Response to pegylated interferon and ribavirin in Asian American patients with chronic hepatitis C genotypes 1 vs 2/3 vs 6.
Chronic hepatitis C is generally underappreciated in Asian Americans, and most pivotal studies were conducted in western countries and only included a small numbers of Asian patients. Our goal was to examine and compare treatment outcomes in these patients with genotypes 1 vs 2/3 vs 6. We performed a retrospective cohort study of 167 consecutive treatment-naïve Asian American patients treated with pegylated interferon (PEG IFN) plus ribavirin (RBV) at two community clinics in Northern California from 12/00 to 1/08. Primary outcome was sustained virological response rate by intention-to-treat analysis. The overall completion rate was 76%, and treatment adherence (completion of ≥ 75-80% PEG IFN + RBV dose for ≥ 75-80% of intended duration) was 74%. Significant depression was noted in only 4% of patients. Sustained virologic response in patients with genotype 6 treated for 48 weeks was similar to that seen in those with genotype 2/3 (74%vs 75%, P = 0.89) and significantly higher than those with genotype 1 (74%vs 49%, P = 0.016). On multivariate analysis inclusive of sex, age, body mass index (≤ 25 vs > 25) and viral load, only treatment adherence and genotype (2/3 and 6 treated for 48 weeks) were found to be significant predictors of sustained virologic response. We conclude that significant depression is rare in Asian American patients (4%). Patients with genotype 6 treated for 48 weeks appear to have a similar treatment response rate as patients with genotype 2/3 and a significantly higher response rate than those with genotype 1.


Meeting the long-term needs of families who adopt children out of foster care: a three-year follow-up study.
The purpose of this study was to assess the extent to which agency and nonagency supportive resources contributed to the stability and well-being of 34 newly adoptive families over 3 years. Results revealed significant pre- to post-adoption declines in families' contact and satisfaction with formal and informal helping resources. Greater pre-adoption contact with formal adoption agency staff predicted adoption stability and lower levels of family conflict at the 3-year assessment. The results highlight the importance of providing adoptive families with formal and informal support that meets their evolving needs.


A collaborative study on larval excretory/secretory antigens of Toxocara canis for the immunodiagnosis of human toxocariasis with ELISA.
Two batches of excretory/secretory (E/S) antigens from second stage larvae of Toxocara canis maintained in vitro were prepared independently in two different laboratories (Zürich and Basel) and analysed in order to obtain information for future efforts to standardize the enzyme-linked immunosorbent assay (ELISA) used for the serodiagnosis of human toxocariasis. SDS-PAGE and "Western-blotting" revealed at least 10 different antigenic components common to the two antigen preparations. However, distinct qualitative and quantitative differences among the two E/S-antigens were observed, since one antigen had a more complex composition than the other. Despite these differences, an accordance of serodiagnosis was obtained in 80% of 25 sera from patients with suspected Toxocara infection tested independently in two different ELISA systems (Basel and Zürich) with the corresponding E/S-antigens. The specificity was 93% as determined (BS-antigen, BS-ELISA) by testing 46 out of 3396 sera from patients with parasitologically proven extra-intestinal helminthic infections. Cross-reactions occurred mainly with sera from patients infected with filariae (5 from 13 cases) exhibiting very high extinction values in their homologous ELISA-system. The reproducibility (intra- and inter-test variations) of two ELISA systems using the corresponding E/S-antigens varied from 5-15%. The results demonstrate that T. canis E/S-antigens may well be applicable for standardization of the ELISA used for the serodiagnosis of human toxocariasis.


Nicotinic cholinergic receptors in esophagus: Early alteration during carcinogenesis and prognostic value.
To compare expression of nicotinic cholinergic receptors (CHRNs) in healthy and squamous cell carcinoma-affected esophagus and determine the prognostic value. We performed RT-qPCR to measure the expression of CHRNs in 44 esophageal samples from healthy individuals and in matched normal surrounding mucosa, and in tumors from 28 patients diagnosed with esophageal squamous cell carcinoma (ESCC). Next, we performed correlation analysis for the detected expression of these receptors with the habits and clinico-pathological characteristics of all study participants. In order to investigate the possible correlations between the expression of the different CHRN subunits in both healthy esophagus and tissues from ESCC patients, correlation matrices were generated. Subsequently, we evaluated whether the detected alterations in expression of the various CHRNs could precede histopathological modifications during the esophageal carcinogenic processes by using receiver operating characteristic curve analysis. Finally, we evaluated the impact of CHRNA5 and CHRNA7 expression on overall survival by using multivariate analysis. CHRNA3, CHRNA5, CHRNA7 and CHRNB4, but not CHRNA1, CHRNA4, CHRNA9 or CHRNA10, were found to be expressed in normal (healthy) esophageal mucosa. In ESCC, CHRNA5 and CHRNA7 were overexpressed as compared with patient-matched surrounding non-tumor mucosa (ESCC-adjacent mucosa; P < 0.0001 and P = 0.0091, respectively). Positive correlations were observed between CHRNA3 and CHRNB4 expression in all samples analyzed. Additionally, CHRNB4 was found to be differentially expressed in the healthy esophagus and the normal-appearing ESCC-adjacent mucosa, allowing for distinguishment between these tissues with a sensitivity of 75.86% and a specificity of 78.95% (P = 0.0002). Finally, CHRNA5 expression was identified as an independent prognostic factor in ESCC; patients with high CHRNA5 expression showed an increased overall survival, in comparison with those with low expression. The corresponding age- and tumor stage-adjusted hazard ratio was 0.2684 (95%CI: 0.075-0.97, P = 0.0448). Expression of CHRNs is homogeneous along healthy esophagus and deregulated in ESCC, suggesting a pathogenic role for these receptors in ESCC development and progression.


Natural history of HFE simple heterozygosity for C282Y and H63D: a prospective 12-year study.
The risk of hemochromatosis-related morbidity for HFE simple heterozygosity for either the C282Y or H63D substitutions in the HFE protein was assessed using a prospective community-based cohort study. HFE genotypes were measured for 31,192 persons of northern European descent, aged between 40 and 69 years when recruited to the Melbourne Collaborative Cohort Study, and subjects were followed for an average of 12 years. For a random sample of 1438 participants stratified according to HFE genotype, two sets of biochemical iron indices performed 12 years apart and, at follow-up only, the presence/absence of six disease features associated with hereditary hemochromatosis were obtained. Summary data for 257 (139 female) C282Y simple heterozygotes and 123 (74 female) H63D simple heterozygotes were compared with 330 (181 female) controls with neither HFE mutation. At baseline, mean transferrin saturation (TS) (95% confidence interval) and prevalence of TS > 55% were 35.14% (33.25, 37.04) and 3/112 (3%), 33.03% (29.9, 36.15) and 0/39 (0%), and 29.67% (27.93, 31.4) and 3/135 (2%) for C282Y, H63D and wild-type male participants, respectively. At follow-up, mean TS levels remained similar to baseline levels for both men and women irrespective of simple heterozygosity for either mutation. No HFE C282Y or H63D simple heterozygotes had documented iron overload (based on hepatic iron measures or serum ferritin greater than 1000 mg/L at baseline with documented therapeutic venesection). No documented iron overload was observed for HFE simple heterozygotes for either C282Y or H63D, and morbidity for both HFE simple heterozygote groups was similar to that of HFE wild-type participants.


[Study on PPARgamma and aP2 mRNA expression of adipose tissues in obesity and obesity resistant rats].
To observe the difference of serum triglyceride, total cholesterol levels and expression of PPARgamma and aP2 mRNA of adipose tissues between obesity and obesity resistant rats induced by high-fat diet. Thirty-one healthy male Wistar rats were randomly divided into two groups. Seven of them were fed with standard diet as control group and 24 rats were fed with high-fat diet as high-fat group. At the end of the 8th week, according to the body weight increment, five rats were selected as obesity group, and five rats were selected as obesity resistant group from high-fat feeding rats. Serum triglyceride, total cholesterol, and the expressions of PPARgamma and aP2 mRNA of epididymal adipose tissues were detected. Serum triglyceride of obesity group were higher than those of control (P < 0.05). Total cholesterol levels of obesity group were higher than those of control and obesity resistant group (P < 0.05, P < 0.01). The expressions of PPARgamma and aP2 mRNA of obesity group were also much higher than those of control and obesity resistant group. The expressions of PPARgamma and aP2 mRNA of obesity and obesity resistant rats induced by high-fat diet existed difference.


Development and validation of a custom panel including 183 Y-SNPs for Chinese Y-chromosomal haplogroups dissection using a MALDI-TOF MS system.
Y-chromosome SNP haplogroups exhibit geographic structuring in many populations around the world. Therefore, Y-chromosome haplogroups have been widely used to infer paternal biogeographical ancestry and high-resolution paternal lineage classification. In the present study, we designed a customized panel containing 183 Y-SNPs based on previous studies and evaluated the genotyping performance and repeatability, concordance, sensitivity, and ability of analysing case-type samples using a MALDI-TOF MS platform. The average call rate for duplicate typing of any one SNP in the panel was 97.0%. In the concordance and accuracy study, the results of haplogroup designation obtained from MALDI-TOF MS platform were fully consistent with those obtained from the next-generation sequencing (NGS) platform. The optimal amount of template DNA in the PCR seemed to be 10 ng. However, if less DNA (≥156.25 pg) was available, it was still possible to obtain meaningful haplogroup information. For the application part, this panel could be applied for the detection of blood, semen, and buccal swabs samples. Particularly, blood stain on FTA card samples could be dissected by direct PCR amplification on the MALDI-TOF MS platform. Besides, 371 unrelated male individuals from four Chinese ethnic groups (Han, Hui, Mongolian, and Kazak) were detected using this panel. Total 78 terminal haplogroups were found and the haplogroup diversity was 0.933576. The results demonstrate that this panel could be an accurate, fast, and cost-effective method for database construction where the amount of sample material is less of a concern and when the cost of the assay is taken into consideration.


