Expression of the POTE gene family in human ovarian cancer.
The POTE family includes 14 genes in three phylogenetic groups. We determined POTE mRNA expression in normal tissues, epithelial ovarian and high-grade serous ovarian cancer (EOC, HGSC), and pan-cancer, and determined the relationship of POTE expression to ovarian cancer clinicopathology. Groups 1 & 2 POTEs showed testis-specific expression in normal tissues, consistent with assignment as cancer-testis antigens (CTAs), while Group 3 POTEs were expressed in several normal tissues, indicating they are not CTAs. Pan-POTE and individual POTEs showed significantly elevated expression in EOC and HGSC compared to normal controls. Pan-POTE correlated with increased stage, grade, and the HGSC subtype. Select individual POTEs showed increased expression in recurrent HGSC, and POTEE specifically associated with reduced HGSC OS. Consistent with tumors, EOC cell lines had significantly elevated Pan-POTE compared to OSE and FTE cells. Notably, Group 1 & 2 POTEs (POTEs A/B/B2/C/D), Group 3 POTE-actin genes (POTEs E/F/I/J/KP), and other Group 3 POTEs (POTEs G/H/M) show within-group correlated expression, and pan-cancer analyses of tumors and cell lines confirmed this relationship. Based on their restricted expression in normal tissues and increased expression and association with poor prognosis in ovarian cancer, POTEs are potential oncogenes and therapeutic targets in this malignancy.


Bilateral fetal uropathy: what is the outlook?
To assess the morbidity and mortality associated with a prenatal diagnosis of bilateral fetal uropathy. Retrospective study. Departments of radiology, paediatric surgery, obstetrics, and pathology in two teaching hospitals that serve as referral centres for the Yorkshire region. 126 Cases of fetal uropathy were referred either prenatally or postnatally from hospitals in Yorkshire between August 1982 and December 1987. The disease was bilateral in 54 cases and unilateral in 72 cases. In 14 cases bilateral fetal uropathy was associated with coexistent disease. All cases were managed individually by an obstetrician after discussion with the radiologists and paediatric surgeons. Babies who survived were treated prophylactically with antibiotics after delivery and were operated on if appropriate. Assessment of prognosis for long term renal function for each baby referred between August 1982 and December 1987: follow up ranged from six months to five years. Of the 54 fetuses with bilateral fetal uropathy, 13 were terminated as the prenatal findings of ultrasonography were considered to be incompatible with long term survival. Ten of the liveborn babies died, five of renal or pulmonary insufficiency, or both, and five of associated congenital anomalies. Thirty one infants survived to follow up; four of these had serious coexistent disease and two had impaired renal function. Thus the overall mortality was 43% and the morbidity rate 19%. The renal anomaly was associated with other serious disease in 14 cases (26%) compared with two (3%) of the 72 cases of unilateral fetal uropathy. All but two of the 27 infants with isolated bilateral urinary tract disease had excellent prospects for survival. Although bilateral fetal uropathy is associated with a high morbidity rate and mortality, careful prenatal assessment can help to identify fetuses with a poor prognosis. The outlook for a fetus with isolated renal disease if treated promptly after delivery is excellent and compares favourably with that reported after prenatal surgical intervention.


The Role of Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) in Atrial Fibrillation: Treatment Management Based on Patient and Drug Characteristics.
Data from Turkey revealed that atrial fibrillation patient percentage under adequate anti- coagulation in Turkey is less than that in other countries due to multiple parameters such as treatment adherence problems, failure to follow guideline recommendations, negative perspective on the use of new drugs, drug costs, and payment conditions. The aim of this article is to provide physicians with a compiled resource that focuses on the differences between non-vitamin K antagonist oral anticoagulants and heterogeneity of atrial fibrilla- tion patients by reviewing the global and national data from a multidisciplinary perspective and provide guidance on the choice of non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients. A gastroenterologist, 2 neurologists, and 11 cardiologists from university and training and research hospitals in Turkey who are experienced in atrial fibrillation and non-vitamin K antagonist oral anticoagulant treatments gathered in 3 separate meetings to identify the review topics and evaluate the outcomes of the systematic literature search. Based on the pharmacological characteristics, clinical studies, and real-world data compari- sons, it has been revealed that non-vitamin K antagonist oral anticoagulants are not similar. Thromboembolism and bleeding risks, renal and hepatic functions, coexisting conditions, and concomitant drug usage have been shown to affect the levels of benefits gained from non-vitamin K antagonist oral anticoagulant in atrial fibrillation patients. Although Turkish patients with atrial fibrillation have been observed to be younger, they are more likely to have coexisting cardiovascular conditions compared to the atrial fibrillation patients in other countries. Selection of an appropriate non-vitamin K antagonist oral anticoagulant in line with the available evidence and recent guidelines will provide substantial benefits to atrial fibrillation patients.


