Serum chemokines in patients with psoriatic arthritis treated with cyclosporin A.
To evaluate the levels of serum chemokines in patients with psoriatic arthritis (PsA) before and during cyclosporin A (CyA) treatment. Sixteen outpatients with active PsA were followed for 6 months during low dosage CyA treatment. Serum chemokines of the C-X-C and C-C groups were determined by ELISA at the baseline. Serum RANTES levels were measured at 2 month intervals for 6 months. Serum chemokine levels were related with clinical and laboratory disease activity variables. Serum interleukin 8 and macrophage inflammatory protein 1alpha levels were undetectable at baseline. Mean serum growth related gene product-alpha and monocyte chemoattractant protein 1 values were reduced and serum RANTES were elevated compared to controls. CyA treatment did not change serum RANTES levels. Patients with PsA with persistently normal serum RANTES levels (4 patients) had a more favorable clinical and laboratory response to CyA compared to patients with persistently high serum levels (6 patients). Serum RANTES levels are higher in patients with PsA than in a control population. CyA treatment does not change RANTES values. Patients with PsA with persistently normal RANTES levels have a better response to CyA treatment.


Prevalence and "Red Flags" Regarding Specified Causes of Back Pain in Older Adults Presenting in General Practice.
In a small proportion of patients experiencing unspecified back pain, a specified underlying pathology is present. The purposes of this study were: (1) to identify the prevalence of physician-specified causes of back pain and (2) to assess associations between "red flags" and vertebral fractures, as diagnosed by the patients' general practitioner (GP), in older adults with back pain. The Back Complaints in the Elders (BACE) study is a prospective cohort study. Patients (aged >55 years) with back pain were included when consulting their GP. A questionnaire was administered and a physical examination and heel bone densitometry were performed, and the results determined back pain and patient characteristics, including red flags. Participants received a radiograph, and reports were sent to their GP. The final diagnoses established at 1 year were collected from the GP's patient registry. Of the 669 participants included, 6% were diagnosed with a serious underlying pathology during the 1-year follow-up. Most of these participants (n=33, 5%) were diagnosed with a vertebral fracture. Multivariable regression analysis showed that age of ≥75 years, trauma, osteoporosis, a back pain intensity score of ≥7, and thoracic pain were associated with a higher chance of getting the diagnosis of a vertebral fracture. Of these variables, trauma showed the highest positive predictive value for vertebral fracture of 0.25 (95% confidence interval=0.09, 0.41) and a positive likelihood ratio of 6.2 (95% confidence interval=2.8, 13.5). A diagnostic prediction model including the 5 red flags did not increase these values. Low prevalence of vertebral fractures could have led to findings by chance. In these older adults with back pain presenting in general practice, 6% were diagnosed with serious pathology, mainly a vertebral fracture (5%). Four red flags were associated with the presence of vertebral fracture.


[Retroperitoneal cystic lymphangioma in an adult: case report].
Retroperitoneal cystic lymphangyoma is a benign lesion, extremely rare in adults. In most cases is asymptomatic. The objective of this report is to present the case of an 82 year old woman who presented abdominal pain, food intolerance and a palpable abdominal mass located toward the upper right quadrant. The abdominal CT scan showed a cystic lesion below the liver which extended to the retroperitoneum. The patient underwent laparotomy achieving complete resection of the lesion and she was discharged soon after. After six months of follow up, she has not presented recurrence. The presentation of this lesion is very rare, generally as a consequence of congenital malformations of the lymphatic vessels. These lesions must be considered as part of the differential diagnosis of the cystic type tumors. The ultrasound and abdominal CT scan are useful for diagnosis. Surgical resection is the only therapeutic option.


The semiaquatic nematoceran fly assemblages of three wetland habitats and concordance with plant species composition, a case study from subalpine Fennoscandia.
Semiaquatic flies (Diptera, Nematocera) are an ecologically important and species rich group of insects within the boreal and arctic biomes. Community structure, species richness and abundance of semiaquatic flies were studied in three habitat types (aapa mires, springs and headwater streams), totaling 19 study sites, within the subalpine ecoregion of northern boreal Finland. Concordance of semiaquatic fly species composition with plant assemblages (higher plants and mosses), and geographical and environmental distance matrices were also studied. The collected insect material consisted of 94 species and 9038 specimens. According to non-metric multidimensional scaling ordination (visual inspection), multi-response permutation procedure and analysis of similarity tests, fly assemblages of aapa mires were clearly different from those of springs and headwater streams, but no differences were found between spring and headwater stream assemblages. The cumulative number of species was highest in headwater streams. Alpha diversity varied within the habitat types but was generally highest among headwater streams. Semiaquatic fly communities of headwater streams were the most abundant (number of specimens) and their rank-abundance distributions were relatively skewed; assemblages of aapa mires were less abundant and rather even. Community composition of combined plant material (219 taxa), higher plants (116 taxa) and mosses (103 taxa) were all in concordance with the flies; the strongest matrix correlation was found between higher plants and flies (Mantel test). The influence of geographical distance of the study sites to species composition was statistically significant but rather weak; instead, much stronger concordance was noted with environmental variables (Mantel test). Plants, especially higher plants, may be potential surrogates for semiaquatic fly assemblage composition. However, more studies of community concordance in a larger geographic area and within one habitat type are needed.


[Prevalence and diversity of emotional abuse and neglect in childhood in Iceland].
Parenting styles that include abuse can harm the development of the child's brain with a long or short-term impact on his/her health and behaviour. The scope and diversity of abuse are important determinants, and neglect is one of its most serious manifestations. The aim of the study is to examine the prevalence and diversity of emotional abuse and neglect reported by adult Icelanders in their childhood, and how such experience had influenced their evaluation of their upbringing. Icelanders 18 years and older were randomly selected from the national population register. They were invited to express their perception of their upbringing, and answer questions regarding their experience of 8 specific forms of emotional abuse in childhood, and neglect. Of 966 interviewees, 663 (69%) had experienced one or more of the 8 forms of emotional abuse. Those younger than 30 years were 2.9 times more likely to have such an experience compared to those who were older (95% CI 1.9 to 4.3). The perception of upbringing as bad or acceptable compared to good was significantly related to the number of forms of emotional abuse applied (p<0.0001) and the scope of its application (p<0.0001). In total 105 (11%) considered that they had experienced neglect in childhood. Significantly more men than women had experienced emotional abuse (p= 0.0020), whereas women reported neglect (p=0.0440). More than 2/3 of adult Icelanders report experience of one or more out of 8 different forms of emotional abuse and 1/10 report neglect. Parenting styles can be changed, e.g. with education, social support, and legislation.


Kinetic characterization of early immunoreactive intermediates during the refolding of guanidine-unfolded Escherichia coli tryptophan synthase beta 2 subunits.
This paper deals with stopped-flow studies on the kinetics of the regain of immunoreactivity toward five distinct monoclonal antibodies during the folding of the guanidine-unfolded beta 2 subunit of Escherichia coli tryptophan synthase and of two complementary proteolytic fragments of beta, F1 (N-terminal; Mw = 29,000) and F2 (C-terminal; Mw = 12,000). It is shown that, while selected as being "specific" for the native protein, these antibodies are all able to recognize early folding intermediates. The two antigenic determinants carried by the F2 domain and the antigenic site carried by the hinge peptide linking F1 and F2 are present so early during the folding process that their kinetics of appearance could not be followed. On the contrary, the rate constants of appearance of two "native-like" epitopes, carried by F1, could be determined during the folding of beta chains. The rate constant of appearance of the epitope to antibody 19 was found to be k = 0.065 s-1 at 12 degrees C. This value is very similar to that we reported previously for the appearance of an early epitope to the same antibody during the folding of acid-denatured beta chains. Thus, in spite of the important structural differences between guanidine-unfolded and acid-denatured beta chains, the same early folding events seem to be involved in the appearance of this epitope. The rate constant was found to be significantly smaller (k = 0.02 s-1 at 12 degrees C) for the appearance of the epitope to antibody 9. This shows that the regain of immunoreactivity is not concerted within the F1 domain.(ABSTRACT TRUNCATED AT 250 WORDS)


The effect of macromolecular architecture in nanomaterials: a comparison of site isolation in porphyrin core dendrimers and their isomeric linear analogues.
The influence of macromolecular architecture on the physical properties of polymeric materials has been studied by comparing poly(benzyl ether) dendrons with their exact linear analogues. The results clearly confirm the anticipation that dendrimers are unique when compared to other architectures. Physical properties, from hydrodynamic volume to crystallinity, were shown to be different, and in a comparative study of core encapsulation in macromolecules of different architecture, energy transduction from the polymer backbone to a porphyrin core was shown to be different for dendrimers as compared to that of isomeric four- or eight-arm star polymers. Fluorescence excitation revealed strong, morphology dependent intramolecular energy transfer in the three macromolecular isomers investigated. Even at high generations, the dendrimers exhibited the most efficient energy transfer, thereby indicating that the dendritic architecture affords superior site isolation to the central porphyrin it surrounds.


sconce: a cosmic web finder for spherical and conic geometries.
The latticework structure known as the cosmic web provides a valuable insight into the assembly history of large-scale structures. Despite the variety of methods to identify the cosmic web structures, they mostly rely on the assumption that galaxies are embedded in a Euclidean geometric space. Here, we present a novel cosmic web identifier called sconce (Spherical and CONic Cosmic wEb finder) that inherently considers the 2D (RA, DEC) spherical or the 3D (RA, DEC, z) conic geometry. The proposed algorithms in sconce generalize the well-known subspace constrained mean shift (scms) method and primarily address the predominant filament detection problem. They are intrinsic to the spherical/conic geometry and invariant to data rotations. We further test the efficacy of our method with an artificial cross-shaped filament example and apply it to the SDSS galaxy catalogue, revealing that the 2D spherical version of our algorithms is robust even in regions of high declination. Finally, using N-body simulations from Illustris, we show that the 3D conic version of our algorithms is more robust in detecting filaments than the standard scms method under the redshift distortions caused by the peculiar velocities of haloes. Our cosmic web finder is packaged in python as sconce-scms and has been made publicly available.


