The Risk of Developing Diabetes in Association With Long Working Hours Differs by Shift Work Schedules.
The impact of long working hours on diabetes is controversial; however, shift work is known to increase the risk of diabetes. This study aimed to investigate the association between long working hours and diabetes among civil servants in Japan separately by shift work schedules. A prospective cohort study was conducted from April 2003 to March 2009. A total of 3195 men aged ≥35 years who underwent an annual health checkup at baseline were analyzed by shift work schedules (2371 non-shift workers and 824 shift workers). Self-reported working hours were categorized as 35-44 and ≥45 hours per week. The incidence of diabetes was confirmed by fasting plasma glucose concentration ≥126 mg/dL and/or self-reported medical diagnosis of diabetes at the annual checkup. A Cox proportional model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for developing diabetes associated with long working hours. The median follow-up period of non-shift and shift workers was 5.0 and 4.9 years, respectively. During this period, 138 non-shift workers and 46 shift workers developed diabetes. A decreased HR was found among non-shift workers working ≥45 hours per week (HR 0.84; 95% CI, 0.57-1.24); however, shift workers working ≥45 hours per week had a significantly increased risk of diabetes (HR 2.43; 95% CI, 1.21-5.10) compared with those working 35-44 hours per week. An analysis restricted to non-clerical workers also showed similar results. The risk of diabetes associated with long working hours differed by shift work schedules.


Overview of platelet transfusion.
Most platelet transfusions are given to prevent bleeding in thrombocytopenic patients undergoing chemotherapy for malignancy or hematopoietic stem cell transplant. In stable, uncomplicated patients the risk of bleeding is similar until the platelet count falls to <5,000/microL. However, many patients have clinical complications that necessitate transfusion at higher counts. Therefore, the recommended indication for prophylactic transfusion is a platelet count of 10,000/microL. The usual dose of platelets is 1 apheresis unit or a pool of four to six concentrates from individual units of whole blood. The likelihood of bleeding is the same if half or double the usual dose is given, but half-dose transfusions must be given more often and double-dose transfusions less often than the standard dose. For patients with inherited defects of platelet function or acquired defects such as due to drugs or uremia, the platelet count is usually normal and prophylactic transfusion is not recommended. Transfusion may be helpful to treat serious bleeding. Patients undergoing cardiopulmonary bypass may be slightly thrombocytopenic but usually have platelet dysfunction. Transfusion is helpful to treat nonsurgical serious bleeding. In idiopathic thrombocytopenic purpura, platelet survival is short and transfusion is useful only for severe bleeding.


Algorithm for femoral and periacetabular osteotomies in complex hip deformities.
Residual acetabular dysplasia of the hip in most patients can be corrected by periacetabular osteotomy. However, some patients have intraarticular abnormalities causing insufficient coverage, containment or congruency after periacetabular osteotomy, or extraarticular abnormalities that limit either acetabular correction or hip motion. For these patients, we believe an additional proximal femoral osteotomy can improve coverage, containment, congruency and/or motion. We provide algorithms for (1) identifying patients we believe will benefit from proximal femoral osteotomy, (2) selecting the appropriate osteotomy, and (3) choosing the sequence of these osteotomies. Anteroposterior, false-profile and functional radiographs and MR can identify most patients we believe will benefit from periacetabular and femoral osteotomies. Recently described techniques, including relative femoral neck lengthening, femoral neck osteotomy and femoral head osteotomy have expanded indications for a combined procedure. Historically performed first, periacetabular osteotomy is now frequently performed following femoral osteotomy. The rate of intertrochanteric osteotomy performed with periacetabular osteotomy has decreased from approximately 10% in the first 500 surgeries to about 2% currently. Among 151 relative neck lengthenings (23 with PAO), 53 femoral neck osteotomies (4 with PAO) and 14 femoral head osteotomies (11 with PAO), eleven complications occurred including osteonecrosis in two and delayed unions in eight. No complication occurred following a combined procedure. Although isolated periacetabular osteotomy can provide sufficient coverage, containment and congruency for most patients with residual hip dysplasia, some may benefit from an additional proximal femoral osteotomy. Knowing the appropriate indications, selection, and sequencing of these osteotomies is critical for enhancing patient outcomes.


Clinical anatomy of the internal oblique muscle.
In recent years microvascular free tissue transfer has become a well accepted reconstructive technique. The current trend in flap research seems to be the development of more refined flaps to meet specific needs with minimal donor site morbidity. The internal oblique muscle provides a broad, thin, well-vascularized flap which is ideally suited for restoration of contour with excellent aesthetic results. In addition, the iliac crest may be raised in continuity based on the same vascular pedicle, i.e. the deep circumflex iliac vessels. The purpose of this article is to describe the anatomic details necessary for the clinical application of this versatile flap. Thirty specimens of the internal oblique muscle flap were dissected and studied using Microfil injection techniques, including xerograms. In about 80 percent of the flaps, a single ascending branch of the deep circumflex iliac artery (DCIA) enters the undersurface of the muscle, arborizing within the muscle. In the remaining 20 percent, two or three branches enter the muscle separately, originating on the DCIA. The arc of rotation extends into the ipsilateral groin for coverage of exposed femoral vessels, along the pubis and the anterior perineum. The length of the vascular pedicle is to 6 to 7 cm and the vessel diameter is 2.0 to 3.0 mm, making the flap suitable for free tissue transfer.


Use of Wearable Sensor Device and Mobile Application for Objective Assessment of Pain in Post-surgical Patients: A Preliminary Study.
Effective post-operative pain management requires an accurate and frequent assessment of the pain experienced by the patients. The current gold-standard of pain assessment is through patient self-evaluation (e.g., numeric rating scale, NRS) which is subjective, prone to recall-bias, and does not provide comprehensive information of the pain intensity and its trends. We conducted a study to explore the potential of wearable biosensors and machine learning-based analysis of physiological parameters to estimate the pain intensity. The results from our study of post-operative knee surgery patients monitored over a period of 30 days demonstrate the feasibility of the system in ambulatory setting, with a substantial agreement (Cohen's Kappa = 0.70, 95% CI 0.68-0.72) between the pain intensity estimation and the patient reported numerical rating scale. Therefore, the wearable biosensors coupled with the machine learning-derived pain estimation are capable of remotely assessing the pain intensity.


Kernel map compression for speeding the execution of kernel-based methods.
The use of Mercer kernel methods in statistical learning theory provides for strong learning capabilities, as seen in kernel principal component analysis and support vector machines. Unfortunately, after learning, the computational complexity of execution through a kernel is of the order of the size of the training set, which is quite large for many applications. This paper proposes a two-step procedure for arriving at a compact and computationally efficient execution procedure. After learning in the kernel space, the proposed extension exploits the universal approximation capabilities of generalized radial basis function neural networks to efficiently approximate and replace the projections onto the empirical kernel map used during execution. Sample applications demonstrate significant compression of the kernel representation with graceful performance loss.


[Kidney-related hypertension].
Secondary hypertension is due to renal parenchymal disease in 3 of 4 pediatric patients. Among the unilateral renal diseases, reflux nephropathy is the most important condition, leading to hypertension in 10-20% of such patients (hence the need for yearly blood pressure recordings). Among the bilateral renal diseases, acute glomerulonephritis is still the best known cause of hypertension, although the various forms of chronic glomerulonephritis and renal insufficiency are nowadays of greater importance. Newer forms of hypertension may be observed after catheterisation of the umbilical artery in newborns, and after renal transplantation. Effective therapy of hypertension is essential.


Continuous arteriovenous hemofiltration: an alternative to hemodialysis.
An introduction to the procedure of continuous arteriovenous hemofiltration (CAVH) for management of acute renal failure, as well as a review of hemodialysis, is presented. Initially developed for the management of hemodynamically unstable patients with acute renal failure, CAVH now is also used for management of fluid overload and acid-base disturbances resulting from conditions such as acute pulmonary edema, congestive heart failure, septic shock, and oliguric states in which pharmacologic or parenteral nutrition therapy necessitates administration of large volumes of fluids. CAVH, in contrast to hemodialysis, does not typically involve use of blood pumps but uses the patient's own mean arterial pressure to generate a driving force across the hemofilter membrane. CAVH, like hemodialysis, can remove excess fluid and uremic toxins; however, fluid removal by CAVH is characterized by the slow, continuous process of ultrafiltration and thus avoids the risk of hypotension, muscle cramps, or disequilibrium syndrome. Furthermore, CAVH does not require fluid restriction, allowing for increased administration of parenteral nutrition and intravenous medications; neither does it require expensive equipment or highly trained personnel. Although CAVH membrane materials may differ, they all permit the removal of plasma water and non-protein-bound solutes with molecular weights less than 10,000. To prevent blood from clotting in the hemofilter, most patients will require administration of heparin, which in some patients may increase the possibility of hemorrhaging. CAVH also can remove pharmacologic agents from the blood; however, only the non-protein-bound fraction of the drug has the potential to be cleared from the bloodstream by CAVH.(ABSTRACT TRUNCATED AT 250 WORDS)


Immune Checkpoint Inhibitor-Induced Upper Gastrointestinal Tract Inflammation Shows Morphologic Similarities to, but Is Immunologically Distinct From, Helicobacter pylori Gastritis and Celiac Disease.
Immune checkpoint inhibitor (CPI) therapies are associated with multi-organ immune-related adverse events. Although colonic mucosal changes have been described, inflammatory changes incited by CPIs in the upper gastrointestinal tract have not been well characterized. To investigate morphologic and immunologic changes incited by CPI therapy in the upper gastrointestinal tract. We compared the morphology and immune cell phenotype of gastric and duodenal biopsies from patients treated with anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) or anti-programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) antibodies with biopsies from patients with Helicobacter pylori gastritis, patients with celiac disease, and normal controls. Gastric biopsies from patients on CPIs showed chronic gastritis mimicking H pylori gastritis. However, CPI gastritis demonstrated greater numbers of CD8+ intraepithelial lymphocytes, less lamina propria inflammation, fewer plasma cells and CD20+ B cells, fewer lymphoid aggregates, and reduced CD4:CD8 ratio in both the lamina propria and the epithelial layer. There were no differences between anti-CTLA-4 and anti-PD-1/PD-L1 gastritis, except for more lymphoid aggregates in anti-PD-1/PD-L1 gastritis. Duodenal biopsies from patients on CPIs revealed chronic duodenitis with villous blunting, mimicking celiac disease. Compared with celiac disease, CPI duodenitis demonstrated higher prevalence of neutrophilic infiltrates and erosions, increased lamina propria CD3 and CD8 T cells, and reduced CD4:CD8 ratio. Upper gastrointestinal biopsies were more inflamed than concomitant colonic biopsies in the majority of patients. The morphologic and immunophenotypic distinctions between CPI-associated upper gastrointestinal injuries and common infectious and autoimmune diseases may provide useful discriminators when clinicians are confronted with gastric and duodenal inflammatory changes in patients receiving CPI therapy.