Full-length HIV-1 Gag determines protease inhibitor susceptibility within in vitro assays.
There is evidence that gag contributes to protease inhibitor susceptibility in treatment-experienced patients. Moreover, protease inhibitor resistance-associated mutations can arise in gag in the absence of protease mutations in vitro. We wished to assess the contribution of full-length Gag to protease inhibitor susceptibility in viruses unexposed to protease inhibitors, in particular from the most common HIV-1 subtypes, namely subtype A and C. We compared the drug resistance profiles of subtype A and C cognate gag-protease (from viruses not previously exposed to protease inhibitor) to protease combined with a generic subtype B gag as in routine phenotypic testing. We amplified gag-protease sequences from plasma-derived virus or molecular clones, and used a single cycle transfection-based drug resistance assay to compare the fold changes in the concentration of drug required to inhibit 50% of viral replication of these viruses to a generic subtype B. We made a series of chimeras to explore phenotypes further. In some cases, use of protease sequences without the cognate gag overestimated susceptibility to protease inhibitors, in particular to lopinavir. We provide evidence that gag sequences from wild-type viruses can contribute as much as 14-fold reduction in susceptibility to lopinavir, and that cognate protease can balance this by partially restoring susceptibility. Our findings demonstrate the importance of considering protease inhibitor susceptibility in the context of full-length gag, particularly with respect to the range of HIV-1 subtypes circulating worldwide.


The epidemiology of invasive group A streptococcal disease in Victoria, Australia.
To estimate the incidence and severity of invasive group A streptococcal infection in Victoria, Australia. Prospective active surveillance study. Public and private laboratories, hospitals and general practitioners throughout Victoria. People in Victoria diagnosed with group A streptococcal disease notified to the surveillance system between 1 March 2002 and 31 August 2004. Confirmed invasive group A streptococcal disease. We identified 333 confirmed cases: an average annual incidence rate of 2.7 (95% CI, 2.3-3.2) per 100,000 population per year. Rates were highest in people aged 65 years and older and those younger than 5 years. The case-fatality rate was 7.8%. Streptococcal toxic shock syndrome occurred in 48 patients (14.4%), with a case-fatality rate of 23%. Thirty cases of necrotising fasciitis were reported; five (17%) of these patients died. Type 1 (23%) was the most frequently identified emm sequence type in all age groups. All tested isolates were susceptible to penicillin and clindamycin. Two isolates (4%) were resistant to erythromycin. The incidence of invasive group A streptococcal disease in temperate Australia is greater than previously appreciated and warrants greater public health attention, including its designation as a notifiable disease.


Phylogenomic analyses of deep gastropod relationships reject Orthogastropoda.
Gastropods are a highly diverse clade of molluscs that includes many familiar animals, such as limpets, snails, slugs and sea slugs. It is one of the most abundant groups of animals in the sea and the only molluscan lineage that has successfully colonized land. Yet the relationships among and within its constituent clades have remained in flux for over a century of morphological, anatomical and molecular study. Here, we re-evaluate gastropod phylogenetic relationships by collecting new transcriptome data for 40 species and analysing them in combination with publicly available genomes and transcriptomes. Our datasets include all five main gastropod clades: Patellogastropoda, Vetigastropoda, Neritimorpha, Caenogastropoda and Heterobranchia. We use two different methods to assign orthology, subsample each of these matrices into three increasingly dense subsets, and analyse all six of these supermatrices with two different models of molecular evolution. All 12 analyses yield the same unrooted network connecting the five major gastropod lineages. This reduces deep gastropod phylogeny to three alternative rooting hypotheses. These results reject the prevalent hypothesis of gastropod phylogeny, Orthogastropoda. Our dated tree is congruent with a possible end-Permian recovery of some gastropod clades, namely Caenogastropoda and some Heterobranchia subclades.


Current Drug Repurposing Strategies for Rare Neurodegenerative Disorders.
Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.


The Measurable Benefits of a Workplace Wellness Program in Canada: Results After One Year.
The aim of this study was to evaluate the impact of an employee wellness program in Canada. A comprehensive program including web-based lifestyle challenges was evaluated with annual health screenings. Among 730 eligible employees, 688 (94%) registered for the program, 571 (78%) completed a health screening at baseline, and 314 (43%) at 1 year. Most (66%) employees tracked their activity for more than 6 weeks. At 1-year follow-up, there were significant clinical improvements in systolic blood pressure -3.4 mm Hg, and reductions in poor sleep quality (33% to 28%), high emotional stress (21% to 15%), and fatigue (11% to 6%). A positive dose-response was noted where the greatest improvements were observed among those who participated the most. The program had high employee engagement. After 1 year, the benefits included clinically important improvements in physical and mental health.


