HLA-DRB1 alleles encoding an aspartic acid at position 70 protect against development of rheumatoid arthritis.
To determine whether the association between rheumatoid arthritis (RA) and HLA-DRB1 is influenced by the amino acid residue encoded at position 70 (beta70) of the third hypervariable region (HVR3) of the HLA-DRbeta chain. The frequencies of HLA-DRB1 alleles encoding different amino acid residues at beta70 were compared between patients with RA and controls in a population from the UK and in a confirmatory population from northwestern Spain. HLA-DRB1 typing was done by polymerase chain reaction methods on 476 clinic based patients with RA and 180 healthy controls from Staffordshire and Cheshire in the UK, and on 179 clinic patients and 145 controls from Lugo, Spain. Associations were investigated using chi-square analyses and regression analyses. The extended Mantel-Haenszel procedure was used for trend analysis. Carriage of 2 shared epitope (SE)+ alleles encoding a glutamine at beta70 (Q70SE+/Q70SE+) was associated with the greatest risk of RA in the UK and Spanish population (odds ratios 7.93 and 4.66, respectively), while possession of 2 SE- alleles encoding an aspartic acid at beta70 (D70SE-D70SE-) was associated with the lowest risk (OR 0.23 and 0.34, respectively). In individuals carrying one SE+ allele and an accompanying D70SE- allele there was no increased risk of developing RA [OR 0.93 (UK) and 1.30 (Spain)]. Possession of D70SE- was more strongly protective than possession of Q70SE. Analysis of trend indicated that the strength of association of different DRB1 genotypes with RA could be ranked in order (from Q70SE+/Q70SE+ to D70SE-/D70SE-) according to which amino acid residues were encoded at beta70, and whether or not they formed part of a SE sequence. The severity of radiographic damage could not be ranked in the same fashion. The amino acid residue at position 70 of the HVR3 in HLA-DRbeta molecules influences susceptibility to RA. The strength of the association of DRB1 genotypes with RA is dependent not only on SE status, but also on which amino acid residues are encoded at beta70 of the DRB1 alleles. Presence of an aspartic acid residue at beta70 protects against development of RA. However, the severity of erosive damage does not appear to be associated with the amino acid substitution at 1370.


An evaluation of the family history method for ascertaining psychiatric disorders.
This methodologic study assessed the accuracy of family history data in ascertaining psychiatric disorders in relatives. Comparison of diagnoses based on family history with diagnoses based on direct interview indicated that the specificity for the family history method is high, but that the sensitivity is generally low. Accuracy was better for affective disorders and alcoholism than for less severe disorders; spouses and offspring provided more accurate information than parents and siblings. The use of multiple information increased sensitivity somewhat, with little adverse effect on specificity. However, because errors were often correlated when more than one person provided information about a particular relative, the use of multiple informants generally did not improve accuracy substantially. Analysis of family-genetic studies should take account of the differential quality of data obtained by the family history method vs direct interview.


Sex-specific associations with cerebrospinal fluid biomarkers in dementia with Lewy bodies.
Dementia with Lewy bodies (DLB) is more prevalent in men than in women. In addition, post-mortem studies found sex differences in underlying pathology. It remains unclear whether these differences are also present antemortem in in vivo biomarkers, and whether sex differences translate to variability in clinical manifestation. The objective of this study was to evaluate sex differences in cerebrospinal fluid (CSF) biomarker concentrations (i.e., alpha-synuclein (α-syn), amyloid β1-42 (Aβ42), total tau (Tau), phosphorylated tau at threonine 181 (pTau)) and clinical characteristics in DLB. We included 223 DLB patients from the Amsterdam Dementia Cohort, of which 39 were women (17%, age 70 ± 6, MMSE 21 ± 6) and 184 men (83%, age 68 ± 7, MMSE 23 ± 4). Sex differences in CSF biomarker concentrations (i.e., α-syn, Aβ42, Tau, and pTau) were evaluated using age-corrected general linear models (GLM). In addition, we analyzed sex differences in core clinical features (i.e., visual hallucinations, parkinsonism, cognitive fluctuations, and REM sleep behavior disorder (RBD) and cognitive test scores using age- and education-adjusted GLM. Women had lower CSF α-syn levels (F 1429 ± 164 vs M 1831 ± 60, p = 0.02) and CSF Aβ42 levels (F 712 ± 39 vs M 821 ± 18, p = 0.01) compared to men. There were no sex differences for (p) Tau concentrations (p > 0.05). Clinically, women were older, had a shorter duration of complaints (F 2 ± 1 vs M 4 ± 3, p < 0.001), more frequent hallucinations (58% vs 38%, p = 0.02), and scored lower on MMSE and a fluency task (MMSE, p = 0.02; animal fluency, p = 0.006). Men and women did not differ on fluctuations, RBD, parkinsonism, or other cognitive tests. Women had lower Aβ42 and α-syn levels than men, alongside a shorter duration of complaints. Moreover, at the time of diagnosis, women had lower cognitive test scores and more frequent hallucinations. Based on our findings, one could hypothesize that women have a more aggressive disease course in DLB compared to men. Future research should investigate whether women and men with DLB might benefit from sex-specific treatment strategies.


Genetic demography at the leading edge of the distribution of a rabies virus vector.
The common vampire bat, Desmodus rotundus, ranges from South America into northern Mexico in North America. This sanguivorous species of bat feeds primarily on medium to large-sized mammals and is known to rely on livestock as primary prey. Each year, there are hotspot areas of D. rotundus-specific rabies virus outbreaks that lead to the deaths of livestock and economic losses. Based on incidental captures in our study area, which is an area of high cattle mortality from D. rotundus transmitted rabies, it appears that D. rotundus are being caught regularly in areas and elevations where they previously were thought to be uncommon. Our goal was to investigate demographic processes and genetic diversity at the north eastern edge of the range of D. rotundus in Mexico. We generated control region sequences (441 bp) and 12-locus microsatellite genotypes for 602 individuals of D. rotundus. These data were analyzed using network analyses, Bayesian clustering approaches, and standard population genetic statistical analyses. Our results demonstrate panmixia across our sampling area with low genetic diversity, low population differentiation, loss of intermediate frequency alleles at microsatellite loci, and very low mtDNA haplotype diversity with all haplotypes being very closely related. Our study also revealed strong signals of population expansion. These results follow predictions from the leading-edge model of expanding populations and supports conclusions from another study that climate change may allow this species to find suitable habitat within the U.S. border.


Characterization of the human protein S gene promoter: a possible role of transcription factors Sp1 and HNF3 in liver.
Protein S is a vitamin-K-dependent plasma glycoprotein that serves as a cofactor for activated protein C in the protein C anticoagulation pathway, which regulates blood coagulation by inactivating factors Va and VIIIa. Mechanisms regulating the expression of the protein S gene remain unknown to date. The aim of this study was to characterize the cis-acting DNA elements of the human protein S gene in liver. We found that liver cell lines (HepG2 and PLC) transcribed the human protein S gene to mRNA, whereas non-liver cell lines (HEK293 and HeLa cells) either transcribed the gene weakly or not at all. Isolation and analysis of tissue-specific gene expression in HepG2 and HeLa cells of the 5'-flanking region from -6183 to +294 of the protein S gene indicated that the consensus binding motifs to HNF3 and Sp1 or MAZ transcription factors in the flanking region are essential for protein S gene expression. Exogenous expression of the Sp1 gene augmented the protein S-reporter gene expression in HepG2 or PLC cells but had no effect in HeLa cells. Taken together, we would conclude that transcription factors of HNF3, MAZ, and Sp1 are required for high-level expression of the protein S gene in hepatic cells, but in non-hepatic cells such as HeLa cells, an unknown factor(s) binds to the Sp1 region and disturbs the action of Sp1 and MAZ.


DNA identification of species of the Anopheles maculipennis complex and first record of An. daciae in Belgium.
The present study aimed at identifying the members of the Anopheles maculipennis complex (Diptera: Culicidae) occurring in Belgium. Therefore, the second internal transcribed spacer of nuclear ribosomal DNA (ITS2) and the mitochondrial cytochrome oxidase subunit I (COI) loci were sequenced in 175 and 111 specimens, respectively, collected between 2007 and 2019. In parallel, the suitability of two species-diagnostic PCR-RFLP assays was tested. The identified specimens included: An. maculipennis s.s. (N = 105), An. daciae (N = 62), An. atroparvus (N = 6) and An. messeae (N = 2). Each species was characterized by unique ITS2 haplotypes, whereas COI only supported the monophyly of An. atroparvus, a historical malaria vector in Belgium. Species identification results were further supported by unique PCR-RFLP banding patterns. We report for the first time An. daciae in Belgium, where it was found to co-occur with An. maculipennis s.s. The latter was the most prevalent in the collection studied (60%) and appears to have the widest distribution in Belgium. As in other studies, An. daciae and An. messeae appeared the most closely related species, up to the point that their species status remains debatable, while their ecological differences, including vector competences, need further study.


Effects of a symbiotic on gut microbiota in Mexican patients with end-stage renal disease.
Gut microbiota provides beneficial effects under physiological conditions, but is able to contribute to inflammatory diseases in susceptible individuals. Thus, we designed this study to test whether additional intake of symbiotic gel affects specific modifications of gut microbiota in patients with end-stage renal disease (ESRD). Eighteen patients with ESRD diagnosis with renal replacement therapy (hemodialysis) were included in this study. They were randomly assigned to 2 treatment groups: (1) test group (nutritional counseling + symbiotic) and (2) control group (nutritional counseling + placebo). Clinical history and the evaluation of Gastrointestinal Symptom Rating Scale were performed. Gut microbiota composition was analyzed by real-time polymerase chain reaction from fecal samples. All subjects were followed for 2 months. Bifidobacterial counts were higher in the second samples (mean: 5.5 ± 1.72 log10 cells/g) than in first samples (4.2 ± 0.88 log 10 cells/g) in the patients of the test group (P = .0344). Also, lactobacilli counts had a little decrease in the test group (2.3 ± 0.75 to 2.0 ± 0.88 log 10 cells/g) and the control group (2.2 ± 0.90 to 1.8 ± 1.33 log 10 cells/g), between the first and the second samples. Gastrointestinal symptoms scores (scale 8-40) were reduced in the test group (start 12 [10-14] and end 9 [8-10]) compared with control group (start 11 [8-21] and end 11 [9-15]). Short-term symbiotic treatment in patients with ESRD can lead to the increase of Bifidobacterium counts, maintaining the intestinal microbial balance.