Multi locus variable-number tandem repeat (MLVA) typing tools improved the surveillance of Salmonella enteritidis: a 6 years retrospective study.
Surveillance of Salmonella enterica subsp. enterica serovar Enteritidis is generally considered to benefit from molecular techniques like multiple-locus variable-number of tandem repeats analysis (MLVA), which allow early detection and confinement of outbreaks. Here, a surveillance study, including phage typing, antimicrobial susceptibility testing and MLVA on 1,535 S. Enteritidis isolates collected between 2007 and 2012, was used to evaluate the added value of MLVA for public health surveillance in Belgium. Phage types PT4, PT8, PT21, PT1, PT6, PT14b, PT28 and PT13 dominate the Belgian S. Enteritidis population. The isolates of S. Enteritidis were most frequently susceptible to all antibiotics tested. 172 different MLVA profiles were detected, of which 9 frequent profiles included 67.2% of the S. Enteritidis population. During a serial passage experiment on selected isolates to investigate the in vitro stability of the 5 MLVA loci, no variations over time were observed indicating that the MLVA profiles were stable. The MLVA profile of isolates originating from different outbreaks in the Democratic Republic of the Congo (DRC) between 2010 and 2011 were distinct from any of the MLVA profiles found in Belgian isolates throughout the six year observational period and demonstrates that MLVA improves public health surveillance of S. Enteritidis. However, MLVA should be complemented with other subtyping methods when investigating outbreaks is caused by the most common MLVA profile.


Malignant solid tumors associated with congenital immunodeficiency disorders.
This objective of this study was to evaluate patients with immunodeficiency syndromes who had developed malignant solid tumors and to examine survival rates and prognosis with respect to type of immunodeficiency disease. Twenty-two patients who were diagnosed with malignant solid tumors and immunodeficiency syndromes between January 1972 and February 2003 were analyzed retrospectively. There were 12 (55%) patients with non-Hodgkin lymphoma, 8 (37%) with Hodgkin disease, 1 (5%) with mucinous adenocarcinoma of the colon, and 1 (5%) with brain stem glioma. Fifteen (68%) patients had ataxia-telangiectasia, 3 (14%) had common variable immunodeficiency disease, 2 (9%) had Bloom syndrome, 1 (5%) had combined immunodeficiency, and 1 (5%) had selective immunoglobulin A deficiency. Out of the 15 patients with ataxia-telangiectasia 9 patients had non-Hodgkin lymphoma, 5 had Hodgkin disease, and 1 had brain stem glioma. Two patients with common variable immunodeficiency disease had non-Hodgkin lymphoma and 1 had Hodgkin disease. One of the patients with Bloom syndrome had Hodgkin disease and 1 had colon carcinoma. The overall survival for the whole group was 24%. Overall survival rates in non-Hodgkin lymphoma, Hodgkin disease, colon carcinoma, and brain stem glioma were 17, 44, 0, and 0% (p =.25), respectively. Overall survival in ataxia-telangiectasia patients was 20%. In this series, most of the patients had ataxia-telangiectasia (68%). The survival rates of the malignant diseases were very poor in immunodeficiency. Overall survival in non-Hodgkin lymphoma patients was relatively worse than Hodgkin disease patients.


High-Resolution AMS Dating of Architecture, Boulder Artworks and the Transition to Farming at Lepenski Vir.
The archaeological site of Lepenski Vir is widely known after its remarkable stone art sculptures that represent a unique and unprecedented case of Holocene hunter-gatherer creativity. These artworks were found largely associated with equally unique trapezoidal limestone building floors around their centrally located rectangular stone-lined hearths. A debate has raged since the discovery of the site about the chronological place of various discovered features. While over years different views from that of the excavator about the stratigraphy and chronology of the site have been put forward, some major disagreements about the chronological position of the features that make this site a key point of reference in European Prehistory persist. Despite challenges of re-analyzing the site's stratigraphy from the original excavation records, taphonomic problems, and issues of reservoir offsets when providing radiocarbon measurements on human and dog bones, our targeted AMS (Accelerator Mass Spectrometry) dating of various contexts from this site with the application of Bayesian statistical modelling allows us to propose with confidence a new and sound chronological framework and provide formal estimates for several key developments represented in the archaeological record of Lepenski Vir that help us in understanding the transition of last foragers to first farmers in southeast Europe as a whole.


Factors associated with dietary behaviour change support in patients: A qualitative study among community nurses.
To explore which factors, influencing dietary behaviour change support among patients by Dutch community nurses (CNs; nurses), are key focal points in training programmes. Nurses have an important role in counselling patients towards healthier dietary behaviour to prevent or delay long-term complications from chronic lifestyle-related diseases. Most nurses do not incorporate dietary behaviour change support in their routines to the fullest potential. A qualitative descriptive study. Data were collected in the Netherlands in 2018-2019 via semi-structured face-to-face interviews with 18 nurses. Interview guide themes were informed by the COM-B model, using validated descriptions in Dutch. Data were recorded, transcribed and analysed using inductive thematic analysis. Factors that affected dietary behaviour change support were linked to (1) the nurse (role identity, dietary knowledge and competences such as methodical approach, behaviour change techniques and communication techniques), (2) nurse-patient encounter (building a relationship with a patient, supporting patient autonomy and tailoring the approach) and (3) cooperation and organizational context. It is of utmost importance to pay attention to nurses' role identity regarding dietary behaviour change support, as this underlies professional behaviour. This should be accompanied by improving competences on dietary behaviour change support. Focus on competences regarding the application of behaviour change technique is crucial. Furthermore, having a relationship of trust with a patient was important for discussing sensitive topics such as diet. The promotion of a healthy diet provides opportunities to contribute to patient autonomy and self-management. Well-fitted training offers for (senior) nurses will lead to improved professional practice of nurses, leading to healthier dietary behaviour of patients. A nurse provided feedback on the interview guide.


Pain management in children with terminal illnesses.
Managing pain in children at the end of life is a complex area that requires an understanding of the unique challenges offered by this young population. The following article will assist the practitioner with the management of pain associated with terminal illnesses in children. Discussion will focus on concepts and principles that form the foundation of pediatric pain management. Prior to the presentation, an overview is presented to address the pharmacologic concerns in the younger patients and the assessment of pain in the different age groups.


Genomic Prediction of Tendinopathy Risk in Elite Team Sports.
The authors investigated the association between risk of tendinopathies and genetic markers in professional team sports. The authors studied 363 (mean [SD]; 25 [6] y, 89% male) elite players (soccer, futsal, basketball, handball, and roller hockey) from a top-level European team (FC Barcelona, Spain). Of 363, 55% (cases) had experienced 1+ episodes of tendinopathy during 2008-2018 and 45% (controls) remained injury free. The authors first examined the association between single-nucleotide polymorphisms (SNPs) and tendinopathy risk in a hypothesis-free case-control genome-wide association study (495,837 SNPs) with additional target analysis of 58 SNPs that are potential candidates to influence tendinopathy risk based on the literature. Thereafter, the authors augmented the SNP set by performing synthetic variant imputation (1,419,369 SNPs) and then used machine learning-based multivariate modeling (support vector machine and random forest) to build a reliable predictive model. Suggestive association (P < 10-5) was found for rs11154027 (gap junction alpha 1), rs4362400 (vesicle amine transport 1-like), and rs10263021 (contactin-associated protein-like 2). Carriage of 1+ variant alleles for rs11154027 (odds ratio = 2.11; 95% confidence interval, 1.07-4.19, P = 1.01 × 10-6) or rs4362400 (odds ratio = 1.98; 95% confidence interval, 1.05-3.73, P = 9.6 × 10-6) was associated with a higher risk of tendinopathy, whereas an opposite effect was found for rs10263021 (odds ratio = 0.42; 95% confidence interval, 0.20-0.91], P = 4.5 × 10-6). In the modeling approach, one of the most robust SNPs was rs10477683 in the fibrillin 2 gene encoding fibrillin 2, a component of connective tissue microfibrils involved in elastic fiber assembly. The authors have identified previously undescribed genetic predictors of tendinopathy in elite team sports athletes, notably rs11154027, rs4362400, and rs10263021.


Impact of secondary hyperparathyroidism on ventricular mass regression after aortic valve replacement for aortic stenosis in hemodialysis-dependent patients.
In hemodialysis (HD)-dependent patients, secondary hyperparathyroidism induces cardiac hypertrophy. This study investigated whether parathyroid hormone (PTH) levels affect the degree of left ventricular (LV) mass regression in HD patients after aortic valve replacement (AVR) for aortic stenosis (AS). We retrospectively obtained preoperative and 2-year postoperative echocardiography and intact PTH measurements in 88 HD patients who underwent AVR, with bioprostheses (n = 35, 40%) and mechanical valves (n = 53, 60%) of effective orifice area >0.80 cm2/m2, between January 1997 and December 2010. The LV mass decreased significantly from 308 ± 88 to 217 ± 68 g at follow-up of 28 ± 4 months after AVR (p < 0.001). The LV mass regression at follow-up was inversely related to preoperative PTH values (R = 0.44, p = 0.001). The LV mass regression at follow-up was significantly smaller in the patients (n = 47) with PTH ≥100 pg/mL than in those (n = 41) with PTH <100 pg/mL throughout the study period (61 ± 75 versus 108 ± 49 g, p < 0.0001). After adjusting for female sex, hypertension, and baseline LV mass, high PTH values were found to be independent predictor of less LV mass regression at 2-year follow-up (β = 0.23, r2 = 0.24, p = 0.02). In conclusion, the HD patients with high levels of PTH presented with less LV mass regression after AVR for AS without patient-prosthesis mismatch. Secondary hyperparathyroidism may impair regression of cardiac hypertrophy after AVR in HD patients with AS.