Epidemiology of Invasive Pulmonary Aspergillosis Among Intubated Patients With COVID-19: A Prospective Study.
We evaluated the incidence of invasive pulmonary aspergillosis among intubated patients with critical COVID-19 and evaluated different case definitions of invasive aspergillosis. Prospective, multicenter study in adult patients with microbiologically confirmed COVID-19 receiving mechanical ventilation. All included participants underwent a screening protocol for invasive pulmonary aspergillosis with bronchoalveolar lavage galactomannan and cultures performed on admission at 7 days and in case of clinical deterioration. Cases were classified as coronavirus-associated pulmonary aspergillosis (CAPA) according to previous consensus definitions. The new definition was compared with putative invasive pulmonary aspergillosis (PIPA). 108 patients were enrolled. Probable CAPA was diagnosed in 30 (27.7%) patients after a median of 4 (2-8) days from intensive care unit (ICU) admission. Kaplan-Meier curves showed a significantly higher 30-day mortality rate from ICU admission among patients with either CAPA (44% vs 19%, P = .002) or PIPA (74% vs 26%, P < .001) when compared with patients not fulfilling criteria for aspergillosis. The association between CAPA (OR, 3.53; 95% CI, 1.29-9.67; P = .014) or PIPA (OR, 11.60; 95% CI, 3.24-41.29; P < .001) with 30-day mortality from ICU admission was confirmed, even after adjustment for confounders with a logistic regression model. Among patients with CAPA receiving voriconazole treatment (13 patients; 43%) a trend toward lower mortality (46% vs 59%; P = .30) and reduction in galactomannan index in consecutive samples were observed. We found a high incidence of CAPA among critically ill COVID-19 patients and its occurrence seems to change the natural course of disease.


Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19.
Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients.


Duration of viable virus shedding in SARS-CoV-2 omicron variant infection.
Clinical features of SARS-CoV-2 Omicron variant infection, including incubation period and transmission rates, distinguish this variant from preceding variants. However, whether the duration of shedding of viable virus differs between omicron and previous variants is not well understood. To characterize how variant and vaccination status impact shedding of viable virus, we serially sampled symptomatic outpatients newly diagnosed with COVID-19. Anterior nasal swabs were tested for viral load, sequencing, and viral culture. Time to PCR conversion was similar between individuals infected with the Delta and the Omicron variant. Time to culture conversion was also similar, with a median time to culture conversion of 6 days (interquartile range 4-8 days) in both groups. There were also no differences in time to PCR or culture conversion by vaccination status.


Radium-223 Safety, Efficacy, and Concurrent Use with Abiraterone or Enzalutamide: First U.S. Experience from an Expanded Access Program.
In the phase III ALSYMPCA trial, metastatic castration-resistant prostate cancer (mCRPC) patients had few prior life-prolonging therapies. Following ALSYMPCA, which demonstrated radium-223 survival benefit, and before radium-223 U.S. commercial availability, an expanded access program (EAP) providing early-access radium-223 allowed life-prolonging therapies in current use. This phase II, open-label, single-arm, multicenter U.S. EAP (NCT01516762) enrolled patients with symptomatic mCRPC, ≥2 bone metastases, and no lung, liver, or brain metastases. Patients received radium-223 55 kBq/kg intravenously every 4 weeks × 6. Primary outcomes were acute and long-term safety. Additional analyses were done by number of radium-223 injections, and prior or concomitant abiraterone or enzalutamide use. Of 252 patients, 184 received radium-223: 165/184 (90%) had Eastern Cooperative Oncology Group (ECOG) performance status 0-1; 183 (99%) had prior systemic anticancer therapy. Treatment-related adverse events occurred in 93/184 (51%) patients during treatment and 11 (6%) during follow-up. Median overall survival was 17 months, with 134/184 (73%) patients censored because of short follow-up due to radium-223 approval. In post hoc analyses, patients with ≥3 prior anticancer medications, baseline ECOG performance status ≥2, and lower baseline hemoglobin were less likely to receive 5-6 radium-223 injections and unlikely to benefit from radium-223. Radium-223 was well tolerated regardless of concurrent or prior abiraterone or enzalutamide. Radium-223 was well tolerated, with no new safety concerns; safety was maintained with abiraterone or enzalutamide. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline characteristics and therapy sequence for greatest clinical value. In this phase II U.S. expanded access program, radium-223 was well tolerated, with a median overall survival of 17 months in metastatic castration-resistant prostate cancer patients. In post hoc analyses, radium-223 was safe regardless of concurrent abiraterone or enzalutamide, and median overall survival appeared longer when radium-223 was used earlier in patients with less prior treatment. Patients with more advanced disease were less likely to benefit from radium-223. Clinicians should consider baseline clinical characteristics and therapy sequence to provide the greatest clinical value to patients.