Logical identification of an allantoinase analog (puuE) recruited from polysaccharide deacetylases.
The hydrolytic cleavage of the hydantoin ring of allantoin, catalyzed by allantoinase, is required for the utilization of the nitrogen present in purine-derived compounds. The allantoinase gene (DAL1), however, is missing in many completely sequenced organisms able to use allantoin as a nitrogen source. Here we show that an alternative allantoinase gene (puuE) can be precisely identified by analyzing its logic relationship with three other genes of the pathway. The novel allantoinase is annotated in structure and sequence data bases as polysaccharide deacetylase for its homology with enzymes that catalyze hydrolytic reactions on chitin or peptidoglycan substrates. The recombinant PuuE protein from Pseudomonas fluorescens exhibits metal-independent allantoinase activity and stereospecificity for the S enantiomer of allantoin. The crystal structures of the protein and of protein-inhibitor complexes reveal an overall similarity with the polysaccharide deacetylase beta/alpha barrel and remarkable differences in oligomeric assembly and active site geometry. The conserved Asp-His-His metal-binding triad is replaced by Glu-His-Trp, a configuration that is distinctive of PuuE proteins within the protein family. An extra domain at the top of the barrel offers a scaffold for protein tetramerization and forms a small substrate-binding cleft by hiding the large binding groove of polysaccharide deacetylases. Substrate positioning at the active site suggests an acid/base mechanism of catalysis in which only one member of the catalytic pair of polysaccharide deacetylases has been conserved. These data provide a structural rationale for the shifting of substrate specificity that occurred during evolution.


Thrombosis with thrombocytopenia after AZD1222 (ChAdOx1 nCov-19) vaccination: Case characteristics and associations.
Post-marketing surveillance for COVID-19 vaccines during the pandemic identified an extremely rare thrombosis with thrombocytopenia syndrome (TTS) reported post-vaccination, requiring further characterisation to improve diagnosis and management. We searched the AstraZeneca Global Safety Database (through April 26, 2021) for cases with co-reported thrombocytopenia and thrombosis (using standardised MedDRA queries/high-level terms) following AZD1222 (ChAdOx1 nCoV-19). Cases were adjudicated by experts as 'typical','possible', 'no' or 'unknown' according to available TTS criteria. Additional confirmatory datasets (May 20-June 20, October 1-December 28) were evaluated. We identified 573 reports, including 273 (47.6 %) 'typical' and 171 (29.8 %) 'possible' TTS cases. Of these 444 cases, 275 (61.9 %) were female, median age was 50.0 years (IQR: 38.0-60.0). Cerebral venous sinus thrombosis was reported in 196 (44.1 %) cases, splanchnic venous thrombosis in 65 (14.6 %) and thromboses at multiple sites in 119 (26.8 %). Median time to onset was 12.0 days (IQR: 9.0-15.0). Comparison with a pre-pandemic reference population indicated higher rates of autoimmune disorders (13.8 %, 4.4 %), previous heparin therapy (7.4 %, 1.2 %), history of thrombosis (5.5 %, 1.4 %), and immune thrombocytopenia (6.1 %, 0.2 %). Fatality rate was 22.2 % (127/573) overall and 23.6 % (105/444) in 'typical'/'possible' TTS, which decreased from 39.0 % (60/154) in February/March to 15.5 % (45/290) in April. Overall patterns were similar in confirmatory datasets. The reporting rate of 'typical'/'possible' TTS post first-dose vaccination in this dataset is 7.5 per million vaccinated persons; few cases were reported after subsequent doses, including booster doses. Peak reporting coincided with media-driven attention. Medical history differences versus a reference population indicate potentially unidentified risk factors. The decreasing fatality rate correlates with increasing awareness and publication of diagnostic/treatment guidelines. Adjudication was hindered by unreported parameters, and an algorithm was developed to classify potential TTS cases; comprehensive reporting could help further improve definition and management of this extremely rare syndrome.


IsoFinder: computational prediction of isochores in genome sequences.
Isochores are long genome segments homogeneous in G+C. Here, we describe an algorithm (IsoFinder) running on the web (http://bioinfo2.ugr.es/IsoF/isofinder.html) able to predict isochores at the sequence level. We move a sliding pointer from left to right along the DNA sequence. At each position of the pointer, we compute the mean G+C values to the left and to the right of the pointer. We then determine the position of the pointer for which the difference between left and right mean values (as measured by the t-statistic) reaches its maximum. Next, we determine the statistical significance of this potential cutting point, after filtering out short-scale heterogeneities below 3 kb by applying a coarse-graining technique. Finally, the program checks whether this significance exceeds a probability threshold. If so, the sequence is cut at this point into two subsequences; otherwise, the sequence remains undivided. The procedure continues recursively for each of the two resulting subsequences created by each cut. This leads to the decomposition of a chromosome sequence into long homogeneous genome regions (LHGRs) with well-defined mean G+C contents, each significantly different from the G+C contents of the adjacent LHGRs. Most LHGRs can be identified with Bernardi's isochores, given their correlation with biological features such as gene density, SINE and LINE (short, long interspersed repetitive elements) densities, recombination rate or single nucleotide polymorphism variability. The resulting isochore maps are available at our web site (http://bioinfo2.ugr.es/isochores/), and also at the UCSC Genome Browser (http://genome.cse.ucsc.edu/).


Pulmonary malignancies in the immunocompromised patient.
Clinicians should be familiar with immunodeficiency-related malignancies, as their incidence is expected to increase further with the rise in the number and survival of immunocompromised patients. The most common malignancies affecting the lungs in those patients are Kaposi's sarcoma, non-Hodgkin's lymphoma and, to a far less extent, Hodgkin's disease and bronchogenic carcinoma. However, their relative frequency depends on the types of immune deficiency, including those due to congenital disorders, AIDS and drug treatments. This review will summarize epidemiological data on the frequency of immmunodeficiency-related malignancies, recent advances on their pathogenesis and current approaches to their diagnosis and treatment in the various immunosuppressed groups.


Depolarizing agent-induced cyclic AMP accumulation in isolated rat spinal cord.
The stimulation of cyclic adenosine 3',5'-monophosphate (cyclic AMP) accumulation by the depolarizing agents K+, ouabain and veratridine, was studied in rat and guinea pig spinal cord tissue slices. Significantly increased accumulation of cyclic AMP was produced by each of the agents in a concentration-dependent manner. Veratridine and ouabain were equipotent (EC50 = 5 x 10(-5)M) and approximately 500 fold more potent than K+ (EC50 = 10(-2)M). Depolarizing agent-induced cyclic AMP accumulation in slices from guinea pig spinal cord was approximately double the response in rat spinal cord. Maximum stimulation occurred within 2.5 min of incubation with these agents and lasted for at least 30 min. Regional studies demonstrated that the maximal accumulation of cyclic AMP occurred to a greater degree in tissue slices from the dorsal section of spinal cord from both rat and guinea pig. Whereas the ouabain and veratridine stimulatory responses are completely dependent on extracellular Ca++, the K+ response is only partially dependent. Stimulation due to ouabain and veratridine is dependent, and K+ is independent, of release of neurohumoral substances such as norepinephrine or adenosine from spinal neurons. These experiments indicate the possible modulatory role of depolarization-linked events in regulating the spinal cord cyclic AMP system.


MET expression during prostate cancer progression.
Tyrosine-kinase inhibitors of the hepatocyte growth factor receptor MET are under investigation for the treatment of hormone-refractory prostate cancer (HRPC) metastasis. Analysis of MET protein expression and genetic alterations might contribute to therapeutic stratification of prostate cancer patients. Our objective was to investigate MET on protein, DNA and RNA level in clinical prostate cancer at various stages of progression. Expression of MET was analyzed in hormone-naive primary prostate cancers (N=481), lymph node (N=40) and bone (N=8) metastases, as well as HRPC (N=54) and bone metastases (N=15). MET protein expression was analyzed by immunohistochemistry (D1C2 C-terminal antibody). MET mRNA levels and MET DNA copy numbers were determined by in situ hybridization. None of the hormone-naive primary prostate cancer or lymph node metastases demonstrated MET protein or mRNA expression. In contrast, MET protein was expressed in 12/52 (23%) evaluable HRPC resections. RNA in situ demonstrated cytoplasmic signals in 14/54 (26%) of the HRPC patients, and was associated with MET protein expression (p=0.025, χ2), in absence of MET amplification or polysomy. MET protein expression was present in 7/8 (88%) hormone-naive and 10/15 (67%) HRPC bone metastases, without association of HRPC (p=0.37; χ2), with MET polysomy in 8/13 (61%) evaluable cases. In conclusion, MET was almost exclusively expressed in HRPC and prostate cancer bone metastasis, but was not related to MET amplification or polysomy. Evaluation of MET status could be relevant for therapeutic stratification of late stage prostate cancer.


Coronary artery ectasia: remains a clinical dilemma.
Coronary artery ectasia (CAE) is defined as localized coronary dilatation that exceeds the diameter of normal adjacent segments or the diameter of the patient's largest coronary vessel by 1.5 times. The incidence of CAE varies from 1.5 to 5% in most literature; however, it was reported as high as 10% in some nations. Although, the pathogenesis of CAE is not fully understood, atherosclerosis remains the main association with CAE, in the western world. Kawasaki disease is another common cause of acquired heart disease in children, causing CAE. Kawasaki disease prevalence is overstated by its geographical distribution. Current modalities of investigation looked at the anatomical distribution of the disease and its possible ischemic effects. Biomarkers were studied in depth to explain the active nature of CAE; however, the common association with atherosclerosis weakens its significance. Here we reviewed CAE, its prevalence, relationship to other systemic anomalies in the vascular bed, pathogenesis and diagnostic tools currently in use.


