Investigating substrate-induced motion between the scaffold and transport domains in the glutamate transporter EAAT1.
Excitatory amino acid transporter 1 plays an important role in keeping the synaptic glutamate concentration below neurotoxic levels by translocating this neurotransmitter into the cell. Both reentrant hairpin loops, HP1 and -2, have been shown to take part in binding the substrate and the more deeply buried sodium ion, and might therefore be a part of the intra- or extracellular gate of the transporter. However, the shape of the motion of either loop relative to transmembrane domain (TM) 4 during the transport cycle has not yet been fully resolved. Using copper(II) (1,10-phenanthroline)3 (CuPh) for cross-linking cysteine pairs, we found strong inhibition of transport when A243C (TM4) was combined with S366C (HP1), I453C (HP2), or T456C (HP2). These findings were reinforced by the impact of cadmium on transport activity, and both approaches consistently showed that proximity was exclusively intramonomeric. Under conditions that promote the inward-facing state, inhibition by CuPh in A243C/S366C was reduced, while the opposite was seen when the outward-facing one was stabilized, suggesting that the two positions are farther apart in the former conformation than in the latter. Surprisingly, maximal cross-linking of A243C with I453C or T456C was not observed under conditions that promote the inward-facing state. Altogether, our data suggest that the transporter may undergo complex relative movement between these positions on TM4 and HP1/HP2 during the transport cycle.


Costal Chondrocyte-Derived Pellet-Type Autologous Chondrocyte Implantation versus Microfracture for Repair of Articular Cartilage Defects: A Prospective Randomized Trial.
To compare the efficacy and safety of costal chondrocyte-derived pellet-type autologous chondrocyte implantation (CCP-ACI) with microfracture (MFx) for repair of articular cartilage defects of the knee. Thirty subjects with an International Cartilage Repair Society (ICRS) grade 3 to 4 chondral defect (2-10 cm2 in area; ≤4 cm3 in volume) were randomized at a ratio of 2:1 (CCP-ACI:MFx). Twenty patients were allocated in the CCP-ACI group and 10 patients in the MFx group. CCP-ACI was performed by harvesting costal cartilage at least 4 weeks before surgery. Implantation was performed without any marrow stimulation. Efficacy and safety were assessed at weeks 8, 24, and 48 after surgery according to the magnetic resonance observation of cartilage repair tissue (MOCART) score and clinical outcomes. MOCART scores improved from baseline to 24 and 48 weeks postoperatively in both treatment groups. The improvement in MOCART scores in the CCP-ACI group was significantly greater than that in the MFx group at 24 and 48 weeks (39.1 vs 21.8 and 43.0 vs 24.8, respectively). The proportions of complete defect repair and complete integration were significantly higher in the CCP-ACI group than the MFx group at 48 weeks. Improvement in Lysholm score and KOOS subscores, including Function (Sports and Recreational Activity) and knee-related quality of life was significantly greater in the CCP-ACI group than the MFx group at 48 weeks (35.4 vs 31.5, 35.7 vs 28.5, and 27.9 vs 11.6, respectively). Treatment of cartilage defects with CCP-ACI yielded satisfactory cartilage tissue repair outcomes, with good structural integration with native cartilage tissue shown by magnetic resonance imaging at 24 and 48 weeks after surgery. Level 1: Randomized controlled study.


Further Evidence for RFWD3 Gene Causing Fanconi Anemia Complementation Group W: Detailed Clinical Report of the Second Case in the Literature.
Fanconi anemia (FA) is a heterogeneous genetic disorder that is characterized by progressive bone marrow failure, congenital malformations, predisposition to malignancy, and short stature. The RFWD3 gene was recently associated with FA complementation group W, and only 1 patient is reported in the literature so far. Here, we report the second patient, a 10-year-old male, who has failure to thrive, central nervous system abnormalities, bilateral radial ray defects, urogenital anomalies, facial dysmorphism, and thrombocytopenia. The patient was suspected to have FA according to the aforementioned findings, and the homozygous c.1501C>T variant in the RFWD3 gene was detected by whole-exome sequencing. The diepoxybutane test and mitomycin C-induced peripheral blood cultures revealed 0.46 and 0.90 chromosomal breaks, respectively. In this article, clinical findings of the second patient with FA complementation group W are discussed in detail, aiming to expand the clinical and molecular spectrums of the disease.


Comparing Analytic Methods for Longitudinal GWAS and a Case-Study Evaluating Chemotherapy Course Length in Pediatric AML. A Report from the Children's Oncology Group.
Regression analysis is commonly used in genome-wide association studies (GWAS) to test genotype-phenotype associations but restricts the phenotype to a single observation for each individual. There is an increasing need for analytic methods for longitudinally collected phenotype data. Several methods have been proposed to perform longitudinal GWAS for family-based studies but few methods are described for unrelated populations. We compared the performance of three statistical approaches for longitudinal GWAS in unrelated subjectes: (1) principal component-based generalized estimating equations (PC-GEE); (2) principal component-based linear mixed effects model (PC-LMEM); (3) kinship coefficient matrix-based linear mixed effects model (KIN-LMEM), in a study of single-nucleotide polymorphisms (SNPs) on the duration of 4 courses of chemotherapy in 624 unrelated children with de novo acute myeloid leukemia (AML) genotyped on the Illumina 2.5 M OmniQuad from the COG studies AAML0531 and AAML1031. In this study we observed an exaggerated type I error with PC-GEE in SNPs with minor allele frequencies < 0.05, wheras KIN-LMEM produces more than expected type II errors. PC-MEM showed balanced type I and type II errors for the observed vs. expected P-values in comparison to competing approaches. In general, a strong concordance was observed between the P-values with the different approaches, in particular among P < 0.01 where the between-method AUCs exceed 99%. PC-LMEM accounts for genetic relatedness and correlations among repeated phenotype measures, shows minimal genome-wide inflation of type I errors, and yields high power. We therefore recommend PC-LMEM as a robust analytic approach for GWAS of longitudinal data in unrelated populations.


A lyophilized colorimetric RT-LAMP test kit for rapid, low-cost, at-home molecular testing of SARS-CoV-2 and other pathogens.
Access to fast and reliable nucleic acid testing continues to play a key role in controlling the COVID-19 pandemic, especially in the context of increased vaccine break-through risks due to new variants. We report a rapid, low-cost (~ 2 USD), simple-to-use nucleic acid test kit for self-administered at-home testing without lab instrumentation. The entire sample-to-answer workflow takes < 60 min, including noninvasive sample collection, one-step RNA preparation, reverse-transcription loop-mediated isothermal amplification (RT-LAMP) in a thermos, and direct visual inspection of a colorimetric test result. To facilitate long-term storage without cold-chain, a fast one-pot lyophilization protocol was developed to preserve all required biochemical reagents of the colorimetric RT-LAMP test in a single microtube. Notably, the lyophilized RT-LAMP assay demonstrated reduced false positives as well as enhanced tolerance to a wider range of incubation temperatures compared to solution-based RT-LAMP reactions. We validated our RT-LAMP assay using simulated infected samples, and detected a panel of SARS-CoV-2 variants with successful detection of all variants that were available to us at the time. With a simple change of the primer set, our lyophilized RT-LAMP home test can be easily adapted as a low-cost surveillance platform for other pathogens and infectious diseases of global public health importance.


[Actual problems in diagnosis and treatment of imported malaria].
Analyzing 66 cases of imported malaria, recorded among the patients treated at Moscow Infective Clinical Hospital No. 1 has indicated that despite its typical clinical picture and specific epidemiological history, the prehospital diagnosis of tropical and vivax malaria was correctly made in 20 and 22% of patients, respectively. As few as 3 patients had chemoprophylaxis on an individual basis during their stay in the focus, but they did not comply with the regimen recommended. The severity of the disease, in non-immunized patients with tropical malaria, in particular, is related to the time of admittance (diagnosis) and to that of the initiation of adequate specific treatment.


Spectroscopic and Electrochemical Studies of Imogolite and Fe-Modified Imogolite Nanotubes.
Carbon nanotubes and other forms of carbon nanoparticles, as well as metal nanoparticles have been widely used in film electrochemistry because they allow for the immobilization of larger amounts of catalyst (either biological or inorganic) on the top of the modified electrodes. Nevertheless, those nanoparticles present high costs of synthesis and of separation and purification that hamper their employment. On the other hand, imogolites (Im), with the general formula (OH)₃Al₂O₃SiOH, are naturally-occurring nanomaterials, which can be obtained from glassy volcanic ash soils and can also be synthesized at mild conditions. In this research paper, we characterize through spectroscopic techniques (i.e., fourier transform infrared spectroscopy (FTIR) spectroscopy, powder X-ray diffraction (XRD) and transmission electron microscopy (TEM)) synthetized Im and Fe-modified imogolite (Im(Fe)). Moreover, the Im and Im(Fe) were physically adsorbed on the top of a graphite electrode (GE) and were characterized electrochemically in the potential region ranging from -0.8 to 0.8 V vs. the saturated calomel electrode (SCE). When the film of the Im or of the Im(Fe) was present on the top of the electrode, the intensity of the charging/discharging current increased two-fold, but no redox activity in the absence of O₂ could be appreciated. To show that Im and Im(Fe) could be used as support for catalysts, iron phthalocyanine (FePc) was adsorbed on the top of the Im or Im(Fe) film, and the electrocatalytic activity towards the O₂ reduction was measured. In the presence of the Im, the measured electrocatalytic current for O₂ reduction increased 30%, and the overpotential drastically decreased by almost 100 mV, proving that the Im can act as a good support for the electrocatalysts.


A systematic review of the keystone design perforator island flap in lower extremity defects.
The keystone design perforator island flap is useful for the reconstruction of lower extremity defects. We performed a systematic review with the objective of identifying complication rates associated with using the keystone design perforator island flap to treat such defects. The MEDLINE, PubMed Central, Embase, and Cochrane databases were searched from January 2003 to August 2016 for articles describing keystone design perforator island flaps in lower extremities. The study selection was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Nine articles that involved a total of 282 keystone design perforator island flaps satisfied the inclusion criteria. In these articles, the most common cause of lower extremity defects was oncologic resection (89.0%). Most such defects were in the middle third of the lower leg (32.7%). Complications occurred in 9.6% of patients; these complications included partial flap loss (1.1%) and complete flap loss (0.7%). Given its high success rate and low technical complexity, if applicable, the keystone design perforator island flap should be the preferred approach for lower extremity reconstruction.