Plasma kinins increase after angiotensin-converting enzyme inhibition in human subjects.
1. In patients treated with angiotensin-converting enzyme inhibitors, kinin-related effects have been postulated repeatedly, but information on changes in plasma kinin levels in these patients is sparse. Difficulties in the measurement of plasma kinins account for this, at least in part. 2. The main purpose of the present study was to investigate, in normal human subjects, the effect of the angiotensin-converting enzyme inhibitor quinapril on plasma kinins. 3. High-affinity antisera (Kd < 10(-11) mol/l) of C-terminal specificity were raised in rabbits for radioimmunoassay of immunoreactive kinins activating the bradykinin B2-receptor, and three different liquid- and solid-phase extraction methods for plasma kinins were evaluated. Ethanol and subsequent petroleum ether extraction of 5-40 fmol of bradykinin added to plasma yielded recoveries of 39 +/- 16% (mean +/- SD); normal kinin levels in human plasma were 18.6 +/- 3.3 pmol/l (mean +/- SEM). Solid-phase extraction on urea-equilibrated phenylsilylsilica produced recoveries of 89 +/- 5% and normal values of 36.4 +/- 18 pmol/l. Finally, with an assay based on ethanol extraction alone, recoveries of 100 +/- 16% and normal values of 16.8 +/- 5.8 pmol/l were obtained, with a detection limit of 1.5 fmol/ml of plasma. Blanks were below the detection limit. Serial dilution of plasma extracts (n = 4) provided linear kinin concentrations (r = 0.99). For two different plasma pools, coefficients of variation for within-assay precision were 16.7% and 21.7%, respectively. Between-assay coefficients of variation were 12.8% and 17.4%.(ABSTRACT TRUNCATED AT 250 WORDS)


Postmortem investigation of fatalities following vaccination with COVID-19 vaccines.
Thorough postmortem investigations of fatalities following vaccination with coronavirus disease 2019 (COVID-19) vaccines are of great social significance. From 11.03.2021 to 09.06.2021, postmortem investigations of 18 deceased persons who recently received a vaccination against COVID-19 were performed. Vaxzevria was vaccinated in nine, Comirnaty in five, Spikevax in three, and Janssen in one person. In all cases, full autopsies, histopathological examinations, and virological analyses for the severe acute respiratory syndrome coronavirus 2 were carried out. Depending on the case, additional laboratory tests (anaphylaxis diagnostics, VITT [vaccine-induced immune thrombotic thrombocytopenia] diagnostics, glucose metabolism diagnostics) and neuropathological examinations were conducted. In 13 deceased, the cause of death was attributed to preexisting diseases while postmortem investigations did not indicate a causal relationship to the vaccination. In one case after vaccination with Comirnaty, myocarditis was found to be the cause of death. A causal relationship to vaccination was considered possible, but could not be proven beyond doubt. VITT was found in three deceased persons following vaccination with Vaxzevria and one deceased following vaccination with Janssen. Of those four cases with VITT, only one was diagnosed before death. The synopsis of the anamnestic data, the autopsy results, laboratory diagnostic examinations, and histopathological and neuropathological examinations revealed that VITT was the very likely cause of death in only two of the four cases. In the other two cases, no neuropathological correlate of VITT explaining death was found, while possible causes of death emerged that were not necessarily attributable to VITT. The results of our study demonstrate the necessity of postmortem investigations on all fatalities following vaccination with COVID-19 vaccines. In order to identify a possible causal relationship between vaccination and death, in most cases an autopsy and histopathological examinations have to be combined with additional investigations, such as laboratory tests and neuropathological examinations.