Financing teaching hospital missions: a context.
The issue of what teaching hospitals do, how much it costs, and how it should be financed has been the subject of ongoing debate. This Perspective provides a context for considering the implications of the latest contribution to that debate: the paper by Lane Koenig and colleagues that presents new estimates of teaching hospitals' mission-related costs. I address the system through which teaching hospital activities are financed, the difficulty in identifying and estimating the costs of teaching hospitals' missions, and the problems involved in determining how those missions should be underwritten.


An MRI contrast agent based on a zwitterionic metal-chelating polymer for hepatorenal angiography and tumor imaging.
MRI contrast agents such as paramagnetic Gd(iii)-chelates, can improve the ability of MRI in differentiating diseased and healthy tissues, and have been widely used in clinical diagnosis. However, the enhancement effect of small molecular MRI contrast agents is unsatisfied due to their relative high rotation rates. Furthermore, the small molecular contrast agents also suffer from the short blood half-life and nonspecific extracellular diffusion in tissues, which also restricts their applications. To address these issues, we developed a macromolecular MRI contrast agent based on a zwitterionic metal-chelating polymer. Poly(acrylic acid) (PAA) was chosen as the main chain, and diethylenetriamine pentaacetic acid (DTPA) as the metal-chelating group was coupled through the carboxyl groups of PAA using diethylenetriamine (DET) as a linker. The macromolecular MRI contrast agent constructed by chelating with Gd3+ (Gd-PAA) exhibited a much higher longitudinal relaxation rate (r1) than the clinical contrast agent Gd-DTPA. Importantly, due to the stealth ability of the zwitterionic structure, Gd-PAA can reside in the blood long enough without any microvascular leakage in the extracellular space of normal tissues, which allows it to be used for precise blood MR imaging, such as hepatorenal angiography, but also for tumor imaging because of the enhanced permeability and retention (EPR) effecta. Besides, the result of long-term toxicity tests highlights the safety feature of the current contrast agent. Hence, the current contrast agent overcomes the defect of traditional small molecular Gd(iii)-based T1-weighted contrast agents and shows great prospects for future clinical applications.


Minimally Invasive Techniques for Hirschsprung Disease.
Background: Surgical treatment of Hirschsprung disease (HD) evolved in the last decades with the introduction of new innovative minimally invasive techniques. The aim of present study is to compare the results from two centers, applying similar minimal access approaches, total transanal endorectal pull-through (TEPT) and laparoscopic-assisted transanal pull-through (LA-TAPT). Materials and Methods: Data of all patients admitted between January 2011 and December 2016 in two Italian referral Hospitals for HD were retrospectively collected and analyzed. Exclusion criteria were as follows: redo procedure, patients with total colonic aganglionosis (ileostomy), patients lost at follow-up, or missing data. Patients who underwent TEPT and LA-TAPT were compared for gestational age, birth weight, age and weight at surgery, associated malformation, genetic syndrome, length of hospital stay, and early postoperative complications (within 30 days). Statistical analysis: Fisher's test and Mann-Whitney test; statistical significance set at P < .05. Results: None of the patients who underwent TEPT required laparotomy or laparoscopic assistance. Patients who underwent TEPT had lower age (P = .001), lower body weight (P < .0001), a significant higher rate of associated congenital heart disease (P = .006), and longer postoperative stay. In addition, the prevalence of perianal dermatitis was higher in TEPT patients (17/61 [28%] versus 2/46 [4%], P = .001). The two groups were similar in terms of postoperative enterocolitis, redo surgery, anastomotic stenosis, and other infective complications. Conclusion: Both minimally invasive techniques allow surgical advantages and outcomes; TEPT avoids pneumoperitoneum and the transperitoneal approach, with no need for laparoscopic instrumentation. TEPT group had longer postoperative stay, probably due to the higher prevalence of associated cardiac anomalies, and higher prevalence of perianal dermatitis, probably due to the lower age at operation.


Cellular microbiology of intracellular Salmonella enterica: functions of the type III secretion system encoded by Salmonella pathogenicity island 2.
The facultative intracellular pathogen Salmonella enterica resides in a special membrane compartment of the host cell and modifies its host to achieve intracellular survival and proliferation. The type III secretion system encoded by Salmonella pathogenicity island 2 (SPI2) has a central role in the interference of intracellular Salmonella with host cell functions. SPI2 function affects antimicrobial defense mechanisms of the host, intracellular transport processes, integrity and function of the cytoskeleton and host cell death. These modifications are mediated by translocation of a large number of effector proteins by the SPI2 system. In this review, we summarize recent work on the cellular phenotypes related to SPI2 function and contribution of SPI2 effector proteins to these manipulations. These studies reveal a complex set of pathogenic interferences between intracellular Salmonella and its host cells.


Cerebral vascular hamartomas in five dogs.
Vascular hamartomas are considered developmental lesions rather than true neoplasms. Reports of such anomalies in the canine brain are scarce, and their classification is confusing. This case series of vascular hamartomas from the brains of five dogs was characterized using histochemistry and immunohistochemistry, in addition to gross and microscopic findings. All five hamartomas were located in the telencephalon, three in the pyriform lobe, without any predilection for the left or right side. Each hamartoma consisted of a proliferation of thin-walled vessels which varied in caliber. These vessels were elastin-negative, with varying amounts of collagen and no muscular component. In four of the five hamartomas, lining cells were actin- and factor VIII-positive. All five hamartomas contained glial fibrillary acid protein (GFAP)-positive parenchyma at moderate to high frequency, and four contained neurofilament-positive axons between component vessels. This report shows that vascular hamartomas in the canine brain are structural malformations for which immunohistochemistry is useful for accurate classification.


Population genomic transformations induced by isolation of wild bird avian influenza viruses (Orthomyxoviridae) in embryonated chicken eggs.
Isolation and cultivation of wild-type viruses in model organism cells or tissues is standard practice in virology. Oftentimes, the virus host species is distantly related to the species from which the culture system was developed. Thus, virus culture in these tissues and cells basically constitutes a host jump, which can lead to genomic changes through genetic drift and/or adaptation to the culture system. We directly sequenced 70 avian influenza virus (Orthomyxoviridae) genomes from oropharyngeal/cloacal swabs collected from wild bird species and paired virus isolates propagated from the same samples following isolation in specific-pathogen-free embryonated chicken eggs. The data were analyzed using population genetic approaches including evaluation of single nucleotide polymorphism (SNP) frequencies and divergence with pooled-sequencing analyses, consensus sequence placement in neighbor-joining trees, and haplotype reconstruction and networks. We found that propagation of virus in eggs leads to skewed SNP mutation spectra with some SNPs going to fixation. Both synonymous and nonsynonmous SNP frequencies shifted. We found multiple consensus sequences that differed between the swabs and the isolates, with some sequences from the same sample falling into divergent genetic clusters. Twenty of 23 coinfections detected had different dominant subtypes following virus isolation, thus sequences from both the swab and isolate were needed to obtain full subtype data. Haplotype networks revealed haplotype frequency shifts and the appearance or loss of low-frequency haplotypes following isolation. The results from this study revealed that isolation of wild bird avian influenza viruses in chicken eggs leads to skewed populations that are different than the input populations. Consensus sequence changes from virus isolation can lead to flawed phylogenetic inferences, and subtype detection is biased. These results suggest that for genomic studies of wild bird influenza viruses the biological field should move away from chicken egg isolation towards directly sequencing the virus from host samples.


Nanoencapsulation Enhances Anticoagulant Activity of Adenosine and Dipeptide IleTrp.
It is well-known that drugs administered into an organism intravenously or through the gastrointestinal tract are degraded by enzymes of the body, reducing their therapeutic effect. One of the ways to decrease this undesirable process is through the inclusion of drugs in nanomaterials. Earlier strong anticoagulant activity was demonstrated for dipeptide IleTrp (IW) and adenosine (Ado). In this work, the effect of inclusion in nanomaterials on the biological activity of IW and Ado was studied. For this purpose, Ado and IW were incorporated into thermosensitive nanogel composed of pluronic P123-grafted heparin. The prepared nanocarrier was characterized by transmission electron microscopy, dynamic light scattering, and ζ-potential. Biological activity was determined by measuring the bleeding time from mouse tail in vivo and the time of clot formation in vitro. It was found that encapsulation of Ado and IW into nanomaterial significantly increased their effects, resulting in an increase in the bleeding time from mouse tail and clot formation time. Thus, inclusion of low molecular weight anticoagulants Ado and IW into nanomaterials may be considered a way to increase their biological activity.


General theory for multiple input-output perturbations in complex molecular systems. 1. Linear QSPR electronegativity models in physical, organic, and medicinal chemistry.
In general perturbation methods starts with a known exact solution of a problem and add "small" variation terms in order to approach to a solution for a related problem without known exact solution. Perturbation theory has been widely used in almost all areas of science. Bhor's quantum model, Heisenberg's matrix mechanincs, Feyman diagrams, and Poincare's chaos model or "butterfly effect" in complex systems are examples of perturbation theories. On the other hand, the study of Quantitative Structure-Property Relationships (QSPR) in molecular complex systems is an ideal area for the application of perturbation theory. There are several problems with exact experimental solutions (new chemical reactions, physicochemical properties, drug activity and distribution, metabolic networks, etc.) in public databases like CHEMBL. However, in all these cases, we have an even larger list of related problems without known solutions. We need to know the change in all these properties after a perturbation of initial boundary conditions. It means, when we test large sets of similar, but different, compounds and/or chemical reactions under the slightly different conditions (temperature, time, solvents, enzymes, assays, protein targets, tissues, partition systems, organisms, etc.). However, to the best of our knowledge, there is no QSPR general-purpose perturbation theory to solve this problem. In this work, firstly we review general aspects and applications of both perturbation theory and QSPR models. Secondly, we formulate a general-purpose perturbation theory for multiple-boundary QSPR problems. Last, we develop three new QSPR-Perturbation theory models. The first model classify correctly >100,000 pairs of intra-molecular carbolithiations with 75-95% of Accuracy (Ac), Sensitivity (Sn), and Specificity (Sp). The model predicts probabilities of variations in the yield and enantiomeric excess of reactions due to at least one perturbation in boundary conditions (solvent, temperature, temperature of addition, or time of reaction). The model also account for changes in chemical structure (connectivity structure and/or chirality paterns in substrate, product, electrophile agent, organolithium, and ligand of the asymmetric catalyst). The second model classifies more than 150,000 cases with 85-100% of Ac, Sn, and Sp. The data contains experimental shifts in up to 18 different pharmacological parameters determined in >3000 assays of ADMET (Absorption, Distribution, Metabolism, Elimination, and Toxicity) properties and/or interactions between 31723 drugs and 100 targets (metabolizing enzymes, drug transporters, or organisms). The third model classifies more than 260,000 cases of perturbations in the self-aggregation of drugs and surfactants to form micelles with Ac, Sn, and Sp of 94-95%. The model predicts changes in 8 physicochemical and/or thermodynamics output parameters (critic micelle concentration, aggregation number, degree of ionization, surface area, enthalpy, free energy, entropy, heat capacity) of self-aggregation due to perturbations. The perturbations refers to changes in initial temperature, solvent, salt, salt concentration, solvent, and/or structure of the anion or cation of more than 150 different drugs and surfactants. QSPR-Perturbation Theory models may be useful for multi-objective optimization of organic synthesis, physicochemical properties, biological activity, metabolism, and distribution profiles towards the design of new drugs, surfactants, asymmetric ligands for catalysts, and other materials.