Beneficial effect of xylo-oligosaccharides and fructo-oligosaccharides in streptozotocin-induced diabetic rats.
The beneficial influences of xylo-oligosaccharides (XOS) obtained from alkali-pretreated corncob and fructo-oligosaccharides (FOS) obtained from cane sugar were evaluated in experimental diabetes. These oligosaccharides were supplemented at 10 % (w/w) in the basal diet of streptozotocin-induced diabetic Wistar rats, while the control rats were fed with a basal diet for a period of 6 weeks. Both the oligosaccharides exerted favourable influences in diabetic rats by significantly improving body weight and reducing hyperglycaemia and cholesterol. The characteristic diabetic complications such as severe glucosuria, proteinuria and advanced glycation end products in renal tissue, diabetic nephropathy, and blood creatinine and urea concentrations were notably reduced. Besides, these oligosaccharide supplementations significantly increased the activity of antioxidant enzymes - catalase and glutathione reductase - in the blood of diabetic rats. Supplementation of XOS and FOS resulted in a significant increase in the bifidobacteria and lactobacilli population in the caecum. The present study indicates that XOS and FOS have an ameliorating influence on metabolic abnormalities associated with diabetes, besides conferring an optimal milieu of lactobacilli and bifidobacteria, thus suggesting their potential health benefit in diabetics.


Concentrated citrate locking in order to reduce the long-term complications of central venous catheters: a randomized controlled trial in patients with hematological malignancies.
Central venous catheter (CVC)-related thrombosis and infections are frequently occurring complications in patients with hematological malignancies. At present, heparin is most often used as a locking solution. Trisodium citrate (TSC) had been shown to be a very effective antimicrobial catheter locking in hemodialysis patients. We performed a prospective randomized phase III multicenter trial to determine the efficacy of TSC as a locking solution compared to heparin in preventing CVC-related thrombosis and infections in patients with hematological malignancies. Thirty-four episodes of CVC-related bloodstream infections (CVC-BSI) occurred in the 108 patients who were randomized to locking with heparin compared with 35 episodes in the 99 patients who were randomized to locking with TSC (P = 0.654). We did find seven times more CVC-BSI with gram-negative rods in CVCs locked with heparin (P = 0.041). The cumulative incidence of symptomatic thrombosis was 10% in the heparin group and 5% in the TSC group (hazard ratio 0.525; 95% confidence interval 0.182-1.512). This study shows that locking with TSC in patients with hematological malignancies significantly reduced the incidence of CVC-BSI with gram-negative rods. However, the incidence of CVC-BSI with coagulase-negative staphylococcus or CVC-related thrombosis was not reduced by TSC locking.


Clinical and molecular characterization of long-term survivors with extensive-stage small cell lung cancer treated with first-line atezolizumab plus carboplatin and etoposide.
In the Phase I/III IMpower133 study, first-line atezolizumab plus carboplatin and etoposide (CP/ET) treatment for extensive-stage small cell lung cancer (ES-SCLC) significantly improved overall survival (OS) and progression-free survival versus placebo plus CP/ET. We explored patient and disease characteristics associated with long-term survival in IMpower133, and associations of differential gene expression and SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-inflamed (SCLC-I) transcriptional subtypes with long-term survival. Patients with previously untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo. Long-term survivors (LTS) were defined as patients who lived ≥ 18 months post randomization. A generalized linear model was used to evaluate the odds of living ≥ 18 months. Differential gene expression was analyzed using RNA-sequencing data in LTS and non-LTS. OS was assessed by T-effector and B-cell gene signature expression. Distribution of SCLC transcriptional subtypes was assessed in LTS and non-LTS. More LTS were in the atezolizumab arm (34%) than in the placebo arm (20%). The odds ratio for living ≥ 18 months in the atezolizumab arm versus the placebo arm was 2.1 (P < 0.03). Enhanced immune-related signaling was seen in LTS in both arms. Exploratory OS analyses showed atezolizumab treatment benefit versus placebo across T-effector and B-cell gene signature expression subgroups. A higher proportion of LTS than non-LTS in both arms had the SCLC-I subtype; this difference was particularly pronounced in the atezolizumab arm. These exploratory analyses suggest that long-term survival is more likely with atezolizumab than placebo in ES-SCLC, confirming the treatment benefit of the IMpower133 regimen. gov Identifier: NCT02763579.


Staphylococcus aureus bacteremia in patients with hematologic malignancies: a retrospective case-control study.
Staphylococcus aureus bacteremia (SAB) continues to be a major problem related to both community and nosocomially acquired infection. Nevertheless few data are presently available in literature about this infection in patients with hematologic malignancies. The purpose of this retrospective study was to report further data on the clinical characteristics and outcome of patients with SAB. All episodes of SAB occurring between January 1997 and June 2001 were identified and defined by analysis of the patients' clinical records. The nosocomial mortality rate was only 3.5% and no patient developed secondary complications. Comparison between neutropenic hematologic patients with SAB and neutropenic hematologic patients with Gram-negative bacteremia (GNB) revealed an higher mortality in the latter group (p=0.03); furthermore, severe sepsis and septic shock were more frequent in patients with GNB (p<0.001). Comparison between neutropenic patients with hematologic malignancies and non-neutropenic ones with other underlying diseases revealed significantly higher morbidity and mortality rates in the latter group. Non neutropenic patients seemed to be more susceptible to both early complications, such as severe sepsis or septic shock (p=0.002) and to later ones, such as endocarditis and metastatic abscesses (p=0.02). Our results seem to suggest that SAB in patients with hematologic malignancies is often a low inoculum infection associated with negligible morbidity and mortality rates, especially when adequate antistaphylococcal therapy is administered promptly.


Expression profile analysis of prognostic long non-coding RNA in adult acute myeloid leukemia by weighted gene co-expression network analysis (WGCNA).
Background: Long non-coding RNAs (lncRNAs), which are over 200 nt in length, have a key role in tumorigenesis and disease progression. To explore the role of prognostic lncRNAs in adult acute myeloid leukemia (AML), the expression profiles of lncRNAs and mRNAs in AML were analyzed. Methods: The RNAseq data of 167 adult AML patients and the corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA), which is a publicly available database. The RPKM values of the RNAseq data were subjected to weighted gene co-expression network analysis (WGCNA) in modularization. Results: We identified survival specific lncRNAs and mRNAs, which were divided into modules by coexpression analysis. The lncRNAs were mainly annotated into "Fc gamma R-mediated phagocytosis". The hub lncRNA and co-expressed mRNAs were further selected for analysis of risk stratification. LncRNA-LOC646762 may contribute to AML through the "endocytosis" signaling pathway. Finally, the expression levels of LOC646762 and co-expressed CCND3, CBR1, C10orf54, CD97 and BLOC1S1 in the adult AML patients and healthy volunteers were validated by qRT-PCR, and then their roles in prognosis and risk stratification were identified. Conclusions: Prognostic lncRNA-LOC646762, which may contribute to AML through the "endocytosis" signaling pathway, may act as a biomarker for predicting the survival of adult AML patients, as well as for risk stratification.


Hepatic PEcoma: an unusual tumor in an infrequent location.
Perivascular epithelioid cell neoplasms (PEComas) are a tumor family defined as such just a couple of decades ago. They make an unusual group of neoplasms, which can appear in different locations of the organism. PEComas are usually considered to be benign tumors, but there are some histological features that make some subgroups suspicious of malignancy. The treatment of these tumors consist in their surgical resection, with no current effective complementary oncological treatment known. We present the clinical case of a woman that underwent surgery for a resection of a hepatic lesion labeled afterwards as a PEComa with malignant features.


What is the impact of COVID-19 on head and neck squamous cell carcinoma patients?
Data sources It is not made clear in this review the different databases selected or how they conducted their search. The studies used are from 1975-2020Study selection The authors have performed a scoping review using 84 studies ranging from 1975-2020. The majority of these are from before the 2019-2020 COVID-19 outbreak period. This is indicative of the lack of evidence on this topic and exemplifies why a scoping review was carried out rather than a systematic review. The studies that were reviewed were predominately cohort and case studies. With regards to previous treatment outcomes, a few systematic reviews were included, but again, the novel nature of this outbreak means that largely, there are only cohort or case studies available for review.Data extraction and synthesis There are ten authors, with no indication of how many performed the literature review or if a mediator was involved in the final decision making on what papers would be reviewed.Results Excessive consumption of alcohol, history of tobacco use, an ageing population, and comorbidities such as cardiopulmonary issues are substantial risk factors for episodes of unfavourable respiratory outcomes. The risk of these outcomes is increased by some of the toxic effects of treatments such as chemotherapy or radiotherapy.Conclusions The COVID-19 outbreak has a potentially disproportionate impact on the cohort of head and neck cancer patients, and the respiratory effects this has on these patients may increase morbidity and mortality. It is important to include alcohol and smoking cessation, along with good oral hygiene instruction in the care of these patients.


Pipeline embolization device retraction and foreshortening after internal carotid artery blister aneurysm treatment.
Background Subarachnoid hemorrhage (SAH) secondary to rupture of a blister aneurysm (BA) results in high morbidity and mortality. Endovascular treatment with the pipeline embolization device (PED) has been described as a new treatment strategy for these lesions. We present the first reported case of PED retraction and foreshortening after treatment of a ruptured internal carotid artery (ICA) BA. Case description A middle-aged patient presented with SAH secondary to ICA BA rupture. The patient was treated with telescoping PED placement across the BA. After 5 days from treatment, the patient developed a new SAH due to re-rupture of the BA. Digital subtraction angiography revealed an increase in caliber of the supraclinoid ICA with associated retraction and foreshortening of the PED that resulted in aneurysm uncovering and growth. Conclusions PED should be oversized during ruptured BA treatment to prevent device retraction and aneurysm regrowth. Frequent imaging follow up after BA treatment with PED is warranted to ensure aneurysm occlusion.