Rice GTPase OsRacB: potential accessory factor in plant salt-stress signaling.
As the sole ubiquitous signal small guanosine triphosphate-binding protein in plants, Rop gene plays an important role in plant growth and development. In this study, we focus on the relationship between the novel rice Rop gene OsRacB and plant salt tolerance. Results show that OsRacB transcription is highly accumulated in roots after treatment with salinity, but only slightly accumulated in stems and leaves under the same treatment. Promoter analysis showed that OsRacB promoter is induced by salinity and exogenous salicylic acid, not abscisic acid. To elucidate its physiological function, we generated OsRacB sense and antisense transgenic tobacco and rice. Under proper salinity treatment, sense transgenic plants grew much better than the control. This suggests that overexpression of OsRacB in tobacco and rice can improve plant salt tolerance. But under the same treatment, no difference could be observed between OsRacB antisense plants and the control. The results indicated that OsRacB is only an accessory factor in plant salt tolerance.


Inhibition of cartilage degradation and suppression of PGE2 and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis.
Osteoarthritis (OA) is characterized by cartilage degradation in the affected joints. Pomegranate fruit extract (PFE) inhibits cartilage degradation in vitro. The aim of this study was to determine whether oral consumption of PFE inhibits disease progression in rabbits with surgically induced OA. OA was surgically induced in the tibiofemoral joints of adult New Zealand White rabbits. In one group, animals were fed PFE in water for 8 wk postsurgery. In the second group, animals were fed PFE for 2 wk before surgery and for 8 wk postsurgery. Histologic assessment and scoring of the cartilage was per Osteoarthritis Research Society International guidelines. Gene expression and matrix metalloproteinases (MMP) activity were determined using quantitative reverse transcriptase polymerase chain reaction and fluorometric assay, respectively. Interleukin (IL)-1 β, MMP-13, IL-6, prostaglandin (PG)E2, and type II collagen (COL2A1) levels in synovial fluid/plasma/culture media were quantified using enzyme-linked immunosorbent assay. Expression of active caspase-3 and poly (ADP-ribose) polymerase p85 was determined by immunohistochemistry. Effect of PFE and inhibitors of MMP-13, mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB was studied in IL-1 β-stimulated rabbit articular chondrocytes. Safranin-O-staining and chondrocyte cluster formation was significantly reduced in the anterior cruciate ligament transaction plus PFE fed groups. Expression of MMP-3, MMP-9, and MMP-13 mRNA was higher in the cartilage of rabbits given water alone but was significantly lower in the animals fed PFE. PFE-fed rabbits had lower IL-6, MMP-13, and PGE2 levels in the synovial fluid and plasma, respectively, and showed higher expression of aggrecan and COL2A1 mRNA. Significantly higher numbers of chondrocytes were positive for markers of apoptosis in the joints of rabbits with OA given water only compared with those in the PFE-fed groups. PFE pretreatment significantly reduced IL-1 β induced IL-6 and MMPs expression in rabbit articular chondrocytes. These effects were also mimicked using MMP-13, MAPK, and NF-κB inhibitors in IL-1 β-stimulated rabbit chondrocytes. In an in vitro activity assay, PFE blocked the activity of MMP-13. Like MAPK and NF-κB inhibitors, PFE was also effective in inhibiting IL-1 β-induced PGE2 production in rabbit chondrocytes. PFE also reversed the inhibitory effect of IL-1β on COL2A1 mRNA and protein expression in IL-1 β-stimulated rabbit chondrocytes. The present data highlight the chondroprotective effects of PFE oral consumption in a model of posttraumatic OA and suggest that PFE-derived compounds may have potential value in the management of OA.


DsbA-L deficiency exacerbates mitochondrial dysfunction of tubular cells in diabetic kidney disease.
Excessive mitochondrial fission has been identified as the central pathogenesis of diabetic kidney disease (DKD), but the precise mechanisms remain unclear. Disulfide-bond A oxidoreductase-like protein (DsbA-L) is highly expressed in mitochondria in tubular cells of the kidney, but its pathophysiological role in DKD is unknown. Our bioinformatics analysis showed that tubular DsbA-L mRNA levels were positively associated with eGFR but negatively associated with Scr and 24h-proteinuria in CKD patients. Furthermore, the genes that were coexpressed with DsbA-L were mainly enriched in mitochondria and were involved in oxidative phosphorylation. In vivo, knockout of DsbA-L exacerbated diabetic mice tubular cell mitochondrial fragmentation, oxidative stress and renal damage. In vitro, we found that DsbA-L was localized in the mitochondria of HK-2 cells. High glucose (HG, 30 mM) treatment decreased DsbA-L expression followed by increased mitochondrial ROS (mtROS) generation and mitochondrial fragmentation. In addition, DsbA-L knockdown exacerbated these abnormalities, but this effect was reversed by overexpression of DsbA-L. Mechanistically, under HG conditions, knockdown DsbA-L expression accentuated JNK phosphorylation in HK-2 cells. Furthermore, administration of a JNK inhibitor (SP600125) or the mtROS scavenger MitoQ significantly attenuated JNK activation and subsequent mitochondrial fragmentation in DsbA-L-knockdown HK-2 cells. Additionally, the down-regulation of DsbA-L also amplified the gene and protein expression of mitochondrial fission factor (MFF) via the JNK pathway, enhancing its ability to recruit DRP1 to mitochondria. Taken together, these results link DsbA-L to alterations in mitochondrial dynamics during tubular injury in the pathogenesis of DKD and unveil a novel mechanism by which DsbA-L modifies mtROS/JNK/MFF-related mitochondrial fission.