The osteo-odonto-keratoprosthesis.
To describe the practice of and recent developments in the osteo-odonto-keratoprosthesis. Formal psychological assessment and support have been described. A sub-aqua system for fashioning the osteo-odonto-keratoprosthesis lamina; adoption of thicker laminae; use of bisphosphonate drugs; advances in laminar imaging; and use of bone augmentation and bone morphogenetic protein have been described for prevention, detection, and management of laminar resorption. Two systems of optical cylinders available commercially. A stepladder approach to buccal mucous membrane overgrowth onto the optical cylinder has been described, including use of mitomycin-C. Orbital decompression has been used for cosmetic improvement. Detection of glaucoma may be aided by an intraocular pressure sensor, whereas surgical treatment is mainly by way of glaucoma drainage devices, as endolaser ciliary ablation and recti muscle disinsertion and reinsertion not having prolonged and significant long-term beneficial effect. Sublingual timolol has been described. The use of endoscopy has been proposed for preoperative evaluation of the posterior segment, ciliary ablation and for vitreoretinal surgery although wide-angle viewing systems remains standard practice. The osteo-odonto-keratoprosthesis is the procedure of choice for rehabilitation of corneal blindness for end-stage ocular surface disease, serving a completely different patient group to the Boston Type 1 KPro.


Hypervascular nodule in a fibrotic liver overloaded with iron: identification of a premalignant area with preserved liver architecture.
BACKGROUND: The presence of a hypervascular nodule in a patient with cirrhosis is highly suggestive of a hepatocellular carcinoma. CASE PRESENTATION: A 55 year old man with idiopathic refractory anaemia was addressed for the cure of a recently appeared 3.3 cm hypervascular liver nodule. The nodule was not visible on the resected fresh specimen, but a paler zone was seen after formalin fixation. The surrounding liver was fibrotic (METAVIR score F3) and overloaded with iron. However, the paler zone, thought to be the nodule, had in fact a normal architecture, was less fibrotic, and contained some "portal tract-like structures" (but with arteries only); moreover, this paler area was devoid of iron, contained less glycogen and was characterized by foci of clear hepatocytes. CONCLUSION: In spite of the absence of architectural distortion, and a normal proliferative index, the possibility of premalignancy or malignancy should be considered in this type of hypervascular and hyposiderotic nodule, occurring in the context of an iron overloaded liver.


Neutrophil-to-Lymphocyte Ratio (NLR) in Canine Inflammatory Bowel Disease (IBD).
Inflammatory bowel disease (IBD) is a multifactorial chronic inflammatory disorder leading to structural changes in the intestinal wall. In humans, the neutrophil-to-lymphocyte ratio (NLR) has been proposed as a promising marker of IBD. This study evaluated the possible clinical and prognostic significance of the NLR in dogs with IBD. This retrospective study enrolled 41 dogs diagnosed with IBD presented to University of Pisa from January 2017 to January 2018. For each dog, age, sex, canine chronic enteropathy clinical activity index (CCECAI), endoscopic and histopathological grading were recorded. Complete blood count, serum total protein, albumin, cholesterol, and C-reactive protein at the time of endoscopy were recorded. A control group (CG) of healthy dogs from a blood donor database was built. NLR was calculated for both IBD and CG as the ratio between absolute neutrophils and lymphocytes. Presence of crypt distension, lacteal dilation (LD), mucosal fibrosis, intraepithelial lymphocytes was recorded. Follow-up information was obtained from electronic medical records and dogs were classified as responders and non-responders based on CCECAI variation between admission and the first recheck. IRE dogs showed higher NLR compared to healthy dogs. NLR correlated negatively with total protein, albumin, and cholesterol and correlated positively with CCECAI. Dogs with LD showed higher NLR than dogs without LD. Non-responders showed higher NLR compared to responders. In conclusion, as in IBD human patients, the NLR acts as an inflammatory marker providing further information on severity of the disease and could be useful in predicting treatment response.


Polygenic Contributions to Suicidal Thoughts and Behaviors in a Sample Ascertained for Alcohol Use Disorders.
Suicidal thoughts and behaviors have partially distinct genetic etiologies. We used PRS-CS to create polygenic risk scores (PRSs) from GWAS of non-suicidal self-injury, broad-sense self-harm ideation, nonfatal suicide attempt, death by suicide, and depression. Using mixed-effect models, we estimated whether these PRSs were associated with a range of suicidal thoughts and behaviors in the Collaborative Study on the Genetics of Alcoholism (N = 7,526). All PRSs were significantly associated with suicidal ideation and suicide attempt (betas = 0.08-0.44, false discovery rate [FDR] <0.023). All PRSs except non-suicidal self-injury PRS were associated with active suicidal ideation (betas = 0.14-0.22, FDR <0.003). Several associations remained significant in models where all significant PRSs were included as simultaneous predictors, and when all PRSs predicted suicide attempt, the PRS together explained 6.2% of the variance in suicide attempt. Significant associations were also observed between some PRSs and persistent suicidal ideation, non-suicidal self-injury, compounded suicide attempt, and desire to die. Our findings suggest that PRS for depression does not explain the entirety of the variance in suicidal thoughts and behaviors, with PRS specifically for suicidal thoughts and behaviors making additional and sometimes unique contributions.


Gastroesophageal reflux disease: extraesophageal manifestations and therapy.
Gastroesophageal reflux disease (GERD) can present with both typical symptoms such as heartburn and regurgitation as well as atypical symptoms. These symptoms may include chest pain, asthma, chronic cough, hoarseness, otitis media, atypical loss of dental enamel, idiopathic pulmonary fibrosis, recurrent pneumonia, chronic bronchitis and even sudden infant death. The diagnosis of GERD in these patients can often present a challenge and usually requires a combination of selected testing and therapeutic trials. Acid suppression by using proton pump inhibitors remains the treatment of choice in GERD, but some patients will also respond well to antireflux surgery. This article addresses the presentations, diagnostic challenges, and therapeutic opportunities in GERD patients with atypical presentations.


Relationship between fibropapillomatosis and environmental quality: a case study with Chelonia mydas off Brazil.
We documented the presence of fibropapillomatosis (FP), a debilitating tumor-forming disease, in marine turtles in Espirito Santo Bay (Brazil) from March 2007 to April 2008, and assessed the value of a specific environmental index for predicting the prevalence of FP. Turtles were captured monthly with entanglement nets and scored for presence and severity of FP. For the assessment of habitat quality, we used the ecological evaluation index (EEI) based on benthic macrophytes. The FP-free control area was classified as good quality (EEI = 8) and the study area, with high FP prevalence, was classified as bad quality (EEI= 2). Prevalence of FP in the study area was 58.3% with an average of 40 tumors per individual, and prevalence varied positively with curved carapace length (CCL). No FP was seen in the control area. The number of turtles heavily afflicted (tumor score category 3) was 10 times larger than those lightly affected (tumor score category 1). Most tumors were found on or near the front and rear flippers; no oral tumors or internal tumors were found. At recapture, 41% of formerly tumor-free turtles revealed FP, often increasing in severity with time, and very few turtles showed signs of disease regression. From the results of this study we concluded that FP is particularly severe in Espírito Santo Bay. Future studies should focus on evaluating how widespread FP is in Brazil, whether prevalence is increasing or decreasing, and elucidating the pathology and pathogenesis of FP in sea turtles in Brazil.


[Accumulation of lipids in hepatocyte cytosol after local hyperthermia and partial hepatectomy].
The effects of local hyperthermia and partial hepatectomy of the liver as well as of copper ions on the lipid content in liver cell cytosol and microsomes and in blood serum have been studied. It has been found that these effects provoke significant changes in the lipid content of the cytosol and, particularly, of triacylglycerides. Within one hour after partial hepatectomy the lipid content in the liver cytosol increases 2-fold, while by the moment of completion of the regenerative process (day 8th) it decreases sharply--down to 18.7 micrograms per mg of cytosolic protein, being several times lower in comparison with the control level. The results obtained are discussed in terms of the lipid response to stress.


Global warming favours light-coloured insects in Europe.
Associations between biological traits of animals and climate are well documented by physiological and local-scale studies. However, whether an ecophysiological phenomenon can affect large-scale biogeographical patterns of insects is largely unknown. Insects absorb energy from the sun to become mobile, and their colouration varies depending on the prevailing climate where they live. Here we show, using data of 473 European butterfly and dragonfly species, that dark-coloured insect species are favoured in cooler climates and light-coloured species in warmer climates. By comparing distribution maps of dragonflies from 1988 and 2006, we provide support for a mechanistic link between climate, functional traits and species that affects geographical distributions even at continental scales. Our results constitute a foundation for better forecasting the effect of climate change on many insect groups.


Echocardiographic diagnosis of coronary artery fistula in both dizygotic twin brothers: environmental mechanism?
A congenital coronary artery fistula (CAF) is a rare form of heart disease in which a coronary artery and a cardiac chamber or another vascular structure communicate. CAF could worsen ventricular perfusion and function, favoring ventricular ischemia and arrhythmias. To our knowledge, this is the first report of CAF, draining in the pulmonary artery, in two asymptomatic dizygotic twin brothers, diagnosed by echocardiography. Dizygotic twins are siblings with different genes exposed to the same environmental experience during the pregnancy. The occurrence of CAF (with similar instrumental findings) in both twin brothers could depend on a poorly identified environmental factor during pregnancy.


Influence of adenosine receptor blockade on renal function and renal autoregulation.
Experiments were conducted in anesthetized dogs to evaluate the effects of adenosine receptor blockade on renal function and on autoregulation of total RBF and outer cortical blood flow. After control measurements, the adenosine receptor antagonist, 1,3-dipropyl-8-p-sulfophenylxanthine (PSPX) was infused intrarenally for 45 min at 2 or 6 microM/min. Responses to PSPX were compared with those obtained during infusions of either aminophylline or theophylline. PSPX infusion led to substantial increases in urine flow and sodium excretion (four- to fivefold). RBF increased significantly; however, outer cortical blood flow and GFR were not significantly altered. PRA increased twofold during PSPX infusion. The vasoconstrictor responses to bolus injections of 2-chloroadenosine (100 mumol) were attenuated by 58 and 86% during the low and high doses of PSPX and to a lesser extent with aminophylline/theophylline infusions. At renal arterial pressures above the inflection point, the slope of the average pressure-flow relationship during PSPX infusion was close to zero and was not significantly different from control. Similarly, autoregulatory capability was not altered during infusions of theophylline or aminophylline. These data provide further evidence that endogenous adenosine contributes substantially to the control of renin release but only modestly to the control of RBF and GFR and to renal autoregulatory capability. The natriuretic responses during adenosine blockade, which occurred in the face of elevated renin levels, support the hypothesis that endogenous adenosine enhances tubular sodium reabsorption rate.