Characterization of the Early Life Microbiota Development and Predominant Lactobacillus Species at Distinct Gut Segments of Low- and Normal-Birth-Weight Piglets.
Microbial exposure during early life plays a pivotal role in modulating the health and intestinal development of the host. Our recent study showed that the low-birth-weight (LBW) piglets harbored a different fecal microbiota compared to normal-birth-weight (NBW) piglets during early life with a lower abundance of the genus Lactobacillus. Considering the spatial variations in gut microbiota at distinct gut locations, this study was designed to further investigate the differences in the microbiota composition and predominant Lactobacillus species in the ileum and colon between LBW and NBW piglets during early life, including day 7 (D7), day 21 (D21, before weaning), and day 35 (D35, 2 weeks after weaning). Compared with the normal group, LBW piglets harbored a significantly lower proportion of short-chain fatty acids producing microbes, such as Ruminococcaceae and Prevotellaceae in the ileum on D7, Alistipes and Lachnospiraceae in the colon on D7, Blautia in the colon on D21, and Ruminiclostridium 9 in the colon on D35. The relative abundance of the phylum Bacteroidetes was also declined in both ileum and colon of LBW piglets on D7. Meanwhile, the levels of total SCFAs on D7, D21, and D35, acetate and valerate on D7 and D21, propionate on D21, and lactate on D21 and D35, were also declined in the colon of LBW piglets. Moreover, functional alterations in the gut microbiota of LBW piglets were characterized by differentially abundant microbial genes involved in multiple pathways such as amino acid metabolism, energy metabolism, replication and repair, and metabolism of cofactors and vitamins in the colon. Additionally, lower numbers of L. salivarius on D7 and L. amylovorus on D21 resided in the colon of LBW piglets compared to those in the normal ones. Collectively, LBW piglets have altered bacterial communities, microbial metabolism and gene functions in the ileum and colon during early life, especially the colonic community. This work will help to develop novel ideas in identifying the reliable biomarkers affecting the gut microbiota development in LBW piglets during early life and facilitate the development of new nutritional interventions.


Antithrombin affects hemostatic response to recombinant activated factor VII in factor VIII deficient plasma.
Thromboembolic complications can occur with recombinant activated factor VII (rFVIIa) treatment in trauma and surgical patients but they are infrequent in hemophiliacs. Bleeding diathesis in these conditions is often attributed to reduced thrombin generation, which may be improved with rFVIIa. Normally, thrombin that diffuses from local vascular injury sites is quickly inactivated by antithrombin (AT). Evaluating the influence of AT levels on thrombin generation in hypocoagulable FVIII-deficient plasma would be a simple approach to better understand how procoagulant stimuli, such as rFVIIa, might result in postoperative thrombotic complications. We hypothesize that reduced AT concentrations would increase the procoagulant effects of rFVIIa in FVIII-deficient plasma. Thrombin generation was evaluated in vitro in FVIII-deficient and AT/FVIII-deficient plasma using thrombelastography and a thrombin generation assay (Thrombinoscope). The effect of added rFVIIa on these variables was evaluated. Delayed thrombus formation based on thrombelastography in FVIII-deficient plasma was predictably reversed by rFVIIa. Improved thrombus formation and responses to rFVIIa were observed when AT levels were 20%-50% of normal. Thrombin generation in FVIII-deficient plasma increased in an inverse relationship to AT levels. Supplemental rFVIIa decreased the lag time of thrombin generation but not the amount of thrombin generated. Using FVIII-deficient plasma as a model of reduced thrombin generation, we demonstrate that low AT levels enhance in vitro hemostatic responses to rFVIIa. Reduced AT levels in trauma and surgical patients with normal or increased FVIII levels may be considered potentially prothrombotic. Monitoring of AT levels during rFVIIa therapy may thus reduce thrombotic complications in nonhemophiliacs.


Life Course Socioeconomic Status, Allostatic Load, and Kidney Health in Black Americans.
Low socioeconomic status confers unfavorable health, but the degree and mechanisms by which life course socioeconomic status affects kidney health is unclear. We examined the association between cumulative lifetime socioeconomic status and CKD in black Americans in the Jackson Heart Study. We used conditional process analysis to evaluate allostatic load as a potential mediator of this relation. Cumulative lifetime socioeconomic status was an age-standardized z-score, which has 1-SD units by definition, and derived from self-reported childhood socioeconomic status, education, and income at baseline. Allostatic load encompassed 11 baseline biomarkers subsuming neuroendocrine, metabolic, autonomic, and immune physiologic systems. CKD outcomes included prevalent CKD at baseline and eGFR decline and incident CKD over follow-up. Among 3421 participants at baseline (mean age 55 years [SD 13]; 63% female), cumulative lifetime socioeconomic status ranged from -3.3 to 2.3, and 673 (20%) had prevalent CKD. After multivariable adjustment, lower cumulative lifetime socioeconomic status was associated with greater prevalence of CKD both directly (odds ratio [OR], 1.18; 95% confidence interval [95% CI], 1.04 to 1.33 per 1 SD and OR, 1.45; 95% CI, 1.15 to 1.83 in lowest versus highest tertile) and via higher allostatic load (OR, 1.09; 95% CI, 1.06 to 1.12 per 1 SD and OR, 1.17; 95% CI, 1.11 to 1.24 in lowest versus highest tertile). After a median follow-up of 8 years (interquartile range, 7-8 years), mean annual eGFR decline was 1 ml/min per 1.73 m2 (SD 2), and 254 out of 2043 (12%) participants developed incident CKD. Lower cumulative lifetime socioeconomic status was only indirectly associated with greater CKD incidence (OR, 1.04; 95% CI, 1.01 to 1.07 per 1 SD and OR, 1.08; 95% CI, 1.02 to 1.14 in lowest versus highest tertile) and modestly faster annual eGFR decline, in milliliters per minute (OR, 0.01; 95% CI, 0.00 to 0.02 per 1 SD and OR, 0.02; 95% CI, 0.00 to 0.04 in lowest versus highest tertile), via higher baseline allostatic load. Lower cumulative lifetime socioeconomic status was substantially associated with CKD prevalence but modestly with CKD incidence and eGFR decline via baseline allostatic load.


Algal Parasite Herpodiscus durvillaeae (Phaeophyceae: Sphacelariales) Inferred to have Traversed the Pacific Ocean with its Buoyant Host.
The parasitic phaeophycean endophyte Herpodiscus durvillaeae (Lindauer) G. R. South has previously only been recorded from New Zealand, in association with a single host species, Durvillaea antarctica (Chamisso) Hariot (southern bull-kelp). Here we use DNA sequence data from plastid and nuclear markers (chloroplast rbcL, ribosomal LSU, and a nuclear pseudogene copy of COI) to test for the presence of H. durvillaeae beyond the New Zealand region, and on host species other than D. antarctica. Analyses of samples from the Falkland Islands confirm the first record of H. durvillaeae from the Atlantic Ocean. We report that Falkland Islands H. durvillaeae are genetically indistinguishable from samples of this species from New Zealand's sub-Antarctic Campbell Island, suggesting recent dispersal of the parasite across the Pacific Ocean, presumably by rafting with its buoyant macroalgal host. We also here record H. durvillaeae from New Zealand endemics Durvillaea poha Fraser et al. and D. willana Lindauer.


Stenosis of afferent vessels of intracranial arteriovenous malformations.
Four women are described with stenoses of the feeding arteries to cerebral arteriovenous malformations. These stenoses were hemodynamically significant in that the nidus malformations filled late in the arterial phase of angiography and the draining veins did not fill much earlier than the usual venous phase. In two of these patients, who were referred for possible embolization, the stenosis served as an impediment to balloon navigation in the feeding vessel in one and served as a partial contraindication to embolization in the other. It is possible that if these stenoses progress, they may lead to thrombosis of the arteriovenous malformations.


Microgeographic maladaptive performance and deme depression in response to roads and runoff.
Despite theoretical understanding and empirical detection of local adaptation in natural environments, our knowledge of such divergence in fragmented habitats remains limited, especially in the context of microgeographic spatial scales and contemporary time scales. I used a combination of reciprocal transplant and common garden exposure experiments to evaluate potential microgeographic divergence in a pool-breeding amphibian occupying a landscape fragmented by roads. As indicated by reduced rates of survival and increased rates of malformation, I found evidence for maladaptation in road adjacent populations. This response is in direct counterpoint to recently described local adaption by a cohabiting species of amphibian. These results suggest that while divergence might commonly follow habitat modification, the direction of its outcome cannot be generalized even in identical habitats. Further, maladaptive responses can be associated with a more generalized depression effect that transcends the local environment. Alongside recent reports, these results suggest that maladaptive responses may be an emerging consequence of human-induced environmental change. Thus future studies should carefully consider the population unit as a key level for inference.


The Clinical Usefulness of the PillCam Progress Indicator for Route Selection in Double Balloon Endoscopy.
Objective The utility of capsule endoscopy (CE) findings in the route selection for double balloon endoscopy (DBE) has not been adequately discussed. The PillCam Progress Indicator in the RAPID 6.5 software program graphically demonstrates the progress of the capsule endoscope through the small-bowel. This study aimed to clarify the usefulness of the PillCam Progress Indicator in choosing the initial DBE route. Methods We retrospectively examined 50 consecutive patients with 50 target lesions detected on both CE and DBE at Hiroshima University Hospital from January 2011 to February 2018. In this study, we selected antegrade DBE on the basis of % Capsule Progress <50% as a clinical trial. The association between the PillCam Progress Indicator data and the DBE route to the target lesion was analyzed. Results The target lesion was reached via the initial DBE route in 96% (48/50) of cases. The cutoff values for selecting an antegrade route for DBE were 50% for % Capsule Progress and 42% for % SB Time. At the cutoff value, the sensitivity, specificity, and positive and negative predictive values for route selection were 100%, 91%, 93%, and 100% for % Capsule Progress and 96%, 91%, 93%, and 95% for % SB Time. Conclusion The PillCam Progress Indicator was useful for determining the appropriate initial DBE route.


Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain.
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.