Complete Fifth Ray Amputation With Peroneal Tendon Transfer to the Cuboid: A Review of Consecutive Cases Involving Lateral Column Neuropathic Foot Ulceration and Osteomyelitis.
Nonhealing wounds along the fifth metatarsal associated with neuropathy and bone deformity frequently become complicated with osteomyelitis. Our surgical technique for complete fifth ray amputation with peroneal tendon transfer has been previously published. The present study evaluated the outcomes regarding success with initial healing and intermediate-term limb survival after this procedure, which is intended to resolve infection, remove bone deformity, heal and prevent recurrence of lateral column wounds, and maintain functional stability of the foot. An institutional review board-approved retrospective review of 21 consecutive cases was performed on patients who had undergone complete fifth ray amputation from August 2006 to September 2015. Comorbid conditions were assessed in relation to outcome. The typical stage 1 procedure involved complete fifth toe and metatarsal amputation, antibiotic bead placement, and preliminary wound closure. The stage 2 procedure was performed 2 weeks later and involved removal of the antibiotic beads, biopsy and remodeling of the cuboid, and peroneus longus tendon transfer to the cuboid. All cases involved ulceration along the fifth metatarsal. Of the 21 patients, 10 (47.6%) had undergone previous partial fifth ray amputation with recurrent ulceration at the residual metatarsal stump. Osteomyelitis of the fifth metatarsal was confirmed by bone culture and/or positive pathologic findings for osteomyelitis in 19 of 21 cases (90.5%). A total of 15 patients (71.4%) were completely healed at 10 weeks, and 10 patients (47.6%) required subsequent surgery, including 4 below-the-knee amputations and 1 Symes amputation. The average follow-up period was 37.0 (range 2.9 to 105) months. Despite the 10 patients (47.6%) requiring revision surgery, the limb salvage rate was 76.2% (16 of 21) at an average follow-up period of >3 years in this high-risk patient population.


Sequence-specific DNA recognition by cyclic pyrrole-imidazole cysteine-derived polyamide dimers.
Pyrrole-imidazole (PI) polyamides bind to the minor groove of the DNA duplex in a sequence-specific manner and thus have the potential to regulate gene expression. To date, various types of PI polyamides have been designed as sequence-specific DNA binding ligands. One of these, cysteine cyclic PI polyamides containing two β-alanine molecules, were designed to recognize a 7 bp DNA sequence with high binding affinity. In this study, an efficient cyclization reaction between a cysteine and a chloroacetyl residue was used for dimerization in the synthesis of a unit that recognizes symmetrical DNA sequences. To evaluate specific DNA binding properties, dimeric PI polyamide binding was measured by using a surface plasmon resonance (SPR) method. Extending this molecular design, we synthesized a large dimeric PI polyamide that can recognize a 14 bp region in duplex DNA.


Cloning and expression of cDNA for rat heme oxygenase.
Two cDNA clones for rat heme oxygenase have been isolated from a rat spleen cDNA library in lambda gt11 by immunological screening using a specific polyclonal antibody. One of these clones has an insert of 1530 nucleotides that contains the entire protein-coding region. To confirm that the isolated cDNA encodes heme oxygenase, we transfected monkey kidney cells (COS-7) with the cDNA carried in a simian virus 40 vector. The heme oxygenase was highly expressed in endoplasmic reticulum of transfected cells. The nucleotide sequence of the cloned cDNA was determined and the primary structure of heme oxygenase was deduced. Heme oxygenase is composed of 289 amino acids and has one hydrophobic segment at its carboxyl terminus, which is probably important for the insertion of heme oxygenase into endoplasmic reticulum. The cloned cDNA was used to analyze the induction of heme oxygenase in rat liver by treatment with CoCl2 or with hemin. RNA blot analysis showed that both CoCl2 and hemin increased the amount of hybridizable mRNA, suggesting that these substances may act at the transcriptional level to increase the amount of heme oxygenase.