Parenting stress and psychological functioning among mothers of preschool children with autism and developmental delay.
Parents of children with developmental disabilities, particularly autism spectrum disorders (ASDs), are at risk for high levels of distress. The factors contributing to this are unclear. This study investigated how child characteristics influence maternal parenting stress and psychological distress. Participants consisted of mothers and developmental-age matched preschool-aged children with ASD (N = 51) and developmental delay without autism (DD) ( N = 22). Evidence for higher levels of parenting stress and psychological distress was found in mothers in the ASD group compared to the DD group. Children's problem behavior was associated with increased parenting stress and psychological distress in mothers in the ASD and DD groups. This relationship was stronger in the DD group. Daily living skills were not related to parenting stress or psychological distress. Results suggest clinical services aiming to support parents should include a focus on reducing problem behaviors in children with developmental disabilities.


Effect of ether, chloroform and carbon dioxide on monoamine inactivation.
To determine if anaesthetic agents alter monoamine inactivation, we exposed tissue homogenates (liver, kidney and brain) from mice and rabbits to ether and chloroform vapors and carbon dioxide gas. These anaesthetic agents inhibited monoamine oxidase (MAO) activity against typtamine and serotonin. Concentrations of anaesthetic agents that are achieved in the plasma of man during general anaesthesia caused a 27% (ether) and 49% (chloroform) reduction in mouse liver MAO; higher concentrations caused a 95% inhibition mouse or rabbit liver MAO. Kinetic analysis with tryptamine as substrate indicate that ether and chloroform are noncompetitive, reversible MAO inhibitors that preferentially inhibit Type B MAO. Ether and chloroform cause noncompetitive inhibition of serotonin oxidation by mouse liver MAO and competitive inhibition of serotonin oxidation by mouse brain and kidney MAO. Ether or chloroform did not alter catechol-O-methyltransferase activity from tissues of mice. Isolated blood platelets (rabbit and human) were used as a model system for neuronal uptake. Ether caused an irreversible inhibition of serotonin uptake by platelets.


What is the role of apelin regarding cardiovascular risk and progression of renal disease in type 2 diabetic patients with diabetic nephropathy?
To evaluate the association of different apelin levels with cardiovascular mortality, hospitalization, renal function, and cardiovascular risk factors in type 2 diabetic patients with mild to moderate CKD. An observational, prospective study involving 150 patients divided into groups according to baseline apelin levels: 1 ≤ 98 pg/mL, 2 = 98-328 pg/mL, and 3 ≥ 329 pg/mL. Baseline characteristics were analyzed and compared. Multivariate Cox regression was used to find out predictors of cardiovascular mortality, and multivariate logistic regression was used to find out predictors of hospitalization and disease progression. Simple linear regressions and Pearson correlations were used to investigate correlations between apelin and renal disease and cardiovascular risk factors. Patients' survival at 83 months in groups 1, 2, and 3 was 39%, 40%, and 71.2%, respectively (P = 0.046). Apelin, age, and eGFR were independent predictors of mortality, and apelin, creatinine, eGFR, resistin, and visfatin were independent predictors of hospitalization. Apelin levels were negatively correlated with cardiovascular risk factors and positively correlated with eGFR. Patients with lower apelin levels were more likely to start a depurative technique. Apelin levels might have a significant clinical use as a marker/predictor of cardiovascular mortality and hospitalization or even as a therapeutic agent for CKD patients with cardiovascular disease.


[Hepatobiliogastroscintigraphy in assessment of the hepatobiliary system in primary cancer of the liver].
Primary cancer of the liver is characterized not only by laboratory evidence for cytolytic (87.5% cases), cholestatic (100% cases) syndromes, high levels of oncomarkers (CA-19-9, 50%; CEA, 68.75%; alpha FP, 43.75%) and activation of hemostasis system but, as shown at hepatobiligastroscintigraphy with 99m-Tc-brommeside, by at least 2-fold decline in absorptive and excretory function of hepatic polygonal cells (in 75% cases), at least a 5-fold decline in secretory function of the gallbladder (in 100% cases), cholestasis (in 100% cases) manifesting as a 3.8-fold reduction, on the average, of the ratio of secretory function of the gallbladder to that of the intrahepatic bile ducts, dilation of the latter (in 50% cases), Oddi's sphincter hypotonicity (in 50% cases). None of the patients showed duodenogastric reflux.


Effect of intranasal and oral administration of levetiracetam on the temporal and spatial distributions of SV2A in the KA-induced rat model of SE.
To investigate the effectiveness of nasal delivery of levetiracetam (LEV) on the distributions of synaptic vesicle protein 2 isoform A (SV2A) in epileptic rats with injection of kainic acid (KA) into amygdala. A total of 138 rats were randomly divided into four groups, including the Sham surgery group, the epilepsy group (EP), and the LEV oral administration (LPO) and nasal delivery (LND) groups. The rat intra-amygdala KA model of epilepsy was constructed. Pathological changes of rat brain tissue after status epilepticus (SE) were detected using haematoxylin and eosin staining. Expression of SV2A in rat hippocampus after SE was evaluated using the western blotting analysis. Expression and distribution of SV2A in rat hippocampus after SE were detected based on immunofluorescence staining. The EP group showed evident cell loss and tissue necrosis in the CA3 area of hippocampus, whereas the tissue damage in both LPO and LND groups was significantly reduced. Western blotting analysis showed that the expressions of SV2A in the hippocampus of both EP and LND groups were significantly decreased 1 week after SE, increased to the similar levels of the Sham group in 2 weeks, and continuously increased 4 weeks after SE to the level significantly higher than that of the Sham group. Results of immunofluorescence revealed largely the same expression patterns of SV2A in the CA3 area of hippocampus as those in the entire hippocampus. Our study revealed the same antiepileptic and neuronal protective effects by the nasal and oral administrations of LEV, without changing the expression level of SV2A.


Phylogenetic analyses of Bradyrhizobium strains nodulating soybean (Glycine max) in Thailand with reference to the USDA strains of Bradyrhizobium.
To elucidate the phylogenetic relationships between Thai soybean bradyrhizobia and USDA strains of Bradyrhizobium, restriction fragment length polymorphism (RFLP) analysis using the nifDK gene probe and sequencing of the partial 16S rRNA gene were performed. In our previous work, Thai isolates of Bradyrhizobium sp. (Glycine max) were separated clearly from Bradyrhizobium japonicum and Bradyrhizobium elkanii based on the RFLP analysis using the nodDYABC gene probe. RFLP analysis using the nifDK gene probe divided 14 Thai isolates and eight USDA strains of B. japonicum into different groups, respectively, but categorized into the same cluster. All of seven strains within these Thai isolates had the same sequence of the partial 16S rRNA gene, and it was an intermediate sequence between those of B. japonicum USDA 110 and B. elkanii USDA 76T. Furthermore, three USDA strains of B. japonicum, USDA of (B. japonicum ATCC 10324T), USDA 115 and USDA 129, had the same partial 16S rRNA gene sequence that seven Thai isolates had. These results suggest that Thai isolates of Bradyrhizobium sp. (Glycine max) are genetically distinct from USDA strains of B. japonicum and B. elkanii, but also indicate a close relationship between Thai isolates and USDA strains of B. japonicum.


Identification of a geographic area characterized by extreme longevity in the Sardinia island: the AKEA study.
High prevalence and low female/male ratio for validated centenarians are observed in Sardinia and these findings appear to be thus far unique to this island. Moreover a specific region on the island is characterized by exceptional male longevity. We calculated the extreme longevity index (ELI), defined as the percentage of persons born in Sardinia between 1880 and 1900, who became centenarians. A gaussian smoothing method was used in order to identify the so-called 'Blue Zone', where longevity is concentrated in the central-eastern part of the island and covers all the mountainous areas of central Sardinia. The estimated life expectancy in the 'Blue Zone' is longer than in the remaining territory of the island especially for men and the male to female ratio among centenarians born in this area is 1.35 compared to 2.43 in the rest of Sardinia. The specific mechanism by which persons living in this territory were more likely to reach extreme longevity remains unknown but it is interesting to note that most of the 'longevity hot spots' identified in various regions of the world over the years have been located in mountainous geographical areas even if none of these longevity regions have been fully validated. An alternative and interesting hypothesis is that the high rate of inbreeding determined by frequent marriages between consanguineous individuals and low immigration rates have progressively decreased the variability of the genetic pool and facilitated the emergence of genetic characteristics that protect individuals from diseases that are major causes of mortality particularly in older individuals. Given the exceptionally high prevalence of male centenarians in the 'Blue Zone', it is reasonable to assume that either the environmental characteristics or the genetic factors, or both, exert their favorable effect more strongly in men than in women. Thus, the mechanism involved may be modulated by the hormonal milieu, or may be associated with genes located in the sex chromosomes.


Self-ambivalence and resistance to subtle self-change attempts.
Recent research has demonstrated the malleability of self-views to subtle situational influence but has not uncovered features of the self-concept representation that make it susceptible to such change. Using research on attitude ambivalence as a foundation, the current article predicted that the self would be most likely to respond to a subtle change induction when the targeted self-beliefs were objectively ambivalent (e.g., possessed both positive and negative features). Using self-esteem conditioning (Experiment 1) and outgroup stereotype priming (Experiment 2), it was found that people were more susceptible to subtle change inductions as objective self-ambivalence increased. Notably, the consistency between dominant self-views (positive or negative) and the change induction did not influence these results. These effects held for objective ambivalence, but not subjective ambivalence, and only when the objective ambivalence measure was relevant to the change induction. Mechanisms of the observed moderation and the implications of self-ambivalence for understanding self-change are discussed.


Contrasting selection pressures on components of the Ras-mediated signal transduction pathway in Drosophila.
The molecular genetics of several signal transduction pathways is well characterized, providing an opportunity to address the nature of the population genetic forces acting on functionally related suites of pleiotropic regulatory genes. Signal transduction is the process by which signals are transmitted from the cell surface to the nucleus or other cellular structures. It plays a fundamental role in regulating a wide range of developmental and physiological processes, many of which are likely to be subject to buffering mechanisms. Here we infer that contrasting selection pressures act on six components of the Ras signal transduction pathway by comparing sequences obtained from 25 alleles of Drosophila melanogaster with one allele of the sibling species D. simulans. The three most upstream components of the cascade, Ras, Drk and polehole, experience strong purifying selection, as they show no fixed amino acid differences between the species and just a handful of rare replacement polymorphisms within D. melanogaster. This portion of the pathway is likely to act as a control point in signal transduction, because the more downstream components Dsor1, corkscrew and Ksr, each show several amino acid replacements between the species. Furthermore, Ksr is nearly monomorphic within D. melanogaster, and application of the HKA and McDonald and Kreitman tests indicate that this gene may have experienced a recent selective sweep, suggesting that modifiers of Ras kinase signalling are the most likely source of quantitative variation associated with this core regulatory pathway.