Postoperative peri-axillary seroma following axillary artery cannulation for surgical treatment of acute type A aortic dissection.
The arterial cannulation site for optimal tissue perfusion and cerebral protection during cardiopulmonary bypass (CPB) for surgical treatment of acute type A aortic dissection remains controversial. Right axillary artery cannulation confers significant advantages, because it provides antegrade arterial perfusion during cardiopulmonary bypass, and allows continuous antegrade cerebral perfusion during hypothermic circulatory arrest, thereby minimizing global cerebral ischemia. However, right axillary artery cannulation has been associated with serious complications, including problems with systemic perfusion during cardiopulmonary bypass, problems with postoperative patency of the artery due to stenosis, thrombosis or dissection, and brachial plexus injury. We herein present the case of a 36-year-old Caucasian man with known Marfan syndrome and acute type A aortic dissection, who had direct right axillary artery cannulation for surgery of the ascending aorta. Postoperatively, the patient developed an axillary perigraft seroma. As this complication has, not, to our knowledge, been reported before in cardiothoracic surgery, we describe this unusual complication and discuss conservative and surgical treatment options.


Effect of extremely low-frequency electromagnetic fields on antioxidant activity in the human keratinocyte cell line NCTC 2544.
Some epidemiological studies have suggested possible associations between exposure to extremely low-frequency electromagnetic fields (ELF-EMFs) and various diseases. Recently, ELF-EMF has been considered as a therapeutic agent. To support ELF-EMF use in regenerative medicine, in particular in the treatment of skin injuries, we investigated whether significant cell damage occurs after ELF-EMF exposure. Reactive oxygen species (ROS) production was evaluated in the human keratinocyte exposed for 1 H to 50 Hz ELF-EMF in a range of field strengths from 0.25 to 2 G. Significant ROS increases resulted at 0.5 and 1 G and under these flux densities ROS production, glutathione content, antioxidant defense activity, and lipid peroxidation markers were assessed for different lengths of time. Analyzed parameters of antioxidant defense and membrane integrity showed a different trend at two selected magnetic fluxes, with a greater sensitivity of the cells exposed to 0.5 G, especially after 1 H. All significant alterations observed in the first 4 H of exposure reverted to controls 24 H after suggesting that under these conditions, ELF-EMF induces a slight oxidative stress that does not overwhelm the metabolic capacity of the cells or have a cytotoxic effect.


Ragweed hay fever: genetic control and linkage to HL-A haplotypes.
Clinical ragweed pollenosis (hay fever) and IgE antibody production specific for antigen E (the major purified protein antigen from ragweed pollen extract) correlated closely with HL-A haplotypes in successive generations of seven families. HL-A associated IgE antibody responsiveness was antigen specific and extended also to IgE antibody production. These data indicate an immune response (Ir) gene specific for antigen E necessary but not sufficient for the development of hay fever. This appears to be the first documentation of an Ir gene in man.


[Study on the natural foci of Marmota himalayana plague in Sichuan province].
To explore the existence of natural foci on Marmota himalayana plague in Sichuan province and to provide basis for prevention and control of the disease. Both epidemiological investigation and laboratory tests were used to provide the host animal and fleas of the vectors with Yersinia pestis carriers. 30 species of animals were found to belong to 10 orders. Ochotona curzoniae and M. himalayana were the most common ones while 7 species of the fleas belonged to 7 genera and 3 families. M. himalayana was the main reservoirs while Callopsylla dolabris and Oropsylla silantiewi served as vectors. The 13 Y. pestis were identified from 43 Marmota samples. 8 samples were identified under IHA, with the highest titer of herding-dogs serum as 1:10,240. 19 samples were F1 antigen positive using RIHA and the highest titer of M. himalayana serum was 1:409,600. The major foci was 4545 km2, distributed at Dege county in Sichuan province. We have confirmed the existence of natural foci on M. himalayana plague in Sichuan province.


A role for LAX2 in regulating xylem development and lateral-vein symmetry in the leaf.
The symmetry of venation patterning in leaves is highly conserved within a plant species. Auxins are involved in this process and also in xylem vasculature development. Studying transgenic Arabidopsis plants ectopically expressing the sunflower transcription factor HaHB4, it was observed that there was a significant lateral-vein asymmetry in leaves and in xylem formation compared to wild type plants. To unravel the molecular mechanisms behind this phenotype, genes differentially expressed in these plants and related to auxin influx were investigated. Candidate genes responsible for the observed phenotypes were selected using a co-expression analysis. Single and multiple mutants in auxin influx carriers were characterized by morphological, physiological and molecular techniques. The analysis was further complemented by restoring the wild type (WT) phenotype by mutant complementation studies and using transgenic soybean plants ectopically expressing HaHB4 . LAX2 , down-regulated in HaHB4 transgenic plants, was bioinformatically chosen as a candidate gene. The quadruple mutant aux1 lax1 lax2 lax3 and the single mutants, except lax1, presented an enhanced asymmetry in venation patterning. Additionally, the xylem vasculature of the lax2 mutant and the HaHB4 -expressing plants differed from the WT vasculature, including increased xylem length and number of xylem cell rows. Complementation of the lax2 mutant with the LAX2 gene restored both lateral-vein symmetry and xylem/stem area ratio in the stem, showing that auxin homeostasis is required to achieve normal vascular development. Interestingly, soybean plants ectopically expressing HaHB4 also showed an increased asymmetry in the venation patterning, accompanied by the repression of several GmLAX genes. Auxin influx carriers have a significant role in leaf venation pattering in leaves and, in particular, LAX2 is required for normal xylem development, probablt controlling auxin homeostasis.


Time evolution of the organization of multi-muscle postural responses to sudden changes in the external force applied at the trunk level.
We studied muscle activation patterns in response to perturbations of posture (sudden changes in the external force applied to the thorax) during two time intervals corresponding to pre-programmed postural reactions and voluntary corrections of posture. A hypothesis was tested that a set of postural muscles could be used to form stable groups (M-modes) whose composition changes in different time intervals after a perturbation. Perturbations were applied at the sternum level to standing subjects at an unexpected time. Principal component analysis with factor extraction allowed to identify sets of three factors (M-modes) during the two time intervals, 80-180 ms (T(1)) and 250-450 ms (T(2)) after the perturbation. The composition of M-modes was similar within each time interval across subjects and perturbations but differed significantly between T(1) and T(2). In particular, M-modes during T(1) were characterized by more co-contraction patterns. The results suggest that the neural controller is able to rearrange M-mode composition in real time based on a safety-efficacy trade-off. The results also support the idea that M-modes represent synergies in the muscle space, while they may be used as elemental variables to form synergies at a higher hierarchical level to produce desired mechanical effects.


Synovial Sarcoma Mimicking Pleomorphic Hyalinizing Angiectatic Tumor of Soft Parts: A Case Report.
Synovial sarcoma is a high-grade sarcoma commonly affecting young adults. The sites of involvement include soft tissue near joints, lung, pleura, mediastinum, larynx, kidney, and buttocks. Histologic types include monophasic, biphasic, and undifferentiated. We report a unique case of synovial sarcoma with low-grade histologic features mimicking pleomorphic hyalinizing angiectatic tumor (PHAT) with indolent behavior for a period of 10 years. The tumor showed angiectatic blood vessels with fibrinous cuffing, hypocellular and hypercellular spindle cell areas with rare mitoses, and focal atypia in a myxoid background. TLE1 was positive with SYT gene translocation detected on fluorescent in situ hybridization. Cases of myxoinflammatory fibroblastic sarcoma and myxofibrosarcoma have been reported as exhibiting histologic features of PHAT. However, to the best of our knowledge, cases of synovial sarcoma mimicking PHAT have not been reported.


Embryo implantation is closely associated with dynamic expression of proprotein convertase 5/6 in the rabbit uterus.
Proprotein convertase 5/6 (PC5/6) is critical for embryo implantation in women, regulating both uterine epithelial receptivity and stromal cell decidualization. PC5/6 is likewise essential for implantation in mice, but involved only in decidualization. An alternative animal model is required to address the function of PC5/6 in the uterine epithelium. This study aimed to establish whether PC5/6 is associated with embryo implantation in rabbits. Virgin New-Zealand white rabbits aged 3-4 moths were mated with males of the same strain, or pseudo-pregnancy induced. After mating, uterine tissues were collected over a 10 day (d) period (n = 3 per time point) for RNA, protein and histological analyses to determine the temporal and spatial uterine expression pattern of PC5/6 during the initial stages of pregnancy or induced pseudo-pregnancy. PC5/6 mRNA was up-regulated just prior to embryo attachment on d6, and the elevated expression was maintained throughout implantation on d6.5-10. Western analysis revealed a preferential up-regulation of PC5/6 in the implantation sites. Immunohistochemical analysis identified that both the amount and cellular localization of PC5/6 changed with increasing pregnancy stages. Before embryo attachment, PC5/6 was low and localised in the luminal and glandular epithelium. It increased on d6.5 in the basal glands and mucosal folds, and then strongly intensified on d7-10 in the multinucleated luminal symplasma and decidual cells at the site of embryo implantation. In contrast, the pseudo-pregnant uterus displayed relatively low and static PC6 mRNA expression throughout the 10 days, with no obvious changes in either PC5/6 level or cellular localization. These findings demonstrate that embryo implantation in the rabbit is closely associated with dynamic expression of uterine PC5/6, and that the rabbit may be an appropriate model to investigate the function of PC5/6 in the uterine epithelium during embryo attachment.


The Association between Symptomatic Rotavirus Infection and Histo-Blood Group Antigens in Young Children with Diarrhea in Pretoria, South Africa.
Recently, histo-blood group antigens (HBGAs) have been identified as receptors or attachment factors of several viral pathogens. Among rotaviruses, HBGAs interact with the outer viral protein, VP4, which has been identified as a potential susceptibility factor, although the findings are inconsistent throughout populations due to HBGA polymorphisms. We investigated the association between HBGA phenotypes and rotavirus infection in children with acute gastroenteritis in northern Pretoria, South Africa. Paired diarrheal stool and saliva samples were collected from children aged ≤ 59 months (n = 342) with acute moderate to severe diarrhea, attending two health care facilities. Rotaviruses in the stool samples were detected by commercial EIA and the rotavirus strains were characterized by RT-PCR targeting the outer capsid VP7 (G-type) and VP4 (P-type) antigens for genotyping. Saliva-based ELISAs were performed to determine A, B, H, and Lewis antigens for blood group typing. Blood type O was the most common blood group (62.5%) in this population, followed by groups A (26.0%), B (9.3%), and AB (2.2%). The H1-based secretors were common (82.7%) compared to the non-secretors (17.3%), and the Lewis antigen positive phenotypes (Le(a+b+)) were predominant (54.5%). Blood type A children were more likely to be infected by rotavirus (38.8%) than any other blood types. P[4] rotaviruses (21/49; 42.9%) infected only secretor individuals, whereas P[6] rotaviruses (3/49; 6.1%) only infected Le(a-b-), although the numbers were very low. On the contrary, P[8] rotaviruses infected children with a wide range of blood group phenotypes, including Le(a-b-) and non-secretors. Our findings demonstrated that Lewis antigens, or the lack thereof, may serve as susceptibility factors to rotaviral infection by specific VP4 genotypes as observed elsewhere. Potentially, the P[8] strains remain the predominant human VP4 genotype due to their ability to bind to a variety of HBGA phenotypes.


