, regulatory signaling, and lytic activity. In contrast, the postsynaptic (cancer cell) counterpart has remained relatively unexplored. Nevertheless, both indirect and direct evidence has begun to illuminate the significant and profound consequences of cytoskeletal changes within cancer cells on the outcome of the lytic immunological synapse. Here, we explore the understudied role of the cancer cell actin cytoskeleton in modulating the immune response within the immunological synapse. We shed light on the intricate interplay between actin dynamics and the evasion mechanisms employed by cancer cells, thus providing potential routes for future research and envisioning therapeutic interventions targeting the postsynaptic side of the immunological synapse in the realm of cancer immunotherapy. This review article highlights the importance of actin dynamics within the immunological synapse between cytotoxic lymphocytes and cancer cells focusing on the less-explored postsynaptic side of the synapse. It presents emerging evidence that actin dynamics in cancer cells can critically influence the outcome of cytotoxic lymphocyte interactions with cancer cells.


Axis establishment and microtubule-mediated waves prior to first cleavage in Beroe ovata.
The single axis (oral-aboral) and two planes of symmetry of the ctenophore Beroe ovata become established with respect to the position of zygote nucleus formation and the orientation of first cleavage. Bisection of Beroe eggs at different times revealed that differences in egg organisation are established in relation to the presumptive oral-aboral axis before first cleavage. Lateral fragments produced after but not before the time of first mitosis developed into larvae lacking comb-plates on one side. Time-lapse video demonstrated that waves of cytoplasmic reorganisation spread through the layer of peripheral cytoplasm (ectoplasm) of the egg during the 80 minute period between pronuclear fusion and first cleavage, along the future oral-aboral axis. These waves are manifest as the progressive displacement and dispersal of plaques of accumulated organelles around supernumerary sperm nuclei, and a series of surface movements. Their timing and direction of propagation suggest they may be involved in establishing cytoplasmic differences with respect to the embryonic axis. Inhibitor experiments suggested that the observed cytoplasmic reorganisation involves microtubules. Nocodazole and taxol, which prevent microtubule turnover,blocked plaque dispersal and reduced surface movements. The microfilament-disrupting drug cytochalasin B did not prevent plaque dispersal but induced abnormal surface contractions. We examined changes in microtubule organisation using immunofluorescence on eggs fixed at different times and in live eggs following injection of rhodamine-tubulin. Giant microtubule asters become associated with each male pronucleus after the end of meiosis. Following pronuclear fusion they disappear successively, those nearest the zygote nucleus shrinking first, to establish gradients of aster size within single eggs. Regional differences in microtubule behaviour around the time of mitosis were revealed by brief taxol treatment, which induced the formation of small microtubule asters in the region of the nucleus or spindle during both first and second cell cycles. The observed wave of change may thus reflect the local appearance and spreading of mitotic activity as the zygote nucleus approaches mitosis.


Antimicrobial Peptide LCN2 Inhibited Uropathogenic Escherichia coli Infection in Bladder Cells in a High-Glucose Environment through JAK/STAT Signaling Pathway.
JAK/STAT plays a key role in regulating uropathogenic Escherichia coli (UPEC) infection in urothelial cells, probably via antimicrobial peptide (AMP) production, in diabetic patients with urinary tract infections. Whether multiple pathways regulate AMPs, especially lipid-carrying protein-2 (LCN2), to achieve a vital effect is unknown. We investigated the effects of an LCN2 pretreatment on the regulation of the JAK/STAT pathway in a high-glucose environment using a bladder cell model with GFP-UPEC and phycoerythrin-labeled TLR-4, STAT1, and STAT3. Pretreatment with 5 or 25 μg/mL LCN2 for 24 h dose-dependently suppressed UPEC infections in bladder cells. TLR-4, STAT1, and STAT3 expression were dose-dependently downregulated after LCN2 pretreatment. The LCN2-mediated alleviation of UPEC infection in a high-glucose environment downregulated TLR-4 and the JAK/STAT transduction pathway and decreased the UPEC-induced secretion of exogenous inflammatory interleukin (IL)-6 and IL-8. Our study provides evidence that LCN2 can alleviate UPEC infection in bladder epithelial cells by decreasing JAK/STAT pathway activation in a high-glucose environment. LCN2 dose-dependently inhibits UPEC infection via TLR-4 expression and JAK/STAT pathway modulation. These findings may provide a rationale for targeting LCN2/TLR-4/JAK/STAT regulation in bacterial cystitis treatment. Further studies should explore specific mechanisms by which the LCN2, TLR-4, and JAK/STAT pathways participate in UPEC-induced inflammation to facilitate the development of effective therapies for cystitis.


Effects of sodium selenite addition on ruminal fermentation, microflora and urinary excretion of purine derivatives in Holstein dairy bulls.
Researches on sodium selenite (SS) mainly focus on production performance and rumen fermentation in ruminants, and the influence of dietary Se addition on ruminal microbial population and enzyme activity in dairy bulls is scarce. This study mainly evaluated the effects of SS on ruminal fermentation, microflora and urinary excretion of purine derivatives (PD) in dairy bulls. Eight ruminally cannulated dairy bulls were used in a replicated 4 × 4 Latin square design. Treatments were control, low SS (LSS), medium SS (MSS) and high SS (HSS) with 0, 0.1, 0.3 and 0.5 mg/kg of selenium (Se) from SS in dietary dry matter (DM), respectively. The supplement of SS (1.0 g/kg of Se) was mixed into the first third of the daily ration. Bulls were fed a total mixed ration with corn silage to concentrate ratio of 50:50 on a DM basis. Dry matter intake was not affected, average daily gain linearly increased, while feed conversion ratio quadratically decreased with increasing Se addition. The linearly increased digestibility of DM, organic matter, crude protein, ether extract, neutral detergent fibre and acid detergent fibre was observed. Both ruminal pH and ammonia-N concentration linearly decreased, whereas total volatile fatty acid concentration linearly increased. A lower acetate to propionate ratio was observed due to the unchanged acetate proportion and increased propionate proportion. Activity of cellobiase, xylanase, pectinase, α-amylase and protease, populations of total bacteria, fungi, protozoa, Ruminococcus (R.) albus, R. flavefaciens, Fibrobacter succinogenes, Butyrivibrio fibrisolvens and Ruminobacter amylophilus as well as urinary total PD excretion linearly increased, whereas populations of total methanogens and Prevotella ruminicola linearly decreased. The data indicated that dietary Se addition stimulated ruminal microbial growth and enzyme activity, and resulting in the increased nutrient digestion and growth performance, and the optimum supplementary dose of Se was 0.3 mg/kg dietary DM from SS in dairy bulls.