Brahma regulates a specific trans-splicing event at the mod(mdg4) locus of Drosophila melanogaster.
The mod(mdg4) locus of Drosophila melanogaster contains several transcription units encoded on both DNA strands. The mod(mdg4) pre-mRNAs are alternatively spliced, and a very significant fraction of the mature mod(mdg4) mRNAs are formed by trans-splicing. We have studied the transcripts derived from one of the anti-sense regions within the mod(mdg4) locus in order to shed light on the expression of this complex locus. We have characterized the expression of anti-sense mod(mdg4) transcripts in S2 cells, mapped their transcription start sites and cleavage sites, identified and quantified alternatively spliced transcripts, and obtained insight into the regulation of the mod(mdg4) trans-splicing. In a previous study, we had shown that the alternative splicing of some mod(mdg4) transcripts was regulated by Brahma (BRM), the ATPase subunit of the SWI/SNF chromatin-remodeling complex. Here we show, using RNA interference and overexpression of recombinant BRM proteins, that the levels of BRM affect specifically the abundance of a trans-spliced mod(mdg4) mRNA isoform in both S2 cells and larvae. This specific effect on trans-splicing is accompanied by a local increase in the density of RNA polymerase II and by a change in the phosphorylation state of the C-terminal domain of the large subunit of RNA polymerase II. Interestingly, the regulation of the mod(mdg4) splicing by BRM is independent of the ATPase activity of BRM, which suggests that the mechanism by which BRM modulates trans-splicing is independent of its chromatin-remodeling activity.


An amphioxus Emx homeobox gene reveals duplication during vertebrate evolution.
Members of the Emx homeobox gene class are expressed during embryogenesis in the brain and/or other head structures of phylogenetically diverse phyla. Here, we describe sequence, genomic structure, and molecular phylogenetic analysis of a cephalochordate (amphioxus) Emx class gene termed AmphiEmxA. The genomic structure of AmphiEmxA is very similar to that of vertebrate Emx genes, with two conserved intron sites. The Drosophila homolog empty spiracles (ems) has just one intron, which may be shared with chordates; the other has been secondarily lost in this Drosophila gene and in a cnidarian Emx-related gene. We identify a highly conserved peptide motif close to the amino terminus of Emx proteins, demonstrate its similarity to a sequence found in a variety of transcription factors, and argue that it arose through convergent evolution in homeobox and forkhead genes. Finally, our molecular phylogenetic analysis strongly supports the presence of a single Emx gene in the ancestor of chordates and gene duplication along the vertebrate lineage.


Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 lowers intraocular pressure in patients with ocular hypertension.
Intraocular pressure (IOP) is maintained by a balance between aqueous humour (AH) production (dependent on sodium transport across a ciliary epithelial bi-layer) and drainage (predominantly through the trabecular meshwork). In peripheral epithelial tissues, sodium and water transport is regulated by corticosteroids and the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isozymes (11beta-HSD1 activating cortisol from cortisone, 11beta-HSD2 inactivating cortisol to cortisone). To analyse expression of 11beta-HSD in the human eye and investigate its putative role in AH formation. Multipart prospective study, including a randomized controlled clinical trial. The expression of 11beta-HSD1 in normal human anterior segments was evaluated by in situ hybridization (ISH). RT-PCR for 11beta-HSDs, glucocorticoid and mineralocorticoid receptors (GR, MR) was performed on human ciliary body tissue. AH cortisol and cortisone concentrations were measured by radioimmunoassay on specimens taken from patients with primary open-angle glaucoma (POAG) and age-matched controls. Randomized, placebo-controlled studies of healthy volunteers and patients with ocular hypertension (OHT, raised IOP but no optic neuropathy) assessed the effect of oral carbenoxolone (CBX, an inhibitor of 11beta-HSD) on IOP. ISH defined expression of 11beta-HSD1 in the ciliary epithelium, while RT-PCR analysis of ciliary body tissue confirmed expression of 11beta-HSD1, with additional GR and MR, but not 11beta-HSD2 expression. In both POAG patients and controls, AH concentrations of cortisol exceeded those of cortisone. The CBX-treated healthy volunteers who demonstrated the largest change in urinary cortisol metabolites, indicative of 11beta-HSD1 inhibition, had the greatest fall in IOP. Patients with OHT showed an overall reduction of IOP by 10% following CBX administration, compared to baseline (p<0.0001). CBX lowers IOP in patients with ocular hypertension. Our data suggest that this is mediated through inhibition of 11beta-HSD1 in the ciliary epithelium. Selective and topical inhibitors of 11beta-HSD1 could provide a novel treatment for patients with glaucoma.


Activation of Rac-1 and RhoA contributes to podocyte injury in chronic kidney disease.
Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.


Ubiquitin-dependent intramembrane rhomboid protease promotes ERAD of membrane proteins.
The ER-associated degradation (ERAD) pathway serves as an important cellular safeguard by directing incorrectly folded and unassembled proteins from the ER to the proteasome. Still, however, little is known about the components mediating ERAD of membrane proteins. Here we show that the evolutionary conserved rhomboid family protein RHBDL4 is a ubiquitin-dependent ER-resident intramembrane protease that is upregulated upon ER stress. RHBDL4 cleaves single-spanning and polytopic membrane proteins with unstable transmembrane helices, leading to their degradation by the canonical ERAD machinery. RHBDL4 specifically binds the AAA+-ATPase p97, suggesting that proteolytic processing and dislocation into the cytosol are functionally linked. The phylogenetic relationship between rhomboids and the ERAD factor derlin suggests that substrates for intramembrane proteolysis and protein dislocation are recruited by a shared mechanism.


Quantifying the impact of COVID-19 on essential health services: a comparison of interrupted time series analysis using Prophet and Poisson regression models.
Coronavirus disease 2019 (COVID-19) altered healthcare utilization patterns. However, there is a dearth of literature comparing methods for quantifying the extent to which the pandemic disrupted healthcare service provision in sub-Saharan African countries. To compare interrupted time series analysis using Prophet and Poisson regression models in evaluating the impact of COVID-19 on essential health services. We used reported data from Uganda's Health Management Information System from February 2018 to December 2020. We compared Prophet and Poisson models in evaluating the impact of COVID-19 on new clinic visits, diabetes clinic visits, and in-hospital deliveries between March 2020 to December 2020 and across the Central, Eastern, Northern, and Western regions of Uganda. The models generated similar estimates of the impact of COVID-19 in 10 of the 12 outcome-region pairs evaluated. Both models estimated declines in new clinic visits in the Central, Northern, and Western regions, and an increase in the Eastern Region. Both models estimated declines in diabetes clinic visits in the Central and Western regions, with no significant changes in the Eastern and Northern regions. For in-hospital deliveries, the models estimated a decline in the Western Region, no changes in the Central Region, and had different estimates in the Eastern and Northern regions. The Prophet and Poisson models are useful in quantifying the impact of interruptions on essential health services during pandemics but may result in different measures of effect. Rigor and multimethod triangulation are necessary to study the true effect of pandemics on essential health services.


Periprocedural monitoring with regional cerebral oxygen saturation in carotid artery stenting.
Hemodynamic instability during and after carotid artery stenting (CAS) may reduce cerebral blood flow (CBF), leading to cerebral ischemia. To investigate changes in CBF in the periprocedural period, we continuously recorded the regional cerebral oxygen saturation (rSO2) using near-infrared spectroscopy. In 46 consecutive patients with carotid artery stenosis, rSO2 was continuously recorded during and after CAS. In addition, the patients underwent SPECT to evaluate a change in CBF on the next day after CAS. Introprocedural bradycardia (heart rate < 50 bpm) occurred in 21 patients (46%) including one transient cardiac arrest. Intraprocedural hypotension (systolic blood pressure < 80 mmHg) occurred in 18 patients (39%), and 16 of them showed prolonged hypotension. The rSO2 in patients with bradycardia/hypotension during CAS was significantly less than that in patients without them (p < 0.01). Moreover, the SPECT on the next day after CAS demonstrated that the ipsilateral CBF in patients with bradycardia/hypotension during CAS significantly more than that in patients without them (p < 0.05). Intraprocedural hemodynamic instability resulted in a significant decrease in rSO2, leading to a possible severe cerebral ischemia. In addition, intraprocedural bradycardia/hypotension might be related with postprodedural hyperperfusion, causing the morbidity and mortality after CAS.


[Dispersion analysis of viral suspensions by the technic of optical mixing spectroscopy].
To evaluate the heterogeneity of virus populations and determinations of virus monoparticle size in suspensions, a dispersion analysis by the method of spectroscopy of optic mixing was developed. The parameters of influenza USSR/Khabarovsk and parainfluenza Sendai virus suspensions were measured in correlation spectrometer and the results were computerized.


Potential associations between fecal shedding of Salmonella in feedlot cattle treated for apparent respiratory disease and subsequent adverse health outcomes.
A prospective cohort study was used to assess whether Salmonella fecal shedding in commercial feedlot cattle treated with antimicrobials for respiratory disease was associated with subsequent adverse health outcomes. Feces were collected per rectum from cattle that were examined for apparent respiratory disease, had a rectal temperature > or = 40 degrees C, and subsequently received antimicrobial treatment. Salmonella were recovered from 918 (73.7%) of 1 245 fecal samples and weekly prevalence estimates ranged from 49 to 100% over the 3-month study. Genotypic and phenotypic characteristics of Salmonella strains in the population were determined. Serogroup E Salmonella were most common (73.3%), followed by C1 (11.0%), C3 (8.6%), and B (1.1%). Predominant serotypes were Orion (46.5%), Anatum (19.8%), Kentucky (8.7%), Montevideo (7.5%), and Senftenberg (4.9%). Few isolates (36/918) were positive for antimicrobial resistance-associated integron gene intI1. Phenotypic susceptibility was associated with isolate intI1 status. Crude re-pull, re-treatment and case fatality risks were higher for cattle that were Salmonella-positive versus -negative at initial treatment, but not statistically different on multivariable analysis. However, case fatality risk was higher for cattle shedding Group B Salmonella than for cattle shedding other serogroups. Lots (groups) with a higher Salmonella prevalence at first treatment had a higher proportion of mortalities occur in a hospital pen, higher overall re-treatment risks, and were more likely to be sampled later in the study. Results indicate a high prevalence of Salmonella in this population of cattle treated for apparent respiratory disease, but that effects associated with clinical outcomes may depend on the Salmonella strain.