Regulation of gene expression by insulin.
While insulin has long been known to modulate intracellular metabolism by altering the activity or intracellular location of various enzymes, it is only in the past 10 years that the regulation of gene expression by insulin has been recognized as a major action of this hormone. This review principally focuses on the regulation of gene transcription by insulin, although recent progress in the understanding of insulin-regulated mRNA stability and translation is also summarized. The identification of cis-acting elements and associated trans-acting factors through which insulin either increases or decreases the transcription of specific genes is reviewed in detail. Recent advances in the understanding of the mechanisms of insulin signaling are discussed in the context of insulin-regulated gene transcription, and emphasis is placed on the gaps that remain between the upstream signaling molecules and the downstream trans-acting factors whose binding/transactivation potential is ultimately regulated. Finally, potential gene expression defects that may contribute to the pathophysiology of non-insulin-dependent diabetes mellitus and hypertriglyceridemia are considered.


Exposure to Inhalable Dust, Endotoxin, and Total Volatile Organic Carbons on Dairy Farms Using Manual and Automated Feeding Systems.
Agricultural workers tend to have high exposures to organic dusts which may induce or exacerbate respiratory disorders. Studies investigating the effect of work tasks and farm characteristics on organic dust exposures among farm workers suggest that handling of animal feed is an important exposure determinant; however, the effect of the animal feeding system has not been explored in any detail. To measure the exposure of Irish dairy farmers to inhalable dust, endotoxin, and total volatile organic compounds (TVOCs) during parlour work and to explore whether levels of exposure to these agents depend on the applied feeding system in the farms. Thirty-eight personal exposure measurements were collected from farmers across seven dairy farms. The farms used manual, loft, or semi-automated feeding systems. Information on worker tasks and farm characteristics was collected during the surveys. Associations between exposure concentrations and feeding systems, worker tasks, and other farm characteristics were explored in linear mixed-effect regression models with farmer identity treated as a random effect. Exposure concentrations were variable and had a geometric mean (GM; geometric standard deviation) of 1.5 mg m-3 (1.8) for inhalable dust and 128 EU m-3 (2.5) for endotoxin. More than 50% of the exposure measurements for endotoxin, and organic dust exceeded recommended health-based occupational exposure limits. Endotoxin levels were somewhat lower in farms using semi-automatic feeding systems when compared to those using manual feeding systems but in multivariate regression analysis associations were not statistically significant (β = -0.54, P = 0.4). Performance of activities related to handling and spreading of hay or straw was the strongest determinant for both inhalable dust and endotoxin exposure (β = 0.78, P ≤ 0.001; β = 0.72, P = 0.02, respectively). The level of dust exposure increased also as a consequence of a lower outdoor temperature, and higher ratio of distributed feed per cow (P = 0.01). Stationary measurements of TVOC and CO2 concentrations inside the dairy parlours had a GM of 180 ppb (1.9) and 589 ppb (1.3), respectively. The use of cow teat disinfectants and building ventilation were both strong predictors of TVOC concentrations within parlours. Dairy farm workers can be exposed to high and variable levels of inhalable dust and endotoxin and may be at risk of respiratory disease. Results from this study suggest that exposure control strategies for organic dusts and TVOCs exposures should consider building ventilation and work tasks such as spreading of bedding material, using spray disinfectants and animal feeding. Until effective permanent engineering controls are established farm workers should be encouraged to wear respiratory protective equipment during these tasks.


Selection of slow growing organisms as a means for improving aerobic granular sludge stability.
Recently, several groups have showed the occurrence of aerobic granular sludge. The excellent settling characteristics of aerobic granular sludge allow the design of very compact wastewater treatment plants. In laboratory experiments, high oxygen concentrations were needed to obtain stable granulation. However, in order to obtain energy efficient aeration and good denitrification low oxygen concentrations would be required. From earlier research on biofilm morphology, it was learned that slow growing organisms influence the density and stability of biofilms positively. To decrease the growth rate of the organisms in the aerobic granules, easily degradable substrate (e.g. acetate) has to be converted to slowly degradable COD like microbial storage polymers (e.g. PHA). Phosphate or glycogen accumulating bacteria perform this conversion step most efficiently. In this paper it is shown that the selection of such bacteria in aerobic granules indeed led to stable granular sludge, even at low oxygen concentrations.


Diversification in indigenous and ethnic food culture.
A diversified food supply is contingent on underlying biodiversity in the locality where one lives or at a distance from it, if trade routes are established. Indigenous people generally settled at the water's edge so that aquatic foods made up part of their diversified diet, with the rest of the diversity dependent on how much they hunted and gathered, on herded animals, engagement in subsistence agriculture, the ability to process and preserve food and/or food commodities traded. The rapid urbanization of much of the world's population distances people from the origin of their food, the understanding of the required commodities in the human diet (e.g., aquatic food, plant foods, lean animal foods, what animals are fed, basics of freshness). At the same time, adequacy of food intake may be more reliably achieved when the food supply can continue irrespective of season, climate or distant conflict. Urban gardens partly rectify this discord between urbanization and a genuinely varied diet, replaced by purported variety where the same basic commodity is presented in many different forms (e.g., wheat grains such as bread, breakfast cereal of various kinds, pasta and baked goods). However, diversified processing may 'dilute out' health adverse techniques. The health benefits of a diversified diet relate in part to the environmental integrity, which the required biodiversity provides, in part to minimizing adverse factors, which may exceed acceptable thresholds in a narrow diet, and to the need for the wide spectrum of food components, macronutrients, micronutrients and phytochemicals, which Homo sapiens' physiology requires. Whilst most food diversity is attributable to plant sources, animal sources often provide significant nutritional security (e.g., fish and eggs for vitamin D, fish for n-3 fatty acids, lean meat for iron and zinc and in readily assimilable forms). Food diversity assumes greater importance with aging populations as their physical activity usually (if not necessarily) declines and the required food component diversity of the diet increases correspondingly. There are ways in which the required food diversity (probably 20-30 biologically different distinct foods over the course of a week) can be reduced. This is by the inclusion of more food component dense foods--like fish, lean meat, eggs, seeds and nuts. Not only does food diversity have relevance in a public health and food policy sense, but also in individual counseling in clinical practice. Assessment of a patient's food variety can be rapid and semi-quantitative, encouraging small and consequential changes in diet. When ethnicity is taken into account, in the clinical setting, this process can be even more rewarding for the practitioner and patient.


Uncompleted emergency department care: patients who leave against medical advice.
To compare the patient characteristics, clinical conditions, and short-term recidivism rates of emergency department (ED) patients who leave against medical advice (AMA) with those who leave without being seen (LWBS) or complete their ED care. All eligible patients who visited the ED between July 1, 2004, and June 30, 2005 (N = 31,252) were classified into one of four groups: 1) AMA (n = 857), 2) LWBS (n = 2,767), 3) admitted (n = 8,894), or 4) discharged (n = 18,734). The patient characteristics, primary diagnosis, and 30-day rates of emergent hospitalizations, nonemergent hospitalizations, and ED discharge visits were compared between patients who left AMA and each of the other study groups. A Cox proportional hazards model was used to examine the influence of study group status on the risk of emergent hospitalization, adjusted for patient characteristics. Patients who left AMA were significantly more likely to be uninsured or covered by Medicaid compared with those admitted or discharged (p < 0.001). The AMA visit rates were highest for nausea and vomiting (9.7%), abdominal pain (7.9%), and nonspecific chest pain (7.6%). During the 30-day follow-up period, patients who left AMA had significantly higher emergent hospitalization and ED discharge visit rates compared with each of the other study groups (p < 0.001). Insurance status, male gender, and higher acuity level were also associated with a significantly higher emergent hospitalization rate. Patients who leave AMA may do so prematurely, as evidenced by higher emergent hospitalization rates compared with those who LWBS or complete their care.


Smoking in Pregnancy and Fetal Growth: The Case for More Intensive Assessment.
Many studies on prenatal tobacco exposure (PTE) effects have relied on single item retrospective measures of PTE. However, it is unclear how these single item measures may relate to more intensive maternal self-reports and to biological markers of maternal use and/or fetal exposure. It is also unclear whether these measures may be more valid predictors of fetal growth (gestational age, birthweight, head circumference, and birth length). Data were obtained from 258 women during their pregnancy. PTE was assessed by four methods: a single item question, a calendar-based self-report measure from each trimester of pregnancy, maternal salivary cotinine assays, and nicotine and metabolites in infant meconium. We hypothesized that the more intensive measures and biological assays would account for additional variance in birth outcomes, above and beyond the single item measure. The single item self-report measure was not related to fetal growth. However, the more intensive calendar based self-report measure and the biological assays of PTE (ie, maternal salivary assays and infant meconium) were significant predictors of poor fetal growth, even with the single item measure in the model. The negative effects of PTE on important child outcomes may be greatly underestimated in the literature as many studies use single item self-report measures to ascertain PTE. Whereas more intensive self-report measures or biological assays may be cost prohibitive in large scale epidemiological studies, using a combination of measures when possible should be considered given their superiority both identifying prenatal smokers and predicting poor fetal growth. The present work underscores the importance of measurement issues when assessing associations between PTE and fetal growth. Results suggest that we may be greatly underestimating the negative effects of prenatal smoking on fetal growth and other important child outcomes if we rely solely on restricted single item self-report measures of prenatal smoking. Researchers should consider more intensive prospective self-report measures and biological assays as viable and superior alternatives to single item self-report measures.