Survival and late effects on development of patients with infantile brain tumor.
Most infants with brain tumor may have a poor prognosis. The aim of the present study was to retrospectively analyze the survival and outcome with regard to mental and physical development in 11 subjects with brain tumor; these tumors were diagnosed when the patients were under 1 year of age. The histological diagnoses of these tumors were astrocytoma, n = 3; pineocytoma, n = 2; teratoma, n = 1; ependymoma, n = 1; atypical teratoid/rhabdoid tumor, n = 1; glioblastoma, n = 1; medulloblastoma, n = 1; and choroid plexus papilloma, n = 1. Surgical resection was performed in eight patients, and adjuvant chemotherapy was administered to all except one patient with choroid plexus papilloma. Radiotherapy was additionally performed for four of the 10 chemotherapy patients. Six patients survived. Among the surviving patients, five were under no treatment for 50-167 months after the diagnosis (median duration, 89 months), while one received chemotherapy for 20 months. Five patients exhibited mental retardation, and one patient experienced normal development after surgical removal of his choroid plexus papilloma. Diencephalic syndrome developed in one patient with pilomyxoid astrocytoma that necessitated hormone replacement therapy, and bodyweight over +2 SD was observed in two patients. The remaining five patients died 11-111 months after diagnosis (median duration, 24 months). The prognosis of infantile brain tumor with regard to mortality and developmental outcome remains poor. Furthermore, survivors require comprehensive medical and social support for an extended period.


Lenalidomide with dexamethasone to multiple myeloma patients relapsing from bortezomib-based induction therapies: A prospective, observational study.
Lenalidomide with dexamethasone (Len/Dex) is considered to be an effective and well-tolerated regimen to treat multiple myeloma (MM) patients relapsing after bortezomib induction therapy. With the increase in novel agents targeting refractory and relapsed MM, the identification of clinical or laboratory variables that can predict the appropriate candidates of Len/Dex is essential. To address this question, we prospectively assessed 38 adult MM patients who received bortezomib-based induction therapy and were administered Len/Dex for their first relapse. These 38 patients were stratified into the symptomatic relapse group (n = 10) and biological relapse group (n = 28) according to the disease status when Len/Dex was initiated. The overall response rate in the symptomatic group and biological relapse group was 70.0% (7/10) and 60.7% (17/28), respectively (P = 0.964). These two groups harbored a comparable median Len/Dex treatment duration (139 vs. 225 days; P = 0.876) and progression-free survival 2 (PFS2) (501 vs. 1289 days; P = 0.410). Multivariate analyses failed to show that treating biological relapse (hazard ratio [HR]: 1.29; 95% confidence interval [CI]: 0.43-3.88; P = 0.648), PFS with bortezomib-based induction therapies ≥18 months (HR: 1.79; 95% CI: 0.64-5.01; P = 0.266), autologous hematopoietic stem cell transplantation (HR: 2.18; 95% CI: 0.56-8.55; P = 0.262), and high-risk cytogenetics (HR: 0.85; 95% CI: 0.18-3.93; P = 0.835) were attributed to depth of Len/Dex treatment. In conclusion, whether MM patients treated by Len/Dex for biological relapse would have a better outcome than those prescribed for symptomatic relapse remains inconclusive. Treating significant biological relapse and symptomatic relapse remains the current consensus.


Bullet embolism: a rare cause of acute ischaemia.
Embolization of a bullet or shrapnel from the heart (left ventricle) to the peripheral arterial circulation is practically unknown. We present a 38-year-old man with no comorbidities who was referred to our centre with a bullet injury to the left side of his chest. The patient complained of mild pain and numbness in his right lower limb. A trauma series was advised. A contrast angiogram of the peripheral lower limbs showed a bullet in the right popliteal artery with no flow in the tibial arteries. A bullet was removed from the distal popliteal artery at its bifurcation with a long thrombus proximal to it. Removal of the foreign body is the widely accepted management, especially when it leads to symptoms like ischaemia or signs of infection, as was the situation in our case.


A meta-analysis of continuous positive airway pressure therapy in prevention of cardiovascular events in patients with obstructive sleep apnoea.
To assess whether continuous positive airway pressure (CPAP) therapy reduces major adverse cardiovascular events (MACE) in patients with moderate-to-severe obstructive sleep apnoea (OSA). A total of 235 articles were recovered using MEDLINE, EMBASE and Cochrane library (inception-December 2016) and references contained in the identified articles. Seven randomized controlled trials (RCTs) were selected for final analysis. Analysis of 4268 patients demonstrated non-significant 26% relative risk reduction in MACE with CPAP [risk ratio (RR) 0.74; 95% confidence interval (CI) 0.47-1.17; P = 0.19, I2 = 48%]. A series of sensitivity analyses suggested that increased CPAP usage time yielded significant risk reduction in MACE. and stroke. Subgroup analysis revealed that CPAP adherence time ≥4 hours (h)/night reduced the risk of MACE by 57% (RR 0.43; 95% CI 0.23-0.80; P = 0.01, I2 = 0%). CPAP therapy showed no beneficial effect on myocardial infarction (MI), all-cause mortality, atrial fibrillation/flutter (AF), or heart failure (HF) (P > 0.05). CPAP had positive effect on mood and reduced the daytime sleepiness [Epworth Sleepiness Scale (ESS): mean difference (MD) -2.50, 95% CI - 3.62, -1.39; P < 0.001, I2 = 81%]. CPAP therapy might reduce MACE and stroke among subjects with CPAP time exceeding 4 h/night. Additional randomized trials mandating adequate CPAP time adherence are required to confirm this impression.


A gamma Gly-268 to Glu substitution is responsible for impaired fibrin assembly in a homozygous dysfibrinogen Kurashiki I.
A new type of gamma Gly-268 (GGA) to Glu (GAA) substitution has been identified in a homozygous dysfibrinogen by analyses of the affected polypeptide and its encoding gene derived from a 58 year-old man manifesting no major bleeding or thrombosis. The functional abnormality was characterized by impaired fibrin assembly most likely due to failure to construct properly aligned double-stranded fibrin protofibrils. This presumption was deduced from the following findings: (1) Factor XIIIa-catalyzed cross-linking of the fibrin gamma-chains progressed in a normal fashion, indicating that the contact between the central E domain of one fibrin monomer and the D domain of another took place normally; (2) Nevertheless, factor XIIIa-catalyzed cross-linking of the fibrinogen gamma-chains was obviously delayed, suggesting that longitudinal association of D domains of different fibrin monomers, ie, D:D association was perturbed; (3) Plasminogen activation catalyzed by tissue-type plasminogen activator was not as efficiently facilitated by polymerizing fibrin monomer derived from the patient as by the normal counterpart. Therefore, gamma Gly-268 would not be involved in the 'a' site residing in the D domain, which functions as a complementary binding site with the thrombin-activated 'A' site in the central E domain, but would be rather involved in the D:D self association sites recently proposed for human fibrinogen. Thus, the gamma Glu-268 substitution newly identified in this homozygous dysfibrinogen seems to impair proper alignment of adjacent D domains of neighboring fibrin molecules in the double-stranded fibrin protofibril, resulting in delayed fibrin gel formation.


Compressed Sensing with Gaussian Sampling Kernel for Ultrasound Imaging.
Recently, compressed sensing (CS) has been applied to ultrasound imaging for either data reduction or frame rate improvement. However, there are no detailed reports yet on strategies for lateral undersampling of channel data in conventional focused beamforming (CFB) and its recovery exploiting the CS approach. We propose a strategic lateral undersampling approach for channel data using the Gaussian sampling scheme and compare it with a direct extension of the often-used uniform undersampling reported for axial undersampling to the lateral direction and 2-D random sampling reported in the literature. As opposed to the reported 2-D random undersampling, we explore undersampling of channel data in the lateral direction by acquiring radiofrequency data from only a reduced number of chosen receive elements and subjecting these data to further undersampling in the axial direction. The effect of the sampling schemes on CS recovery was studied using data from simulations and experiments for various lateral and axial undersampling rates. The results suggest that CS-recovered data from the Gaussian distribution-based channel data subsampling yielded better recovery and contrast in comparison to those obtained from the often-used uniform distribution-based undersampling. Although 90% of the samples from the original data using the proposed sampling scheme were discarded, the contrast of the CS-recovered image was comparable to that of the reference image. Thus, CS with the proposed Gaussian sampling scheme for channel data subsampling not only reduces the data size significantly, but also strategically uses only a few active receive elements in the process; thus, it can provide an attractive option for the affordable point-of-care ultrasound system.


[QT interval variability in adjacent areas on standard ecg during ectopic activity in patients with acute coronary syndrome].
Clinical and experimental evidence closely link malignant ventricular arrhythmia with increased dispersion of refractoriness and thus electrical heterogeneity in different kinds of heart diseases. Most increased dispersion of refractoriness is due to inhomogenous action potential duration in adjacent areas, decreased local conduction velocity or both. The article focuses on ectopic ventricular activity and on QT interval variability in adjacent segments on standard ECG in patients with acute coronary syndrome. The adjacent QT dispersion was defined as a difference between two adjacent leads. Seventy nine patients aged 54+/-6,5 in 6 hour interval after the attack with elevation of ST segments on ECG were studied. Fifteen patients aged 48+/-7 without elevation of ST segment on ECG served as control subjects. Patients were allocated to two groups: one included patients with 1-2 ectopic degree; group two included patients with 3-5 ectopic degree. In patients with acute coronary syndrome QT max and QTd was significantly higher than in control subjects (p<0,05). The increase of ventricular ectopic degree is linked with the increased adjacent QT dispersion.


Microtubules are not an essential component of phytohemagglutinin-dependent signal transduction in Jurkat T lymphocytes.
We have used two disruptors of the cytoskeleton microtubular network (colchicine and vinblastine) to investigate the role of microtubules in Phaseolus vulgaris phytohemagglutinin (PHA) signal transduction in Jurkat T cells. Both drugs decreased but did not abolish the PHA-dependent Ca2+ response of Jurkat cells. Neither colchicine nor vinblastine had any major effects on the PHA-dependent turnover of the mono-, di-, tri-, and tetra-substituted phosphorylated derivatives of D-myo-inositol or the cellular distribution of protein kinase C (PKC) activity. However, both microtubule disruptors increased interleukin-2 (IL-2) production. Whereas vinblastine enhanced IL-2 production approximately twofold at all the concentrations tested (0.1, 1.0, and 10 microM), colchicine did so only at a 10 microM concentration. When a combination of PHA and 12-O-tetradecanoyl-13-O-acetyl phorbol (TPA) was used, a small increase in IL-2 production was observed only in the presence of vinblastine (10 microM). In contrast to recent reports that microfilaments may be involved in the regulation of signal transduction, our data suggest that this is not the case for microtubules in PHA-dependent signal transduction in Jurkat T cells.


Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.
We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.


[Transperitoneal laparoscopic partial nephrectomy in the renal tumor treatment].
Laparoscopic surgery is a surgical technique the urologist should add to his surgical armamentarium. Its performance tries to mimic the surgical phases of open surgery, and also its indications. Laparoscopic partial nephrectomy is a sophisticated technique that requires wide experience in the performance of endoscopic strategies. We are submitting our experience with 35 laparoscopic partial transperitoneal nephrectomies with a mean follow-up of 25 months. The mean surgical time was 200 minutes, the mean bleeding 190 cc, and the mean hospitalisation five days. Two postoperative bleedings were identified, there were no conversions, and positive margins were notified in two cases, where upon a conservative attitude was adopted.


[Cytologic diagnosis of malignant tumors of the cervix].
Cytologic patterns of squamous-cell carcinoma, adenocarcinoma, malignant adenoma, and carcinoid of the cervix uteri are presented. Problems in the differential diagnosis of these conditions are discussed. Special attention is paid to the cytologic criteria for detection of intraepithelial and microinvasive squamous-cell and glandular carcinomas. Cytologic investigation may essentially contribute to timely diagnosis of the condition.


Rapid categorization of faces and objects in a patient with impaired object recognition.
We tested rapid-categorization in a patient who was impaired in face and object recognition. Photographs of natural scenes were displayed for 100 ms. Participants had to press a key when they saw an animal among various objects as distractors or human faces among animal faces as distractors. Though the patient was impaired at figure/ground segregation, recognized very few objects and faces, she categorized animals and faces with a performance ranging between 70 and 86% correct. Displaying pictures in isolation did not improve performance. The results suggest that rapid categorization can be accomplished on the basis of coarse information without overt recognition.


Adjuvant effects of aluminium hydroxide-adsorbed allergens and allergoids - differences in vivo and in vitro.
Allergen-specific immunotherapy (SIT) is a clinically effective therapy for immunoglobulin (Ig)E-mediated allergic diseases. To reduce the risk of IgE-mediated side effects, chemically modified allergoids have been introduced. Furthermore, adsorbance of allergens to aluminium hydroxide (alum) is widely used to enhance the immune response. The mechanisms behind the adjuvant effect of alum are still not completely understood. In the present study we analysed the effects of alum-adsorbed allergens and allergoids on their immunogenicity in vitro and in vivo and their ability to activate basophils of allergic donors. Human monocyte derived dendritic cells (DC) were incubated with native Phleum pratense or Betula verrucosa allergen extract or formaldehyde- or glutaraldehyde-modified allergoids, adsorbed or unadsorbed to alum. After maturation, DC were co-cultivated with autologous CD4(+) T cells. Allergenicity was tested by leukotriene and histamine release of human basophils. Finally, in-vivo immunogenicity was analysed by IgG production of immunized mice. T cell proliferation as well as interleukin (IL)-4, IL-13, IL-10 and interferon (IFN)-γ production were strongly decreased using glutaraldehyde-modified allergoids, but did not differ between alum-adsorbed allergens or allergoids and the corresponding unadsorbed preparations. Glutaraldehyde modification also led to a decreased leukotriene and histamine release compared to native allergens, being further decreased by adsorption to alum. In vivo, immunogenicity was reduced for allergoids which could be partly restored by adsorption to alum. Our results suggest that adsorption of native allergens or modified allergoids to alum had no consistent adjuvant effect but led to a reduced allergenicity in vitro, while we observed an adjuvant effect regarding IgG production in vivo.


Carbon-13 "magic-angle" sample-spinning nuclear magnetic resonance studies of human myelin, and model membrane systems.
We have obtained high-field (11.7 Tesla), high-resolution carbon-13 solid-state "magic-angle" sample-spinning nuclear magnetic resonance (NMR) spectra of a variety of phospholipids, sphingolipids, myelin and white matter samples, resolving and assigning over 40 resonances in the spectra of human and bovine myelin. The NMR results indicated no large spectral changes due to sample preparation, sample freezing, or brain location, and also no changes in myelin structure detectable via light microscopy, electron microscopy, thin layer chromatography, or sodium dodecyl sulfate-polyacrylamide gel electrophoresis, attributable to the sometimes lengthy NMR data acquisition process. Human myelin and white matter chemical shift assignments were made based on 13C "magic angle" sample spinning (MAS) NMR spectra of individual model lipids, as well as on spectra of lipid mixtures. In all myelin samples there were essentially no features attributable to membrane proteins, with the exception of one small feature due to C zeta of Arg residues, primarily in the myelin basic proteins. The general similarity between the model lipid and intact myelin spectra suggested no major effects of protein on lipid mobility. We have also investigated human myelin samples as a function of developmental age (4, 15, 48 months and adult), and our results showed only small changes in overall lipid composition, although there were significant decreases in lipid hydrocarbon chain unsaturation with age, as determined by computer line-shape simulations of myelin and model compounds. The spectrum of an infant leukoencephalopathy myelin showed marked decreases in galactocerebrosides. Overall, the ability to resolve and assign over 40 resonances in the 13C MAS NMR spectra of myelin, and to detect changes as a function of development and disease, should provide a useful starting point for further more detailed studies of myelin membrane molecular motions, and function.


Relative ellipsoid zone reflectivity and its association with disease severity in age-related macular degeneration: a MACUSTAR study report.
Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p < 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression.


[Erythroblastopenia: chronic idiopathic or associated with chronic lymphoid leukemia. Value of cultures of erythroblastic progenitors and therapeutic strategy].
Fifty cases of chronic pure red cell aplasia in adults (idiopathic in 32 cases, associated with chronic lymphocytic leukaemia in 18) were followed up after studying their erythroblastic precursors in vitro. Analysis of response to immunomodulators confirmed the existence, in patients with idiopathic chronic pure red cell aplasia, of a relationship between in vitro behaviour and obtention of a remission: patients with normal differentiation of erythroblasts consistently responded to treatments, whereas treatments were usually ineffective when the erythroblasts did not differentiate in vitro. When in vitro differentiation was below normal, responses to treatments were varied. In patients with chronic lymphocytic leukaemia, the erythroblastic precursors were normal in 15/18 cases, and response to immunomodulators was observed in 13/18 cases. A second objective of this study was to determine, on a large series, the most adequate immunomodulator treatment. In idiopathic chronic pure red cell aplasia the most efficient therapy was corticosteroids and cyclophosphamide administered separately or together. The antilymphocyte serum gave disappointing results. In pure red cell aplasia associated with leukaemia cyclophosphamide was the most frequently effective drug, with corticosteroids taking second rank; however, infections were frequent. The treatments to be considered when both corticosteroids and cyclophosphamide fail are discussed.


Microenvironment alters epigenetic and gene expression profiles in Swarm rat chondrosarcoma tumors.
Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. An animal model of chondrosarcoma has been established--namely, the Swarm Rat Chondrosarcoma (SRC)--and shown to resemble the human disease. Previous studies with this model revealed that tumor microenvironment could significantly influence chondrosarcoma malignancy. To examine the effect of the microenvironment, SRC tumors were initiated at different transplantation sites. Pyrosequencing assays were utilized to assess the DNA methylation of the tumors, and SAGE libraries were constructed and sequenced to determine the gene expression profiles of the tumors. Based on the gene expression analysis, subsequent functional assays were designed to determine the relevancy of the specific genes in the development and progression of the SRC. The site of transplantation had a significant impact on the epigenetic and gene expression profiles of SRC tumors. Our analyses revealed that SRC tumors were hypomethylated compared to control tissue, and that tumors at each transplantation site had a unique expression profile. Subsequent functional analysis of differentially expressed genes, albeit preliminary, provided some insight into the role that thymosin-β4, c-fos, and CTGF may play in chondrosarcoma development and progression. This report describes the first global molecular characterization of the SRC model, and it demonstrates that the tumor microenvironment can induce epigenetic alterations and changes in gene expression in the SRC tumors. We documented changes in gene expression that accompany changes in tumor phenotype, and these gene expression changes provide insight into the pathways that may play a role in the development and progression of chondrosarcoma. Furthermore, specific functional analysis indicates that thymosin-β4 may have a role in chondrosarcoma metastasis.


Tumour necrosis factor/cachectin: biology and relevance to disease.
Tumour necrosis factor/cachectin (TNF) is considered a primary mediator in the pathogenesis of injury, infection and inflammation and seems to be essential for host defense and tissue homeostasis. On the other hand, TNF can also cause septic shock, tissue injury and cachexia. There is a close interaction between TNF and other cytokines such as interferon, interleukin-1 and interleukin-2, and prostaglandins. TNF is responsible for the deleterious effects of endotoxaemia, and passive immunization against it substantially mitigates the lethal effect of endotoxin. It is also a potent pyrogen, causes bone resorption, activates neutrophil adherence and degranulation and phagocytosis, and ultimately participates in inflammatory diseases of the skin, gastrointestinal tract, joints, muscle and central nervous system and in neoplastic diseases.


Extracting Neural Oscillation Signatures of Laser-Induced Nociception in Pain-Related Regions in Rats.
Previous studies have shown that multiple brain regions are involved in pain perception and pain-related neural processes by forming a functionally connected pain network. It is still unclear how these pain-related brain areas actively work together to generate the experience of pain. To get a better insight into the pain network, we implanted electrodes in four pain-related areas of rats including the anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), primary somatosensory cortex (S1) and periaqueductal gray (PAG). We analyzed the pattern of local field potential (LFP) oscillations under noxious laser stimulations and innoxious laser stimulations. A high-dimensional feature matrix was built based on the LFP characters for both experimental conditions. Generalized linear models (GLMs) were trained to classify recorded LFPs under noxious vs. innoxious condition. We found a general power decrease in α and β bands and power increase in γ band in the recorded areas under noxious condition. After noxious laser stimulation, there was a consistent change in LFP power and correlation in all four brain areas among all 13 rats. With GLM classifiers, noxious laser trials were distinguished from innoxious laser trials with high accuracy (86%) using high-dimensional LFP features. This work provides a basis for further research to examine which aspects (e.g., sensory, motor or affective processes) of noxious stimulation should drive distinct neural activity across the pain network.