Associations of physical strength with facial shape in an African pastoralist society, the Maasai of Northern Tanzania.
Previous research has documented associations of physical strength and facial morphology predominantly in men of Western societies. Faces of strong men tend to be more robust, are rounder and have a prominent jawline compared with faces of weak men. Here, we investigate whether the morphometric patterns of strength-face relationships reported for members of industrialized societies can also be found in members of an African pastoralist society, the Maasai of Northern Tanzania. Handgrip strength (HGS) measures and facial photographs were collected from a sample of 185 men and 120 women of the Maasai in the Ngorongoro Conservation Area. In young-adults (20-29 years; n = 95) and mid-adults (30-50 years; n = 114), we digitized 71 somatometric landmarks and semilandmarks to capture variation in facial morphology and performed shape regressions of landmark coordinates upon HGS. Results were visualized in the form of thin-plate plate spline deformation grids and geometric morphometric morphs. Individuals with higher HGS tended to have wider faces with a lower and broader forehead, a wider distance between the medial canthi of the eyes, a wider nose, fuller lips, and a larger, squarer lower facial outline compared with weaker individuals of the same age-sex group. In mid-adult men, these associations were weaker than in the other age-sex groups. We conclude that the patterns of HGS relationships with face shape in the Maasai are similar to those reported from related investigations in samples of industrialized societies. We discuss differences between the present and related studies with regard to knowledge about the causes for age- and sex-related facial shape variation and physical strength associations.


Human herpesvirus 6.
Human herpesvirus 6 (HHV-6) is a T-lymphotropic herpesvirus, which infects almost all children by the age of two years and persists lifelong. Two distinct variants of HHV-6, HHV-6A and HHV-6B, have been described, and the latter has been shown to be a common cause of acute febrile illnesses in young children, including exanthem subitum (roseola). HHV-6 has also been associated with a number of neurological disorders, including encephalitis and seizures, and the virus has been postulated to play a role in acquired immunodeficiency syndrome (AIDS), multiple sclerosis (MS) and chronic fatigue immunodeficiency syndrome (CFIDS). This review provides a critical summary of research conducted on HHV-6.


CBD-1 organizes two independent complexes required for eggshell vitelline layer formation and egg activation in C. elegans.
Metazoan eggs have a specialized coat of extracellular matrix that aids in sperm-egg recognition. The coat is rapidly remodeled after fertilization to prevent polyspermy and establish a more permanent barrier to protect the developing embryo. In nematodes, this coat is called the vitelline layer, which is remodeled into the outermost layer of a rigid and impermeable eggshell. We have identified three key components of the vitelline layer structural scaffold - PERM-2, PERM-4 and CBD-1, the first such proteins to be described in the nematode C. elegans. CBD-1 tethered PERM-2 and PERM-4 to the nascent vitelline layer via two N-terminal chitin-binding domains. After fertilization, all three proteins redistributed from the zygote surface to the outer eggshell. Depletion of PERM-2 and PERM-4 from the scaffold led to a porous vitelline layer that permitted soluble factors to leak through the eggshell and resulted in embryonic death. In addition to its role in vitelline layer assembly, CBD-1 is also known to anchor a protein complex required for fertilization and egg activation (EGG-1-5/CHS-1/MBK-2). We found the PERM complex and EGG complex to be functionally independent, and structurally organized through distinct domains of CBD-1. CBD-1 is thus a multifaceted regulator that promotes distinct aspects of vitelline layer assembly and egg activation. In sum, our findings characterize the first vitelline layer components in nematodes, and provide a foundation through which to explore both conserved and species-specific strategies used by animals to build protective barriers following fertilization.


Oenothein B, a cyclic dimeric ellagitannin isolated from Epilobium angustifolium, enhances IFNγ production by lymphocytes.
Oenothein B is a polyphenol isolated from Epilobium angustifolium and other plant sources, which has been reported to exhibit immunomodulatory properties. Oenothein B is known to activate myeloid cells and induce the production of IL-1 and other cytokines. However, its effects on lymphocytes are unknown. In this report, we show that oenothein B stimulated innate lymphocytes, including bovine and human γδ T cells and NK cells, resulting in either increased CD25 and/or CD69 expression. We also demonstrate that oenothein B enhanced the production of interferon-γ (IFNγ) by bovine and human NK cells alone and in combination with interleukin-18 (IL-18), a response not observed with other commonly studied polyphenols. Furthermore, we demonstrate that oenothein B enhanced the production of IFNγ by human T cells. Since IFNγ contributes to antitumor, antibacterial, and antiviral cell responses, these data suggest an additional mechanism that could account, at least in part, for the immune enhancing properties of oenothein B.


High prevalence and correlates of low bone mineral density in young adults with sickle cell disease.
Sickle cell disease (SCD) is a prevalent genetic disorder in which sickle hemoglobin leads to tissue hypoxia and adverse effects on bone. Published studies suggest that children with SCD often have undiagnosed osteopenia or osteoporosis. Minimal data exist on the prevalence of low bone mineral density (BMD) in adults. Our objective was to describe the prevalence of osteopenia and osteoporosis in adults with SCD and to identify patient or disease characteristics associated with low BMD. We conducted a cross-sectional study of adults with SCD. Through questionnaires, we collected data about disease course and osteoporosis risk factors. Patients underwent dual X-ray absorptiometry (DXA) measurement of BMD at the hip, spine, and forearm and sampling of blood and urine for markers of bone turnover, sickle cell disease severity, and secondary causes of osteoporosis. Our main outcome measure was prevalence of osteopenia and osteoporosis as defined by WHO criteria. Of 32 adults with SCD (14 men and 18 women) with a mean age of 34 years, 72% (95% confidence interval 53-86%) had low BMD at one or more anatomic sites. Thirteen patients were classified as osteoporotic and 10 as osteopenic. The prevalence of low BMD was greatest in the lumbar spine (66% of patients). Significant correlates of decreased BMD included low BMI (P < 0.01), male sex (P = 0.02), and low serum zinc concentrations (P < 0.01). The prevalence of osteopenia and osteoporosis in young adults with SCD is extremely high. Further research is needed to address fracture risk and therapeutic interventions.


Accurate Localization in Acoustic Underwater Localization Systems.
In underwater localization systems several sources of error may impact in different ways the accuracy of the final position estimates. Through simulations and statistical analysis it is possible to identify and characterize such sources of error and their relative importance. This is especially of use when an accurate localization system has to be designed within required accuracy prescriptions. This approach allows one to also investigate how much these sources of error influence the final position estimates achieved by an Extended Kalman Filter (EKF). This paper presents the results of experiments designed in a virtual environment used to simulate real acoustic underwater localization systems. The paper intends to analyze the main parameters that significantly influence the position estimates achieved by a Short Baseline (SBL) system. Specifically, the results of this analysis are presented for a proprietary localization system constituted by a surface platform equipped with four acoustic transducers used for the localization of an underwater target. The simulator here presented has the purpose of simulating the hardware system and modifying some of its design parameters, such as the base-line length and the errors on the GPS and Inertial Measurement Unit (IMU) units, in order to understand which parameters have to modify for improving the accuracy of the entire positioning system. It is shown that statistical analysis techniques can be of help in determining the best values of these parameters that permit to improve the performance of a real hardware system.


Reconstruction options for acetabular revision.
This article summarizes reconstruction options available for acetabular revision following total hip arthroplasty. A thoughtful methodology to the evaluation and treatment of patients with implant failure after joint replacement is essential to guarantee accurate diagnoses, appropriate triage to reconstruction options, and optimal clinical outcomes. In the majority of patients who undergo acetabular revision, factors such as bone loss and pelvic discontinuity provide a challenge in the selection and implementation of the proper reconstruction option. With advanced evaluation algorithms, imaging techniques, and implant designs, techniques have evolved to rebuild the compromised acetabulum at the time of revision surgery. However, clinical outcomes data for these techniques continue to lag behind the exponential increase in revision hip arthroplasty cases predicted to occur over the next several years. We encourage those involved in the treatment of patients undergoing hip replacement surgery to participate in well-designed clinical studies to enhance evidence-based knowledge regarding revision acetabular reconstruction options.


Pancreatic Cancer Cells Induce MicroRNA Deregulation in Platelets.
Pancreatic cancer is a pathology with a high mortality rate since it is detected at advanced stages, so the search for early-stage diagnostic biomarkers is essential. Liquid biopsies are currently being explored for this purpose and educated platelets are a good candidate, since they are known to present a bidirectional interaction with tumor cells. In this work, we analyzed the effects of platelets on cancer cells' viability, as determined by MTT, migration using transwell assays, clonogenicity in soft agar and stemness by dilution assays and stem markers' expression. We found that the co-culture of platelets and pancreatic cancer cells increased the proliferation and migration capacity of BXCP3 cells, augmented clonogenicity and induced higher levels of Nanog, Sox2 and Oct4 expression. As platelets can provide horizontal transfer of microRNAs, we also determined the differential expression of miRNAs in platelets obtained from a small cohort of pancreatic cancer patients and healthy subjects. We found clear differences in the expression of several miRNAs between platelets of patients with cancer healthy subjects. Moreover, when we analyzed microRNAs from the platelets of the pancreatic juice and blood derived from each of the cancer patients, interestingly we find differences between the blood- and pancreatic juice-derived platelets suggesting the presence of different subpopulations of platelets in cancer patients, which warrant further analysis.


Enriching 2D transition metal borides via MB XMenes (M = Fe, Co, Ir): Strong correlation and magnetism.
Recently, two-dimensional (2D) FeSe-like anti-MXenes (or XMenes), composed of late d-block transition metal M and p-block nonmetal X elements, have been both experimentally and theoretically investigated. Here, we select three 2D borides FeB, CoB and IrB for a deeper investigation by including strong correlation effects, as a fertile ground for understanding and applications. Using a combination of Hubbard corrected first-principles calculations and Monte Carlo simulations, FeB and CoB are found to be ferro- and anti-ferro magnetic, contrasting with the non-magnetic nature of IrB. The metallic FeB XMene monolayer, superior to most of the MXenes or MBenes, exhibits robust ferromagnetism, driven by intertwined direct-exchange and super-exchange interactions between adjacent Fe atoms. The predicted Curie temperature (TC) of the FeB monolayer via the Heisenberg model reaches an impressive 425 K, with the easy-axis oriented out-of-plane and high magnetic anisotropic energy (MAE). The asymmetry in the spin-resolved transmission spectrum induces a thermal spin current, providing an opportunity for spin filtration. This novel 2D FeB material is expected to hold great promise as an information storage medium and find applications in emerging spintronic devices.