Sexual dimorphism in minor physical anomalies in schizophrenic patients and normal controls.
The aim of the current study was to investigate the gender effecton minor physical anomalies (MPA) in schizophrenic patients and normal controls. Seventy-six schizophrenic patients (43 males and 33 females) and 82 normal control subjects (42 males and 40 females) were examined for MPA using a modified version of the Waldrop Physical Anomaly Scale. Men tended to be more stigmatized with MPA than women both in normal subjects and in schizophrenics (with this difference slightly expanding in schizophrenics). In both genders schizophrenic patients were significantly more likely to have MPA than normal controls, but the difference tended to be more pronounced in males. There was a tendency towards sex-related predilection for the increase of MPA in schizophrenics in terms of individual anomalies and topographic regions affected. Among schizophrenics, genders showed a somewhat opposite topography of MPA stigmatization, with relatively more pronounced peripheral dysmorphy in males and craniofacial dysmorphy in females. These data suggest greater vulnerability of the male fetus to endogenous or exogenous factors and different susceptibilities to developmental adversities in male and female schizophrenics. This finding is in accord with the increasing evidence that sex differences in the epidemiology of schizophrenia may be broader and more fundamental than previously thought.


Therapeutic options for essential thrombocythemia and polycythemia vera.
Several options exist for treating essential thrombocythemia and polycythemia vera. One approach is to assign the patient to a risk category from which treatment recommendations follow. The principal risks of essential thrombocythemia include thrombosis, major hemorrhage, and conversion to leukemia or myelofibrosis. Risk factors for thrombosis include age and prior thrombosis. Smoking and obesity have been implicated in isolated series. High-risk patients with essential thrombocythemia can be defined as those 60 years of age or older or those who have had a thrombosis at any age. These patients should be treated with hydroxyurea. If hydroxyurea cannot be tolerated, anagrelide and interferon-alpha (IFN-alpha) are alternatives. Low-dose aspirin (40 to 325 mg) can be used for patients whose platelet counts are < 1,500 x10(9)/L. Low-risk patients are those less than 60 years old who have not had thrombosis, who have no cardiovascular risk factors, and whose platelet counts are < 1,500 x 10(9)/L. These patients can be observed or placed on low-dose aspirin. Intermediate-risk patients are those less than 60 years who have not had thromboses, but who have platelet counts > 1,500 x 10(9)/L or who have significant cardiovascular risk factors. These patients should have their risk factors treated and may be given low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. They can be observed or treated with anagrelide, hydroxyurea, or IFN-alpha. The Mayo Clinic experience suggests that no specific treatment affects outcomes of pregnancies. In high-risk pregnant women who need treatment, IFN-alpha is used. The principal risks of polycythemia vera are thrombosis, postpolycythemia myeloid metaplasia, and acute leukemia. Risk factors for thrombosis include age, the use of phlebotomies, the rate of phlebotomies, and a prior history of thrombosis. Platelet counts have not been definitively linked to an increased risk of thrombosis. High-risk polycythemia vera patients are those 60 years of age or older (some groups use 70 years) or those of any age who have had thrombosis. They should be treated with phlebotomy and hydroxyurea or IFN-alpha. Selected patients may be treated with anagrelide. A typical target range for phlebotomy is a hematocrit of < 42% for women and < 45% for men. Low-dose aspirin can be used if the platelet count is < 1,500 x 10(9)/L. Low-risk patients are those less than 60 years old who have had no thrombosis, no cardiovascular risk factors, and whose platelets are < 1,500 x 10(9)/L. These patients can be managed with phlebotomy alone or phlebotomy and low-dose aspirin. Intermediate-risk patients are those who are less than 60 years old, who have not had thrombosis, but who have platelet counts > 1,500 x 10(9)/L or who have cardiovascular risk factors. The cardiovascular risk factors should be treated, along with phlebotomy alone or with IFN-alpha. Low-dose aspirin is reasonable for those with platelet counts < 1,500 x 10(9)/mL. Anagrelide can be used with phlebotomy in selected patients. Women of childbearing age who are in the low-risk or intermediate-risk group can be treated with phlebotomy alone and low-dose aspirin if the platelet count is < 1,500 x 10(9)/L. For high-risk patients or pregnant patients, IFN-alpha can be added.


[Vascular component of the fibrinolytic system of blood (plasminogen activator of vascular wall) in patients with duodenal ulcer with a history of hemorrhagic complications].
It has been established that patients with duodenal ulcer complicated by hemorrhage in the past are characterized by the low response of the fibrinolytic system (FS) to two different exposures--local venous occlusion and administration of the sympathomimetic alupent. The rate of plasminogen the lower limit of normal in almost 2/3 of patients with activator release (RPAR) from vascular depots was under hemorrhages and in 1/4 of those with uncomplicated duodenal ulcer. The low RPAR was coupled with hereditary aggravation and hyperplasia of the parietal glandulocytes of the stomach. In duodenal ulcer complicated by hemorrhages, the normal parameters of the fibrinolysis kinetics and RPAR were encountered 3 times less frequently than in uncomplicated duodenal ulcer, whereas activated blood fibrinolysis coupled with the low RPAR 5 times as frequently. The shifts can severe a discriminant prognostic criterion painting to a potential risk of hemorrhage and making it possible to carry out the different prophylaxis. The treatment with epsilon-aminocaprotic acid given in courses makes the FS including its vascular component return to normal.


Myocardial Injury in the Era of High-Sensitivity Cardiac Troponin Assays: A Practical Approach for Clinicians.
Traditionally, elevated troponin concentrations were synonymous with myocardial infarction. But with improvements in troponin assays, elevated concentrations without overt myocardial ischemia are now more common; this is referred to as myocardial injury. Physicians may be falsely reassured by the absence of myocardial ischemia; however, recent evidence suggests that myocardial injury is associated with even more detrimental outcomes. Accordingly, this article reviews the definition, epidemiology, differential diagnosis, diagnostic evaluation, and management of myocardial injury. Current epidemiological evidence suggests that myocardial injury without overt ischemia represents about 60% of cases of abnormal troponin concentrations when obtained for clinical indications, and 1 in 8 patients presenting to the hospital will have evidence of myocardial injury. Myocardial injury is a concerning prognosis; the 5-year mortality rate is approximately 70%, with a major adverse cardiovascular event rate of 30% in the same period. The differential diagnosis is broad and can be divided into acute and chronic precipitants. The initial workup involves an assessment for myocardial ischemia. If infarction is ruled out, further evaluation includes a detailed history, physical examination, laboratory testing, a 12-lead electrocardiogram, and (if there is no known history of structural or valvular heart disease) an echocardiogram. Unfortunately, no consensus exists on routine management of patients with myocardial injury. Identifying and treating the underlying precipitant is the most practical approach. Myocardial injury is the most common cause of abnormal troponin results, and its incidence will likely increase with an aging population, increasing prevalence of cardiovascular comorbidities, and greater sensitivity of troponin assays. Myocardial injury represents a challenge to clinicians; however, given its serious prognosis, it warrants a thorough evaluation of its underlying precipitant. Future strategies to prevent and/or manage myocardial injury are needed.


Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival.
Communication between the endoplasmic reticulum (ER) and mitochondrion is important for bioenergetics and cellular survival. The ER supplies Ca(2+) directly to mitochondria via inositol 1,4,5-trisphosphate receptors (IP3Rs) at close contacts between the two organelles referred to as mitochondrion-associated ER membrane (MAM). We found here that the ER protein sigma-1 receptor (Sig-1R), which is implicated in neuroprotection, carcinogenesis, and neuroplasticity, is a Ca(2+)-sensitive and ligand-operated receptor chaperone at MAM. Normally, Sig-1Rs form a complex at MAM with another chaperone, BiP. Upon ER Ca(2+) depletion or via ligand stimulation, Sig-1Rs dissociate from BiP, leading to a prolonged Ca(2+) signaling into mitochondria via IP3Rs. Sig-1Rs can translocate under chronic ER stress. Increasing Sig-1Rs in cells counteracts ER stress response, whereas decreasing them enhances apoptosis. These results reveal that the orchestrated ER chaperone machinery at MAM, by sensing ER Ca(2+) concentrations, regulates ER-mitochondrial interorganellar Ca(2+) signaling and cell survival.


[Modern computer data base "necropsy protocol": potential and prospects].
Basic principles in developing computer variant of necropsy protocol with wide illustrative possibilities are presented. Perspectives in the use of this information base for research and practice and for teaching the staff of the research and clinical institutions are demonstrated.


Biventricular pacing in patients with congestive heart failure: two prospective randomized trials. The VIGOR CHF and VENTAK CHF Investigators.
Epidemiologic studies suggest that 20-30% of patients diagnosed with symptomatic congestive heart failure (CHF) have intraventricular conduction disorders characterized by a discoordinate contraction pattern and wide QRS. Biventricular pacing is an emerging therapy allowing simultaneous electrical stimulation of the right and left ventricles with the use of an implantable pacing system. The aim of this article is to describe 2 prospective randomized multicenter trials examining the effects of biventricular pacing on functional capacity, quality of life, and hemodynamic status in patients with dilated cardiomyopathy and intraventricular delay. The VIGOR CHF Trial is designed to assess functional and symptomatic improvement in heart failure patients with biventricular pacing and without a concomitant indication for conventional bradycardia pacemaker therapy. To assess for potential placebo effects, patients are randomized to receive either biventricular pacemaker therapy or no pacing therapy for the first 6 weeks, after which both groups receive pacing therapy. The VENTAK CHF trial uses an implantable cardioverter defibrillator system (ICD) designed to provide chronic biventricular pacing therapy in addition to treating ventricular tachyarrhythmias. All patients receive conventional ICD and CHF therapy throughout the study and are randomized in a 2-period crossover design to receive either no pacing or biventricular pacing for 3-month intervals. Patient enrollment in both studies is ongoing, with a closed analysis. The unique designs of these trials provide the opportunity to study this therapy in high-risk patients who have been optimally treated for heart failure.