The relationship between the BOLD-induced T(2) and T(2)(*): a theoretical approach for the vasculature of myocardium.
Recently the blood oxygenation level-dependent (BOLD)-related T(2)* of myocardium was derived as an analytical function of intracapillary blood volume, blood oxygenation, and nuclear spin diffusion. The basis of this approach was to approximate the diffusion-induced field fluctuations a nuclear spin is subjected to by strong collision dynamics, i.e., the field fluctuations are uncorrelated. The same analysis is now performed for spin echo experiments that gives myocardial T(2) as a function of the parameters above and the echotime. An analytical relationship between T(2) and T(2)* relaxation is derived. The dependence of T(2) on diffusion, echo time, and blood oxygenation is congruent with simulation and experimental data. Magn Reson Med 42:1004-1010, 1999.


Investigating tautomeric polymorphism in crystalline anthranilic acid using terahertz spectroscopy and solid-state density functional theory.
Terahertz spectroscopy is sensitive to the interactions between molecules in the solid-state and recently has emerged as a new analytical tool for investigating polymorphism. Here, this technique is applied for the first time to the phenomenon of tautomeric polymorphism where the crystal structures of anthranilic acid (2-aminobenzoic acid) have been investigated. Three polymorphs of anthranilic acid (denoted Forms I, II and III) were studied using terahertz spectroscopy and the vibrational modes and relative polymorph stabilities analyzed using solid-state density functional theory calculations augmented with London dispersion force corrections. Form I consists of both neutral and zwitterionic molecules and was found to be the most stable polymorph as compared to Forms II and III (both containing only neutral molecules). The simulations suggest that a balance between steric interactions and electrostatic forces is responsible for the favoring of the mixed neutral/zwitterion solid over the all neutral or all zwitterion crystalline arrangements.


A different approach in thoracic surgery: Guillotine lobectomy.
In this study, we aimed to compare the surgical results of video-assisted thoracoscopic lobectomy with the guillotine technique to the results of conventional video-assisted thoracoscopic lobectomy. Between January 2013 and December 2019, a total of 49 patients (20 males, 29 females; median age: 45 years; range, 11 to 73 years) who underwent video-assisted thoracoscopic lobectomy for benign lung pathologies were retrospectively analyzed. The patients were divided into two groups: the guillotine technique group (n=31) who had simultaneous cutting of the lobar artery and lobar bronchus with a single stapler, and the control group (n=18) who received conventional video-assisted thoracoscopic lobectomy. Demographic features of the patients, type of surgery, type of pulmonary resection, duration of the operation, postoperative length of hospital stay, postoperative pathological examination result, complications, and follow-up data were recorded. The median operation time was 142.5 (range, 60 to 237) min and 90 (range, 55 to 180) min in the control and the guillotine technique groups, respectively, indicating a statistically significant difference (p<0.05). Bronchiectasis was the most common histopathological diagnosis in both groups. No intraoperative complication, long-term complications or mortality were observed in any of the patients. The guillotine lobectomy technique significantly reduces the duration of the operation. The adventitia and connective tissue around the lobar artery and lobar bronchus enable the closure of these structures with the supporting tissue and, therefore, reinforces the staples. The guillotine technique in video-assisted thoracoscopic lobectomy seems to be a cost-effective, reliable, and practical method that provides intraoperative convenience and shortens the operation time.


Has monitoring of the contralateral breast improved the prognosis in patients treated for primary breast cancer?
Bilateral breast cancer has a cumulative incidence of about 7% in patients with primary operable breast cancer, and most of these lesions are metachronous. Most retrospective studies have shown that a majority of these patients have invasive cancer in the second breast, and varying percentages have nodal metastases, which may be of a higher stage than the first cancer. Physicians are now more aware of the importance of careful monitoring of the second breast after ipsilateral mastectomy, and improvements have been made in mammographic surveillance. A retrospective, comparative analysis of two separate breast cancer populations at risk for bilateral breast cancer was done on patients who entered into the system before effective mammographic monitoring (BEM) and after effective mammographic monitoring (AEM). The first group of patients consisted of 500 consecutive patients with primary breast cancer diagnosed during the years 1969 through 1975, of whom 37 (7.4%) had bilateral breast cancer. The second group consisted of 557 consecutive patients diagnosed during the years 1977 through 1984, of whom 36 (6.5%) had bilateral breast cancer. The staging percentages of the second breast cancer in the BEM group were Stage 0, 5.4%; Stage I, 48.6%; Stage II, 10.8%; Stage III, 21.6%; and Stage IV, 13.5%. The second group had an improvement in stage, with 33.3% being Stage 0, 22.2% Stage I, 29.6% Stage II, 3.7% Stage III, and 3.7% Stage IV (P less than 0.05). The median interval between primary lesions was 39 months in the first group and 19 months in the second group (in part, this difference may represent increased identification of synchronous cancers). The second breast cancer was undetected by mammography in 9 of 34 (26%) patients. Six were detected by contralateral biopsy (all were lobular carcinomas in situ), and three were found by clinical examination (all were invasive cancers). It was concluded that more aggressive monitoring of the second breast by frequent clinical examination, mammography, and selected contralateral biopsy appears to have increased the early detection rate of second breast cancers in patients under observation.


An HIV-1 and HIV-2 cross-reactive cytotoxic T-cell epitope.
The HLA-B27-restricted HIV gag cytotoxic T-lymphocyte (CTL) epitope, 265-279, is highly conserved amongst HIV-1 isolates, only one, HIV-1ELI, having a single amino acid substitution. Over the same region HIV-2 differs by five amino acids. As a broadly cross-protective AIDS vaccine should protect against infection from all isolates of HIV-1 and HIV-2, we tested CTL specific for the HIV-1 265-279 epitope with peptide analogues from HIV-1ELI, HIV-2 and two simian immunodeficiency virus (SIV) isolates, and with recombinant vaccinia viruses expressing the respective gag genes, to determine whether there was any cross-reactivity for this CTL epitope. CTL from the HIV-1-infected donor could recognize the HIV-1ELI peptide, the HIV-2 peptide and recombinant vaccinia virus-infected target and one of the two SIV peptide-treated targets. Epitopes that exhibit such cross-reactivity may be valuable in vaccine design.


Cap polyposis of the colon and rectum: an analysis of endoscopic findings.
Because of the rarity of cap polyposis of the colon and rectum, the endoscopic features of this condition have not been specified to date. The aim of this study is to characterize the endoscopic features of cap polyposis. The diagnosis of cap polyposis was established by histologic findings in specimens obtained endoscopically or surgically from four patients. Colonoscopic findings in the four patients were retrospectively reviewed. The endoscopic features were divided into semipedunculated type (three patients) and flat-topped protruding type (one patient). In the semipedunculated type, the polyps were characterized by reddish protrusions of various configurations with eroded surface in the rectosigmoid colon. In the remaining patient, all the lesions were flat protrusions with a reddish central depression. The polyps of both types became smaller in size and fewer in number at the proximal part of the sigmoid colon. Multiple white specks were observed in the intervening mucosa in all four patients. The prominence of the polyps at the distal part of the colon and rectum and multiple white specks in the intervening mucosa seem to be the additional endoscopic features suggestive of cap polyposis.


Development of novel molecularly imprinted solid-phase microextraction fiber and its application for the determination of triazines in complicated samples coupled with high-performance liquid chromatography.
A novel molecularly imprinted polymer (MIP) coated solid-phase microextraction (SPME) fiber that could be coupled directly to high-performance liquid chromatography (HPLC) was prepared with prometryn as the template molecule. The characteristics and application of this fiber were investigated. Electron microscope photographs indicated that the MIP coating with average thickness of 25.0 microm was homogeneous and porous. The extraction yield of prometryn with the MIP-coated fibers was 10 times as much as that with the non-imprinted polymer (NIP) coated fibers. And special selectivity to other triazines which have similar structure to prometryn was discovered with the MIP-coated fibers. A method for the determination of triazines by the MIP-coated SPME coupled with HPLC was developed. The optimized extraction conditions were studied. Detection limits for the triazines studied were within the range of 0.012-0.090 microg/L. The method was applied to five triazines determination in the spiked soybean, corn, lettuce, and soil samples with the recoveries of 78.0-103.5%, 82.4-113.4%, 75.5-83.4%, and 81.0-106.1%, respectively. The MIP-coated fibers are suitable for the selective extraction of trace triazines in complicated samples.