A putative transmembrane leucine zipper of agrobacterium VirB10 is essential for t-pilus biogenesis but not type IV secretion.
The Agrobacterium tumefaciens VirB/VirD4 type IV secretion system is composed of a translocation channel and an extracellular T pilus. Bitopic VirB10, the VirB7 lipoprotein, and VirB9 interact to form a cell envelope-spanning structural scaffold termed the "core complex" that is required for the assembly of both structures. The related pKM101-encoded core complex is composed of 14 copies each of these VirB homologs, and the transmembrane (TM) α helices of VirB10-like TraF form a 55-Å-diameter ring at the inner membrane. Here, we report that the VirB10 TM helix possesses two types of putative dimerization motifs, a GxxxA (GA4) motif and two leucine (Leu1, Leu2) zippers. Mutations in the Leu1 motif disrupted T-pilus biogenesis, but these or other mutations in the GA4 or Leu2 motif did not abolish substrate transfer. Replacement of the VirB10 TM domain with a nondimerizing poly-Leu/Ala TM domain sequence also blocked pilus production but not substrate transfer or formation of immunoprecipitable complexes with the core subunits VirB7 and VirB9 and the substrate receptor VirD4. The VirB10 TM helix formed weak homodimers in Escherichia coli, as determined with the TOXCAT assay, whereas replacement of the VirB10 TM helix with the strongly dimerizing TM helix from glycophorin A blocked T-pilus biogenesis in A. tumefaciens. Our findings support a model in which VirB10's TM helix contributes to the assembly or activity of the translocation channel as a weakly self-interacting membrane anchor but establishes a heteromeric TM-TM helix interaction via its Leu1 motif that is critical for T-pilus biogenesis.


Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients.
See Thompson and Woollams (doi:10.1093/brain/awx264) for a scientific commentary on this article. Previous research with aphasic patients has shown that picture naming can be facilitated by concurrent phonemic cueing [e.g. initial phoneme(s) of the word that the patient is trying to retrieve], both as an immediate word retrieval technique, and when practiced repeatedly over time as a long-term anomia treatment. Here, to investigate the neural mechanisms supporting word retrieval, we adopted—for the first time—a functional magnetic resonance imaging task using the same naming procedure as it occurs during the anomia treatment process. Before and directly after a 6-week anomia treatment programme, 18 chronic aphasic stroke patients completed our functional magnetic resonance imaging protocol—a picture naming task aided by three different types of phonemic cues (whole words, initial phonemes, final phonemes) and a noise-control condition. Patients completed a naming task based on the training materials, and a more general comprehensive battery of language tests both before and after the anomia treatment, to determine the effectiveness and specificity of the therapy. Our results demonstrate that the anomia treatment was effective and specific to speech production, significantly improving both patients' naming accuracy and reaction time immediately post-treatment (unstandardized effect size: 29% and 17%, respectively; Cohen's d: 3.45 and 1.83). Longer term gains in naming were maintained 3 months later. Functional imaging results showed that both immediate and long-term facilitation of naming involved a largely overlapping bilateral frontal network including the right anterior insula, inferior frontal and dorsal anterior cingulate cortices, and the left premotor cortex. These areas were associated with a neural priming effect (i.e. reduced blood oxygen level-dependent signal) during both immediate (phonemically-cued versus control-cue conditions), and long-term facilitation of naming (i.e. treated versus untreated items). Of note is that different brain regions were sensitive to different phonemic cue types. Processing of whole word cues was associated with increased activity in the right angular gyrus; whereas partial word cues (initial and final phonemes) recruited the left supplementary motor area, and right anterior insula, inferior frontal cortex, and basal ganglia. The recruitment of multiple and bilateral areas may help explain why phonemic cueing is such a successful behavioural facilitation tool for anomia treatment. Our results have important implications for optimizing current anomia treatment approaches, developing new treatments, and improving speech outcome for aphasic patients.


Nuclear upregulation of class I phosphoinositide 3-kinase p110β correlates with high 47S rRNA levels in cancer cells.
The class I phosphoinositide 3-kinase (PI3K) catalytic subunits p110α and p110β are ubiquitously expressed but differently targeted in tumours. In cancer, PIK3CB (encoding p110β) is seldom mutated compared with PIK3CA (encoding p110α) but can contribute to tumorigenesis in certain PTEN-deficient tumours. The underlying molecular mechanisms are, however, unclear. We have previously reported that p110β is highly expressed in endometrial cancer (EC) cell lines and at the mRNA level in primary patient tumours. Here, we show that p110β protein levels are high in both the cytoplasmic and nuclear compartments in EC cells. Moreover, high nuclear:cytoplasmic staining ratios were detected in high-grade primary tumours. High levels of phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3] were measured in the nucleus of EC cells, and pharmacological and genetic approaches showed that its production was partly dependent upon p110β activity. Using immunofluorescence staining, p110β and PtdIns(3,4,5)P3 were localised in the nucleolus, which correlated with high levels of 47S pre-rRNA. p110β inhibition led to a decrease in both 47S rRNA levels and cell proliferation. In conclusion, these results present a nucleolar role for p110β that may contribute to tumorigenesis in EC.This article has an associated First Person interview with Fatemeh Mazloumi Gavgani, joint first author of the paper.


Pathophysiology of tethered cord syndrome and other complex factors.
There are different interpretations of tethered cord syndrome (TCS) partly due to difficulty in understanding the concept of this syndrome as a functional disorder not merely based on gross anatomy of congenital anomalies. The essential mechanical factor of cord tethering is that any of the inelastic structures fastening the caudal end of the spinal cord produces traction effects on the lumbosacral cord. The production of such traction is the key to understanding this disorder. In a significant number of patients who present with the typical clinical signs and symptoms of TCS, the diameter of the filum terminale is found within normal limits and the caudal end of the spinal cord is located in the normal position. Therefore, the definition of TCS requires the demonstration that there is a posterior displacement of the conus and filum by MRI, lack of viscoelasticity by the stretch test of the filum during surgery, and fibrous displacement of glial tissue within the filum by histological studies. This is because there is inconsistency from such studies as ultrasonography, MRI and CT myelography, which attempt to establish the presence of a tight filum terminale. A goal of this article is to provide basic understanding of TCS so that clinicians can use the concept of stretch-induced spinal cord dysfunction for proper diagnosis and treatment of this disorder.


The Use of Opioids for Treatment of Pediatric Neuropathic Pain: A Literature Review.
Pediatric neuropathic pain is caused by a spectrum of disorders that are generally challenging to treat. Many of the underlying altered neurological processes are being elucidated through mechanistic studies. Few randomized control trials have evaluated the use of opioids for the treatment of adult neuropathic pain conditions, and there have been none in pediatric populations. With sparse data to provide guidance and an incomplete understanding of the underlying mechanisms, the use of opioids remains unclear. Our clinical experience and typical risk versus benefit considerations suggest a limited, if any, role for using opioids to treat pediatric neuropathic pain. In this literature review, we review the available adult and pediatric data and provide general guidance on this subject matter.


Biochemistry and clinical relevance of lipoprotein X.
Lipoprotein X (LP-X) is an abnormal lipoprotein that appears in the sera of patients with obstructive jaundice and is thus a marker for cholestasis. The presence of LP-X in serum does not allow discrimination between intra- and extra-hepatic cholestasis. In addition LP-X is present in the plasma of patients with familial plasma lecithin: cholesterol acyl transferase (LCAT) deficiency. It is a spherical particle that aggregates strongly. Phospholipids and unesterified cholesterol make up the bulk of LP-X, which is a low density lipoprotein. Protein, cholesterol esters, and triglycerides together make up 12 percent of the composition of LP-X. Lithocholic acid is the major bile acid in LP-X. Three species of LP-X have been isolated (LP-X1, LP-X2 and LP-X3). Because of its aggregating properties, LP-X complexes with enzymes, such as alkaline phosphatase. Electrophoretic and immunochemical methods are available for assay of LP-X. The fact that bile lipoprotein can be converted to LP-X by addition of albumin, and LP-X can be converted to bile lipoprotein by the addition of bile salts may suggest that the integrity of the LPX molecule depends on a certain critical bile salts to albumin ratio. Phospholipase in plasma is implicated in the catabolism of LP-X. The role of LP-X in cholestasis is apparently related to the removal of free cholesterol from the circulation as a consequence of its aggregating properties.


Felodipine-associated gingival overgrowth in a type 2 diabetic patient: A case report and literature review.
Gingival overgrowth (GO) includes gingival enlargement and hyperplasia and may be induced by certain drugs, including calcium channel blockers (CCBs), particularly first-generation CCBs. However, to date, only few cases of GO induced by second- or third-generation CCBs have been reported. The present study reports on a case of a 48-year-old diabetic male who was admitted to the First Hospital of Jilin University (Changchun, China) due to poor blood glucose control. This patient was diagnosed with GO. Review of the patient's medical history revealed diagnoses of type 2 diabetes and hypertension, as well as the use of felodipine, a second-generation CCB, to control hypertension. The hypertensive drugs were replaced and the new drugs helped the patient control his blood glucose levels. Additionally, the patient was instructed on methods he could use to improve his oral hygiene, including rinsing of the teeth following each meal and increasing the frequency of tooth brushing per day. After 3 months, the clinical symptoms of GO were relieved. The relevant literature was also reviewed to gain an improved understanding of the correlation between GO and CCBs, as well as diabetes and poor oral hygiene.


Operationalisation of the construct of access to dental care: a position paper and proposed conceptual definitions.
'Access' is a term readily used in a political and policy context, but one which has not leant itself to measurement of progress towards policy goals or comparisons between health systems. Like 'quality', 'access' is a multi-dimensional construct, but currently often remains a vague and abstract concept which is difficult to translate into something specific, concrete and therefore measureable. The paper describes previous work and identifies a need for a greater consensus and conceptual clarity in the selection of metrics for dental access. The construct of dental access is described as involving the concepts of 1: opportunity for access; 2, realised access (utilisation); 3, equity and 4, outcomes. Proposed conceptual definitions are given and a case made for measuring 'initial utilisation' separately from 'continued utilisation', reflecting modern approaches which distinguish 'entry access' (gaining entry to the dental care system), from the process of gaining access to higher levels of care. Using a distinction between 'entry access' and 'effective access' allows a choice of whether to restrict measurement to mainly supply side considerations, or alternatively to extend the measurement to include whether there is equity in the proportion of patients who are able obtain effective needed interventions. A development of conceptual definitions of dental access could facilitate measurement of progress towards policy goals and operationalisation of the construct.