PI3K-AKT Signaling via Nrf2 Protects against Hyperoxia-Induced Acute Lung Injury, but Promotes Inflammation Post-Injury Independent of Nrf2 in Mice.
Lung epithelial and endothelial cell death accompanied by inflammation contributes to hyperoxia-induced acute lung injury (ALI). Impaired resolution of ALI can promote and/or perpetuate lung pathogenesis, including fibrosis. Previously, we have shown that the transcription factor Nrf2 induces cytoprotective gene expression and confers protection against hyperoxic lung injury, and that Nrf2-mediated signaling is also crucial for the restoration of lung homeostasis post-injury. Although we have reported that PI3K/AKT signaling is required for Nrf2 activation in lung epithelial cells, significance of the PI3K/AKT-Nrf2 crosstalk during hyperoxic lung injury and repair remains unclear. Thus, we evaluated this aspect using Nrf2 knockout (Nrf2(-/-)) and wild-type (Nrf2(+/+)) mouse models. Here, we show that pharmacologic inhibition of PI3K/AKT signaling increased lung inflammation and alveolar permeability in Nrf2(+/+) mice, accompanied by decreased expression of Nrf2-target genes such as Nqo1 and Hmox1. PI3K/AKT inhibition dampened hyperoxia-stimulated Nqo1 and Hmox1 expression in lung epithelial cells and alveolar macrophages. Contrasting with its protective effects, PI3K/AKT inhibition suppressed lung inflammation in Nrf2(+/+) mice during post-injury. In Nrf2(-/-) mice exposed to room-air, PI3K/AKT inhibition caused lung injury and inflammation, but it did not exaggerate hyperoxia-induced ALI. During post-injury, PI3K/AKT inhibition did not augment, but rather attenuated, lung inflammation in Nrf2(-/-) mice. These results suggest that PI3K/AKT-Nrf2 signaling is required to dampen hyperoxia-induced lung injury and inflammation. Paradoxically, the PI3K/AKT pathway promotes lung inflammation, independent of Nrf2, during post-injury.


Thermal and photochemical reactions of methanol on nanocrystalline anatase TiO2 thin films.
The catalytic and photo-catalytic activity of well-defined anatase TiO2 nanocrystals for the partial oxidation of methanol was investigated using temperature-programmed desorption (TPD) in ultra-high vacuum in order to determine how crystallite size and shape affect reactivity. The TiO2 films used in this study were prepared from well-defined TiO2 nanocrystals synthesized by colloidal methods. These nanocrystals had a truncated bi-pyramidal shape which exposes primarily (101) and to a lesser extent (001) surfaces and ranged in size from 10 to 25 nm. Two distinct regimes of reactivity were investigated, namely in the dark and under UV light illumination. In the dark, methanol adsorbed dissociatively on the (001) planes and only molecularly on the (101) surfaces. Dissociated methoxy groups on the (001) surfaces coupled to produce dimethyl ether, suggesting the presence of fourfold coordinate Ti cations. Under UV light illumination, the nanocrystals were additionally found to be active for the photo-catalytic oxidation of methanol to methyl formate. On the (101) surfaces, this reaction proceeded in a stepwise photocatalytic pathway involving dehydrogenation of methanol to form methoxy groups and then formaldehyde, followed by coupling of these latter two species to form methyl formate. The (001) surfaces were also found to be photo-catalytically active but surface methoxy groups could be produced thermally and the reaction proceeds only to formaldehyde in the absence of molecularly adsorbed methanol. The overall photocatalytic activity of the nanocrystals was also was found to increase with increasing crystallite size. The results of this study show that thin films of well-defined nanocrystals are excellent model systems that can be used to help bridge the materials gap between studies of single crystal surfaces and high surface area polycrystalline catalysts.


Provider and care characteristics associated with timing of dialysis initiation.
There is a trend in the United States to maintenance dialysis initiation at higher levels of estimated GFR. This study aimed to determine whether provider characteristics and pre-ESRD nephrology care and vascular access are independently associated with higher estimated GFR at initiation. This retrospective cohort study used US Renal Data System data for patients who initiated dialysis in 2006 (n=83,621) and American Medical Association Physician Master File data for provider characteristics. Patient characteristics and estimated GFR were defined, and providers at dialysis initiation were identified. Earlier dialysis initiation was defined as initiation at estimated GFR>10 ml/min per 1.73 m(2). Nephrologist density per 100 ESRD patients was calculated by Health Service Area in 2006. Associations between provider characteristics and estimated GFR were determined using logistic regression and linear regression models, accounting for provider clustering. Of the cohort, 47.8% of patients initiated dialysis at estimated GFR>10 ml/min per 1.73 m(2), and 16.2% of patients initiated dialysis at estimated GFR≥15 ml/min per 1.73 m(2). Predialysis nephrologist care for 0-12 months was associated with greater odds of earlier initiation compared with no care. Patients initiating with an arteriovenous fistula or graft were more likely to initiate earlier than patients initiating with a catheter. Provider sex was not associated with timing of dialysis initiation as measured by estimated GFR. Care by providers who graduated from nondomestic medical schools was associated with greater odds of earlier initiation. Greater provider experience was associated with lower likelihood of earlier initiation. This study supports the hypothesis that provider factors are associated with timing of dialysis initiation in the United States.


[Drainage of the thoracic lymphatic duct and lymphovenous anastomosis in treating portal hypertension].
To correct the portal blood flow 52 operations on the thoracic lympheduct (TLD) were performed on 43 patients with decompensated portal hypertension syndrome. The external drainage of the TLD (lymphaticostomy) was carried out upon 22 patient and the internal drainage of TLD (lympho-venous anastomosis-LVA) upon 26 patients. 4 patients underwent other operations. The authors conclude that the selection of a LVA variant should be individual, depending on peculiarities of topographo-anatomical correlations between TLD and the anastomosed vein.


Epidemiology and treatment of multidrug resistant tuberculosis.
Multidrug resistant tuberculosis is now thought to afflict between 1 and 2 million patients annually. Although significant regional variability in the distribution of disease has been recorded, surveillance data are limited by several factors. The true burden of disease is likely underestimated. Nevertheless, the estimated burden is substantial enough to warrant concerted action. A range of approaches is possible, but all appropriate interventions require scale-up of laboratories and early treatment with regimens containing a sufficient number of second-line drugs. Ambulatory treatment for most patients, and improved infection control, can facilitate scale-up with decreased risk of nosocomial transmission. Several obstacles have been considered to preclude worldwide scale-up of treatment, mostly attributable to inadequate human, drug, and financial resources. Further delays in scale-up, however, risk continued generation and transmission of resistant tuberculosis, as well as associated morbidity and mortality.


The MD-MEd Joint-Degree Program at Vanderbilt University: Training Future Expert Medical Educators.
Some medical students are drawn to medical education as an area of academic specialization. However, few options exist for medical students who wish to build a scholarly foundation for future careers in medical education. In 2011, Vanderbilt University School of Medicine (VUSM) and Peabody College of Education and Human Development at Vanderbilt University partnered to establish a novel dual-degree program that, through transfer of credit, allows students to graduate with both an MD and a master of education (MEd) degree in five years. The MD-MEd joint-degree program equips students with robust knowledge and skills related to general education while providing opportunities through independent studies and capstone projects to contextualize these ideas in medical education. This innovation at Vanderbilt University demonstrates the feasibility of an MD-MEd joint-degree program. MD-MEd graduates' demonstrated commitment to medical education and credentials will allow them to take on greater educational responsibilities earlier in their careers and quickly gain experience. The three author participants feel their experiences allowed them to achieve desired competencies as educators. They have each gained early experience by chairing the Student Curriculum Committee and contributing to major curricular reform at VUSM. The authors plan to integrate specific medical education competencies into the program, which will require MD-MEd students to develop and demonstrate proficiency in the knowledge and skills expected of dedicated medical educators. Graduates' career trajectories will be tracked to explore whether they become medical educators, conduct educational research, and assume leadership positions.


Inhibition of antibodies to nuclear antigen and to DNA in New Zealand mice infected with lactate dehydrogenase virus.
New Zealand mice developed antibodies to nuclear antigen leading to immune-complex nephritis. Humoral antibody was directed primarily against denatured DNA, although antibody to native DNA was also found. Persistent infection with lactate dehydrogenase virus significantly lowered antibodies both to nuclear antigen and to DNA in these mice. In addition, female (NZB x W)F(1) mice infected with lactate dehydrogenase virus were protected from the usual nephritic death occurring after the trapping of complexes of nuclear antigen and its antibody and of DNA and its antibody in the glomerular filter.


Lithium insertion in silicon nanowires: an ab initio study.
The ultrahigh specific lithium ion storage capacity of Si nanowires (SiNWs) has been demonstrated recently and has opened up exciting opportunities for energy storage. However, a systematic theoretical study on lithium insertion in SiNWs remains a challenge, and as a result, understanding of the fundamental interaction and microscopic dynamics during lithium insertion is still lacking. This paper focuses on the study of single Li atom insertion into SiNWs with different sizes and axis orientations by using full ab initio calculations. We show that the binding energy of interstitial Li increases as the SiNW diameter grows. The binding energies at different insertion sites, which can be classified as surface, intermediate, and core sites, are quite different. We find that surface sites are energetically the most favorable insertion positions and that intermediate sites are the most unfavorable insertion positions. Compared with the other growth directions, the [110] SiNWs with different diameters always present the highest binding energies on various insertion locations, which indicates that [110] SiNWs are more favorable by Li doping. Furthermore, we study Li diffusion inside SiNWs. The results show that the Li surface diffusion has a much higher chance to occur than the surface to core diffusion, which is consistent with the experimental observation that the Li insertion in SiNWs is layer by layer from surface to inner region. After overcoming a large barrier crossing surface-to-intermediate region, the diffusion toward center has a higher possibility to occur than the inverse process.


Glucose metabolism in epitrochlearis muscle of acutely exercised and trained rats.
Effects of insulin on glycogen synthesis (GS), glycolytic utilization (GU), and glucose uptake (GT) were studied in isolated epitrochlearis muscles from exercise-trained or sedentary rats during recovery from acute exercise or at rest. During the 1st h after acute exercise, the enhanced basal and insulin-stimulated GT was directed mainly toward replenishment of glycogen but basal GU was also increased. During the second through third hours after exercise, basal GS decreased but remained greater than rest and basal GU and GT returned to normal. Insulin sensitivity of these parameters was enhanced. Training alone reduced basal GS but enhanced insulin sensitivity of GT and GU. Training reduced the acute exercise-stimulated increase in basal and insulin sensitivity of GS during recovery from acute exercise, probably due to elevated glycogen stores. Thus recovery from acute exercise or training, either alone or in combination, enhances insulin stimulated GT in muscle; however, the increased glucose is primarily channeled toward GS after acute exercise, which is reduced by prior training and is directed to GU in trained animals either at rest or after acute exercise.