Somatic MYH7, MYBPC3, TPM1, TNNT2 and TNNI3 mutations in sporadic hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a clinically heterogeneous genetic heart disease characterized by left ventricular hypertrophy in the absence of another disease that could explain the wall thickening. Elucidation of the genetic basis of HCM lead to the identification of several genes encoding sarcomeric proteins, such as MYH7, MYBPC3, TPM1, TNNT2, and TNNI3. Sarcomeric genes are mutated in approximately 40% of HCM patients and a possible explanation for the incomplete yield of mutation-positive HCM may be somatic mutations. We studied 104 unrelated patients with non-familial HCM. Patients underwent clinical evaluation and mutation screening of 5 genes implicated in HCM (MYH7, MYBPC3, TPM1, TNNT2, and TNNI3) in genomic DNA isolated from resected cardiac tissue; 41 of 104 were found to carry a mutation, but as several patients carried the same mutations, the total amount of different mutations was 37; 20 of these mutations have been previously described, and pathogenicity has been assessed. To determine the effect of the 17 new mutations an in silico assay was performed and it predicted that 4 variants were damaging mutations. All identified variants were also seen in the DNA isolated from the corresponding blood, which demonstrated the absence of somatic mutations. Somatic mutations in MYH7, MYBPC3, TPM1, TNNT2, and TNNI3 do not represent an important etiologic pathway in HCM.


Infrequent origin of a peripheral embolism: Arterial thoracic outlet syndrome in a young woman.
Arterial thoracic outlet syndrome (TOS) is caused by the compression of the subclavian or axillary artery between the ribs and the scalene muscles. Patients may present with various clinical conditions. Herein, we report a case of arterial TOS who presented with peripheral embolism. Arterial TOS is an uncommon cause of peripheral embolism. The diagnostic approach and treatment methods used are discussed. Clinicians should keep this diagnosis in mind and manage these cases according to the clinical appearance.


Close-range vocal interaction in the common marmoset (Callithrix jacchus).
Vocal communication in animals often involves taking turns vocalizing. In humans, turn-taking is a fundamental rule in conversation. Among non-human primates, the common marmoset is known to engage in antiphonal calling using phee calls and trill calls. Calls of the trill type are the most common, yet difficult to study, because they are not very loud and uttered in conditions when animals are in close proximity to one another. Here we recorded trill calls in captive pair-housed marmosets using wearable microphones, while the animals were together with their partner or separated, but within trill call range. Trills were exchanged mainly with the partner and not with other animals in the room. Animals placed outside the home cage increased their trill call rate and uttered more trills in response to their partner compared to strangers. The fundamental frequency, F0, of trills increased when animals were placed outside the cage. Our results indicate that trill calls can be monitored using wearable audio equipment and that minor changes in social context affect trill call interactions and spectral properties of trill calls.


Fine-Scale Genetic Structure in Finland.
Coupling dense genotype data with new computational methods offers unprecedented opportunities for individual-level ancestry estimation once geographically precisely defined reference data sets become available. We study such a reference data set for Finland containing 2376 such individuals from the FINRISK Study survey of 1997 both of whose parents were born close to each other. This sampling strategy focuses on the population structure present in Finland before the 1950s. By using the recent haplotype-based methods ChromoPainter (CP) and FineSTRUCTURE (FS) we reveal a highly geographically clustered genetic structure in Finland and report its connections to the settlement history as well as to the current dialectal regions of the Finnish language. The main genetic division within Finland shows striking concordance with the 1323 borderline of the treaty of Nöteborg. In general, we detect genetic substructure throughout the country, which reflects stronger regional genetic differences in Finland compared to, for example, the UK, which in a similar analysis was dominated by a single unstructured population. We expect that similar population genetic reference data sets will become available for many more populations in the near future with important applications, for example, in forensic genetics and in genetic association studies. With this in mind, we report those extensions of the CP + FS approach that we found most useful in our analyses of the Finnish data.


Near-infrared photosensitizer based on a cycloimide derivative of chlorin p6: 13,15-N-(3'-hydroxypropyl)cycloimide chlorin p6.
The 13,15-N-(3'-hydroxypropylcycloimide) chlorin p6 (CIC), which absorbs at 711 nm, possesses considerable photoinduced cell-killing activity. It is 43-, 61- and 110-fold more active than chlorin p6, 3-formyl-3-devinyl chlorin p6 and Photogem, respectively, and has no cytotoxicity without irradiation as estimated on A549 human adenocarcinoma cells. To attain the highest intracellular penetration and activity the monomeric form of CIC should be stabilized. This stabilization in an aqueous environment can be achieved using 0.002-0.005% of Cremophor EL emulsion (polyoxyethylene derivative of hydrogenated castor oil). The intracellular accumulation of CIC occurs in cytoplasm in a monomeric form bound to cellular membranes. This form of the dye is characterized by a high quantum yield of singlet oxygen generation (0.66 +/- 0.02). Besides diffuse staining of intracellular membranous structures, CIC accumulates 3- to 4-fold more intensely in mitochondria and Golgi apparatus, thus indicating these organelles to be the initial targets of its photodynamic action. The incubation time providing 50% accumulation level of CIC in cells is 30 +/- 5 min. The time for 50% release of CIC from the cells is 60 +/- 10 min. A 10-fold decrease in CIC intracellular penetration at 22 degrees C proves that temperature-sensitive mechanisms of transport, rather than diffusion, are responsible for the dye uptake. The average cytoplasmic concentration of CIC was seven times the extracellular concentration in the 0.2-1.6 microM range, used for the photodynamic activity measurements. The concentration of CIC and the light dose that correspond to ca 50% level of phototoxicity induce predominantly an apoptotic-type of cell death, whereas the conditions providing 100% level of phototoxicity induced necrosis. The results obtained indicate that cycloimide derivatives of chlorin p6 may serve as a base for the development of an efficient near-IR photosensitizer.


Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage.
Clinical and radiologic predictors of cerebral infarction occurrence and location after aneurysmal subarachnoid hemorrhage have been seldom studied. We evaluated all patients admitted to our hospital with aneurysmal subarachnoid hemorrhage between 1998 and 2000. Cerebral infarction was defined as a new hypodensity located in a vascular distribution on computed tomography (CT) scan. Fifty-seven of 143 patients (40%) developed a cerebral infarction. On univariate analysis, occurrence of cerebral infarction was associated with a worse World Federation of Neurological Surgeons grade (P=0.01), use of ventriculostomy catheter (P=0.01), preoperative vasospasm (P=0.03), surgical clipping (P=0.02), symptomatic vasospasm (P<0.01), and vasospasm on transcranial Doppler ultrasonography (TCD) or repeat angiogram (P<0.01). On multivariable analysis, only presence of symptoms ascribed to vasospasm (P<0.01) and evidence of vasospasm on TCD or angiogram predicted cerebral infarction (P<0.01). TCD and angiogram agreed on the diagnosis of vasospasm in 73% of cases (95% CI, 63% to 81%), but the diagnostic accuracy of this combination of tests was suboptimal for the prediction of cerebral infarction occurrence (sensitivity, 0.72; specificity, 0.68; positive predictive value, 0.67; negative predictive value, 0.72). Location of the cerebral infarction on delayed CT was predicted by neurological symptoms in 74%, by aneurysm location in 77%, and by angiographic vasospasm in 67%. Evidence of vasospasm on TCD and angiogram is predictive of cerebral infarction on CT scan but sensitivity and specificity are suboptimal. Cerebral infarction location cannot be predicted in one quarter to one third of patients by any of the studied clinical or radiological variables.


Haemophilia and the kidney: assessment after 11-year follow-up.
Radiological and biochemical investigations of renal function were performed in 57 patients with haemophilia, 27 of whom had been previously investigated in 1969. Although one-third of patients had a renal radiographic abnormality, only two had abnormalities persisting since 1969 and attributable to renal bleeding. Isotope renography was a sensitive indicator of renal abnormality whereas a history of haematuria was a poor discriminator for patients with abnormal intravenous urograms or impaired creatinine clearance. Haematuria was not associated with progressive loss of renal function and its natural history in haemophilia is probably benign.


A small zinc finger thylakoid protein plays a role in maintenance of photosystem II in Arabidopsis thaliana.
This work identifies LOW QUANTUM YIELD OF PHOTOSYSTEM II1 (LQY1), a Zn finger protein that shows disulfide isomerase activity, interacts with the photosystem II (PSII) core complex, and may act in repair of photodamaged PSII complexes. Two mutants of an unannotated small Zn finger containing a thylakoid membrane protein of Arabidopsis thaliana (At1g75690; LQY1) were found to have a lower quantum yield of PSII photochemistry and reduced PSII electron transport rate following high-light treatment. The mutants dissipate more excess excitation energy via nonphotochemical pathways than wild type, and they also display elevated accumulation of reactive oxygen species under high light. After high-light treatment, the mutants have less PSII-light-harvesting complex II supercomplex than wild-type plants. Analysis of thylakoid membrane protein complexes showed that wild-type LQY1 protein comigrates with the PSII core monomer and the CP43-less PSII monomer (a marker for ongoing PSII repair and reassembly). PSII repair and reassembly involve the breakage and formation of disulfide bonds among PSII proteins. Interestingly, the recombinant LQY1 protein demonstrates a protein disulfide isomerase activity. LQY1 is more abundant in stroma-exposed thylakoids, where key steps of PSII repair and reassembly take place. The absence of the LQY1 protein accelerates turnover and synthesis of PSII reaction center protein D1. These results suggest that the LQY1 protein may be involved in maintaining PSII activity under high light by regulating repair and reassembly of PSII complexes.