Osmotic regulation of toad bladder responsiveness to neurohypophyseal hormones.
The effect of dilution of the interstitial fluids on the responsiveness of the toad urinary bladder to antidiuretic hormones has been examined in vivo and in vitro. Toads were given periodic injections with vasopressin while in water so that their plasma osmolality fell below 190 mosmoles/kg H(2)O. The hydraulic conductivity of bladders which had been removed from the animal and fixed with 1% glutaraldehyde was 10-fold less in overhydrated toads than in normally hydrated controls. A similar inhibitory phenomenon was observed in in vitro studies, when the tonicity of Ringer's fluid in which the bladders were suspended was lowered from its isotonic value. Mannitol, but not urea, could be effectively substituted for one-half of the NaCl content of Ringer's fluid. In other experiments it has been shown that the responsiveness of the bladder to vasotocin is depressed during bulk water movement across the tissue. This "flux inhibition" was found to depend upon the velocity and the duration of water flow from mucosa to the serosa. It is suggested that the responsiveness of the toad bladder to antidiuretic hormones diminishes as the effective osmotic pressure of the interstitial fluids declines.


Socialization through stories of disaster in engineering laboratories.
The initiation of novices into research communities relies on the communication of tacit knowledge, behavioral norms and moral values. Much of this instruction happens informally, as messages subtly embedded in everyday interactions. Through participant-observation and interviews, I investigate how engineers socialize future engineers. Specifically, I study how undergraduate students who work in an engineering laboratory learn their research community's social and technical norms. I found that a key method of conveying knowledge about social behavior and technical practices is the narration of the experience of mistakes and failures. As a powerful tool of socialization, these 'disaster stories' contain messages of self-deprecation, humility, teamwork and mutual learning. They are most often told by the principal investigator or a graduate student to an undergraduate student, thus generously offering novices the opportunity to learn vicariously through more experienced engineers' errors. Disaster stories can reduce hierarchy, normalize learning through mistakes and build relationships among workers through the sharing of humbling personal struggles. The stories promote collaboration, a sense of belonging and the value of continuous learning for all the community's members. They demonstrate the power of storytelling in the acquisition of tacit social and technical knowledge.


[A novel neurocutaneous syndrome: Legius syndrome. A case report].
Legius syndrome is an autosomal dominant disorder caused by the mutation in the SPRED1 gene involving a negative regulator of the RAS-MAPK pathway, similar to neurofibromin and therefore shows some clinical similarities to neurofibromatosis type I (NF1) but less severe. These patients have multiple cafe-au-lait spots, sometimes associated with skin fold freckling, dysmorphic features, lipomas, and mild learning disabilities. However, this syndrome is not associated with neurofibromas, optic gliomas, Lisch nodules or tumor predisposition. We present a 10 months child, without a personal interest history, consulting by hypotonic extremities, cafe-au-lait spots and mild psychomotor difficult. Mother's sister and grandfather have some cafe-au-lait spots. In our patient, NF1 genetic study was negative, but we observe a mutation in the SPRED1 gene, compatible with Legius syndrome. Asymptomatic mother shows the same mutation in SPRED1 gene. We emphasize the relevance of the differential diagnosis of NF1 with respect to numerous complications to appear, with a better prognosis recently described entity as it is Legius syndrome.


Duplication and loss of chromosome 21 in two children with Down syndrome and acute leukemia.
Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.


Dietary advice on prescription: experiences with a weight reduction programme.
To describe overweight persons' experiences with weight reduction and participation in the dietary advice on prescription. Approximately 20% of overweight individuals are able to successfully lose weight. Experiences from earlier weight reduction programmes indicate that those who succeed typically manage to avoid overeating to handle stress and have high motivation to lose weight. Those who fail have low self-control and engage in negative health behaviours such as eating when experiencing negative emotions and stress. The study used a descriptive qualitative design and was conducted at a Primary Health Care Centre in south-west Sweden. The first nineteen study participants who completed the weight reduction programme in two years responded in writing to five open questions about their experiences with the programme. Data were analysed using inductive content analysis. The participants appreciated the face-to-face meetings with the nurse because they felt seen and listened to during these sessions. They also felt their life situations and self-discipline had an impact on how well they were able to follow the programme. Dietary advice on prescription advice was considered to be helpful for achieving behavioural changes and losing weight. People who succeeded in sustainably losing weight described the importance of support from partners or close friends. To achieve sustainable weight reduction, it is important to individualise the programme in order to address each person's life situation and the unique difficulties they may encounter. Motivational interviewing appears to be a good technique for developing a successful relationship between the nurse and the patient. The dietary advice on prescription advice was perceived to be a good way to improve food habits and can easily be used at many Primary Health Care Centres. Patient's partners should also be offered the opportunity to participate in the programme.


EphB4 tyrosine kinase stimulation inhibits growth of MDA-MB-231 breast cancer cells in a dose and time dependent manner.
EphB4 receptor tyrosine kinase is of diagnostic and therapeutic value due to its overexpression in breast tumors. Dual functions of tumor promotion and suppression have been reported for this receptor based on presence or absence of its ligand. To elucidate such discrepancy, we aimed to determine the effect of time- and dose-dependent stimulation of EphB4 on viability and invasion of breast cancer cells via recombinant ephrinB2-Fc. Cells were seeded into multiwell plates and were stimulated by various concentrations of preclustered ephrinB2-Fc. Cell viability was measured on days 3 and 6 following treatment using alamar-blue when cells were in different states of confluence. Stimulation of cells with ephrinB2 did not pose any significant effect on cell viability before reaching confluence, while inhibition of cell growth was detected after 6 days when cells were in postconfluent state following a dose-dependent manner. EphrinB2 treatment did not affect tubular formation and invasion on matrigel. This study showed that EphB4 can differentially inhibit cells at post confluent state and that presence of ligand manifests growth-inhibitory properties of EphB4 receptor. It is concluded that growth inhibition has occurred possibly due to long treatment with ligand, a process which leads to receptor downregulation.


Chemical characteristics of normal, woolly apple aphid-damaged, and mechanically damaged twigs of six apple cultivars, measured in autumn wood.
Chemical characteristics of normal, woolly apple aphid-damaged, and mechanically damaged twigs of six apple cultivars: Red Fuji, Golden Delicious, Qinguan, Zhaojin 108, Starkrimson, and Red General, were examined in autumn wood to provide abetter understanding of factors related to cultivar resistance to the woolly apple aphid, Eriosoma lanigerum (Hausmann). Chemical measures examined included soluble sugars, soluble proteins and amino acids, total phenolics, and polyphenol oxidase (that enhances the resistance of plants to insects) and superoxide dismutase, peroxidase, and catalase (that degrade waste products in plants). Soluble sugar, protein, and amino acid contents in normal (undamaged) twigs of Red Fuji, aphid-susceptible cultivar, were higher than in mechanically damaged and aphid-damaged twigs. Total phenolic compounds, an important group of defensive compounds against aphids, increased by 30.5 and 6.0% in mechanically damaged twigs of Qinguan and Zhaojin 108, respectively, and decreased by 21.7 and 16.1% in aphid-damaged twigs of Red Fuji and Red General, respectively. Compared with normal twigs, in aphid-damaged twigs, superoxide dismutase, peroxidase, and polyphenol activity all decreased in Red Fuji. The resistance of some apple cultivars to woolly apple aphid during the growth of autumn shoots was related to several of the physiological indices we monitored. The thin epidermis of callus tissue over healed wounds showed increased susceptibility to the attack by woolly apple aphid. Apple cultivar Qinguan with the highest level of resistance to woolly apple aphid in autumn had increased in amino acid, total phenolic compound levels, and enzyme activity after aphid feeding.


High surface area electrodes by template-free self-assembled hierarchical porous gold architecture.
The electrode active surface area is a crucial determinant in many electrochemical applications and devices. Porous metal substrates have been employed in electrode design, however construction of such materials generally involves multistep processes, generating in many instances electrodes exhibiting incomplete access to internal pore surfaces. Here we describe fabrication of electrodes comprising hierarchical, nano-to-microscale porous gold matrix, synthesized through spontaneous crystallization of gold thiocyanate in water. Cyclic voltammetry analysis revealed that the specific surface area of the conductive nanoporous Au microwires was very high and depended only upon the amount of gold used, not electrode areas or geometries. Application of the electrode in a pseudo-capacitor device is presented.


[Immune complex hyperuricemic nephritis: aspects of its morphology and pathogenesis].
The authors described the results of an immunohistochemical, electron microscopic and morphometric study of the kidney bioptates of 45 patients with latent glomerulonephritis with hyperuricemia, 8 patients with primary gout and 12 patients with latent glomerulonephritis without hyperuricemia. Two possible variants of the involvement of the renal glomerula were revealed against a background of purine metabolism: typical immunocomplex glomerulonephritis and the so called "reactive" mesangial changes. The expression of interstitial changes (by the results of histometric investigation) was maximum in gout, slightly less in latent nephritis with hyperuricemia and minimum in nephritis without hyperuricemia. The authors emphasized the possibility of immunocomplex nephritis as one of the variants of renal lesion in gout and hyperuricemia and the necessity of specifying therapeutic modalities to be used in this condition including general nephrological approaches to the treatment of latent nephropathies.


A strategy combining imaging and laboratory biomarkers in comparison with a simplified clinical score for risk stratification of patients with acute pulmonary embolism.
This study aimed to assess the performance of two prognostic models-the European Society of Cardiology (ESC) model and the simplified Pulmonary Embolism Severity Index (sPESI)-in predicting short-term mortality in patients with pulmonary embolism (PE). We compared the test characteristics of the ESC model and the sPESI for predicting 30-day outcomes in a cohort of 526 patients with objectively confirmed PE. The primary end point of the study was all-cause mortality. The secondary end point included all-cause mortality, nonfatal symptomatic recurrent VTE, or nonfatal major bleeding. Overall, 40 of 526 patients died (7.6%; 95% CI, 5.3%-9.9%) during the first month of follow-up. The sPESI classified fewer patients as low risk (31% [165 of 526], 95% CI, 27%-35%) compared with the ESC model (39% [207 of 526], 95% CI, 35% to 44%; P < .01). Importantly however, low-risk patients based on the sPESI had no 30-day mortality compared with 3.4% (95% CI, 0.9-5.8) in low-risk patients by the ESC model. The secondary end point occurred in 1.8% of patients in the sPESI low-risk and 5.8% in the ESC low-risk group (difference, 4.0 percentage points; 95% CI, 0.2-7.8). The prognostic ability of the ESC model remained significant in the subgroup of patients at high-risk according to the sPESI model (OR 1.95, 95% CI, 1.41 to 2.71, P < .001). Both the sPESI and the ESC model successfully predict 30-day mortality after acute symptomatic PE, but exclusion of an adverse early outcome does not appear to require routine imaging procedures or laboratory biomarker testing.