Joint Learning of 3D Lesion Segmentation and Classification for Explainable COVID-19 Diagnosis.
Given the outbreak of COVID-19 pandemic and the shortage of medical resource, extensive deep learning models have been proposed for automatic COVID-19 diagnosis, based on 3D computed tomography (CT) scans. However, the existing models independently process the 3D lesion segmentation and disease classification, ignoring the inherent correlation between these two tasks. In this paper, we propose a joint deep learning model of 3D lesion segmentation and classification for diagnosing COVID-19, called DeepSC-COVID, as the first attempt in this direction. Specifically, we establish a large-scale CT database containing 1,805 3D CT scans with fine-grained lesion annotations, and reveal 4 findings about lesion difference between COVID-19 and community acquired pneumonia (CAP). Inspired by our findings, DeepSC-COVID is designed with 3 subnets: a cross-task feature subnet for feature extraction, a 3D lesion subnet for lesion segmentation, and a classification subnet for disease diagnosis. Besides, the task-aware loss is proposed for learning the task interaction across the 3D lesion and classification subnets. Different from all existing models for COVID-19 diagnosis, our model is interpretable with fine-grained 3D lesion distribution. Finally, extensive experimental results show that the joint learning framework in our model significantly improves the performance of 3D lesion segmentation and disease classification in both efficiency and efficacy.


Galanin immunoreactivity in the mudpuppy cardiac ganglion.
The source of galanin-immunoreactive fibers in the cardiac ganglion and on cardiac muscle in mudpuppy (Necturus maculosus) has been determined utilizing immunohistochemical techniques. The galanin-immunoreactive fibers are not processes of afferent fibers originating in either the rostral four dorsal root ganglia or vagal sensory ganglia. Following colchicine treatment, all of the postganglionic parasympathetic neurons and a subpopulation of the small intrinsic neurons in the cardiac ganglion exhibit galanin immunoreactivity. The majority of the galanin-immunoreactive fibers that form complexes on the parasympathetic postganglionic neurons are derived from galanin-immunoreactive small intrinsic neurons, although some of these connections may represent collateral processes from other parasympathetic postganglionic neurons. All of the galanin-immunoreactive processes that innervate cardiac muscle are derived from postganglionic parasympathetic neurons in the cardiac ganglion.


Histological evaluation of a topically applied retinol-vitamin C combination.
Two double-blind studies versus vehicle were carried out to investigate the effects of a topically applied retinol plus vitamin C combination on epidermal and dermal compartments of aged or photoaged human skin. The two studies were performed on postmenopausal women who were selected for treatment based on the mild level of elastosis of their facial skin. At completion of treatment, skin biopsies were collected and processed for classical histology and immunohistochemistry. In the first study (aged skin), 8 volunteers applied the retinol- and vitamin C-containing preparation on the ventral side of one elbow and the vehicle on the other elbow twice daily for 3 months. After the 3-month treatment we observed histological changes mainly within the epidermis. The stratum corneum was thinner with a compact pattern, whereas the epidermal proliferation increased, resulting in a thickening of the viable epidermis. Moreover, the interdigitation index was increased. In the second study (photoaged skin), 11 volunteers were divided in two groups; one applied the retinol- and vitamin C-containing preparation and the other one the vehicle on their face twice daily for 6 months. Facial skin samples presented histologic hallmarks of photoaging, i.e. accumulation of elastotic material in the papillary dermis. After the 6-month topical treatment, the observed histological changes were mainly concentrated at the dermal level. Both treated and control groups showed the same distribution pattern of type I procollagen, however, the high level of type III procollagen originally observed in photoaged skin was reduced in the retinol- and vitamin C-treated group, resulting in a lower type III-to-type I procollagen ratio. Furthermore, a wide band of eosinophilic material just beneath the epidermis, devoid of oxytalan fibers and forming the 'grenz zone', appeared more frequently and was larger in the retinol- and vitamin C-treated group. In conclusion, our results show that repeated topical application of a preparation containing both retinol and vitamin C is able to reverse, at least in part, skin changes induced by both chronologic aging and photoaging.


Qualitative and quantitative differences in spreading of human fibroblasts on various protein coats. Modulation by treatment of the cells with amines.
In contrast to established cell lines, normal human skin fibroblasts spread on their own fibronectin. The present investigation has examined whether human fibroblasts, like established cell lines, would be capable of spreading on substrata coated with proteins with different reactivity towards the cell surface. Coverslips were coated with human serum, fibronectin, alpha 2 macroglobulin-trypsin, a polyspecific anti-fibroblast antibody and a polyspecific anti-calf-serum antibody. The attachment of the cells to these substrate was of the same extent. Spreading was examined qualitatively using phase, interference contrast and reflection contrast optics on live cells, as well as scanning electron microscopy on fixed cells. To quantitate the maximum degree of cell spreading a semi-automated system was used, which measured the cell perimeter on a large number of cells. The distributions of the degree of cell spreading on the five substrata were compared statistically. The qualitative and quantitative differences observed on the various substrata could be further differentiated by adding various amines to the cells during 60 min spreading or during a 30 min preincubation before spreading. No strict correlation could be found between the effect of the amines on attachment or on spreading and their presumed effects on cellular transglutaminases. The results clearly indicate that the spreading of human fibroblasts can be modulated by the nature of the substratum and that, by using quantitative methods, these differences in behaviour can be measured accurately.


[Vitamin D hormone in the 21st century clinic: pleiotropic effects and laboratory evaluation (a lecture)].
The lecture gives general information on recent discoveries of the physiology of the vitamin D hormone system, new views of the broadest spectrum of the peripheral effects of active forms of vitamin D, as well as an update on the clinical value of its deficiency in the occurrence of dysfunctions of the majority of vital organs and systems. It discusses the capacities of laboratory evaluation of cholecalciferol provision to diagnose vitamin D deficiency and to monitor it at the stage of pharmacological correction by determining its major transport form (24-hydroxyvitamin D) in serum. Main indications for the investigation of this biomarker and the current recommendations by the leading experts to present a laboratory result and its clinical interpretation are summarized.


Smoothed dissipative particle dynamics model for mesoscopic multiphase flows in the presence of thermal fluctuations.
Thermal fluctuations cause perturbations of fluid-fluid interfaces and highly nonlinear hydrodynamics in multiphase flows. In this work, we develop a multiphase smoothed dissipative particle dynamics (SDPD) model. This model accounts for both bulk hydrodynamics and interfacial fluctuations. Interfacial surface tension is modeled by imposing a pairwise force between SDPD particles. We show that the relationship between the model parameters and surface tension, previously derived under the assumption of zero thermal fluctuation, is accurate for fluid systems at low temperature but overestimates the surface tension for intermediate and large thermal fluctuations. To analyze the effect of thermal fluctuations on surface tension, we construct a coarse-grained Euler lattice model based on the mean field theory and derive a semianalytical formula to directly relate the surface tension to model parameters for a wide range of temperatures and model resolutions. We demonstrate that the present method correctly models dynamic processes, such as bubble coalescence and capillary spectra across the interface.


The Protective Properties of the Strawberry (Fragaria ananassa) against Carbon Tetrachloride-Induced Hepatotoxicity in Rats Mediated by Anti-Apoptotic and Upregulation of Antioxidant Genes Expression Effects.
The strawberry (Fragaria ananassa) has been extensively used to treat a wide range of ailments in many cultures. The present study was aimed at evaluating the hepatoprotective effect of strawberry juice on experimentally induced liver injury in rats. To this end, rats were introperitoneally injected with carbon tetrachloride (CCl4) with or without strawberry juice supplementation for 12 weeks and the hepatoprotective effect of strawberry was assessed by measuring serum liver enzyme markers, hepatic tissue redox status and apoptotic markers with various techniques including biochemistry, ELISA, quantitative PCR assays and histochemistry. The hepatoprotective effect of the strawberry was evident by preventing CCl4-induced increase in liver enzymes levels. Determination of oxidative balance showed that strawberry treatment significantly blunted CCl4-induced increase in oxidative stress markers and decrease in enzymatic and non-enzymatic molecules in hepatic tissue. Furthermore, strawberry supplementation enhanced the anti-apoptotic protein, Bcl-2, and restrained the pro-apoptotic proteins Bax and caspase-3 with a marked reduction in collagen areas in hepatic tissue. These findings demonstrated that strawberry (F. ananassa) juice possessed antioxidant, anti-apoptotic and anti-fibrotic properties, probably mediated by the presence of polyphenols and flavonoids compounds.


Endoscopic Ultrasound-guided Portal Venous Access: Diagnostic and Therapeutic Implications.
Endoscopic ultrasound (EUS) has evolved from a purely diagnostic to an interventional modality offering minimally invasive alternatives to surgical and radiologic interventions. This has led to a rapidly growing interest in EUS-guided vascular interventions. EUS-guided portal venous access is an emerging technique which opens a new arena for interventional vascular EUS. Portal vein can be accessed under EUS guidance with high precision and low risk of complications thus expanding its application for both benign and malignant conditions. Potential applications of EUS-guided portal vein access include: fine needle aspiration of portal vein thrombus and portal venous blood sampling for circulating tumor cells for diagnosis and staging of occult and known malignancies; portal vein angiography, portal pressure measurement, and creation of endoscopic intrahepatic portosystemic shunt; portal vein embolization and targeted drug delivery. This article will review the current literature on EUS-guided portal vein access, its feasibility and safety in animal and human studies, and current diagnostic and therapeutic applications with future directions.


Erythropoietin response to anaemia in children with sickle cell disease and Fanconi's hypoproliferative anaemia.
The erythropoietin response to anaemia was compared in 30 children with haemolytic anaemia and in 5 children with Fanconi's hypoproliferative anaemia. Serum erythropoietin was measured by radioimmunoassay. In children with haemolytic anaemia the serum erythropoietin concentration increased exponentially with decreasing haematocrit values (r = 0.74; p less than 0.001). Serum erythropoietin levels also correlated with reticulocyte counts (r = 0.62; p less than 0.001). Children with Fanconi's hypoproliferative anaemia had considerably higher serum erythropoietin levels than children with haemolysis for the same degree of anaemia. These data indicate that erythropoietin production in Fanconi's anaemia may be dependent on other factors in addition to the degree of anaemia and relative hypoxaemia.