Trinuclear copper complexes with triplesalen ligands: geometric and electronic effects on ferromagnetic coupling via the spin-polarization mechanism.
A series of trinuclear Cu(II) complexes with the tris(tetradentate) triplesalen ligands H(6)talen, H(6)talen(tBu(2) ), and H(6)talen(NO(2) ), namely [(talen)Cu(II) (3)] (1), [(talen(tBu(2) ))Cu(II) (3)] (2), and [(talen(NO(2) ))Cu(II) (3)] (3), were synthesized and their molecular and electronic structures determined. These triplesalen ligands provide three salen-like coordination environments bridged in a meta-phenylene arrangement by a phloroglucinol backbone. The structure of [(talen)Cu(II) (3)] (1) was communicated recently. The structure of the tert-butyl derivative [(talen(tBu(2) ))Cu(II) (3)] (2) was established in three different solvates. The molecular structures of these trinuclear complexes show notable differences, the most important of which is the degree of ligand folding around the central Cu(II)-phenolate bonds. This folding is symmetric with regard to the central phloroglucinol backbone in two structures, where it gives rise to bowl-shaped overall geometries. For one solvate two trinuclear triplesalen complexes form a supramolecular disk-like arrangement, hosting two dichloromethane molecules like two pearls in an oyster. The FTIR spectra of these complexes indicate the higher effective nuclear charge of Cu(II) in comparison to the trinuclear Ni(II) complexes by the lower C--O and higher C=N stretching frequencies. The UV/Vis/NIR spectra of 1-3 reflect the stronger ligand folding in the tert-butyl complex 2 by an intense phenolate-to-Cu(II) LMCT. This absorption is absent in 1 and is obscured by the nitro chromophore in 3. The more planar molecular structures cause orthogonality of the Cu(II) d(x(2)-y(2) ) orbital and the phenolate O p(z) orbital, which leads to small LMCT dipole strengths. Whereas 1 and 3 exhibit only irreversible oxidations, 2 exhibits a reversible one-electron oxidation at +0.26 V, a reversible two-electron oxidation at +0.59 V, and a reversible one-electron oxidation at +0.81 V versus Fc(+)/Fc. The one-electron oxidized form 2(+) is strongly stabilized with respect to reference mononuclear salen-like Cu complexes. Chemical one-electron oxidation of 2 to 2(+) allows the determination of its UV/Vis/NIR spectrum, which indicates a ligand-centered oxidation that can be assigned to the central phloroglucinol unit by analogy with the trinuclear Ni triplesalen series. Delocalization of this oxidation over three Cu(II)-phenolate subunits causes the observed energetic stabilization of 2(+). Temperature-dependent magnetic susceptibility measurements reveal ferromagnetic couplings for all three trinuclear Cu(II) triplesalen complexes. The trend of the coupling constants can be rationalized by two opposing effects: 1) electron-withdrawing terminal substituents stabilize the central Cu(II)-phenolate bond, which results in a stronger coupling, and 2) ligand folding around the central Cu(II)-phenolate bond opens a bonding pathway between the magnetic Cu(II) d(x(2)-y(2) ) orbital and the phenolate O p(z) orbital, which results in a stronger coupling. Density functional calculations indicate that both spin-polarization and spin-delocalization are operative and that slight geometric variations alter their relative magnitudes.


Subclinical carotid atherosclerosis and early vascular aging from long-term low-dose ionizing radiation exposure: a genetic, telomere, and vascular ultrasound study in cardiac catheterization laboratory staff.
This study sought to assess the association between long-term radiation exposure in the catheterization laboratory (cath lab) and early signs of subclinical atherosclerosis. There is growing evidence of an excess risk of cardiovascular disease at low-dose levels of ionizing radiation exposure. Left and right carotid intima-media thickness (CIMT) was measured in 223 cath lab personnel (141 male; age, 45 ± 8 years) and 222 unexposed subjects (113 male; age, 44±10 years). Leukocyte telomere length (LTL) was evaluated by quantitative reverse transcriptase polymerase chain reaction. The DNA repair gene XRCC3 Thr241Met polymorphism was also analyzed to explore the possible interaction with radiation exposure. The occupational radiological risk score (ORRS) was computed for each subject on the basis of the length of employment, individual caseload, and proximity to the radiation source. A complete lifetime effective dose (mSv) was recorded for 57 workers. Left, right, and averaged CIMTs were significantly increased in high-exposure workers compared with both control subjects and low-exposure workers (all p values<0.04). On the left side, but not on the right, there was a significant correlation between CIMT and ORRS (p=0.001) as well as lifetime dose (p=0.006). LTL was significantly reduced in exposed workers compared with control subjects (p=0.008). There was a significant correlation between LTL and both ORRS (p=0.002) and lifetime dose (p=0.03). The XRCC3 Met241 allele presented a significant interaction with high exposure for right side (pinteraction=0.002), left side (pinteraction<0.0001), and averaged (pinteraction<0.0001) CIMTs. Long-term radiation exposure in a cath lab may be associated with increased subclinical CIMT and telomere length shortening, suggesting evidence of accelerated vascular aging and early atherosclerosis.