Bioethics for clinicians: 14. Ethics and genetics in medicine.
Information about a patient's inherited risk of disease has important ethical and legal implications in clinical practice. Because genetic information is by nature highly personal yet familial, issues of confidentiality arise. Counselling and informed consent before testing are important in view of the social and psychological risks that accompany testing, the complexity of information surrounding testing, and the fact that effective interventions are often not available. Follow-up counselling is also important to help patients integrate test results into their lives and the lives of their relatives. Genetic counselling should be provided by practitioners who have up-to-date knowledge of the genetics of and the tests available for specific diseases, are aware of the social and psychological risks associated with testing, and are able to provide appropriate clinical follow-up. Some physicians may elect to refer patients for genetic counselling and testing. However, it is inevitable that all physicians will be involved in long-term follow-up both by monitoring for disease and by supporting the integration of genetic information into patients' lives.


Home Automation for Adults With Disability Following an Injury: Protocol for a Social Return on Investment Study.
People with disability following a serious injury require long-term care. The most common injuries resulting in long-term disability are spinal cord and acquired brain injuries. While the long-term effects are difficult to predict and will vary between individuals, the costs of care and recovery span well beyond the initial treatment phase and include long-term care. Long-term care is changing with the availability and advances in cost and function of technologies, such as home automation. "Home automation" refers to technology that automates or remotely controls household functions. Home automation costs vastly differ, but home automation has the potential to positively impact the lives of people with disabilities. However, there is a dearth of evidence relating to the impact of home automation for people with a disability and few rigorous evaluations about the costs and return on investment. The purpose of this study is to describe the impact of home automation for people with long-term disability following a serious injury (such as a motor vehicle accident) using case studies, and by conducting an evaluation of the costs and outcomes for individuals, families, and the wider community using a Social Return on Investment (SROI) approach. SROI is a form of economic evaluation that develops a theory of change to examine the relationship among inputs, outputs, and outcomes and, in recent years, has gained popularity internationally, including in Australia. SROI has six phases: (1) identify scope and stakeholders, (2) map outcomes, (3) evidence outcomes and give them value, (4) establish impact, (5) calculate the SROI, and (6) report findings. Individuals with a disability who use home automation and key stakeholders will be interviewed. Stakeholders will be individuals involved in home automation for people with disabilities, such as allied health professionals, medical practitioners, equipment suppliers, engineers, and maintenance professionals. Users of home automation will be people who have a disability following a serious injury, have the capacity to provide consent, and have 1 or more elements of home automation. The impact of home automation will be established with financial proxies and appropriate discounts applied to avoid overestimating the social return. The SROI ratio will be calculated, and findings will be reported. The project was funded in November 2021 by the Lifetime Support Authority. Recruitment is underway, and data collection is expected to be completed by October 2022. The final results of the study will be published in March 2023. To our knowledge, this study represents the first study in Australia and internationally to employ SROI to estimate the social, personal, and community outcomes of home automation for people with a disability following a serious injury. This research will provide valuable information for funders, consumers, researchers, and the public to guide and inform future decision-making. DERR1-10.2196/42493.


In vivo and in vitro antiviral activity of hyperoside extracted from Abelmoschus manihot (L) medik.
To assess the anti-hepatitis B virus (HBV) effect of hyperoside extracted from Abelmoschus manihot (L) medik. The human hepatoma Hep G2.2.15 cell culture system and duck hepatitis B virus (DHBV) infection model were used as in vivo and in vitro models to evaluate the anti-HBV effects. In the cell model, the 50% toxic concentration of hyperoside was 0.115 g/L; the maximum nontoxic concentration was 0.05 g/L. On the maximum nontoxic concentrations, the inhibition rates of hyperoside on HBeAg and HBsAg in the 2.2.15 cells were 86.41% and 82.27% on d 8, respectively. In the DHBV infection model, the DHBV-DNA levels decreased significantly in the treatment of 0.05 g x kg(-1 ) x d(-1 ) and 0.10 g x kg(-1) x d(-1) dosage groups of hyperoside (P<0.01). The inhibition of the peak of viremia was at the maximum at the dose of 0.10 g x kg(-1 ) x d(-1) and reached 60.79% on d 10 and 69.78% on d 13, respectively. These results suggested that hyperoside is a strong inhibitor of HBsAg and HBeAg secretion in 2.2.15 cells and DHBV-DNA levels in the HBV-infected duck model.


Opportunistic thoracic infections. Bacteria, viruses, and protozoa.
The range of potential bacterial, viral, and protozoan pathogens that can cause pulmonary infections in immunocompromised patients is extensive. An aggressive diagnostic approach is essential to maximizing chances for a successful outcome. This article discusses the general diagnostic approach and provides a discussion of the most important bacterial, viral, and protozoan chest infections occurring in this setting.


Molecular validation of anthropophilic Phlebotominae sandflies (Diptera: Psychodidae) in Central Panama.
Six Phlebotominae sand fly species are incriminated as biological vectors of human pathogens in Panama, but molecular corroboration is still needed. We aim at confirming the identity of Phlebotominae species documented as anthropophilic in Panama. Adult sandflies were collected from August 2010 to February 2012 in Central Panama using CDC light traps. Species confirmation was accomplished through molecular barcodes and allied sequences from GenBank. A total of 53,366 sand fly specimens representing 18 species were collected. Five species were validated molecularly as single phylogenetic clusters, but Psychodopygus thula depicted two genetically divergent lineages, which may be indicative of cryptic speciation.


Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding.
Many patients with nonvalvular atrial fibrillation (NVAF) are at a high risk of gastrointestinal (GI) bleeding due to conditions including older age; stage III to V chronic kidney disease (CKD); HAS-BLED (hypertension, kidney or liver disease, stroke history, prior bleeding, unstable international normalized ratio, age >65, drug or alcohol use) score of 3 or greater; corticosteroid, antiplatelet or nonsteroidal anti-inflammatory drug (NSAID) use; or GI conditions. To compare the risk of stroke and/or systemic embolism (SE) and major bleeding (MB) among patients with NVAF and high risk of GI bleeding who received non-vitamin K antagonist oral anticoagulants (NOACs) vs those who received warfarin. This retrospective cohort study included patients with NVAF who were 75 years and older; had stage III to V CKD; had an HAS-BLED score of 3 or greater; used corticosteroids, antiplatelets, or NSAIDs; or had GI conditions. Data were collected from the Centers for Medicare & Medicaid Services and 4 commercial insurance databases between January 1, 2012, and September 30, 2015. Data analysis was conducted from January 2012 to September 2015. New prescription for apixaban, dabigatran, rivaroxaban, or warfarin between January 1, 2013, and September 30, 2015 (identification period). Six propensity score-matched cohorts were created to compare between study drugs. For the primary objective, Cox models were used to estimate stroke and/or SE and MB hazard ratios (HRs). A total of 381 054 patients (187 489 [49.2%] women) with NVAF and at least 1 high-risk GI bleeding factor were identified (HAS-BLED score ≥3: 284 527 [74.7%]; aged ≥75 years: 252 835 [66.4%]; corticosteroid, antiplatelet, or NSAID therapy: 107 675 [28.3%]; prior GI bleeding conditions: 74 818 [19.6%]; and stage III-V CKD: 56 892 [14.9%]). All NOACs were associated with a lower risk of stroke and/or SE vs warfarin (apixaban: HR, 0.60; 95% CI, 0.52-0.68; dabigatran: HR, 0.75; 95% CI, 0.64-0.88; rivaroxaban: HR, 0.79; 95% CI, 0.73-0.86). Compared with warfarin, apixaban and dabigatran were associated with a lower risk of MB (apixaban: HR, 0.59; 95% CI, 0.56-0.63; dabigatran: HR, 0.78; 95% CI, 0.70-0.86), while rivaroxaban was associated with a higher risk (HR, 1.11; 95% CI, 1.05-1.16). In this study of patients with NVAF and high risk of GI bleed, NOACs were associated with lower rates of stroke and/or SE, but NOACs had varying risks of MB compared with warfarin. These results may help inform treatment options in this patient population.


Transperitoneal laparoscopic treatment for recurrence of a giant multilocular prostatic cystadenoma: A case report and review of the literature.
Giant multilocular prostatic cystadenomas (GMPC) are very rare benign tumors that originate from the prostate with extensive spread into the pelvis. The lesion may present as large abdominal mass causing obstructive voiding dysfunction and usually not invading adjacent structures. All of the previously reported patients with GMPC underwent open surgery. Although the natural history of prostatic cystadenoma remains unknown, complete surgical excision may not always be necessary. We report the case of a 74-year-old male who presented a retrovesical recurrence of prostatic cystoadenoma after 16 years, treated with a laparoscopic approach. To our knowledge this is the first case of laparoscopic management of GMPC. In this article we review the current literature about this rare tumor and discuss the diagnostic and management dilemmas posed by this rare pathologic condition. We believe that physicians should at least be aware of the existence of this disease in the differential diagnosis of pelvic cavity tumours and, considering the benignity of GMPC, they should propose--as first--a minimally invasive approach.


Molecular cloning and hormonal regulation of a murine epididymal retinoic acid-binding protein messenger ribonucleic acid.
A complementary DNA encoding the mouse epididymal secretory protein MEP 10 (mouse epididymal protein 10) was cloned and is now renamed murine epididymal retinoic acid binding protein (mE-RABP). The analysis of the predicted primary amino acid sequence showed that mE-RABP has a 75% identity with rat ESP I (epididymal secretory protein I), another epididymal retinoic acid-binding protein. The homology strongly suggests that mE-RABP is the mouse orthologue of rat ESP I. A computer analysis of the predicted three-dimensional structure confirmed that mE-RABP can accommodate retinoic acid as ligand. In the rat, ESP I messenger RNA (mRNA) is expressed in the efferent ducts and in the entire caput epididymidis. However, in the mouse, the expression of a 950-bp mE-RABP mRNA was detected only in principal cells of the mid/distal caput epididymidis, suggesting that the regulation of region-specific expression is different in rat and mouse. Northern blot analyses showed that mE-RABP gene expression is no longer detected 10 days after castration but progressively rebounds between days 15 and 60. However, mE-RABP protein could not be detected by Western blot 30 days after castration. Androgen replacement, begun 5 days after castration and continued for 4 days restored significant expression of mE-RABP mRNA. Efferent duct ligation for 10 days did not affect gene expression. Taken together, these results indicate that mE-RABP mRNA expression is regulated by androgens but not by testicular factors. The overall similarity in the primary amino acid sequence of mE-RABP with ESP I and other members of the lipocalin superfamily suggests that they are evolutionarily related.