The role of the reticulo-endothelial system in hemorrhagic shock.
"Blockade" of the RES by thorotrast so lowered the tolerance of hemorrhagic shock in rabbits and dogs that a reversible degree of hemorrhagic shock became irreversible. This was true not only in normal rabbits, but in rabbits made resistant to hemorrhagic shock by producing resistance to endotoxins. Rabbits which had been pretreated with thorotrast and then subjected to hemorrhagic shock displayed at death the hemorrhagic lesions and the renal cortical necrosis characteristic of the Shwartzman reaction, in addition to the intramural hemorrhages in the gut which are characteristic of animals dying of hemorrhagic or of endotoxic shock. Elimination of the Shwartzman reaction by the prior administration of nitrogen mustard did not prevent the endotoxemia or the death in shock. Rabbits made more resistant to thorotrast than normal rabbits by prior repeated administration of this substance were also more resistant than normal rabbits to endotoxin, and survived an ordinarily lethal exposure to hemorrhagic shock. During the first few hours after its administration thorotrast induced excessive vulnerability not only to endotoxin and to hemorrhagic shock, but also to an additional small dose of thorotrast. Moreover, a non-absorbable antibiotic given by gavage shortly after thorotrast produced the same lesions as these other agents; i.e. endotoxic shock, the Shwartzman reaction, and death. These data indicate that the lesions induced by thorotrast are produced by endotoxins which the injured or blockaded RES cannot inactivate. The presence of endotoxins in the blood of these rabbits was indicated by the lethal effect of this blood in test recipients. The foregoing observations did not apply to rabbits with an intestinal flora free of coliform bacteria. Over 80 per cent of such rabbits were resistant to an ordinarily lethal exposure to hemorrhagic shock, and they escaped the damage caused by the usual doses of thorotrast. They did, however, develop endotoxic shock and die if given a large dose of thorotrast. These data were taken to indicate that coliform-free rabbits are not entirely free of endotoxins. (In the ordinary environment animals cannot avoid swallowing endotoxin and coliform bacteria.) The absence of the Shwartzman reaction in the coliform-free rabbits is taken to signify that this reaction requires the participation of the endotoxins derived from the intraintestinal bacteria. The absence of endotoxic shock in the coliform-free rabbits is taken to signify that the endotoxins of the coliform bacteria are involved in the shock and death of the coliform-bearing rabbits. Finally the prevention by dibenamine of both the Shwartzman reaction and endotoxic shock and death in rabbits with a normal flora demonstrates that adrenergic activity plays an indispensable role in both phenomena. The foregoing data provide strong support for the thesis that when the RES is severely disabled by any agent, endotoxins which normally and continuously enter the circulation from the gut will produce endotoxic shock and death.


[Incidence of tuberculosis among indigenous people in the municipality of São Gabriel Cachoeira, AM].
Starting in 1999, the Ministry of Health implemented its Tuberculosis Control Program in the municipality of São Gabriel da Cachoeira, State of Amazonas. With the aim of investigating whether this strategy had promoted changes in tuberculosis incidence among indigenous people in that area, the medical records of 768 patients were studied retrospectively, divided in two groups. Group I consisted of cases treated between 1994 and 1998 and Group II consisted of cases treated between 1999 and 2003. The mean annual incidence rates were, respectively, 239 and 284 cases of all tuberculosis forms per 100,000 inhabitants. The pulmonary form predominated, accounting for 88.2% and 85.9% of the cases, and the cure rate was high (97.2% and 91.5%), respectively in Groups I and II. There was no impact with regard to reducing the incidence rate of this disease, thus showing that a high risk of contracting tuberculosis persists among indigenous people in that area.


Obesity differences between African-American men and women.
The purpose of this study was to examine the socio-demographic and behavioral differences related to obesity between African-American men and women. Obesity was defined as a body mass index of greater than 27.3 kg/m2 for women and 27.8 kg/m2 for men. Data were collected from 661 African-Americans, 418 women and 243 men, residing in wards 7 and 8 in Washington, DC through telephone interviews. Obesity was prevalent among 38.3% of the women and 20.1% of the men (p < 0.01). For women age 55 or older, annual income over $20K, having less than a high school education, and alcohol and tobacco consumption were associated with being overweight in the initial bivariate analysis (p < 0.05). For men, being 35 years or older and unemployment were significant factors associated with obesity. Our final analysis, when known dietary risk factors were adjusted, revealed that in women, obesity was associated with age, hard liquor consumption and non use of tobacco. For men, older age was a primary association. We concluded that gender, with increasing age, plays a significant role in predicting obesity, as defined by concurrent national standards. African American men 55 years of age or older are the most likely group to be overweight even after predisposing and behavioral risk factors are considered.


Optimisation of oxygen ion transport in materials for ceramic membrane devices.
Oxygen transport in ceramic oxide materials has received much attention over the past few decades. Much of this interest has stemmed from the desire to construct high temperature electrochemical devices for energy conversion, an example being the solid oxide fuel cell. In order to achieve high performance for these devices, insights are needed in how to achieve optimum performance from the functional components such as the electrolytes and electrodes. This includes the optimisation of oxygen transport through the crystal lattice of electrode and electrolyte materials and across the homogeneous (grain boundary) and heterogeneous interfaces that exist in real devices. Strategies are discussed for the optimisation of these quantities and current problems in the characterisation of interfacial transport are explored.


Variation in the Effect of Communities That Care on Community Adoption of a Scientific Approach to Prevention.
Tested and effective approaches are available to prevent mental, emotional, and behavioral problems in youth, but such approaches are underused. Communities That Care (CTC) is a coalition-based strategy that aims to increase the use of tested and effective programs by combining the use of scientific evidence and stakeholder consensus to support the community adoption of a scientific approach to preventing mental, emotional, and behavioral problems in youth. A community-randomized trial of CTC was conducted with a sample of 24 communities matched in pairs and assigned randomly to a control or an intervention condition. The findings demonstrate that CTC significantly increases the community-wide adoption of a science-based approach to prevention. Using a meta-analysis technique, this study shows that despite uniformly high-fidelity implementation of CTC in intervention communities, the effect of CTC on the adoption of a scientific approach to prevention varies significantly across the 12 community pairs. Understanding the extent of variation in the effect of CTC on adopting a science-based approach to prevention lays a foundation for identifying aspects of coalition structure, functioning, or capacity that not only may help explain variation in adoption, but may in turn be targeted to strengthen the effect of CTC on the adoption of a science-based approach to prevention within communities.


Possible therapeutic targets in cardiac myocyte apoptosis.
Since Kerr described programmed cell death (apoptosis) as a process distinct from necrosis, there have been many studies of apoptosis in disease, especially of immunological origin. Because cardiac myocytes are terminally differentiated cells, they have typically been assumed to die exclusively by necrosis. However, during the last decade this view has been challenged by several studies demonstrating that a significant number of cardiac myocytes undergo apoptosis in myocardial infarction, heart failure, myocarditis, arrhythmogenic right ventricular dysplasia, and immune rejection after cardiac transplantation, as well as in other conditions of stress. These are potentially relevant observations, because apoptosis--unlike necrosis--can be blocked or reversed at early stages. Specific inhibition of this process may confer a considerable degree of cardioprotection, but requires a thorough understanding of the underlying mechanisms. Recent progress includes a better understanding of the importance of mitochondria-initiated events in cardiac myocyte apoptosis, of factors inducing apoptosis in heart failure and during hypoxia, and of the dual pro-apoptotic and anti-apoptotic effects of hypertrophic stimuli such as beta-adrenoceptor agonists, angiotensin converting enzyme inhibitors, nitric oxide and calcineurin. The investigation of cytoprotective and apoptotic signal transduction pathways has revealed important new insights into the roles of the mitogen-activated protein kinases p38, extracellular signal regulated kinase and c-Jun N-terminal kinase in cardiac cell fate. Our present review focuses on the intracellular signal transduction pathways of cardiac myocyte apoptosis and the possibility of specific inhibition of the process.


Metabolic Pathways and Potencies of New Fentanyl Analogs.
Up to now, little is known about the metabolic pathways of new fentanyl analogs that have recently emerged on the drug markets worldwide with high potential for producing addiction and severe adverse effects including coma and death. For some of the compounds, limited information on the metabolism has been published, however, for others so far no information is available. Considering the well characterized metabolism of the pharmaceutically used opioid fentanyl and the so far available data, the metabolism of the new fentanyl analogs can be anticipated to generally involve reactions like hydrolysis, hydroxylation (and further oxidation steps), N- and O-dealkylation and O-methylation. Furthermore, phase II metabolic reactions can be expected comprising glucuronide or sulfate conjugate formation. When analyzing blood and urine samples of acute intoxication cases or fatalities, the presence of metabolites can be crucial for confirmation of the uptake of such compounds and further interpretation. Here we present a review on the metabolic profiles of new fentanyl analogs responsible for a growing number of severe and fatal intoxications in the United States, Europe, Canada, Australia, and Japan in the last years, as assessed by a systematic search of the scientific literature and official reports.


Anti-inflammatory effects of Passiflora foetida L. in LPS-stimulated RAW264.7 macrophages.
Passiflora foetida L. (Passifloraceae), a perennial climber in general, is used for treating many ailments in conventional medicine. In this study, the anti-inflammatory effect of methanolic extracts of P. foetida L. (PFME) and the involvement of nuclear factor-κB (NF-κB) signalling in the regulation of inflammation were investigated. PFME prevented the production of prostaglandin E2 (PGE2) and the expression of inducible cyclooxygenase-2 (COX-2) in lipopolysaccharide (LPS)-induced macrophage cells. Additionally, PFME reduced the release of pro-inflammatory cytokines. Moreover, in LPS-induced RAW264.7 cells, the phosphorylation of MAPKs (ERK1/2, p38 and JNK) was suppressed by PFME. Furthermore, PFME inhibited the NF-κB activation induced by LPS, which was associated with nuclear p65 levels with the abrogation of IκBα degradation and subsequent decreases. These results indicated that the PFME inhibited the LPS-induced inflammatory and oxidative responses. Therefore, we propose that the PFME may be therapeutic for treating inflammatory diseases.