Morphometric Study of the Posterior Fossa: Identification of Practical Parameters for Tailored Selection of Surgical Routes to the Petroclival Region.
Introduction The petroclival region is an integral part of the skull base. It can harbor different pathologies and provides access to the petroclival junction and cerebellopontine angle. We present the results of the morphometric analysis of the posterior fossa and a prediction model to enable skull base surgeons to choose an optimal surgical corridor considering patient's bony anatomy. Methods Ninety patients (14 to assess interobserver reliability) with temporal bone computed tomography were selected. Exclusion criteria included patients <18 years of age, radiographic evidence of trauma, infection, or previous surgery. The images were analyzed using OsiriX MD (Bernex, Switzerland). We recorded clival length, vertical angle, and surface area, and petroclival angle, petrous apex, and translabyrinthine corridors volume. Results The average age was 49.5 years (55%) for males. The mean clival length and surface areas were 44.2 mm (standard deviation [SD] ± 4.1) and 8.1 cm 2 (SD ± 1.3). The mean petrous apex and translabyrinthine corridors volumes were 2.2 cm 3 (SD ± 0.6) and 10.1 cm 3 (SD ± 3.7). The mean petroclival angle at the internal auditory canal (IAC) was 154.9 degrees (SD ± 9). The clival length correlated positively with clival surface area (rho = 0.6, p <0.05), petrous apex volume (rho = 0.3, p < 0.05), and translabyrinthine volume (rho = 0.3, p < 0.05). Conclusion The petroclival region is complex and with high variability of surgical significance. The use of preoperative measurements of the clival length and petroclival angle as part of surgical planning that could help the surgeon to choose an optimal surgical corridor by overcoming the anatomical variability elements.


Remote Assessments of Hand Function in Neurological Disorders: Systematic Review.
Loss of fine motor skills is observed in many neurological diseases, and remote monitoring assessments can aid in early diagnosis and intervention. Hand function can be regularly assessed to monitor loss of fine motor skills in people with central nervous system disorders; however, there are challenges to in-clinic assessments. Remotely assessing hand function could facilitate monitoring and supporting of early diagnosis and intervention when warranted. Remote assessments can facilitate the tracking of limitations, aiding in early diagnosis and intervention. This study aims to systematically review existing evidence regarding the remote assessment of hand function in populations with chronic neurological dysfunction. PubMed and MEDLINE, CINAHL, Web of Science, and Embase were searched for studies that reported remote assessment of hand function (ie, outside of traditional in-person clinical settings) in adults with chronic central nervous system disorders. We excluded studies that included participants with orthopedic upper limb dysfunction or used tools for intervention and treatment. We extracted data on the evaluated hand function domains, validity and reliability, feasibility, and stage of development. In total, 74 studies met the inclusion criteria for Parkinson disease (n=57, 77% studies), stroke (n=9, 12%), multiple sclerosis (n=6, 8%), spinal cord injury (n=1, 1%), and amyotrophic lateral sclerosis (n=1, 1%). Three assessment modalities were identified: external device (eg, wrist-worn accelerometer), smartphone or tablet, and telerehabilitation. The feasibility and overall participant acceptability were high. The most common hand function domains assessed included finger tapping speed (fine motor control and rigidity), hand tremor (pharmacological and rehabilitation efficacy), and finger dexterity (manipulation of small objects required for daily tasks) and handwriting (coordination). Although validity and reliability data were heterogeneous across studies, statistically significant correlations with traditional in-clinic metrics were most commonly reported for telerehabilitation and smartphone or tablet apps. The most readily implementable assessments were smartphone or tablet-based. The findings show that remote assessment of hand function is feasible in neurological disorders. Although varied, the assessments allow clinicians to objectively record performance in multiple hand function domains, improving the reliability of traditional in-clinic assessments. Remote assessments, particularly via telerehabilitation and smartphone- or tablet-based apps that align with in-clinic metrics, facilitate clinic to home transitions, have few barriers to implementation, and prompt remote identification and treatment of hand function impairments.


High-efficiency metal-semiconductor-metal photodetectors on heteroepitaxially grown Ge on Si.
We demonstrate extremely efficient germanium-on-silicon metal-semiconductor-metal photodetectors with responsivities (R) as high as 0.85 A/W at 1.55 microm and 2V reverse bias. Ge was directly grown on Si by using a novel heteroepitaxial growth technique, which uses multisteps of growth and hydrogen annealing to reduce surface roughness and threading dislocations that form due to the 4.2% lattice mismatch. Photodiodes on such layers exhibit reverse dark currents of 100 mA/cm2 and external quantum efficiency up to 68%. This technology is promising to realize monolithically integrated optoelectronics.


Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta.
Persistent coinfection with the hepatitis B/D viruses (HDV) represents the most severe form of viral hepatitis. Hepatitis D often leads to liver cirrhosis, hepatic decompensation, and hepatocellular carcinoma. The current treatment options are limited as only pegylated interferon-alpha (PEG-IFNa) has efficacy against HDV. However, treatment response is still unsatisfactory with 25-40% HDV RNA suppression after 1-2 years. In addition, late HDV RNA relapses have been described during long-term follow-up. Fortunately, new treatment options for patients with chronic hepatitis delta are now on the horizon. The hepatocyte entry inhibitor bulevirtide (formerly myrcludex B) and the farnesyl transferase inhibitor lonafarnib are currently explored in patients with chronic hepatitis delta in Phase 3 clinical studies. The nucleic acid inhibitor REP-2139-Ca and PEG-IFN-lambda are studied in Phase 2 trials. We here summarize data on the efficacy of these new antiviral drugs and the existing safety data on the treatment of HDV infection.


[Ocular injuries due to allergic mechanism].
The paper presents the main ocular injuries due to allergic mechanism and it point out the actual data about etiopathogenesis of type 1 hypersensitivity and immunologic mechanism involved in allergic keratoconjunctivitis. Then are exposed the classification of ocular allergy, the main signs and symptoms, the paraclinical methods of diagnosis and the actual agents of therapy.


A clinical comparison of safety and efficacy in phacoemulsification with versus without ophthalmic viscoelastic device.
To evaluate in a comparative manner the safety and efficacy of 1.0% sodium-Hyaluronate used during capsulorhexis and intraocular lens (IOL) implantation in phacoemulsification surgery. 1.0% sodium-Hyaluronate, which is commonly used as one of the ophthalmic viscoelastic devices, was compared to intraocular irrigating solution, which can bring up these effects. In addition, the effect of both methods on occurring corneal endothelial cell (CEC) loss was investigated. Each group comprised 19 eyes. The mean preoperative CEC density was 2525.68 ± 181.85 in Group H and 2514.16 ± 174.59 in Group V; no statistically significant difference was found between the groups (p > 0.05). Preoperative and postoperative first and twelfth week CEC densities were 2438.21 ± 198.12 (p < 0.001) and 2390.74 ± 202.31, respectively, in group H (p < 0.001). Preoperative and postoperative first and twelfth week CEC densities were 2415.32 ± 197.24 (p < 0.001) and 2353.47 ± 212.69 in group V (p < 0.001). Compared with preoperative values, decrease in CEC density on the postoperative first and twelfth weeks was not statistically significant in either group (p > 0.05). Although it was found that there was no statistically difference in terms of preventing CEC loss between 1.0% sodium-Hyaluronate and the irrigation method during phacoemulsification, it was observed clinically that 1.0% sodium-hyaluronate can make the procedure easy, safer, very helpful, especially for understanding phacoemulsification.


Hepatitis A post-viral encephalitis.
We report a seven-year-old girl who developed a hepatitis A viral infection and encephalitis. The patient developed fever, abdominal pains and jaundice. Five days later she became delirious, combative, and did not respond to verbal commands. Laboratory studies showed elevated liver enzymes and elevated serum immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to hepatitis A virus. Cerebrospinal fluid contained IgG antibodies to hepatitis A virus but not IgM antibodies. Polymerase chain reaction, which amplifies a portion of the hepatitis A virus genome, did not demonstrate viral nucleic acid in cerebrospinal fluid. These studies suggest that the patient may have suffered from a post-viral hepatitis A encephalitis from which she fully recovered.


A controlled study of microsurgical versus standard lumbar discectomy.
The purpose of the study was to evaluate whether a microsurgical discectomy (MS), compared with a standard lumbar discectomy (SD), could reduce the stay at the hospital or the postoperative morbidity. The study was prospective and of 79 patients with "virgin' lumbar radiculopathy from only one nerve root, 39 were randomized to MS and 40 to SD. All patients had positive myelography or CT findings. The fascia incision was 31 and 70 mm (p < 0.0001), respectively, but the skin incision was of the same length in both groups to blind the study. For the MS and SD group of patients, the median operation time was 48 and 35 min (p < 0.0001), and the stay at the hospital was 5.2 and 4.6 days, respectively. The two groups were not different in sex, age, localization or type of herniated discs. Use of analgesic medicine and the presence of pain in the back or legs pre- and postoperative was the same. We conclude that in a controlled and prospective study, reducing the fascia incision and the muscular dissection from a median of 70-31 mm, does not shorten the length of a stay at a hospital and it has no influence on postoperative morbidity.