The inhibition of bovine and rat parotid deoxyribonuclease I by skeletal muscle actin. A biochemical and immunocytochemical study.
Rat and bovine parotid gland and pancreas contain deoxyribonuclease I (DNAase I) activities in different amounts. The DNAase I activity in tissue homogenates of bovine and rat parotid gland can be inhibited by addition of monomeric actin, as with the enzyme of bovine pancreas. The isolated DNAase I species from bovine and rat parotid gland differ in their molecular weights and also in their affinities for monomeric actin, being lowest for rat parotid DNAase I (5 X 10(6)M(-1). Antibodies raised against rat and bovine parotid and bovine pancreatic DNAase I can be used to study the subcellular localization of DNAase I in these tissues by indirect immunofluorescence. DNAase I was found to be confined solely to the secretory granules of the tissue from which it was isolated.


TweepFake: About detecting deepfake tweets.
The recent advances in language modeling significantly improved the generative capabilities of deep neural models: in 2019 OpenAI released GPT-2, a pre-trained language model that can autonomously generate coherent, non-trivial and human-like text samples. Since then, ever more powerful text generative models have been developed. Adversaries can exploit these tremendous generative capabilities to enhance social bots that will have the ability to write plausible deepfake messages, hoping to contaminate public debate. To prevent this, it is crucial to develop deepfake social media messages detection systems. However, to the best of our knowledge no one has ever addressed the detection of machine-generated texts on social networks like Twitter or Facebook. With the aim of helping the research in this detection field, we collected the first dataset of real deepfake tweets, TweepFake. It is real in the sense that each deepfake tweet was actually posted on Twitter. We collected tweets from a total of 23 bots, imitating 17 human accounts. The bots are based on various generation techniques, i.e., Markov Chains, RNN, RNN+Markov, LSTM, GPT-2. We also randomly selected tweets from the humans imitated by the bots to have an overall balanced dataset of 25,572 tweets (half human and half bots generated). The dataset is publicly available on Kaggle. Lastly, we evaluated 13 deepfake text detection methods (based on various state-of-the-art approaches) to both demonstrate the challenges that Tweepfake poses and create a solid baseline of detection techniques. We hope that TweepFake can offer the opportunity to tackle the deepfake detection on social media messages as well.


[Hereditary Osler angioedema (report of case)].
A case of Osler's hereditary angioedema, that show a halimark of aedema of facing, neck, hands and foots, respiratory difficulty, to feel sick, to vomit, diarrhoea and abdominal pain, from the seven years old.


Evidencing the relationship between isomer spectra and melting: the 20- and 55-atom silver and gold cluster cases.
The present work highlights the links between melting properties and structural excitation spectra of small gold and silver clusters. The heat capacity curves are computed for Ag20, Au20, Ag55, Au55 and their ions, using a parallel-tempering molecular dynamics scheme to explore the density functional based tight binding (DFTB) potential energy surfaces and the multiple histogram method. It is found that clusters having very symmetric lowest energy structures (Au20, Ag55 and their ions) present sharp or relatively sharp solid-to-liquid transitions and large melting temperatures, important structural excitation energies and a discrete isomer spectrum. Opposite trends are observed for less ordered clusters (Ag20, Au55 and their ions). Regarding the structural evolution with temperature, very symmetric clusters exhibit minor evolution up to the starting melting temperature. The present study also highlights that, in contrast with the case of Au20, a single electron excess or deficiency is not determinant regarding the melting characteristics, even quantitatively, for clusters containing 55 atoms, for gold as for silver.


New perspective for the treatment of Alzheimer diseases: liposomal rivastigmine formulations.
The aim of this study was to determine the transportations of rivastigmine containing from various liposome formulations through Madin Darby Canine Kidney (MDCK) cells monolayer and to compare the in vitro test results with in vivo. There is no other liposome formulation of rivastigmine and the transportations of rivastigmine through MDCK cell monolayers or related study available in the literature. Cytotoxicity (MTT) test was used to determine cell viabilities. The effect of sodium-taurocholate or dimethyl-beta-cyclodextrine as penetration enhancer was also investigated. Characterization and stability studies for liposome formulations were performed. Permeation experiments of rivastigmine were performed through MDCK cells and dialysis membrane. The kinetic of release from liposomes was also investigated. The highest apparent permeability coefficient (log. values) was obtained with sodium-taurocholate liposomes for -1.15 ± 0.16 for MDCK cell. Rivastigmine liposomes and solutions were also administered to mice orally and intraperitonally. Acetylcholinesterase (AChE) activity was determined by Ellman method. AChE% inhibition values were calculated for both blood and brain after administration of rivastigmine solution and liposomes. The highest AChE inhibition was observed for rivastigmine-sodium-taurocholate liposomes. Histological observations of the mice' brains were performed under transmission electron microscope (TEM). The histological results were also indicated and supported all these findings.


A case report of arrhythmogenic ventricular cardiomyopathy presenting with sustained ventricular tachycardia arising from the right and the left ventricles before structural changes are documented.
Arrhythmogenic ventricular cardiomyopathy (AC) is a genetic progressive disease characterized by fibro-fatty replacement of either ventricles in isolation or in combination. Arrhythmogenic ventricular cardiomyopathy is frequently associated with ventricular tachycardia (VT) having a left bundle branch block (LBBB) morphology and much more rarely with VT having right bundle branch block (RBBB) morphology even when the left ventricle is involved. Cardiac magnetic resonance (CMR) imaging plays a key role in the diagnosis of AC. Sustained VT in AC may occur in the concealed stage of the disease before the manifestation of morphological abnormalities on echocardiogram; however, they almost always are accompanied by structural abnormalities of the ventricles on CMR. A 54-year-old man presented with sustained VT of LBBB configuration consistent with the diagnosis of AC but with no right ventricular (RV) anomalies at repeat CMR. Ten years later, he developed sustained VT with RBBB morphology and structural changes at CMR compatible with RV involvement in the setting of AC. Two years later, he suffered from recurrent identical sustained RBBB-VT with typical CMR signs of left ventricular involvement. Genetic analysis was negative for any known mutation. In the present report, we describe a patient with AC who first exhibited LBBB- and 10 years later RBBB-sustained VT. Contrasting with what is usually observed in patients with AC, documentations of the VT's arising from either ventricle were found to precede the structural anomalies in the respective cardiac chambers. This case highlights that normal CMR does not exclude underlying AC contrary to the perceptions of many clinicians. In addition, it strongly encourages repeating CMR after 1-2 years when the diagnosis of AC is highly suspected.


Peripartum hysterectomy in the first decade of the 21st century.
We reviewed the role of peripartum hysterectomy (PH) in the first decade of the 21st century. The study was confined to women who delivered a baby weighing 500 g or more between 2000 and 2009, and who required a hysterectomy within 72 h of delivery for obstetric reasons. Individual case records were reviewed. There were 19 cases of PH in 78,961 deliveries giving an incidence of 1 in 4,156 (0.02%). Of the 19 cases, 95% were delivered by caesarean section and 89% had one or more prior sections. The indications were placental bed pathology (79%), uterine atony (16%) and uterine trauma (5%). Of the 19 hysterectomies, 16 (84%) were total and a gynaecological oncologist was involved in nine (56%) of these cases. There were no maternal or fetal deaths, but a mother required an average blood transfusion of 10 units. The overall rate of PH was remarkably low compared with other studies but it is likely to increase in the future because of the strong association between increasing caesarean section rates and placental bed pathology. The potential involvement of the cervix and other pelvic structures by placental pathology means that PH in the future will be more challenging, and the hysterectomy will need to be total rather than subtotal.


Type-2 diabetes alters the basal phenotype of human macrophages and diminishes their capacity to respond, internalise, and control Mycobacterium tuberculosis.
Type 2 diabetes (T2D) is a risk factor for the development of tuberculosis (TB), although the associated mechanisms are not known. To study the association between T2D and the basal phenotype of macrophages, and their immune response to Mycobacterium tuberculosis (Mtb) infection. We evaluated the influence of T2D on the response of monocyte-derived macrophages (MDM) to Mtb in patients with T2D (n = 10) compared to healthy subjects (n = 9), before and after infection with Mtb clinical isolates bearing different degrees of virulence. The levels of cell surface markers for activation secreted cytokines and chemokines, bacterial association, and intracellular bacterial growth were evaluated. The expression levels of HLA-DR, CD80, and CD86 were low while those of of PD-L1 were high in uninfected MDMs derived from patients with diabetes; as a result of Mtb infection, changes were only observed in the expression levels of PD-L1. The levels of cytokines (e.g., IL-6, IL-1β, IL-10, and IL-12) and chemokines (e.g., MCP-1, MIG, and RANTES) are perturbed in MDMs derived from patients with diabetes, both before infection and in response to Mtb infection. In response to the more virulent Mtb strains, the levels of association and bacterial clearance were diminished in MDMs derived from patients with diabetes. T2D affects the basal activation state of the macrophages and its capacity to respond and control Mtb infection.


Hormone-induced increase in levels of functional mRNA and alpha-amylase mRNA in barley aleurones.
Incubation of barley aleurone cells with gibberellic acid produces a progressive increase in the RNA content of the cells. The activity of poly(A)-containing RNA, measured in an in vitro wheat germ protein-synthesizing system, reaches a maximum approximately 12 hr after hormone addition and declines thereafter. The structurally intact functional mRNA content in these cells, measured as poly(A)-RNA with 5' "caps," also shows a maximum at 12 hr and correlates with the translational capacity of poly(A)-RNA. Activation of mRNA by guanylylation or methylation after addition of gibberellic acid is ruled out. Available evidence indicates that gibberellic acid stimulates protein synthesis by increasing the synthesis of mRNA. Studies with cycloheximide suggest that the induction of synthesis of alpha-amylase mRNA by gibberellic acid requires protein synthesis after hormone addition.