The utility of the "bull's-eye" artifact on breast elasticity imaging in reducing breast lesion biopsy rate.
The objectives of the study were to evaluate the accuracy of the "bull's-eye" artifact of elasticity imaging (EI) in determining the benignity of cystic breast lesions and to determine the utility of such artifact in reducing the biopsy rate of the benign lesions. This study was performed under local institutional review board supervision and was in compliance with the Health Insurance Portability and Accountability Act of 1996. A retrospective review of 383 breast lesions from 309 consecutive patients undergoing diagnostic breast ultrasonography with EI (Siemens Antares or Siemens S2000; Siemens Healthcare, Mountain View, Calif) was conducted. The B-mode characteristics of those lesions determined whether biopsy was conducted. Pathological reports of the biopsied lesions were reviewed. Lesions demonstrating the bull's-eye artifact on EI were determined. The accuracy of the artifact in determining the benignity of cystic breast lesions was determined. Of the 383 lesions, 243 lesions were recommended for biopsy based on the B-mode characteristics (biopsy rate, 63.4%). Of those 243 lesions, 62 lesions demonstrated the bull's-eye artifact on EI, and all were confirmed benign cysts on pathological reports. Of the 181 lesions without the artifact, 116 were benign noncystic lesions, and 65 were malignant noncystic lesions. Hence, within the biopsied lesions, the bull's-eye artifact had perfect sensitivity, specificity, and positive predictive value in determining pathologically proven benign cysts. If the artifact can be used as a criterion to exclude lesions from biopsy, then the biopsy rate will be 181 (47.3%) of 383, significantly lower than the 63.4% biopsy rate without using this criteria (P < 0.001). The bull's-eye artifact seen on EI on Siemens ultrasonography equipment is a promising tool in the evaluation and characterization of benign breast cysts and has the potential to significantly reduce the amount of unnecessary breast biopsy.


RIBAR and xRIBAR: Methods for reproducible relative MS/MS-based label-free protein quantification.
Mass spectrometry-driven proteomics is increasingly relying on quantitative analyses for biological discoveries. As a result, different methods and algorithms have been developed to perform relative or absolute quantification based on mass spectrometry data. One of the most popular quantification methods are the so-called label-free approaches, which require no special sample processing, and can even be applied retroactively to existing data sets. Of these label-free methods, the MS/MS-based approaches are most often applied, mainly because of their inherent simplicity as compared to MS-based methods. The main application of these approaches is the determination of relative protein amounts between different samples, expressed as protein ratios. However, as we demonstrate here, there are some issues with the reproducibility across replicates of these protein ratio sets obtained from the various MS/MS-based label-free methods, indicating that the existing methods are not optimally robust. We therefore present two new methods (called RIBAR and xRIBAR) that use the available MS/MS data more effectively, achieving increased robustness. Both the accuracy and the precision of our novel methods are analyzed and compared to the existing methods to illustrate the increased robustness of our new methods over existing ones.


Relationship between brain structure sizes and performing rapid limb movements. A quantitative magnetic resonance study.
In this study, we aimed to determine the relationship between the size of cerebral structures evaluated by quantitative magnetic resonance technique and the ability of performing rapid-velocity limb movements. Forty-seven healthy women with a mean age of 43.4 years (range 22-68) were included. Exclusion criteria were systemic diseases including alcoholism. Finger and ankle tapping were quantitatively recorded for both right and left extremities. A mean value for the right and left side was calculated. To determine atrophy, we measured the area of the corpus callosum, the cerebrum and the cerebellum on midline sagittal sections. On transverse images, the ventricle-to-brain ratio, the bifrontal ratio and the bicaudate ratio were selected as atrophy parameters. Also, the prevalence of white matter hyperintensities was assessed. Fifteen (32%) had hyperintense white matter lesions. Using simple regression analysis, the frequencies of both finger (r = 0.37, beta = -0.002, p = 0.022) and ankle (r = 0.35, beta = -0.001, p = 0.032) tapping were associated with reduced cerebellar size. No association was found for other atrophy parameters or the number of hyperintense white matter lesions. This study indicates that impaired ability to perform fast limb movements may be related to a relative cerebellar atrophy.


What is society? Social thought and the arts of government.
Following conservative politicians, neoliberal philosophers and radical critics, different strands of social science, including those using Foucault's governmentality approach, joined the questioning of the salience of 'society' and ideas of 'the social' over the last decades. When the social reappeared, it was often in the moral domains of community and civil society. This argument re-evaluates the contribution of Foucauldian histories, or 'genealogies', of the social to these fundamental questions. Drawing upon them, it attends to their arguments concerning the place of social thought on the modern episteme in relation to economics, the emergence of the idea of 'society' with the modern arts of government of the state, and the formation of the 'social question'. The argument here allows that preconditions of formation of 'society' lie in the legal and political techniques of the territorial sovereign state. However, the literature under investigation indicates the implicit normativity of an idea of 'society' as a 'problematic unity' and the enduring necessity of a social domain in a law-governed state with a relatively independent economic sphere. This discussion thus seeks to contribute to the wider revaluation and redeployment of these terms in today's context.


The SHARE road map: Healthgrids for biomedical research and healthcare.
The HealthGrid White Paper was published at the third annual conference in Oxford in 2005. Starting from the conclusions of the White Paper, the EU funded SHARE project (http://www.eu-share.org) has aimed at identifying the most important steps and significant milestones towards wide deployment and adoption of healthgrids in Europe. The project has defined a strategy to address the issues identified in the action plan for European e-Health (COM(2004).356) and has devised a roadmap for the major technological and ethical and legal developments and social and economic investments needed for successful take up of healthgrids in the next 10 years. A "beta" version of the road map underwent full review by a panel of 25 prominent European experts at a workshop in December 2007. The present document is an executive policy summary of the final draft road map. It has sought to reconcile likely conflicts between technological developments and regulatory frameworks by bringing together the project's technical road map and conceptual map of ethical and legal issues and socio-economic prospects. A key tool in this process was a collection of case studies of healthgrid applications.


Quantifying both viscoelasticity and surface tension: why sharp tips overestimate cell stiffness.
Quantifying the mechanical properties of cells is important to better understand how mechanics constrain cellular processes. Furthermore, because pathologies are usually paralleled by altered cell mechanical properties, mechanical parameters can be used as a novel way to characterize the pathological state of cells. Key features used in models are cell tension, cell viscoelasticity (representing the average of the cell bulk), or a combination of both. It is unclear which of these features is the most relevant or if both should be included. To clarify this, we performed microindentation experiments on cells with microindenters of various tip radii, including micron-sized microneedles. We obtained different cell-indenter contact radii and measured the corresponding contact stiffness. We derived a model predicting that this contact stiffness should be an affine function of the contact radius and that at vanishing contact radius, the cell stiffness should be equal to the cell tension multiplied by a constant. When microindenting leukocytes and both adherent and trypsinized adherent cells, the contact stiffness was indeed an affine function of the contact radius. For leukocytes, the deduced surface tension was consistent with that measured using micropipette aspiration. For detached endothelial cells, agreement between microindentation and micropipette aspiration was better when considering these as only viscoelastic when analyzing micropipette aspiration experiments. This work suggests that indenting cells with sharp tips while neglecting the presence of surface tension leads to an effective elastic modulus whose origin is in fact surface tension. Accordingly, using sharp tips when microindenting a cell is a good way to directly measure its surface tension without the need to let the viscoelastic modulus relax.


Health-related quality of life after kidney transplantation in comparison intermittent hemodialysis, peritoneal dialysis, and normal controls.
The purpose of this study was to compare the quality of life (QOL) in renal transplantation patients. QOL is one of the important indicators of the effects of medical treatment. In this cross-sectional study, QOL was analyzed in 302 renal transplant recipients compared with 64 hemodialysis (HD) patients, 207 (PD) peritoneal dialysis patients, and 278 normal controls (NC) matched as closely as possible to the grafted patients regarding age, gender, education, and occupation. All groups were asked to estimate their subjective QOL by responding to sociodemographic data, Turkish adapted instruments of the Nottingham Health profile (NHP), and the Short-form 36 (SF-36). Transplant recipients were significantly younger than the HD and PD patients (P < .0001). There was no statistically significant differences between normal controls and transplant patients ages. Among the three renal replacement methods, QOL in transplants was clearly better than that in HD or PD patients (P < .0001). The QOL measured by the NHP and SF-36 scale showed that the normal population was statistically significantly better than the transplant recipients (P < .0001). Transplant renal replacement therapy provides a better QOL compared with other replacement methods.


A mobile-based airway clearance care system using deep learning-based vision technology to support personalized home-based pulmonary rehabilitation for COAD patients: Development and usability testing.
Excessive mucus secretion is a serious issue for patients with chronic obstructive airway disease (COAD), which can be effectively managed through postural drainage and percussion (PD + P) during pulmonary rehabilitation (PR). Home-based (H)-PR can be as effective as center-based PR but lacks professional supervision and timely feedback, leading to low motivation and adherence. Telehealth home-based pulmonary (TH-PR) has emerged to assist H-PR, but video conferencing and telephone calls remain the main approaches for COAD patients. Therefore, research on effectively assisting patients in performing PD + P during TH-PR is limited. This study developed a mobile-based airway clearance care for chronic obstructive airway disease (COAD-MoAcCare) system to support personalized TH-PR for COAD patients and evaluated its usability through expert validation. The COAD-MoAcCare system uses a mobile device through deep learning-based vision technology to monitor, guide, and evaluate COAD patients' PD + P operations in real time during TH-PR programs. Medical personnel can manage and monitor their personalized PD + P and operational statuses through the system to improve TH-PR performance. Respiratory therapists from different hospitals evaluated the system usability using system questionnaires based on the technology acceptance model, system usability scale (SUS), and task load index (NASA-TLX). Eleven participant therapists were highly satisfied with the COAD-MoAcCare system, rating it between 4.1 and 4.6 out of 5.0 on all scales. The system demonstrated good usability (SUS score of 74.1 out of 100) and a lower task load (NASA-TLX score of 30.0 out of 100). The overall accuracy of PD + P operations reached a high level of 97.5% by comparing evaluation results of the system by experts. The COAD-MoAcCare system is the first mobile-based method to assist COAD patients in conducting PD + P in TH-PR. It was proven to be usable by respiratory therapists, so it is expected to benefit medical personnel and COAD patients. It will be further evaluated through clinical trials.