Achieving National Cholesterol Education Program goals for low-density lipoprotein cholesterol in cardiac patients: importance of diet, exercise, weight control, and drug therapy.
To determine how frequently the National Cholesterol Education Program (NCEP) goal of a low-density lipoprotein (LDL) cholesterol level of 100 mg/dL or less is achieved in clinical practice in patients with coronary artery disease and what fraction of patients can achieve this goal without drug therapy. We examined the results of lipid management in 152 consecutive patients who had completed cardiac rehabilitation after an acute coronary event. Patients were randomized to follow-up by specially trained nurses or by preventive cardiologists, and they were not receiving lipid-lowering drugs at the start of the study. Patients were given aggressive diet and exercise recommendations and lipid-lowering drugs in accordance with NCEP guidelines. Follow-up was continued for a mean of 526 days after the first lipid assessment subsequent to the coronary event. Multiple logistic regression analysis was used to identify independent predictors of a final LDL cholesterol level of 100 mg/dL or less. Of the study group, 39% achieved the NCEP goal LDL cholesterol level of 100 mg/dL or less. Characteristics of the patients with LDL cholesterol levels of 100 mg/dL or less in comparison with those with LDL cholesterol levels of more than 100 mg/dL included a greater frequency of drug therapy (65% versus 38%), more rigorous dietary compliance, longer follow-up (586 +/- 317 days versus 493 +/- 264 days), more favorable weight change (-0.3 +/- 4.9 kg versus +1.7 +/- 5.0 kg), and more extensive weekly exercise (183 +/- 118 minutes versus 127 +/- 107 minutes). The registered nurses managed the lipids of these patients as effectively as did the preventive cardiologists. Appropriate drug therapy was the most important factor in achieving an LDL cholesterol level of 100 mg/dL or less, but 35% of patients attaining this NCEP goal were not receiving drug therapy. Exercise, dietary compliance, and weight loss were also important factors.


Rubbing gastric serosal surface enhances naked plasmid DNA transfer in rats and mice.
We have developed in vivo gene transfer to mesothelial cells on the peritoneal organs, including the stomach. Simple instillation of naked plasmid DNA onto the gastric serosal surface in mice resulted in effective but transient transgene expression. Here, we developed a simple method to improve not only the transfection efficiency but also the duration of transgene expression. Rubbing the gastric serosal surface using a medical spoon immediately after instillation of naked plasmid DNA onto the gastric serosal surface resulted in 59-fold higher transgene expression 24 h after administration in rats. Without rubbing, transgene expression decreased under the detection limit 7 d after administration. On the other hand, rubbing the gastric serosal surface with a medical spoon after instillation of plasmid DNA prolonged transgene expression for one month. Mechanistic study in mice revealed that improved transfection should not be due to stimulation of cell function such as macropinocytosis by rubbing because rubbing before instillation of plasmid DNA did not improve transfection. Plasmid DNA should enter effectively into cells during rubbing. These findings are valuable to develop an effective method of in vivo gene transfer into peritoneal organs.


Impact of SARS-CoV-2 Lockdown on Anthropometric Parameters in Children 11/12 Years Old.
During the great lockdown in Spain due to SARS-CoV-2, in between the months of March and June 2020, dietary and physical activity habits were modified in children. The aim of the study was to determine the impact of the lockdown on anthropometric parameters in children aged 11/12 years. Fifty Spanish children aged 11/12 years (M = 11.40; SD = 0.50) participated: 33 (66%) boys and 17 (34%) girls. For data collection, we used an anthropometry kit; the Alpha-Fitness Battery, a validated instrument to assess dietary intake, habits and practices; and an ad hoc survey to collect sociodemographic and other data under investigation. There were significant differences in the anthropometric parameters measured and in the results obtained for Body Mass Index (BMI) and body fat percentage pre- and post-lockdown in both boys and girls (p < 0.05). No significant differences were found in waist-circumference measurements (p > 0.05). There is evidence of a significant impact of the SARS-CoV-2 lockdown on anthropometric parameters in boys and girls aged 11/12 years.


Pre-exposure prophylaxis as an opportunity for engagement in HIV prevention among South African adolescents.
Pre-exposure prophylaxis (PrEP) offers a potential biomedical strategy to reduce HIV incidence among adolescent populations disproportionately affected by HIV. There is limited evidence on the social and clinical implications, including engagement in HIV prevention efforts, of PrEP for South African adolescents, who face high HIV risk. We conducted a mixed-methods study in Western Cape, South Africa from 2015 to 2016. Adolescents (N = 35) aged 16-17 and clinical service providers working with adolescents (N = 25) were recruited from community and clinic settings. Adolescents and service providers completed a survey about their overall perceptions of PrEP and completed interviews guided by semi-structured protocols. We performed descriptive analysis of quantitative data using SPSS and thematic analysis of qualitative data using NVivo. The majority of adolescents endorsed future PrEP use for themselves and partners, and all clinical service providers endorsed future PrEP use for sexually active adolescents. Both adolescents and service providers identified PrEP as an opportunity to engage youth as active participants in HIV prevention. Service providers also viewed PrEP as a potential mechanism for shifting life trajectories. Findings from this study enhance our understanding of the considerations needed to engage adolescents and clinical service providers in the roll-out of oral PrEP in South Africa.


A comparative assessment of human exposure to tetrabromobisphenol A and eight bisphenols including bisphenol A via indoor dust ingestion in twelve countries.
Tetrabromobisphenol A (TBBPA) and eight bisphenol analogues (BPs) including bisphenol A (BPA) were determined in 388 indoor (including homes and microenvironments) dust samples collected from 12 countries (China, Colombia, Greece, India, Japan, Kuwait, Pakistan, Romania, Saudi Arabia, South Korea, U.S., and Vietnam). The concentrations of TBBPA and sum of eight bisphenols (ƩBPs) in dust samples ranged from <1 to 3600 and from 13 to 110,000 ng/g, respectively. The highest TBBPA concentrations in house dust were found in samples from Japan (median: 140 ng/g), followed by South Korea (84 ng/g) and China (23 ng/g). The highest ∑BPs concentrations were found in Greece (median: 3900 ng/g), Japan (2600 ng/g) and the U.S. (2200 ng/g). Significant variations in BPA concentrations were found in dust samples collected from various microenvironments in offices and homes. Concentrations of TBBPA in house dust were significantly correlated with BPA and ∑BPs. Among the nine target chemicals analyzed, BPA was the predominant compound in dust from all countries. The proportion of TBBPA in sum concentrations of nine phenolic compounds analyzed in this study was the highest in dust samples from China (27%) and the lowest in Greece (0.41%). The median estimated daily intake (EDI) of ∑BPs through dust ingestion was the highest in Greece (1.6-17 ng/kg bw/day), Japan (1.3-16) and the U.S. (0.89-9.6) for various age groups. Nevertheless, in comparison with the reported BPA exposure doses through diet, dust ingestion accounted for less than 10% of the total exposure doses in China and the U.S. For TBBPA, the EDI for infants and toddlers ranged from 0.01 to 3.4 ng/kg bw/day, and dust ingestion is an important pathway for exposure accounting for 3.8-35% (median) of exposure doses in China.


Loss of distinctive features and a broader pattern of priming in Alzheimer's disease.
The results of 2 experiments support the contention that patients with Alzheimer's disease (AD) show a relative loss of the semantic features that distinguish concepts from one another and that the representations of pairs of concepts consequently share a larger proportion of their associated features in AD than in normal aging. In Experiment 1, AD patients listed fewer features for a set of concepts than did healthy older adults and were more deficient at listing features if the features were distinctive to particular concepts than if they were shared by multiple concepts. In Experiment 2, AD patients showed online priming at levels of relatedness at which healthy older adults did not.


Addition of vitamin D reverses the decline in GFR following treatment with ACE inhibitors/angiotensin receptor blockers in patients with chronic kidney disease.
Vitamin D has anti-inflammatory, anti-fibrotic effect, and may block the intrarenal renin-angiotensin system. Adequate vitamin D levels in conjunction with the use of Angiotensin-converting Enzyme Inhibitors/Angiotensin Receptor Blockers may help to slow down chronic kidney disease progression. To study a possible beneficial effect of vitamin D supplementation in chronic kidney disease patients using angiotensin-converting enzyme inhibitors/angiotensin receptor blockers on chronic kidney disease progression we performed a clinical study involving vitamin D supplementation in patients with deficiency of this vitamin. This study was conducted in two chronic kidney disease clinics in the city of Londrina, Brazil, from October 2010 to December 2012. It was involved stage 3 and 4 chronic kidney disease (estimated glomerular filtration rate between 60 and 15mL/min/1.73m2) patients with and without vitamin D deficiency. The patients ingested six-month cholecalciferol 50,000IU oral supplementation to chronic kidney disease patients with vitamin D deficiency. We hypothesize changes in estimated glomerular filtration rate over study period. Our data demonstrate reservation of estimated glomerular filtration with cholecalciferol supplementation to chronic kidney disease patients taking angiotensin-converting enzyme inhibitors/angiotensin receptor blockers. The combination treatment of angiotensin converting enzyme inhibitors/angiotensin receptor blockers with cholecalciferol prevents the decline in estimated glomerular filtration in patients with chronic kidney disease following treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and may represent a valid approach to reduce renal disease progression in chronic kidney disease patients with vitamin D deficiency. This result needs confirmation in prospective controlled clinical trials.


Dynamics of OH formation in the photodissociation of o-nitrobenzoic acid at 295 and 355 nm.
Photodissociation dynamics of o-nitrobenzoic acid at 295 and 355 nm is studied by probing the nascent OH photoproduct employing the single-photon laser-induced fluorescence technique. At both of the photolysis wavelengths, the OH fragments are found to be vibrationally cold but have different rotational state distributions. Upon photolysis at 295 nm, the relative population of OH in different rotational states does not follow the Boltzmann equilibrium distribution, whereas upon photolysis at 355 nm, a Boltzmann distribution is observed with a rotational temperature of 1010 +/- 100 K. Between the two spin-orbit states, (2)Pi(3/2) and (2)Pi(1/2), the former is found to be preferentially populated, and the distribution of the Pi(A') state for the Lambda-doublet is dominant at both of the wavelengths studied. Several possible dissociation pathways of o-nitrobenzoic acid leading to formation of the OH fragment are investigated computationally. On the basis of the theoretical and experimental studies, a possible mechanism of OH formation from the photodissociation of o-nitrobenzoic acid at 295 and 355 nm is proposed.


Exciton Transfer in Array of Epitaxially Connected Nanocrystals.
Recently, epitaxially connected at facets semiconductor nanocrystals (NCs) have been introduced to fascilitate the electron transport between nanocrystals. To fully deploy their potential, a better understanding of the exciton transfer between connected NCs is needed. We go beyond the two well-known transfer mechanisms suggested by Förster and Dexter and propose a third mechanism of exciton tandem tunneling. The tandem tunneling occurs through the intermediate state in which the electron and hole are in different NCs. The corresponding rate for exciton hops is larger than the Dexter rate and for Si is even much larger that the Förster one.