Identification of linear human B-cell epitopes of tick-borne encephalitis virus.
Tick-borne encephalitis (TBE) is a central nervous system infection transmitted to humans by ticks. The causative agent, tick-borne encephalitis virus (TBEV), belongs to the genus Flavivirus (family Flaviviridae), which includes globally important arthropod-borne viruses, such as dengue, Yellow fever, Japanese encephalitis and West Nile viruses. Flaviviruses are highly cross-reactive in serological tests that are currently based on viral envelope proteins. The envelope (E) protein is the major antigenic determinant and it is known to induce neutralizing antibody responses. We synthesized the full-length TBEV proteome as overlapping synthetic 18-mer peptides to find dominant linear IgG epitopes. To distinguish natural TBEV infections from responses to TBE immunization or other flavivirus infections, the peptides were probed with sera of patients infected with TBEV, West Nile virus (WNV) or dengue virus (DENV), sera from TBE vaccinees and negative control sera by SPOT array technique. We identified novel linear TBEV IgG epitopes in the E protein and in the nonstructural protein 5 (NS5). In this study, we screened TBEV structural and nonstructural proteins to find linear epitopes specific for TBEV. We found 11 such epitopes and characterized specifically two of them to be potential for differential diagnostics. This is the first report of identifying dominant linear human B-cell epitopes of the whole TBEV genome. The identified peptide epitopes have potential as antigens for diagnosing TBEV and to serologically distinguish flavivirus infections from each other.


Tailoring the composition of fluoride conversion coatings to achieve better corrosion protection of magnesium for biomedical applications.
The methodology of deposition of fluoride conversion coatings is modified with the use of galvanic coupling, agitation of the electrolyte solution, and addition of K2CO3, which helps to provide a better understanding of the mechanism and new avenues to tailor the composition of the coating. A very good correlation exists between the F/O ratio of the coatings prepared under varying experimental conditions and their icorr, |Z| and phase angle maximum; the higher the F/O ratio, the better the corrosion protective ability of the coatings in Hank's balanced salt solution. The corrosion behaviour of the coatings of the present study suggests that fluoride conversion coatings show much promise for their use for biomedical applications, as long as their uniformity is improved and the composition is tailored to enrich the MgF2 phase, encompassing a higher F/O ratio.


Altered organization of the intermediate filament cytoskeleton and relocalization of proteostasis modulators in cells lacking the ataxia protein sacsin.
Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in the gene SACS, encoding the 520 kDa protein sacsin. Although sacsin's physiological role is largely unknown, its sequence domains suggest a molecular chaperone or protein quality control function. Consequences of its loss include neurofilament network abnormalities, specifically accumulation and bundling of perikaryal and dendritic neurofilaments. To investigate if loss of sacsin affects intermediate filaments more generally, the distribution of vimentin was analysed in ARSACS patient fibroblasts and in cells where sacsin expression was reduced. Abnormal perinuclear accumulation of vimentin filaments, which sometimes had a cage-like appearance, occurred in sacsin-deficient cells. Mitochondria and other organelles were displaced to the periphery of vimentin accumulations. Reorganization of the vimentin network occurs in vitro under stress conditions, including when misfolded proteins accumulate. In ARSACS patient fibroblasts HSP70, ubiquitin and the autophagy-lysosome pathway proteins Lamp2 and p62 relocalized to the area of the vimentin accumulation. There was no overall increase in ubiquitinated proteins, suggesting the ubiquitin-proteasome system was not impaired. There was evidence for alterations in the autophagy-lysosome pathway. Specifically, in ARSACS HDFs cellular levels of Lamp2 were elevated while levels of p62, which is degraded in autophagy, were decreased. Moreover, autophagic flux was increased in ARSACS HDFs under starvation conditions. These data show that loss of sacsin effects the organization of intermediate filaments in multiple cell types, which impacts the cellular distribution of other organelles and influences autophagic activity.


[Dirofilariasis in the countries of the CIS: an analysis of the cases over the years 1915-1996].
A hundred and fourteen cases of subcutaneous dirofilariasis caused by Dirofilaria repens were described in the CIS in 1915-1996. The mean age of the patients was 38.4 years (from 3 to 70 years). Dirofilaria was found in the eye in 45.9% of cases, in the head and neck in 17.5%, in the arms and hands in 11.7%, in the legs in 8.1%, in the viscera in 2 cases, and in the genitalia in 2 cases, they being prevalent in the body's right part. The north boundary of local infection cases was in latitude 53-54 degrees North. The maximum cases were detected in January and June. Dirofilariasis clinically appeared as a migrating subcutaneous tumor occasionally complicated by secondary abscess. The tumor generally contained an immature female, an immature male was found in one case. The sole treatment was surgical helminthic excision. There was a trend of subcutaneous dirofilariasis cases to increase in the RF in the past decades.


A fatal case of self-poisoning through the ingestion of oleander leaves.
Benefits and even dangers of plants are known since time began. The ancients used plants and herbs because of their effects on the human body. Poisoning is a logical consequence of their use: history is full of episodes of plants and herbs poisoning, whether intentional or accidental. Oleander poisoning is generally accidental; an intentional assumption of its leaves to commit suicide is uncommon because the population is not aware of the harmfulness of its cardiotoxic glycosides, therefore we report a fatal case of self-poisoning through the voluntary ingestion of oleander leaves. A diagnosis of oleander self-poisoning was highly suspected on the basis of the circumstantial evidence and the autopsy findings. Toxicological investigations were performed on the samples collected during the autopsy and aimed at confirm the presence of oleandrin at a toxic level. The autopsy revealed a piece of oleander leaf on the posterior third of the tongue's body and several plant residues, similar to the one recovered on the tongue, into the gastric content; petechiae on the deep surface of the scalp, multi-organ congestion, and pulmonary edema were also observed. The histological study corroborated the pulmonary edema macroscopically observed but did not provide any other information. The detection of oleandrin in biological cadaveric samples revealed high, fatal, concentrations. Cases of voluntary ingestion of oleander with a suicidal intent prove to be uncommon: in the case reported the victim was aware about the possibility to commit suicide through the ingestion of oleander leaves.


Ministrokes in channelrhodopsin-2 transgenic mice reveal widespread deficits in motor output despite maintenance of cortical neuronal excitability.
We evaluated the effects of ministrokes targeted to individual pial arterioles on motor function in Thy-1 line 18 channelrhodopsin-2 (ChR2) transgenic mice within the first hours after ischemia. Using optogenetics, we directly assessed both the excitability and motor output of cortical neurons in a manner independent of behavioral state or training. Occlusion of individual arterioles within the motor cortex led to a ministroke that was verified using laser speckle contrast imaging. Surprisingly, ministrokes targeted to a relatively small region of the forelimb motor map, with an ischemic core of 0.07 ± 0.03 mm(2), impaired motor responses evoked from points across widespread areas of motor cortex even 1.5 mm away. Contrasting averaged ChR2-evoked electroencephalographic, spinal (ChR2 evoked potential), and electromyographic responses revealed a mismatch between measures of cortical excitability and motor output within 60 min after stroke. This mismatch suggests that apparently excitable cortical neurons (even >1 mm into peri-infarct areas, away from the infarct core) were impaired in their capacity to generate spinal potentials leading to even more severe deficits in motor output at muscles. We suggest that ischemia, targeted to a subset of motor cortex, leads to relatively small reductions in excitability within motor cortex, and cumulative depression of both descending spinal circuits and motor output in response to the activation of widespread cortical territories even outside of the area directly affected by the ischemia.


Oral administration of Bifidobacterium breve improves anti-angiogenic drugs-derived oral mucosal wound healing impairment via upregulation of interleukin-10.
Recent studies have suggested that long-term application of anti-angiogenic drugs may impair oral mucosal wound healing. This study investigated the effect of sunitinib on oral mucosal healing impairment in mice and the therapeutic potential of Bifidobacterium breve (B. breve). A mouse hard palate mucosal defect model was used to investigate the influence of sunitinib and/or zoledronate on wound healing. The volume and density of the bone under the mucosal defect were assessed by micro-computed tomography (micro-CT). Inflammatory factors were detected by protein microarray analysis and enzyme-linked immunosorbent assay (ELISA). The senescence and biological functions were tested in oral mucosal stem cells (OMSCs) treated with sunitinib. Ligated loop experiments were used to investigate the effect of oral B. breve. Neutralizing antibody for interleukin-10 (IL-10) was used to prove the critical role of IL-10 in the pro-healing process derived from B. breve. Results showed that sunitinib caused oral mucosal wound healing impairment in mice. In vitro, sunitinib induced cellular senescence in OMSCs and affected biological functions such as proliferation, migration, and differentiation. Oral administration of B. breve reduced oral mucosal inflammation and promoted wound healing via intestinal dendritic cells (DCs)-derived IL-10. IL-10 reversed cellular senescence caused by sunitinib in OMSCs, and IL-10 neutralizing antibody blocked the ameliorative effect of B. breve on oral mucosal wound healing under sunitinib treatment conditions. In conclusion, sunitinib induces cellular senescence in OMSCs and causes oral mucosal wound healing impairment and oral administration of B. breve could improve wound healing impairment via intestinal DCs-derived IL-10.


Microvascular, interstitial, and lymphatic interactions in normal heart.
Control of transmicrovascular fluid exchange in the heart is of critical importance in the prevention of myocardial edema formation. To quantify the absolute values for, and the interrelationships between, the forces and flows governing fluid balance within the normal heart, the following variables were measured: arterial pressure (Pa), coronary sinus pressure (Pcs), myocardial interstitial fluid pressure (Pint), plasma protein concentration (Cp), and oncotic pressure (tau cap) along with interstitial protein concentration (CL), interstitial oncotic pressure (tau int), and left ventricular lymph flow rate (Jv). All parameters were recorded under control conditions and during graded venous pressure elevations. Control values were Pa, 125 +/- 21 mmHg; Pcs, 7.3 +/- 1.3 mmHg; Pint, 14.9 +/- 3.1 mmHg; CL/Cp, 0.82 +/- 0.12; and Jv, 7.0 +/- 2.7 ml/h. As Pcs was elevated to eight times control, Pint increased from 15 to 50 mmHg and lymph flow rose sixfold. A filtration-independent value for CL/Cp could not be obtained for total plasma protein, although a washdown CL/Cp value for beta-lipoprotein of 0.04 was obtained. Our data indicate that a large surface area of myocardial exchange vessels coupled with lymphatics of relatively low sensitivity to extravascular volume expansion produce a system that relies on a large increase in interstitial hydrostatic pressure to limit edema formation.