Kinetic characterization of N-acetyl-D-glucosamine kinase from rat liver and kidney.
1. Under normal assay conditions the N-acetyl-D-glucosamine kinases from rat liver and kidney show a pH-dependent lag phase before reaching a steady state, which is probably due to reversible dissociation of the dimeric enzyme. 2. The enzyme catalyses the phosphorylation of N-acetyl-D-glucosamine, N-acetyl-D-mannosamine and D-glucose at pH 7.5, with apparent Km values of 0.06, 0.95 and 600 mM respectively for the enzyme from liver and 0.04, 1.0 and 410 mM respectively for the kidney enzyme. It is strongly inhibited by ADP. 3. The interaction between the enzymes and acceptor substrates shows non-Michaelian kinetics with respect to N-acetyl-D-glucosamine but normal behaviour towards N-acetyl-D-mannosamine and D-glucose. 4. Both N-acetyl-D-glucosamine and N-acetyl-D-mannosamine inhibit the phosphorylation of D-glucose; this inhibition appears to be mixed in character. 5. The facts that the enzymes catalyse the phosphorylation of N-acetyl-D-mannosamine and D-glucose do not detract from the designation of the enzymes as N-acetyl-D-glucosamine kinase. Phosphorylation of glucose in vivo by these kinases is unlikely.


Monospecific antisera against capsid polypeptides of poliovirus type 1 distinguish antigenic structures of poliovirus proteins.
Pure poliovirus polypeptides, namely VP1, VP2, VP3 and VP4, have been isolated by isoelectric focusing after dissociation of poliovirus by urea. When injected into rabbits, all four polypeptides produced monospecific antisera which were used for the characterization of poliovirus particles and poliovirus-infected cells. The specificity of these antisera was determined by immunoprecipitation of polypeptides obtained by dissociation of poliovirus with SDS, followed by characterization by polyacrylamide gel electrophoresis. The antisera revealed differences in the antigenic sites of native poliovirus particles, heated poliovirus particles and naturally occurring empty capsids. Only VP3 antiserum reacted with native poliovirus and showed some neutralization, whereas all antisera precipitated heated virus and empty capsids. These antisera reacted also with the appropriate precursors of the capsid polypeptides demonstrating their usefulness for an analysis of the cleavage pathway by monospecific antibodies and revealed a second protomer (90 kilodalton) polypeptide for the capsid proteins of poliovirus particles.


Controversies in the intramedullary nailing of proximal and distal tibia fractures.
Management of tibia fractures by internal fixation, particularly intramedullary nails, has become the standard for diaphyseal fractures. However, for metaphyseal fractures or those at the metaphyseal-diaphyseal junction, the choice of fixation device and technique is controversial. For distal tibia fractures, nailing and plating techniques may be used, the primary goal for each being to achieve acceptable alignment with minimal complications. Different techniques for reduction of these fractures are available and can be applied with either fixation device. Overall outcomes appear to be nearly equivalent, with minor differences in complications. Proximal tibia fractures can be fixed using nailing, which is associated with deformity of the proximal short segment. A newer technique--suprapatellar nailing--may minimize these problems, and use of this method has been increasing in trauma centers. However, most data are still largely based on case series.


Dependence of dispersion coefficients on atomic environment.
Addition of a dispersion-energy correction to density-functional theory significantly improves potential-energy curves for dispersion-bound complexes. The exchange-hole dipole moment (XDM) model allows non-empirical calculation of atomic and molecular dispersion coefficients using only occupied orbitals and polarizabilities. In this work, the XDM model is applied to examine the dependence of dispersion coefficients on changes in atomic environment, such as charge, oxidation state, and hybridization. The variations in dispersion coefficients, and resulting energy contributions, are assessed for selected chemical examples.


Investigating novel thiazolyl-indazole derivatives as scaffolds for SARS-CoV-2 MPro inhibitors.
COVID-19 is a global pandemic caused by infection with the SARS-CoV-2 virus. Remdesivir, a SARS-CoV-2 RNA polymerase inhibitor, is the only drug to have received widespread approval for treatment of COVID-19. The SARS-CoV-2 main protease enzyme (MPro), essential for viral replication and transcription, remains an active target in the search for new treatments. In this study, the ability of novel thiazolyl-indazole derivatives to inhibit MPro is evaluated. These compounds were synthesized via the heterocyclization of phenacyl bromide with (R)-carvone, (R)-pulegone and (R)-menthone thiosemicarbazones. The binding affinity and binding interactions of each compound were evaluated through Schrödinger Glide docking, AMBER molecular dynamics simulations, and MM-GBSA free energy estimation, and these results were compared with similar calculations of MPro binding various 5-mer substrates (VKLQA, VKLQS, VKLQG) and a previously identified MPro tight-binder X77. From these simulations, we can see that binding is driven by residue specific interactions such as π-stacking with His41, and S/π interactions with Met49 and Met165. The compounds were also experimentally evaluated in a MPro biochemical assay and the most potent compound containing a phenylthiazole moiety inhibited protease activity with an IC50 of 92.9 μM. This suggests that the phenylthiazole scaffold is a promising candidate for the development of future MPro inhibitors.


The perceived functional benefit of dynamic arm supports in daily life.
Dynamic arm supports are provided to assist with activities of daily living (ADLs) in people with limited upper-limb function. However, the perceived functional benefit of these devices in daily life is unknown. Insight into the functional benefit may give direction to the development of new devices and may affect the factors that patients and their health care providers consider during the selection process of a device. A cross-sectional study involving 23 Dutch experienced dynamic arm support users was performed in the Netherlands. The study included a questionnaire, an interview, and an observation of ADL task performance in the domestic setting. Twenty participants completed this study. Five users had a large perceived functional benefit, nine a moderate benefit, and five no benefit (one was unable to indicate the benefit). People with limited functional abilities benefited most. Participants varied in the amount of device use, activities the device is used for, and reasons for using (or not using) the device. On an individual level, selection using a selection tool and a good evaluation of the prescription could improve user-device matches.


Effects of mercury on spermatogenesis studied by velocity sedimentation cell separation and serial mating.
Recently the potential toxicity of environmental mercury has become a major concern. Human tissues contain mercury due to daily environmental exposure. Nearly all of the mercury contaminating food is in the form of methylmercury complexes, due to the biotransformation of inorganic mercury. This report compares the reproductive effects of methylmercury hydroxide and mercuric chloride in male mice. The mercuric compounds were administered intraperitoneally once at a dose of 1 mg/kg (based on Hg++ concentration), or spermatogenic cells were exposed in vitro to Hg+ concentrations ranging from 10(-3) to 10(-8)M. Spermatogenic cells were separated for biochemical studies using the velocity sedimentation technique, and in vivo serial mating was used to assess fertility. The effects of CH3Hg+ or Hg++ on the uptake of 3H-thymidine by spermatogonia, 3H-uridine by early elongated spermatids, and 3H-L-leucine by late elongated spermatids were studied. These in vitro experiments indicated that at 1-(-3) m CH2HgOH reduced thymidine incorporation by spermatogonia by 40%, uridine incorporation by elongated spermatids by 39% and L-leucine incorporation by late elongated spermatids by 40%. Results obtained with HgCl2 were similar but of lesser magnitude. In vivo administration of CH3HgOH and HgCl2 significantly inhibited the uptake of thymidine, uridine and L-leucine by their respective spermatogenic cells. Fertility profiles obtained from serial mating studies indicated that the primary effect of CH3HgOH was on spermatogonial cells, premeiotic spermatocytes and early elongated spermatids, with no apparent effect on spermatozoa in testis, peididymis or vas deferentia. HgCl2 also primarily affected spermatogonial and premeiotic cells, but the effect was less than that seen with CH3HgOH. Statistical analysis indicated significant antifertility effects. Inhibition of uptake of thymidine and uridine was well correlated with the functionality of these cells as reflected in the fertility profile, excep for L-leucine uptake. Mercury ion-induced antifertility effects at the dosage used in these experiments are reversible. Thus, these results suggest spermatogenic effects of methylmercury complexes which might have important health consequences in man.


Colostrogenesis: mass transfer of immunoglobulin G1 into colostrum.
Bovine IgG(1) is thought to be specifically transported by a process of transcytosis across the mammary epithelial cells during colostrogenesis. Mammary IgG(1) appearance in cow colostrum has typically been reported as a concentration and shows IgG(1) concentration to be extremely variable because of animal variation, colostrum milking time, and water dilution effects. To identify animal IgG(1) transfer capacity and separate it from the other effects, our objective was to determine first colostrum IgG(1) total mass. We collected 214 samples of totally milked first colostrum with recorded colostrum weights from 11 Pennsylvania dairy farms that participated in Pennsylvania Dairy Herd Improvement Association, analyzed colostrum for IgG(1) by ELISA, and calculated total IgG(1) mass. Median and mean concentrations of IgG(1) were 29.4 mg/mL and 37.5+/-30.2 mg/mL, respectively, with a range of 9 to 166 mg/mL. However, total mass of IgG(1) had a median of 209.1g, mean of 291.6+/-315.8 g, and a range of 14 to 2,223 g. Colostrum IgG(1) concentration showed no relationship with colostrum volume, but IgG(1) mass had a positive relationship with volume. Colostrum IgG(1) mass was related to IgG(1) concentration (R(2)=0.58). Using DHIA records for 196 animals, we established milk production for these animals to a 15-d equivalent. An established milk secretion relationship to mammary parenchyma tissue (secretory tissue) was calculated and showed no relationship of IgG(1) mass with mammary parenchyma tissue. In addition, we show that approximately 10% of the sampled animals had IgG(1) mass greater than 1 standard deviation above the mean (high mass transfer) and represented all parities tested (1-7). Whereas first-lactation animals showed less overall calculated parenchyma tissue when compared with other parities, approximately 10% of the first-lactation group animals were capable of high mass transfer, with one transporting 2,029 g into first colostrum. Concentration variance of IgG(1) can be attributed to water inclusion, whereas mass transfer provides a clear indication of animal IgG(1) transfer capacity. The specific mechanism of bovine mammary IgG(1) transfer is not clear, but secretory tissue mass does not explain the variation observed. We hypothesize that the animal variation is attributable to endocrine regulation or genetic variation of the transporter(s).