[Clinical observation of visual performance in patients with a apodized diffractive multifocal intraocular lens].
To evaluate and compare the visual performance between the patients with the diffractive multifocal and monofocal intraocular lens (IOL). It was a prospective nonrandomized controlled study. Sixty-five patients (80 eyes) received phacoemulsification and IOL implantation were divided into two groups, 41 patients (50 eyes) in the multifocal group, and 24 patients (30 eyes) in the monofocal group. Three months or longer after surgery, the results of the uncorrected distance, intermediate and near vision; the best-corrected distance, intermediate and near vision; the intermediate and near vision after the distance vision corrected; the contrast sensitivity and the wave-front aberrations were recorded. The subjective visual performance after surgery was evaluated by the questionnaire. The chi-square test was applied to compare categorical variables, and the independent-samples t test was used to compare the measure data. The difference of the uncorrected distance, intermediate vision; the best-corrected distance, intermediate and near vision; intermediate vision after the distance vision corrected between the multifocal and monofocal groups was no statistical significance. The uncorrected near vision (0.82 +/- 0.20 vs 0.33 +/- 0.14, t = 8.99, P = 0.000) and the near vision after the distance vision corrected (0.83 +/- 0.17 vs 0.32 +/- 0.11, t = 9.83, P = 0.000) were statistically better in the multifocal group than the monofocal group. Photopic contrast sensitivity at high spatial frequency (18 c/d) and mesopic sensitivity with glare at medium frequency (6 c/d) was statistically lower in the multifocal group (P < 0.05). The total aberration and spherical aberration of the multifocal group were smaller than the monofocal group (t = 3.74, P = 0.00; t = 3.56, P = 0.00). The spectacle independent rate of multifocal and monofocal group were 70.73% (29/41) and 8.33% (2/24) respectively (chi(2) = 23.63, P = 0.00). The mild and moderate glare and halo were existent in both groups (chi(2) = 0.50, P = 0.78).Moderate visual disturbances were reported 24% (12/50) in the multifocal group and 26.67% (8/30) in the monofocal group.No serious glare and halo phenomenon were reported. Compared with the monofocal intraocular lens, the diffractive multifocal intraocular lens could provide a satisfactory recovery of vision function and good visual performance except the slight decrease of the contrast sensitivity.


[A case of brain metastasis of rhabdomyosarcoma in a child].
We report here a specific case of metastatic brain tumor orienting from rhabdomyosarcoma. An 11-year-old boy came to our hospital with complaints including headache, exophthalmos and tumors in the right frontal and left occipital region. 6 months previously subtotal removal of rhabdomyosarcoma in his right foot had been performed. CT scan demonstrated tumors in the right orbit, right frontal region and left occipital region. The tumors existed bilaterally in the skull and markedly enhanced by contrast medium. But the changes of the cranium were mild, only the dipole was slightly dilated. MRI showed that the tumors were extraaxial masses. Right external carotid angiogram revealed numerous tumor vessels fed by the meningeal artery. On April 3rd, biopsy was performed at the right frontal region. The tumor had spread in the epidural space but the cortical surface seemed to be intact. Histologically, the tumor consisted of small round cells and revealed multinuclear giant cells. It involved the skull bone, dura mater and subdural tissues. Accordingly the tumor was diagnosed as rhabdomyosarcoma. Although tumor increased rapidly, the intracranial region did not change remarkably. It was an interesting phenomenon. Eventually, rhabdomyosarcoma metastasized to the lung, and the patient died due to respiratory distress.


Lysosomal protein trafficking in Giardia lamblia: common and distinct features.
Giardia is a flagellated protozoan parasite that has to face different microenvironments during its life cycle in order to survive. All cells exchange materials with the extracellular medium through the reciprocal processes of endocytosis and secretion. Unlike more evolved cells, Giardia lacks a defined endosomal/lysosomal system, but instead possesses peripheral vacuoles that play roles in endocytosis, degradation, recycling, and secretion of proteins during growth and differentiation of the parasite. This review focuses on recent reports defining the role of different molecules involved in protein trafficking to the peripheral vacuoles, and discusses possible mechanisms of receptor recycling. Since Giardia is an early-branching protist, the study of this parasite may lead to a clearer understanding of the minimal machinery required for protein transport in eukaryotic cells.


Lifetime-based tomographic multiplexing.
Near-infrared (NIR) fluorescence tomography of multiple fluorophores has previously been limited by the bandwidth of the NIR spectral regime and the broad emission spectra of most NIR fluorophores. We describe in vivo tomography of three spectrally overlapping fluorophores using fluorescence lifetime-based separation. Time-domain images are acquired using a voltage-gated, intensified charge-coupled device (CCD) in free-space transmission geometry with 750 nm Ti:sapphire laser excitation. Lifetime components are fit from the asymptotic portion of fluorescence decay curve and reconstructed separately with a lifetime-adjusted forward model. We use this system to test the in vivo lifetime multiplexing suitability of commercially available fluorophores, and demonstrate lifetime multiplexing in solution mixtures and in nude mice. All of the fluorophores tested exhibit nearly monoexponential decays, with narrow in vivo lifetime distributions suitable for lifetime multiplexing. Quantitative separation of two fluorophores with lifetimes of 1.1 and 1.37 ns is demonstrated for relative concentrations of 1:5. Finally, we demonstrate tomographic imaging of two and three fluorophores in nude mice with fluorophores that localize to distinct organ systems. This technique should be widely applicable to imaging multiple NIR fluorophores in 3-D.


Ontogeny of diazepam binding inhibitor/acyl-CoA binding protein mRNA and peripheral benzodiazepine receptor mRNA expression in the rat.
The Diazepam Binding Inhibitor/Acyl-CoA Binding Protein (DBI/ACBP) has been implicated in different functions, as acyl-CoA transporter and as an endogenous ligand at the GABA(A) receptor and the peripheral benzodiazepine receptor (PBR). The latter is thought to be involved in control of steroidogenesis. We studied the ontogeny of DBI/ACBP and PBR mRNA expression in embryos and offspring of time-pregnant Long Evans rats by in-situ hybridization with 33P-endlabelled oligonucleotides. Both mRNAs were present in embryo and placenta at gestational day (G)11, the earliest stage studied. DBI/ACBP mRNA was strongly expressed from embryonic through mid-foetal stages in central nervous system (maximum in neuroepithelium), cranial and sympathetic ganglia, anterior pituitary, adrenal cortex, thyroid, thymus, liver and (late foetal) brown adipose tissue, moderately in testis, heart, lung and kidney. In brain, a late foetal decrease of DBI/ACBP mRNA was followed by an increase at postnatal day 6. Peripheral benzodiazepine receptor mRNA expression started very low and increased to moderate levels in adrenal cortex and medulla, testis, thyroid, brown adipose tissue, liver, heart, lung, salivary gland at mid- to late-foetal stages. Data suggest a significant role of DBI/ACBP at early developmental stages. Both proteins may be involved in the control of foetal steroidogenesis. However, differences in developmental patterns indicate that additional functions may be equally important during ontogeny, such as the involvement in lipid metabolism in the case of DBI/ACBP.


Loss of Mll3 Catalytic Function Promotes Aberrant Myelopoiesis.
Two of the most common myeloid malignancies, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), are associated with exceedingly low survival rates despite recent therapeutic advances. While their etiology is not completely understood, evidence suggests that certain chromosomal abnormalities contribute to MDS and AML progression. Among the most frequent chromosomal abnormalities in these disorders are alterations of chromosome 7: either complete loss of one copy of chromosome 7 (-7) or partial deletion of 7q (del(7q)), both of which increase the risk of progression from MDS to AML and are associated with chemoresistance. Notably, 7q36.1, a critical minimally deleted region in 7q, includes the gene encoding the histone methyltransferase mixed-lineage leukemia 3 (MLL3), which is also mutated in a small percentage of AML patients. However, the mechanisms by which MLL3 loss contributes to malignancy are unknown. Using an engineered mouse model expressing a catalytically inactive form of Mll3, we found a significant shift in hematopoiesis toward the granulocyte/macrophage lineage, correlating with myeloid infiltration and enlargement of secondary lymphoid organs. Therefore, we propose that MLL3 loss in patients may contribute to the progression of MDS and AML by promoting myelopoiesis.


[Genetics of preeclampsia: an approach to genetic linkage studies].
Due to its high prevalence during pregnancies, preeclampsia is considered an important public health problem. Many investigators agree in that its expression is related to the interaction between genetic and environmental factors. Many studies have searched for genetic factors, attempting to identify chromosomal regions or candidate genes whose variants may be related to high preeclampsia susceptibility. Several studies have associated a number of susceptibility genes to preeclampsia, but the results have not been replicated consistently in all populations. Mapping of genes and chromosomal regions by linkage analysis has located potential markers on chromosomes 2 and 4. Identification of the genes located in these candidate regions will pinpoint the genetic risk factors, will lead to a better understanding of the syndrome, and will provide clues for its prevention and treatment.


Primary and salvage chemotherapy in advanced Hodgkin's disease: the Milan Cancer Institute experience.
This paper reviews the most relevant therapeutic results achieved by the Milan Cancer Institute through successive randomized studies in advanced Hodgkin's disease. The experience achieved confirms the therapeutic importance of an anthracycline-containing regimen such as ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine) as salvage treatment and as primary chemotherapy, either when combined with irradiation or cyclically alternated with MOPP (mechlorethamine/vincristine/procarbazine/prednisone). Anthracycline-based combinations can be further refined to decrease toxicity. The biologic aspects of drug-sensitive v drug-resistant tumor cells and the accurate definition of prognostic categories at the time of first treatment failure are also discussed.