Variable life adjusted display methodology for continuous performance monitoring of carotid endarterectomy.
Introduction The aim of this study was to use variable life-adjusted display (VLAD) methodology to monitor performance of six vascular surgeons undertaking carotid endarterectomy in a single institution. Materials and methods This was a prospective study with continuous analysis. A risk score model to predict 30-day stroke or death for individual patients was developed from data collected from 839 patients from 1992 to 1999. The model was used to monitor performance of six surgeons from 2000 to 2009. Individual risk factors and 30-day outcomes were analysed and VLAD plots were created for the whole unit and for each surgeon. Results Among the 941 carotid endarterectomies in the performance analysis, 28 adverse events were recorded, giving an overall stroke or death rate of 3.06%. The risk model predicted there would be 33 adverse events. There was no statistical difference between the predicted and the observed adverse events (P > 0.2, χ2 value 1.25, 4 degrees of freedom). The VLAD plot for the whole unit shows an overall net gain in operative performance, although this could have been chance variation. The individual VLAD plot showed that surgeons 1, 2, 3 and 6 to have an overall net gain in the number of successful operations. The changes observed between the surgeons was not significant (P > 0.05) suggesting chance variation only. Conclusions Performance of carotid endarterectomy can be continuously assessed using VLAD methodology for units and individual surgeons. Early identification and correction of performance variation could facilitate improved quality of care.


A comparative study on the environmental impact of greenhouses: A probabilistic approach.
The aim of this study is to investigate the most important drivers of environmental impacts and identify the influence of parameters on the uncertainty of the environmental impacts in various climate zones and future climate scenarios. We couple a combined greenhouse energy demand-yield simulation tool with a life cycle assessment to identify the drivers for greenhouse energy, water and CO2 demand as well as yield production. Environmental impacts are evaluated using the methods of IPPC for assessing climate change and available water remaining (AWARE) for water scarcity impacts. Furthermore, we compare the results for all five main climate world regions. With a global sensitivity analysis, we identify the parameters with the highest influence on life-cycle impact for each region. Crop growth features (e.g. node development rate and plant density), energy systems (e.g. heating and cooling supply systems), cover materials and inside temperature are the most influential input parameters for climate change impacts, but the ranking between these parameters depends on the location and climatic conditions of the greenhouse. In cold climates and higher latitudes, heating and electricity (mostly for lighting) processes are on average responsible for 85 to 90% of total climate change impacts. In hot climates, active cooling, in addition to natural ventilation, as well as electricity processes rank the highest (in the range of 60 to 75%) and in moderate climates, heating and cooling systems account for 60 to 70% of climate change impacts. Also for the AWARE results, crop growth related parameters are most influential. Among different processes in greenhouse, irrigation is responsible for 90% of water impacts in all regions, but the absolute magnitude of impact varies greatly among the different greenhouse locations.


Remote vascular catastrophes after neurovascular interventional therapy for type 4 Ehlers-Danlos Syndrome.
Type 4 Ehlers-Danlos Syndrome (EDS 4) is the most malignant form of Ehlers-Danlos Syndrome, often accompanied by neurovasacular complications secondary to vessel dissection or aneurysms. The fragile nature of connective tissue in these patients makes exovascular and endovascular treatment hazardous. We have treated four patients with EDS 4 over the last 8 years by using neuroendovascular procedures. Two of these individuals suffered remote vascular injuries around the time of their procedures and ultimately died. The circumstances surrounding their deaths will make up the body of this report.


Detection of milk oligosaccharides in plasma of infants.
Human milk oligosaccharides (HMO) are one of the major components of human milk. HMO are non-digestible by the human gut, where they are known to play important functions as prebiotics and decoys for binding pathogens. Moreover, it has been proposed that HMO may provide sialic acids to the infant that are important in brain development, however this would require absorption of HMO into the bloodstream. HMO have consistently been found in the urine of humans and other mammals, suggesting systemic absorption. Here, we present a procedure for the profiling of milk oligosaccharides (MO) in plasma samples obtained from 13 term infants hospitalized for surgery for congenital heart disease. The method comprises protein denaturation, oligosaccharide reduction, and porous graphitized carbon solid phase extraction for purification followed by analysis using nHPLC-PGC-chip-TOF-MS. Approximately 15 free MO were typically observed in the plasma of human infants, including LNT, LDFP, LNFT, 3'SL, 6'SL, 3'SLN, and 6'SLN, of which the presence was confirmed using fragmentation studies. A novel third isomer of SLN, not found in human or bovine milk was also consistently detected. Differences in the free MO profiles were observed between infants that were totally formula-fed and infants that received at least some part breast milk. Our results indicate that free MO similar in structure to those found in human milk and urine are present in the blood of infants. The method and results presented here will facilitate further research toward the possible roles of free MO in the development of the infant.


Molecular Characterization of HEV Genotype 3 in Italy at Human/Animal Interface.
Hepatitis E virus (HEV) is an emerging public health issue in industrialized countries. In the last decade the number of autochthonous human infections has increased in Europe. Genotype 3 (HEV-3) is typically zoonotic, being foodborne the main route of transmission to humans, and is the most frequently detected in Europe in both humans and animals (mainly pigs and wild boars). In Italy, the first autochthonous human case was reported in 1999; since then, HEV-3 has been widely detected in both humans and animals. Despite the zoonotic characteristic of HEV-3 is well established, the correlation between animal and human strains has been poorly investigated in Italy. In the present study, we compared the subtype distribution of HEV-3 in humans and animals (swine and wild boar) in the period 2000-2018 from Italy. The dataset for this analysis included a total of 96 Italian ORF2 sequences (300 nt long), including both NCBI database-derived (n = 64) and recent sequences (2016-2018, n = 32) obtained in this study. The results show that subtype 3f is the most frequent in humans and pigs, followed by the HEV-3e, HEV-3c and other unassignable HEV-3 strains. Diversely, in wild boar a wider group of HEV-3 subtypes have been detected, including HEV-3a, which has also been detected for the first time in a human patient in Central Italy in 2017, and a wide group of unassignable HEV-3 strains. The phylogenetic analysis including, besides Italian strains, also sequences from other countries retrieved from the NCBI database, indicated that human Italian sequences, in particular those of HEV-3f and HEV-3e, form significant clusters mainly with sequences of animal origin from the same country. Nevertheless, for HEV-3c, rarely detected in Italian pigs, human sequences from Italy are more correlated to human sequences from other European countries. Furthermore, clusters of near-identical human strains identified in a short time interval in Lazio Region (Central Italy) can be recognized in the phylogenetic tree, suggesting that multiple infections originating from a common source have occurred, and confirming the importance of sequencing support to HEV surveillance.


Skin-deep Resilience and Early Adolescence: Neighborhood Disadvantage, Executive Functioning, and Pubertal Development in Minority Youth.
Skin-deep resilience, in which youth overcome adversity and achieve success in psychological and academic domains but at a cost to their physiological well-being, has been documented in late adolescence and adulthood. However, its potential to emerge at earlier developmental stages is unknown. To address this gap, secondary data analyses were executed using waves 1 and 2 of the Adolescent Brain Cognitive Development study (n = 7712; ages 9-10 years at baseline [mean: 9.92; SD = 0.63]; 47.1% female; 66.1% White, 13.4% Black, and 20.6% Hispanic). The results indicated high levels of executive functioning were associated with improved psychological and behavioral outcomes at one-year follow-up. However, for racial and ethnic minority (i.e., Black or Hispanic) youth from disadvantaged neighborhoods, high levels of executive functioning were also associated with accelerated pubertal development. No significant interaction was observed among White youth. The findings suggest the skin-deep resilience pattern may be evident in early adolescence.


Relationships of skin depths and temperatures when varying pulse repetition frequencies from 2.0-microm laser light incident on pig skin.
Human perception of 2.0-microm infrared laser irradiation has become significant in such disparate fields as law enforcement, neuroscience, and pain research. Several recent studies have found damage thresholds for single-pulse and continuous wave irradiations at this wavelength. However, the only publication using multiple-pulse irradiations was investigating the cornea rather than skin. Literature has claimed that the 2.0-microm light characteristic thermal diffusion time was as long as 300-ms. Irradiating the skin with 2.0-microm lasers to produce sensation should follow published recommendations to use pulses on the order of 10 to 100 ms, which approach the theoretical thermal diffusion time. Therefore, investigation of the heating of skin for a variety of laser pulse combinations was undertaken. Temperatures of ex vivo pig skin were measured at the surface and at three depths from pulse sequences of six different duty factors. Differences were found in temperature rise per unit exposure that did not follow a linear relation to duty factor. The differences can be explained by significant heat conduction during the pulses. Therefore, the common heat modeling assumption of thermal confinement during a pulse may need to be experimentally verified if the pulse approaches the theoretical thermal confinement time.


Treatment of cystic hygroma in children with special reference to OK-432 therapy.
During a five-year period, 18 patients with cystic hygroma were treated as follows: 8 patients were treated surgically, 3 patients were treated by sclerosing therapy with Bleomycin (BLM) and 9 patients including 2 secondary to incomplete surgical therapy were treated by sclerosing therapy with OK-432 (Picibanil; Chugai Pharmaceutical Co. Ltd., Tokyo). OK-432 therapy for cystic hygroma showed excellent results; cure was noted in 8 patients, and marked regression with the expectation of subsequent cure was noted in the other patient. Complete excision of the cystic hygromas was possible in 4 patients and resulted in cure; but only partial excisions could be performed in the other 4 patients because of the surrounding tissue and the results were unfavorable. BLM therapy gave insufficient results and was not considered a favorable treatment.


Are coronary artery spasm and progressive damage to the heart associated with the hyperventilation syndrome?
A case of coronary artery vasospasm was studied in a man with a four year history of angina. He had evidence of symptomatic hyperventilation during a spontaneous episode of chest pain. When asked to hyperventilate the pain in his chest and ST elevation were reproduced in the same leads as occurred during the spontaneous attack. This may be the first reported case of spontaneous hyperventilation producing vasoconstriction, and the patient's previous admissions to the coronary care unit may have been associated with coronary vasospasm induced by hyperventilation. When patients with variant angina report pains in the chest in association with dizziness and breathlessness hyperventilation should be considered to be a possible cause of the symptoms. As coronary vasospasm is increasingly implicated in angina after myocardial infarction the role of hyperventilation should be considered more often.