IVIG treatment for myasthenia gravis: effectiveness, limitations, and novel therapeutic strategies.
Acquired myasthenia gravis (MG) is an autoimmune disorder treated with cholinesterase inhibitors and a number of immunotherapies. Intravenous immunoglobulin (IVIG) is an expensive and commonly used immunotherapy for patients with an exacerbation of MG, but its effectiveness has only recently been demonstrated in a randomized clinical trial. This paper describes the study design, results, and limitations of a double-blind, randomized, placebo-controlled trial designed to definitively determine if IVIG benefits patients with MG who present with worsening weakness. Fifty-one patients with worsening weakness due to MG were randomized to receive either 2 g/kg of IVIG over 2 days or an equivalent volume of placebo (5% dextrose in water). The Quantitative MG Score (QMG Score) for Disease Severity, a validated clinical composite scale and the primary outcome measure in the study, was calculated by a masked observer 14 and 28 days after treatment. Patients treated with IVIG demonstrated a significant improvement in QMG Score for Disease Severity at day 14 and the response persisted at day 28. The largest clinical improvement occurred in patients with more severe disease. IVIG was well tolerated with no significant side effects observed. Given the observed efficacy and safety of IVIG demonstrated in this trial, future studies are necessary to determine if there is a role for interval IVIG treatments in chronic MG.


Pelvic osteosarcoma. Resection, reconstruction, local control, and survival statistics.
Nine patients with a malignant tumor in the periacetabular region of the pelvis were treated with a Type IIC resection and were reconstructed using a cementless, adaptable prosthetic system. In two patients, a new planning strategy was applied using three-dimensional reconstruction. There were two chondrosarcomas, three Ewing-sarcomas, two osteosarcomas, and two metastases of thyroid cancer. Excision was wide, marginal, and intralesional in three cases each. Ages ranged from eight to 68 years (average, 40 years), and follow-up periods ranged from 12 to 36 months with an average of 27 months. Overall functional evaluation was good in five cases, fair in three, and poor in one. Four patients died of local recurrences and lung metastases; all of them had marginal or intralesional resections. Histologic analysis of one retrieved specimen revealed bone ingrowth with connective tissue interface. Three-dimensional planning has proven to be a very valuable tool for achieving an anatomic reconstruction of the pelvic ring. These results are encouraging and endorse the authors to continue with the current approach of prosthetic reconstruction following Type IIC resections.


Quality control by portal film analysis in radiotherapy for prostate cancer: a comparison between two different institutions and treatment techniques.
Accuracy and reproducibility of patient setup during radiotherapy for prostate cancer were investigated in two different Institutions (A and B), within their Quality Assurance programs. The purpose of the study was to evaluate and compare setup accuracy and reproducibility in Institutions A and B, which adopt different patient positioning and treatment techniques for prostate irradiation. A retrospective analysis of portal localization films taken during the treatment course was performed: 30 and 21 patients in Institutes A and B, respectively, entered the study. In Institute A, patients were treated in a prone position, utilizing an individualized immobilization cast (either an alpha cradle or a heat and vacuum-formed cellulose acetate cast) with an open table top and individual abdominal wall compressor to minimize small bowel irradiation; a 5-field conformal technique was used. In Institute B, patients were treated in a supine position without any immobilization device; a 6-field BEV-based technique (conformal only for patients treated with a radical aim) was adopted. A total of 598 portal films (420 from Institute A and 178 from Institute B) were analyzed. The mean number of films per patient was 12 (range, 4-29). Systematic and random setup errors were estimated utilizing the statistical method suggested by Bijhold et al. (1992). When patients with a mean (systematic) error larger than 5, 8 and 10 mm in craniocaudal, lateral and posterior-anterior directions, respectively, were compared, no statistically significant difference between the two groups was observed. Similarly, when comparing portal films, a significant difference (P <0.01) appeared only in the craniocaudal direction (errors > 5 mm: Institute A = 24%; Institute B = 11%). In both Institutes, the SD of random and systematic error distribution ranged from 1.8 to 4.2 mm, with a small prevalence of systematic errors. Only for craniocaudal shifts in Institute A was the random error larger than the systematic error, and it was significantly worse than in Institute B (1 SD, 4.2 mm in Institute A vs 1.8 mm in Institute B). Setup errors observed in Institutes A and B were similar and in accord with data reported in the literature. In Institute B, satisfactory geometrical treatment quality was achieved without patient immobilization. In Institute A, the goal of minimizing small bowel irradiation and prostate motion through the aforementioned technique, which makes patient position less comfortable, did not seem to considerably increase daily setup uncertainty.


[Reconstructive operation of the gastric cardia with cardiectomy and ileo-colon replacement of the esophagus, stomach and cardia in gastric cardiac cancer].
After having studied both the advantages and disadvantages of various reconstructive operations, an improved reconstructive operation, i.e. ileo-colon replacement of esophagus, stomach and cardia was performed to avoid regurgitation esophagitis after cardiectomy in gastric cardiac cancer. Twenty patients underwent such reconstructive operation. Clinical observation and measurement of intraluminal pressure in the upper digestive tract before and after operation showed that this kind of operation gave satisfactory short-term results, not only avoiding the regurgitation, but increasing the radical resection rate, reducing the other postoperative complications and improving the diet quantity intake also. This reconstructive operation is better than the traditional routine method and worthy of extensive use. Preparations before, during and after the operation, cooperation in manipulation during the operation are described.


Effectiveness of multiple pre-ischemia electro-acupuncture on attenuating lipid peroxidation induced by cerebral ischemia in adult rats.
Free radicals induced by cerebral ischemia-reperfusion injury can trigger lipid peroxidation, leading to the production of malondialdehyde (MDA) and 4-hydroxy-2(E)-nonenal (4-HNE). Post-ischemia electroacupuncture (EA) therapy was able to reduce extent of lipid peroxidation. However, the effect of pre-ischemic EA therapy has not been reported. In this study, we aim to investigate the effectiveness of pre-ischemic EA therapy on lipid peroxidation in the rat ischemic injury model. Four groups of Sprague-Dawley rats were designed: Placebo group (without EA therapy), NA group (EA therapy on non-acupoint), GB20 group (EA therapy on Fengchi), and ST36 group (EA therapy on Zusanli). Half of each group (n = 6) received 30-minute EA therapy for 3 times and the other half group for 18 times before the occlusion of right middle cerebral artery. Right brains were taken for determination of concentration of MDA and the total of MDA plus 4-HNE. We found that multiple pre-ischemia EA therapy at either GB20 or ST36 can effectively reduce the amount of MDA produced after MCA occlusion. However, this reduction was not observed in the total amount of MDA and 4-HNE. In conclusion, pre-ischemia EA can partly regulate the lipid peroxidation in cerebral ischemia, where both GB20 and ST36 have a similar beneficial effectiveness.


Interaction of non-esterified fatty acid and insulin in control of triacylglycerol secretion by Hep G2 cells.
The role of insulin in the regulation of plasma triacylglycerol is poorly understood. Conflicting actions of insulin on rat liver cells have been reported, insulin inhibiting triacylglycerol secretion in short incubations (less than 24 h) and stimulating triacylglycerol secretion in longer incubations (48-72 h). The present study was undertaken to examine regulation of triacylglycerol secretion by insulin and investigate the interaction between insulin and non-esterified fatty acid over 72 h in human hepatoblastoma (Hep G2) cells. Insulin inhibited triacylglycerol secretion throughout the 72 h period. The inhibition increased from 66% in the first 24 h to 88% in the final 24 h. Increasing the initial concentration of oleic acid from 200 microM to 1000 microM resulted in a 358% increase in triacylglycerol secretion and a 712% increase in accumulation over 24 h. Oleic acid uptake by the cells was rapid, with only 2.4% of the initial concentration (500 microM) remaining after 24 h. Supplementation of the medium with oleic acid to maintain the concentration between 750 microM and 1000 microM throughout a 5 h period resulted in a 350% increase in triacylglycerol secretion. Supplementation also decreased the insulin-induced inhibition of triacylglycerol secretion (18.2 to 7.8%; P less than 0.001). These results demonstrate that there is not a biphasic action of insulin on triacylglycerol secretion by Hep G2 cells. Experiments of this nature have not previously taken into account the rapid uptake of non-esterified fatty acid by hepatocytes and have consequently underestimated the effect of a sustained concentration on triacylglycerol metabolism. Oleic acid is therefore an even more potent stimulus to triacylglycerol synthesis and secretion than has previously been recognized. In addition, in the presence of a sustained increase in oleic acid concentration, there is a decrease in the action of insulin to inhibit triacylglycerol secretion.


CircCHMP5 Contributes to Ox-LDL-induced Endothelial Cell Injury Through the Regulation of MiR-532-5p/ROCK2 axis.
Aberrant expression of circular RNA (circRNA) has been demonstrated to be related to atherosclerosis (AS) formation. However, the mechanism of circCHMP5 (also known as hsa_circ_0003575) in AS formation remains unclear. Oxidized low-density lipoprotein (ox-LDL) was used to treat human umbilical vein endothelial cells (HUVECs) to construct a cell injury model. The expression level of circCHMP5, miR-532-5p, and Rho-associated protein kinase 2 (ROCK2) was measured using quantitative real-time PCR. Cell cycle, apoptosis, proliferation, and angiogenesis were determined by flow cytometry, 5-ethynyl-2'-deoxyuridine (EdU) assay, and tube formation assay. In addition, the protein expression of apoptosis markers, inflammation factors, and ROCK2 was detected by western blot analysis. The interaction between miR-532-5p and circCHMP5 or ROCK2 was assessed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Our results indicated that circCHMP5 was overexpressed in ox-LDL-induced HUVECs. CircCHMP5 knockdown promoted cell cycle, proliferation, and angiogenesis while inhibiting apoptosis and inflammation in ox-LDL-induced HUVECs. MiR-532-5p could be sponged by circCHMP5, and its inhibitor reversed the negative regulation of si-circCHMP5 on ox-LDL-induced HUVECs injury. ROCK2, a target of miR-532-5p, reversed the inhibition effect of miR-532-5p on ox-LDL-induced HUVECs injury. Furthermore, we confirmed that circCHMP5 upregulated ROCK2 by sponging miR-532-5p. To sum up, our data showed that circCHMP5 regulated the miR-532-5p/ROCK2 axis to accelerate ox-LDL-induced HUVECs injury, confirming that circCHMP5 might be a potential target for AS treatment.