Functional peptidomics of amphibian skin secretion: A novel Kunitz-type chymotrypsin inhibitor from the African hyperoliid frog, Kassina senegalensis.
Amphibian skin secretions are, for the most part, complex peptidomes. While many peptide components have been biologically- and structurally-characterised into discrete "families", some of which are analogues of endogenous vertebrate regulatory peptides, a substantial number are of unique structure and unknown function. Among the components of these secretory peptidomes is an array of protease inhibitors. Inhibitors of trypsin are of widespread occurrence in different taxa and are representative of many established structural classes, including Kunitz, Kazal and Bowman-Birk. However, few protease inhibitors with activity against other specific proteases have been described from this source. Here we report for the first time, the isolation and structural characterisation of an inhibitor of chymotrypsin of Kunitz-type from the skin secretion of the African hyperoliid frog, Kassina senegalensis. To this end, we employed a functional peptidomic approach. This scheme involves fractionation of the peptidome, functional end-point screening, structural characterisation of resultant actives followed by molecular cloning of biosynthetic precursor-encoding cDNA(s). The novel mature and active polypeptide identified consisted of 62 amino acid residues (average molecular mass 6776.24 Da), of which 6 were positionally-conserved cysteines. The P(1) position within the active site was occupied by a phenylalanyl residue. Bioinformatic analysis of the sequence using BLAST, revealed a structural similarity to Kunitz-type chymotrypsin inhibitors from other organisms, ranging from silkworms to snakes.


RNA polymerase locations in the simian virus 40 transcription complex.
Transcription complexes of simian virus 40 can be isolated from cells late in infection in a form that retains the ability to continue transcription in vitro. These complexes have been investigated previously to gain information about the nucleoprotein structure of a transcribing gene. However, several studies have reported that the RNA polymerase molecules in such complexes are located almost entirely at the 5' end of the transcription unit. This would indicate that these complexes cannot be those which were in the process of transcribing mRNA in the cell, because the transcribing complexes would be expected to contain polymerase that were distributed throughout the transcription unit at the time of extraction. Since this issue is important to the interpretation of studies which characterize the extracted complexes, we have determined the polymerase locations using two new approaches. The first employs a new application of a procedure in which the transcription complex DNA is radioactively tagged by transcription in vitro. The second is a new method, which analyzes run-off transcripts generated in vitro. Both methods demonstrate that the polymerases are distributed throughout the genome in the transcription complexes. This result indicates that these complexes were in the process of transcribing mRNA at the time of cell lysis.


MYCOBACTERIUM CHIMAERA INFECTIONS AFTER CARDIOVASCULAR SURGERY: LESSONS FROM A GLOBAL OUTBREAK.
A global outbreak of invasive Mycobacterium chimaera infections has been associated with exposure to certain heater-cooler devices (HCDs) used during cardiopulmonary bypass. Outbreak investigations have shown that these HCDs harbor M. chimaera in water circuits and generate bio-aerosols in the operating room, leading to airborne transmission to patients during surgery. Whole genome sequencing data support a common-source outbreak originating at an HCD manufacturing facility. Most clinical infections are associated with implanted devices, diagnosis is often delayed, and treatment requires device removal and prolonged antibiotic therapy. Because it is nearly impossible to eradicate M. chimaera from HCDs using existing disinfection approaches, strict separation of HCD exhaust from operating room air is necessary to prevent patient exposure. Lessons learned from this outbreak include: 1) medical device risks are difficult to predict, requiring improved expert review before approval, and 2) advances in genomics provide powerful tools for outbreak investigation and public health surveillance.


Enhanced Catalytic Activity Induced by the Nanostructuring Effect in Pd Decoration onto Doped Ceria Enabling an Origami Paper Analytical Device for High Performance of Amyloid-β Bioassay.
In this work, we fabricated a novel origami paper-based analytical device (oPAD) assisted by the nanostructuring effect of in situ Pd decoration of Cu/Co-doped CeO2 (CuCo-CeO2-Pd) nanospheres, functionalized with their strongly enhanced electrocatalytic properties to realize an electrochemical and visual signal readout system in oPAD, for highly sensitive detection of amyloid-β (Aβ). The CuCo-CeO2-Pd nanospheres were introduced as an enhanced "signal transducer layer" on account of the electron transfer acceleration caused by catalyzing glucose to produce H2O2 for differential pulse voltammetry signal readout and further 3,3'5,5'-tetramethylbenzidine (TMB) oxidation for colorimetric analysis. Meanwhile, for achieving superior performance of the proposed oPAD, in situ growth of urchin-like gold nanoparticles (Au NPs) onto cellulose fibers was adopted to improve "the recognition layer" in favor of immobilizing antibodies for targeting Aβ through specific antigen-antibody interactions. Combined with the delicate design of oPAD, exhibiting actuation of the conversion procedure between hydrophobicity and hydrophilicity on paper tabs in the assay process, the oPAD successfully enabled sensitive diagnosis of Aβ in a linear range from 1.0 pM to 100 nM with a limit of detection of 0.05 pM (S/N = 3) for electrochemical detection, providing a reliable strategy for quantifying the Aβ protein in clinical applications.


Regulation of sodium transport in the proximal tubule by endothelin.
Human essential hypertension and rodent genetic hypertension are associated with increased sodium transport in the renal proximal tubule and medullary thick ascending limb of Henle. The proximal tubule, which secretes endothelin (ET), expresses the ET(B) receptor. Low (nM) concentrations of ET, via the ET(B) receptor, inhibit sodium and water transport and ATP-driven drug secretion in the proximal tubule. In contrast, very low (pM) and high nM concentrations of ET increase renal proximal sodium transport, but the receptor involved remains to be determined. The natriuretic effect of ET(B) receptor stimulation is impaired in spontaneously hypertensive rats, due in part to a defective interaction with D(3) dopamine and angiotensin II type 1 receptors. Impaired ET(B) receptor function in the renal proximal tubule may be important in the pathogenesis of genetic hypertension.


Echinoid regulates Flamingo endocytosis to control ommatidial rotation in the Drosophila eye.
Planar cell polarity (PCP) refers to a second polarity axis orthogonal to the apicobasal axis in the plane of the epithelium. The molecular link between apicobasal polarity and PCP is largely unknown. During Drosophila eye development, differentiated photoreceptors form clusters that rotate independently of the surrounding interommatidial cells (ICs). Here, we demonstrate that both Echinoid (Ed), an adherens junction-associated cell adhesion molecule, and Flamingo (Fmi), a PCP determinant, are endocytosed via a clathrin-mediated pathway in ICs. Interestingly, we found that Ed binds the AP-2 adaptor and is required for the internalization of Fmi into ICs. Loss of ed led to increased amounts of Fmi on the cell membrane of non-rotating ICs and also to the misrotation of photoreceptor clusters. Importantly, overexpression of fmi in ICs alone was sufficient to cause misrotation of the adjacent photoreceptor clusters. Together, we propose that Ed, when internalized by AP-2, undergoes co-endocytosis with, and thereby decreases, Fmi levels on non-rotating ICs to permit correct rotation of ommatidial clusters. Thus, co-endocytosis of Ed and Fmi provides a link between apicobasal polarity and PCP.


Cervical discogenic syndrome: a cause of chronic head and neck pain.
In patients with persistent pain of the neck, head, shoulder, and periscapular area, the diagnosis of cervical discogenic syndrome should be considered. The intervertebral disc can be a source of persistent pain and the severity of the symptoms should dictate the treatment. Surgical intervention should only be considered as a last resort in someone with significant pain who has failed prolonged conservative therapy. The success of the surgical treatment of this entity is most closely linked to adequate patient selection and rigorous patient preparation.


Advance directives: limitations upon their applicability in elderly care.
Advance directives (ADs) are increasingly used and are seen as a way of directing care after the loss of mental capacity. There are, however, major potential problems associated with their use. They may require the withholding of treatment that will alleviate suffering, and have the potential to cause patients to lose abilities and live with unnecessary suffering or handicap. In short, they may fail to achieve what the patient intended, and may cause outcomes that the patient never intended. The requirements for a valid AD are discussed and a simple model for doctors to assess the validity of ADs is proposed. Doctors will need to become much better at understanding the limitations of mental capacity, and quick mechanisms for rebutting ADs will be needed. In general, this is likely to be when ADs appear to conflict with good clinical care and the best interests of the patient. The prospect of legislation on ADs is not welcomed by the author.


Long-time quantum simulation of the primary charge separation in bacterial photosynthesis.
Accurate quantum mechanical simulations of the primary charge transfer in photosynthetic reaction centers are reported. The process is modeled by three coupled electronic states corresponding to the photoexcited chlorophyll special pair (donor), the reduced bacteriopheophytin (acceptor), and the reduced accessory chlorophyll (bridge) that interact with a dissipative medium of protein and solvent degrees of freedom. The time evolution of the excited special pair is followed over 17 ps by using a fully quantum mechanical path integral scheme. We find that a free energy of the reduced accessory chlorophyll state approximately equal to 400 cm(-1) lower than that of the excited special pair state yields state populations in agreement with experimental results on wild-type and modified reaction centers. For this energetic configuration electron transfer is a two-step process.


Bronchiolitis in Kartagener's syndrome.
The association of diffuse bronchiolitis in patients with Kartagener's syndrome (KS) has not been reported previously. The aim of this study was to present the morphological characteristics of bronchiolitis in patients with KS. Eight patients (four males, four females; mean age 37.9+/-18.7 yrs), clinically diagnosed as KS with the classical triad of chronic pansinusitis, bronchiectasis and situs in versus with dextrocardia, were evaluated. Routine chest radiography showed bronchiectasis and dextrocardia in all patients. Chest computed tomography (CT) showed diffuse centrilobular small nodules up to 2 mm in diameter throughout both lungs in six out of eight patients. Pulmonary function tests revealed marked obstructive impairment in all patients (forced expiratory volume in one second 57.0+/-11.3%, residual volume/total lung capacity 45.+/-12.7%, maximum midexpiratory flow 0.92+/-0.72 L x s(-1), forced vital capacity 74.1+/-12.2% (all mean +/- SD)). The examination of cilial movement of the bronchus revealed immotility in all of the five patients examined. The ultrastructure showed ciliary dynein arm defects in all patients. Histopathological examination of lung specimens obtained at autopsy or by video-assisted thoracoscopic surgery showed obliterative thickening of the walls of the membranous bronchioli with infiltration of lymphocytes, plasma cells and neutrophils, but most of the distal respiratory bronchioli were spared and alveolar spaces were overinflated. Pathologically, the diffuse centrilobular small nodules on the chest CT mainly corresponded to membranous bronchiolitis. This is the first report demonstrating that the association of diffuse bronchiolitis might be one of the characteristic features of the lung in Kartagener's syndrome.