The surgical treatment of low anal defects and vestibular fistulas.
A series of 227 patients with what are traditionally known as "low" anorectal malformations (ARM) are presented. Perineal fistulas (PF; n = 108), anterior perineal anus (APA; n = 22), and vestibular fistulas (VF; n = 97) represented 73% of the 309 patients with ARM operated on primarily. Diagnosis was based on perineal inspection. In cases of PF and APA, the rectum opens at the perineal skin, anterior to the normal site. Associated malformations were found in 23% of patients with PF and in 13% of patients with APA. Anoplasty without a colostomy was performed in patients with PF. Normal continence was achieved in 93.3%, and constipation occurred in 47%. In patients with APA and intractable constipation, a partial sphincterotomy relieved painful evacuations in 96%. VF is not a low defect; the rectum opens in the vaginal introitus, and dissection of the rectovaginal common wall is necessary for reconstruction. In neonates with VF, the authors performed a sigmoid colostomy followed by a limited posterior sagittal anorectoplasty at 2 months of age. Of the 97 patients with VF, associated malformations were found in 57%. Continence was evaluated in 67 patients with repaired VF. Normal continence was found in 71% and constipation in 50%. Only one patient with VF experienced severe complications and incontinence, after surgical mismanagement. Precise clinical diagnosis and meticulous surgical technique are essential in the management of these benign malformations.


Subxiphoid pericardiocentesis guided by contrast two-dimensional echocardiography in cardiac tamponade: experience of 110 consecutive patients.
We evaluated echo-guided pericardiocentesis with contrast study in cardiac tamponade management. From 1982 to 1998 we performed pericardiocentesis in 110 patients (56 +/- 14 years old). Subxiphoid approach was used in 109. Cardiac tamponade was idiopathic (n = 16), secondary to malignant disease (n = 50) and miscellaneous disorders (n = 44). Pericardial fluid was bloody (n=75), serous (n = 29) or turbid (n = 6). Mean volume of fluid removed was 585 +/- 370 ml. When prolonged drainage (60 +/- 26 h) was used (n = 41), total effusion volume was 850 +/- 340 ml. Eleven deaths were observed during the early period following pericardiocentesis. No relation with procedure was demonstrated by autopsy in 10, and death always occurred in critically-ill patients (five malignant diseases, five cardiac ruptures and one septic shock). Other complications were: right ventricular puncture (n = 11) with deleterious effect in one, vasovagal hypotension (n = 6) and paroxysmal arrhythmia (n = 6). Surgical drainage was mandatory in 19 patients. It had to be done as an emergency (within 6 h), because of failure of the procedure in four patients. In 14 patients without prolonged drainage a delayed surgical evacuation was indicated, because of persistent (n = 3) or recurrent (n = 11) cardiac tamponade. Only one surgical procedure was required after prolonged drainage. Echo-guided pericardiocentesis with contrast study is an effective technique which reduces the risk of cardiac tamponade management. It should be considered in patients with critical haemodynamic condition or advanced malignancy, and in patients with poor short-term prognosis.


Solution-Processed Semiconductor Materials as Cathode Interlayers for Organic Solar Cells.
Cathode interlayers (CILs) play a crucial role in improving the photovoltaic efficiency and stability of OSCs. CILs generally consists of two kinds of materials, interfacial dipole-based CILs and SPS-based CILs. With good charge transporting ability, excellent compatibility with large-area processing methods, and highly tunable optoelectronic properties, the SPS-based CILs exhibit remarkable superiorities to their interfacial dipole-based counterparts in practical use, making them promising candidate in developing efficient CILs for OSCs. This mini-review highlights the great potential of SPS-based CILs in OSC applications and elucidates the working mechanism and material design strategy of SPS materials. Afterward, the SPS-based CIL materials are summarized and discussed in four sections, including organic small molecules, conjugated polymers, nonconjugated polymers, and TMOs. The structure-property-performance relationship of SPS-based CIL materials is revealed, which may provide readers new insight into the molecular design of SPS-based CILs. The mechanisms to endow SPS-based CILs with thickness insensitivity, resistance to environmental erosion, and photo-electric conversion ability are also elucidated. Finally, after a brief summary, the remaining issues and the prospects of SPS-based CILs are suggested.


Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation.
The cellular mechanisms by which prions cause neurological dysfunction are poorly understood. To address this issue, we have been using cultured cells to analyze the localization, biosynthesis, and metabolism of PrP molecules carrying mutations associated with familial prion diseases. We report here that mutant PrP molecules are delayed in their maturation to an endoglycosidase H-resistant form after biosynthetic labeling, suggesting that they are impaired in their exit from the endoplasmic reticulum (ER). However, we find that proteasome inhibitors have no effect on the maturation or turnover of either mutant or wild-type PrP molecules. Thus, in contrast to recent studies from other laboratories, our work indicates that PrP is not subject to retrotranslocation from the ER into the cytoplasm prior to degradation by the proteasome. We find that in transfected cells, but not in cultured neurons, proteasome inhibitors cause accumulation of an unglycosylated, signal peptide-bearing form of PrP on the cytoplasmic face of the ER membrane. Thus, under conditions of elevated expression, a small fraction of PrP chains is not translocated into the ER lumen during synthesis, and is rapidly degraded in the cytoplasm by the proteasome. Finally, we report a previously unappreciated artifact caused by treatment of cells with proteasome inhibitors: an increase in PrP mRNA level and synthetic rate when the protein is expressed from a vector containing a viral promoter. We suggest that this phenomenon may explain some of the dramatic effects of proteasome inhibitors observed in other studies. Our results clarify the role of the proteasome in the cell biology of PrP, and suggest reasonable hypotheses for the molecular pathology of inherited prion diseases.


[Prognostic significance of the morphological traits of skin melanoma of the head and neck].
Histologic slides of a primary tumour from 146 patients with the skin melanoma of the head or neck treated only surgically were studied. The significance of different histologic criteria in prognosis of life and metastasis was evaluated by means of unifactorial statistical analysis. The thickness of a tumour, its invasiveness and histologic type are the most informative morphological criteria. The unifactorial analysis allows foreseeing the appearance of metastasis and lethal outcome in 20 to 46% of cases. Multifactorial analysis permits predicting the appearance of metastasis within 3 years in 76,8% of cases and in 85,3% of cases within 5 years.


Upper airway size and collapsibility in snorers: evaluation with digital fluoroscopy.
This study addressed the question of whether there are any differences in the size and collapsibility of the upper airway measured by digital fluoroscopy, between snorers and controls whilst they were awake and breathing normally; and whether there are any correlations between these measurements and other clinical data. The dynamic changes of the upper airway size were evaluated using digital fluoroscopy in 33 patients and 16 normal controls. The measurements were compared with findings in an overnight sleep study, including a static-charge-sensitive bed (SCSB) and oximeter recordings. The minimum anteroposterior dimension at the velopharyngeal level was smaller in patients with partial upper airway obstruction than in controls (p<0.005); patients with complete obstruction did not differ from the controls. The velopharyngeal airways were also more collapsible in patients with severe partial obstruction (p<0.01) than in controls. At the oropharyngeal and hypopharyngeal levels, the dimensions and the collapsibilities were similar in patients and controls. The velopharyngeal collapsibility correlated with body mass index (p<O.001), whereas the airway size did not. The velopharyngeal collapsibility was more pronounced in patients with frequent episodes of arterial oxyhaemoglobin desaturation during sleep. Velopharyngeal collapsibility associated with high body mass index was the important determinant of nocturnal breathing disturbances. Digital fluoroscopy displays the dynamic changes of the upper airways throughout the respiratory cycle.


Extensive mitochondrial diversity within a single Amerindian tribe.
Sequencing of a 360-nucleotide segment of the mitochondrial control region for 63 individuals from an Amerindian tribe, the Nuu-Chah-Nulth of the Pacific Northwest, revealed the existence of 28 lineages defined by 26 variable positions. This represents a substantial level of mitochondrial diversity for a small local population. Furthermore, the sequence diversity among these Nuu-Chah-Nulth lineages is greater than 60% of the mitochondrial sequence diversity observed in major ethnic groups such as Japanese or sub-Saharan Africans. It was also observed that the majority of the mitochondrial lineages of the Nuu-Chah-Nulth fell into phylogenetic clusters. The magnitude of the sequence difference between the lineage clusters suggests that their origin predates the entry of humans into the Americas. Since a single Amerindian tribe can contain such extensive molecular diversity, it is unnecessary to presume that substantial genetic bottlenecks occurred during the formation of contemporary ethnic groups. In particular, these data do not support the concept of a dramatic founder effect during the peopling of the Americas.


[Tinea capitis in children from Goiânia, Brazil].
During the period January 1999 to July 2002 a total de 164 cases of Tinea capitis were diagnosed by mycological examination in Instituto de Patologia Tropical e Saúde Pública of the Universidade Federal de Goiás. Of the 164 patients 94 (57.3%) were males, with an age of 3 months to 13 years. Laboratory studies were performed by direct examination with 20% KOH and cultivated on Mycobiotic agar medium and Sabouraud dextrose agar with chloramphenicol. The following species were identified: Microsporum canis (71.3%), Trichophyton tonsurans (11%), Trichophyton mentagrophytes (7.9%), Trichophyton rubrum (6.7%), and Microsporum gypseum (3%). Our study showed that the most frequent rise of scalp infection was a zoophylic fungi, called Microsporum canis.


Evidence that RNA editing modulates splice site selection in the 5-HT2C receptor gene.
Adenosine to inosine editing of mRNA from the human 5-HT2C receptor gene (HTR2C) occurs at five exonic positions (A-E) in a stable stem-loop that includes the normal 5' splice site of intron 5 and is flanked by two alternative splice sites. Using in vitro editing, we identified a novel editing site (F) located in the intronic part of the stem-loop and demonstrated editing at this site in human brain. We have shown that in cell culture, base substitutions to mimic editing at different combinations of the six sites profoundly affect relative splicing at the normal and the upstream alternative splice site, but splicing at the downstream alternative splice site was consistently rare. Editing combinations in different splice variants from human brain were determined and are consistent with the effects of editing on splicing observed in cell culture. As RNA editing usually occurs close to exon/intron boundaries, this is likely to be a general phenomenon and suggests an important novel role for RNA editing.