Protocol for fabrication of Pt/RuO2/graphene bifunctional oxygen catalyst in Li-O2 batteries.
The commercial mass production of bifunctional oxygen catalysts with high activity and stability is critical for constructing high-performance lithium-oxygen (Li-O2) batteries, but remains challenging. Herein, we describe a protocol for the scalable fabrication of a 2D bifunctional electrocatalyst of Pt/RuO2/graphene by spatial confinement strategy and elaborately evaluate its oxygen reduction/evolution reactions for advanced Li-O2 batteries. We then detail the synthesis steps for preparing materials followed by assembly and evaluation of the three-electrode systems and coin-type Li-O2 batteries. For complete details on the use and execution of this protocol, please refer to Li et al. (2023).1.


Thymic development of gut-microbiota-specific T cells.
Humans and their microbiota have coevolved a mutually beneficial relationship in which the human host provides a hospitable environment for the microorganisms and the microbiota provides many advantages for the host, including nutritional benefits and protection from pathogen infection1. Maintaining this relationship requires a careful immune balance to contain commensal microorganisms within the lumen while limiting inflammatory anti-commensal responses1,2. Antigen-specific recognition of intestinal microorganisms by T cells has previously been described3,4. Although the local environment shapes the differentiation of effector cells3-5 it is unclear how microbiota-specific T cells are educated in the thymus. Here we show that intestinal colonization in early life leads to the trafficking of microbial antigens from the intestine to the thymus by intestinal dendritic cells, which then induce the expansion of microbiota-specific T cells. Once in the periphery, microbiota-specific T cells have pathogenic potential or can protect against related pathogens. In this way, the developing microbiota shapes and expands the thymic and peripheral T cell repertoire, allowing for enhanced recognition of intestinal microorganisms and pathogens.


Identification of co-occurring transcription factor binding sites from DNA sequence using clustered position weight matrices.
Accurate prediction of transcription factor binding sites (TFBSs) is a prerequisite for identifying cis-regulatory modules that underlie transcriptional regulatory circuits encoded in the genome. Here, we present a computational framework for detecting TFBSs, when multiple position weight matrices (PWMs) for a transcription factor are available. Grouping multiple PWMs of a transcription factor (TF) based on their sequence similarity improves the specificity of TFBS prediction, which was evaluated using multiple genome-wide ChIP-Seq data sets from 26 TFs. The Z-scores of the area under a receiver operating characteristic curve (AUC) values of 368 TFs were calculated and used to statistically identify co-occurring regulatory motifs in the TF bound ChIP loci. Motifs that are co-occurring along with the empirical bindings of E2F, JUN or MYC have been evaluated, in the basal or stimulated condition. Results prove our method can be useful to systematically identify the co-occurring motifs of the TF for the given conditions.


Early transcriptional responses of bovine chorioallantoic membrane explants to wild type, ΔvirB2 or ΔbtpB Brucella abortus infection.
The pathogenesis of the Brucella-induced inflammatory response in the bovine placenta is not completely understood. In this study we evaluated the role of the B. abortus Type IV secretion system and the anti-inflammatory factor BtpB in early interactions with bovine placental tissues. Transcription profiles of chorioallantoic membrane (CAM) explants inoculated with wild type (strain 2308), ΔvirB2 or ΔbtpB Brucella abortus were compared by microarray analysis at 4 hours post infection. Transcripts with significant variation (>2 fold change; P<0.05) were functionally classified, and transcripts related to defense and inflammation were assessed by quantitative real time RT-PCR. Infection with wild type B. abortus resulted in slightly more genes with decreased than increased transcription levels. Conversely, infection of trophoblastic cells with the ΔvirB2 or the ΔbtpB mutant strains, that lack a functional T4SS or that has impaired inhibition of TLR signaling, respectively, induced more upregulated than downregulated genes. Wild type Brucella abortus impaired transcription of host genes related to immune response when compared to ΔvirB and ΔbtpB mutants. Our findings suggest that proinflammatory genes are negatively modulated in bovine trophoblastic cells at early stages of infection. The virB operon and btpB are directly or indirectly related to modulation of these host genes. These results shed light on the early interactions between B. abortus and placental tissue that ultimately culminate in inflammatory pathology and abortion.


Propofol significantly attenuates iNOS, CAT-2, and CAT-2B transcription in lipopolysaccharide-stimulated murine macrophages.
Propofol significantly inhibits inducible nitric oxide synthase (iNOS) expression and nitric oxide (NO) biosynthesis in stimulated macrophages. L-arginine transport mediated by the isozymes of type-2 cationic amino acid transporter (including CAT-2 and CAT-2B) has been reported to play a crucial role in regulating iNOS activity. We sought to evaluate the effects of propofol on L-arginine transport and transcription of CAT-2 and CAT-2B. Confluent murine macrophages (RAW264.7 cells) were stimulated with lipopolysaccharide (LPS) to induce NO production, L-arginine transport and the transcriptions of iNOS, CAT-2, and CAT-2B. Propofol (25, 50, and 75 microM) was added to the cells 4 hours before, immediately after, or 4 hours after LPS administration. After reacting with LPS for 18 hours, cell cultures were harvested and assayed. Propofol administered 4 hours before LPS had no significant effects on NO production, L-arginine transport, and the transcriptions of iNOS and CAT-2. To our surprise, NO production and iNOS transcription were significantly enhanced by 25 microM propofol administered immediately after LPS. NO production and iNOS transcription were not affected by 50 microM propofol but significantly inhibited by 75 microM propofol administered immediately after LPS. CAT-2 transcription and L-arginine transport were significantly inhibited by 50 and 75 microM but not 25 microM propofol administered immediately after LPS. When administered 4 hours after LPS, 75 but not 25 and 50 microM propofol significantly inhibited NO production, L-arginine transport, and the transcription of iNOS and CAT-2. In addition, CAT-2B transcription was significantly inhibited by propofol that was administered 4 hours before, immediately after, or 4 hours after LPS. Propofol had significantly inhibitory effects on LPS-induced NO production, L-arginine transport, and the expressions of iNOS, CAT-2 and CAT-2B in stimulated murine macrophages in a dose-dependent manner. In addition, timing of administration also affected this regulatory effect of propofol.


QT dynamics early after exercise as a predictor of mortality.
Exercise and QT dynamics during ambulatory monitoring impact mortality in a variety of populations. Heart rate recovery (HRR) after exercise is a known strong predictor of mortality. This study assessed the independent prognostic significance of the QT response to changing heart rate (QT dynamics) during recovery from exercise. The cohort included patients referred for treadmill exercise stress testing over a 5-year period. Patients had to have at least 4 electrocardiographic tracings within 5 minutes of peak exercise. One had to be recorded 60 seconds into recovery to calculate the HRR. Linear regression of the QT-RR relation during recovery was used to predict the QT interval at cycle lengths of 500 and 600 ms (QT-500 and QT-600). Only studies with an R(2) > or = 0.9 (72%) were retained. Optimal binary cut points were chosen. All-cause mortality was determined from either the Social Security Death Index or hospital records. A total of 2,994 patients met inclusion criteria; 228 (7.6%) died during an average follow-up of 7.6 +/- 1.9 years. Abnormal QT-500 (>316 ms) was the strongest univariate QT dynamics predictor in a Cox proportional hazards model (hazard ratio = 2.13, P <.001). It remained an independent predictor of mortality after adjustment for age, exercise capacity, medications, single photon emission computed tomography defects, and abnormal (<12 beats/min) HRR (hazard ratio = 1.46, P = .014). An abnormal predicted QT interval at 500 ms (120 beats/min) during recovery from exercise independently predicts all-cause mortality. Because QT dynamics in recovery incorporate information on both repolarization and autonomic responsiveness, its role in risk prediction for sudden cardiac death should be further explored.


Dopaminergic polymorphisms and educational achievement: results from a longitudinal sample of Americans.
Although educational attainment has been found to be moderately heritable, research has yet to explore candidate genes for it. Drawing on data from the National Longitudinal Study of Adolescent Health, in the current study, we examined the association between polymorphisms in three dopaminergic genes (DAT1, DRD2, and DRD4), a dopamine index, and educational attainment. Statistically significant effects were found for DAT1, DRD2, DRD4, and the dopamine index for highest level of education. This study is the first to our knowledge that links measured genes to educational attainment.


Functional specialization and convergence in the occipito-temporal cortex supporting haptic and visual identification of human faces and body parts: an fMRI study.
Humans can recognize common objects by touch extremely well whenever vision is unavailable. Despite its importance to a thorough understanding of human object recognition, the neuroscientific study of this topic has been relatively neglected. To date, the few published studies have addressed the haptic recognition of nonbiological objects. We now focus on haptic recognition of the human body, a particularly salient object category for touch. Neuroimaging studies demonstrate that regions of the occipito-temporal cortex are specialized for visual perception of faces (fusiform face area, FFA) and other body parts (extrastriate body area, EBA). Are the same category-sensitive regions activated when these components of the body are recognized haptically? Here, we use fMRI to compare brain organization for haptic and visual recognition of human body parts. Sixteen subjects identified exemplars of faces, hands, feet, and nonbiological control objects using vision and haptics separately. We identified two discrete regions within the fusiform gyrus (FFA and the haptic face region) that were each sensitive to both haptically and visually presented faces; however, these two regions differed significantly in their response patterns. Similarly, two regions within the lateral occipito-temporal area (EBA and the haptic body region) were each sensitive to body parts in both modalities, although the response patterns differed. Thus, although the fusiform gyrus and the lateral occipito-temporal cortex appear to exhibit modality-independent, category-sensitive activity, our results also indicate a degree of functional specialization related to sensory modality within these structures.


Rapid heat treatment for anatase conversion of titania nanotube orthopedic surfaces.
The amorphous to anatase transformation of anodized nanotubular titania surfaces has been studied by x-ray diffraction and transmission electron microscopy (TEM). A more rapid heat treatment for conversion of amorphous to crystalline anatase favorable for orthopedic implant applications was demonstrated. Nanotube titania surfaces were fabricated by electrochemical anodization of Ti6Al4V in an electrolyte containing 0.2 wt% NH4F, 60% ethylene glycol and 40% deionized water. The resulting surfaces were systematically heat treated in air with isochronal and isothermal experiments to study the temperature and time dependent transformation respectively. Energy dispersive spectroscopy shows that the anatase phase transformation of TiO2 in the as-anodized amorphous nanotube layer can be achieved in as little as 5 min at 350 °C in contrast to reports of higher temperature and much longer time. Crystallinity analysis at different temperatures and times yield transformation rate coefficients and activation energy for crystalline anatase coalescence. TEM confirms the (101) TiO2 presence within the nanotubes. These results confirm that for applications where amorphous titania nanotube surfaces are converted to crystalline anatase, a 5 min production flow-through heating process could be used instead of a 3 h batch process, reducing time, cost, and complexity.


Aberrant NFATc1 signaling counteracts TGFβ-mediated growth arrest and apoptosis induction in pancreatic cancer progression.
Given its aggressive tumor biology and its exceptional therapy resistance, pancreatic ductal adenocarcinoma (PDAC) remains a major challenge in cancer medicine and is characterized by a 5-year survival rate of <8%. At the cellular level, PDAC is largely driven by the activation of signaling pathways that eventually converge in altered, tumor-promoting transcription programs. In this study, we sought to determine the interplay between transforming growth factor β (TGFβ) signaling and activation of the inflammatory transcription factor nuclear factor of activated T cells (NFATc1) in the regulation of transcriptional programs throughout PDAC progression. Genome-wide transcriptome analysis and functional studies performed in primary PDAC cells and transgenic mice linked nuclear NFATc1 expression with pro-proliferative and anti-apoptotic gene signatures. Consistently, NFATc1 depletion resulted in downregulation of target genes associated with poor PDAC outcome and delayed pancreatic carcinogenesis in vivo. In contrast to previous reports and consistent with a concept of retained tumor suppressive TGFβ activity, even in established PDAC, TGFβ treatment reduced PDAC cell proliferation and promoted apoptosis even in the presence of oncogenic NFATc1. However, combined TGFβ treatment and NFATc1 depletion resulted in a tremendous abrogation of tumor-promoting gene signatures and functions. Chromatin studies implied that TGFβ-dependent regulators compete with NFATc1 for the transcriptional control of jointly regulated target genes associated with an unfavorable PDAC prognosis. Together, our findings suggest opposing consequences of TGFβ and NFATc1 activity in the regulation of pro-tumorigenic transcription programs in PDAC and emphasize the strong context-dependency of key transcription programs in the progression of this devastating disease.


Differences in the use of everyday technology among persons with MCI, SCI and older adults without known cognitive impairment.
To use valid subjective reports sensible to cognitive decline is vital to identify very early signs of dementia development. Use of everyday technology (ET) has been shown to be sensitive to differentiate adults with mild cognitive impairment (MCI) from controls, but the group with subjective cognitive impairment (SCI) has not yet been examined. This study aims to investigate and compare self-perceived ability in ET use and number of ETs reported as actually used in a sample of older adults with SCI, MCI, and older adults with no known cognitive impairment, i.e. Older adults with MCI (n = 29), SCI ( n = 26), and controls (n = 30) were interviewed with the short version of the Everyday Technology Use Questionnaire (S-ETUQ) to capture self-perceived ability in ET use and number of ETs used. To generate individual measures of ability to use ET, Rasch analysis was used. The measures were then compared group-wise using ANCOVA. The numbers of ETs used were compared group-wise with ANOVA. Controls versus SCI and MCI differed significantly regarding ETs reported as used, but not SCI versus MCI. Similarly, in ability to use ET, controls versus SCI and MCI differed significantly but not SCI versus MCI. The significantly lower numbers of ETs reported as actually used and the lower ability in SCI and MCI groups compared to controls suggest that ET use is affected already in very minor cognitive decline. This indicates that self-reported ET use based on the S-ETUQ is sensitive to detect changes already in SCI.


bwimage: A package to describe image patterns in natural structures.
Currently R is the most popular software for data analyses among biologists. Here, we present bwimage, a package designed to describe patterns from black and white images. The package can be used for a wide range of applications. We implemented functions previously described in the literature to calculate parameters designed originally, but not exclusively, for vegetation structures. Additionally, we propose a new parameter: the aggregation index. We demonstrate applications for field work, providing examples that range from calculation of canopy openness, description of patterns in vertical vegetation structure, to patterns in bird nest structure. We provide advice and illustrated examples of how to produce high quality images for analyses.


Impaired spatial memory in mice lacking CD3ζ is associated with altered NMDA and AMPA receptors signaling independent of T-cell deficiency.
The immunoreceptor-associated protein CD3ζ is known for its role in immunity and has also been implicated in neuronal development and synaptic plasticity. However, the mechanism by which CD3ζ regulates synaptic transmission remains unclear. In this study, we showed that mice lacking CD3ζ exhibited defects in spatial learning and memory as examined by the Barnes maze and object location memory tasks. Given that peripheral T cells have been shown to support cognitive functions and neural plasticity, we generated CD3ζ(-/-) mice in which the peripheral T cells were repopulated to a normal level by syngeneic bone marrow transplantation. Using this approach, we showed that T-cell replenishment in CD3ζ(-/-) mice did not restore spatial memory defects, suggesting that the cognitive deficits in CD3ζ(-/-) mice were most likely mediated through a T-cell-independent mechanism. In support of this idea, we showed that CD3ζ proteins were localized to glutamatergic postsynaptic sites, where they interacted with the NMDAR subunit GluN2A. Loss of CD3ζ in brain decreased GluN2A-PSD95 association and GluN2A synaptic localization. This effect was accompanied by a reduced interaction of GluN2A with the key NMDAR downstream signaling protein calcium/calmodulin-dependent protein kinase II (CaMKII). Using the glycine-induced, NMDA-dependent form of chemical long-term potentiation (LTP) in cultured cortical neurons, we showed that CD3ζ was required for activity-dependent CaMKII autophosphorylation and for the synaptic recruitment of the AMPAR subunit GluA1. Together, these results support the model that the procognitive function of CD3ζ may be mediated through its involvement in the NMDAR downstream signaling pathway leading to CaMKII-dependent LTP induction.


[The effect of vitamin C on the lipolytic activity in type-II diabetics with angiopathy].
Effects produced by different doses of Vit C (2, 3 and 4 gr/day) on lipoprotein and hepatic lipase activities were studied between a group of 35 ambulatory patients, men and women, affected by diabetes mellitus type II with macroangiopathy at lower limbs and/or food. The medium age of patients was 62 years, ranging from 44 to 82 years. Patients were aleatory divided into four groups. One from those four groups was treated with placebo, the other three received Vit C. In the group treated with 3 gr./day of Vit C we found a significant reduction and increase (p less than 0.05) of lipoprotein and hepatic lipase activities, respectively, when we compared outcomes before and after eight weeks of treatment with Vit C. By other hand, when we compared the different groups, we found a significant increase in the hepatic lipase activity in the same group, particularly between the patients whose plasmatic Vit C levels before treatment were reduced. We didn't found any significant change in the rest of parameters.


COVID-19-Related Psychological and Psychosocial Distress Among Parents and Youth With Physical Illness: A Longitudinal Study.
Despite the initial thrust of research aimed at understanding the impact of the COVID-19 pandemic on youth with physical illness and their parents, knowledge gaps in the literature remain, providing the impetus for additional investigation. This study described changes in psychological distress from prior to during the COVID-19 pandemic for parents and youth with physical illness, compared parent-proxy and youth self-reported perceptions of COVID-19-related psychosocial health, and modeled factors associated with psychological and psychosocial distress. There were 147 parent-youth dyads (2-16 years) from MY LIFE-a longitudinal study of youth with physical illness. The Kessler-6 (K6) measured psychological distress for the time before the COVID-19 lockdown (December 19 to March 20) and during the pandemic (December 20 to March 21) among parents and youth. COVID-19-related psychosocial health was measured using the CRISIS. Parents and youth reported increases in K6 scores (d = 0.62 and 0.38). Parent-proxy reports on the K6 were lower vs. youth self-reports prior to and during the pandemic (d = 0.63 for both). In contrast, parents reported lower proxy CRISIS scores for worries (d = 0.38) and effects of social restrictions (d = 0.52). Pandemic parent K6 scores were associated with age, combined in-person and online schooling for youth, COVID-19-related worries, and effects of social restrictions. For youth, only COVID-19-related worries and effects of social restrictions were associated with K6 scores. Parent worries were associated with youth sex, parental stress, family functioning, online and combination learning, and social restrictions. Parental depression and worries were associated with effects of social restrictions. Youth worries were associated with online and combination learning, and social restrictions. Youth disability, online learning, and worries were associated with effects of social restrictions. Few clinical factors are associated with COVID-19-related psychological and psychosocial distress. Instead, parent/family factors and youth learning environment have prominent roles in predicting outcomes and have implications for the health, education, and social services systems.


Naturally occurring parafollicular cell carcinoma of the thyroid in dogs. A histological and ultrastructural study.
Seven cases of parafollicular cell carcinoma in dogs were seen. The diagnosis was based on histological and ultrastructural similarities between neoplastic and normal parafollicular cells. Amyloid was not detected in any of the neoplasms by light or electron microscopy. Argyrophilic secretory granules are important in making a diagnosis of canine thyroid parafollicular cell carcinoma, even when there is no amyloid.


Phospholipid-mediated delivery of anti-GAP-43 antibodies into neuroblastoma cells prevents neuritogenesis.
The neuronal growth-associated protein GAP-43 is expressed during axonal outgrowth and regeneration (for review, see Benowitz and Routtenberg, 1987). In the present study, we demonstrate that GAP-43 is constitutively expressed by NB2a/d1 neuroblastoma cells. The initial, most rapid outgrowth period of neuritogenesis [0-4 hr after dibutyryl adenosine 3',5'-cyclic monophosphate (dbcAMP) treatment] is accompanied by intense GAP-43 immunoreactivity along the entire length of most neurites. However, this immunoreactivity declined nearly to background levels within hours during continued neurite outgrowth and persisted only at varicosities and growth cones. GAP-43 was detectable by metabolic labeling and immunoblot analysis in undifferentiated cells, and synthetic rates and steady-state levels of GAP-43 underwent only a modest (approximately twofold) increase during dbcAMP-induced differentiation. Unlike levels observed in neurites, perikarya of undifferentiated and differentiated cells contained similar, intense levels of GAP-43 immunoreactivity. Neurite elaboration and GAP-43 immunoreactivity were unaffected by treatment with cycloheximide, suggesting that translocation of perikaryal GAP-43 pools, rather than de novo synthesis, contributes to the transient burst of GAP-43 observed in developing neurites. Phosphatidylcholine-mediated delivery of anti-GAP-43 antibodies (alpha GAP) into cells immediately before dbcAMP treatment arrested neuritogenesis but did not induce the retraction of existing neurites. These results indicate that, while GAP-43 expression is insufficient to induce neuritogenesis in NB2a/d1 cells, GAP-43 is nevertheless essential for the initial, dynamic phase of neurite outgrowth.