Periprosthetic joint infections in femoral neck fracture patients treated with hemiarthroplasty - should we use antibiotic-loaded bone cement?
Hemiarthroplasty is the most common treatment in elderly patients with displaced intra-capsular femoral neck fracture (FNF). Prosthetic joint infection (PJI) is one of the most feared and frequent complications post-surgery because of the frail health status of these patients and the need for fast track surgery. Therefore, priorities should lie in effective preventive strategies to mitigate this burden. To determine how much the implementation of the routine use of antibiotic-loaded bone cement (ALBC) as a relatively easy-to-apply amendment to the surgical practice reduces the infection rate in our hemiarthroplasty cohort. We retrospectively assessed all demographic, health status and treatment-related data of our FNF patients undergoing cemented hemiarthroplasty in the period from 2011 to 2017; 241 patients were further analyzed after exclusion of patients with cancer-related sequelae and those who died before the end of the 1-year observation period. The PJI rate as diagnosed on basis of the Musculoskeletal Infection Society (MSIS) criteria 2011 was determined for each included patient and compared in function of the bone cement used for hip stem fixation. Patients were split into a group receiving a plain bone cement in the period from January 2011 to June 2013 (non-ALBC group) and into a group receiving an ALBC in the period July 2013 to December 2017 (ALBC group). Data analysis was performed with statistical software. We further calculated the cost-efficacy of the implementation of routine use of ALBC in the second group balancing the in-hospital infection related treatment costs with the extra costs of use of ALBC. In total 241 FNF patients who received cemented hemiarthroplasty in the period from January 2011 to January 2017 were eligible for inclusion in this retrospective study. There were 8 PJI cases identified in the ALBC group among n = 94 patients, whereas 28 PJI cases were observed in the non-ALBC group among n = 147 patients. The statistical analysis showed an infection risk reduction of 55.3% (in particular due to the avoidance of chronic delayed infections) in the ALBC group (95%CI: 6.2%-78.7%; P = 0.0025). The cost-evaluation analysis demonstrated a considerable cost saving of 3.500 € per patient, related to the implementation of routine use of ALBC in this group. Use of ALBC is a potent infection preventive factor in FNF patients receiving cemented hemiarthroplasties. It was further found to be highly cost-effective.


Tumor shrinkage by cyclopamine tartrate through inhibiting hedgehog signaling.
The link of hedgehog (Hh) signaling activation to human cancer and synthesis of a variety of Hh signaling inhibitors raise great expectation that inhibiting Hh signaling may be effective in human cancer treatment. Cyclopamine (Cyc), an alkaloid from the Veratrum plant, is a specific natural product inhibitor of the Hh pathway that acts by targeting smoothened (SMO) protein. However, its poor solubility, acid sensitivity, and weak potency relative to other Hh antagonists prevent the clinical development of Cyc as a therapeutic agent. Here, we report properties of cyclopamine tartrate salt (CycT) and its activities in Hh signaling-mediated cancer in vitro and in vivo. Unlike Cyc, CycT is water soluble (5-10 mg/mL). The median lethal dose (LD50) of CycT was 62.5 mg/kg body weight compared to 43.5 mg/kg for Cyc, and the plasma half-life (T1/2) of CycT was not significantly different from that of Cyc. We showed that CycT had a higher inhibitory activity for Hh signaling-dependent motor neuron differentiation than did Cyc (IC50 = 50 nmol/L for CycT vs. 300 nmol/L for Cyc). We also tested the antitumor effectiveness of these Hh inhibitors using two mouse models of basal cell carcinomas (K14cre:Ptch1(neo/neo) and K14cre:SmoM2(YFP)). After topical application of CycT or Cyc daily for 21 days, we found that all CycT-treated mice had tumor shrinkage and decreased expression of Hh target genes. Taken together, we found that CycT is an effective inhibitor of Hh signaling-mediated carcinogenesis.


Hospital reimbursement incentives: is there a more effective option?--Part I.
Based on the fiscal incentives inherent in a nation's hospital reimbursement methodology, it is highly predictable how the nation's healthcare executives will manage their organization's resources. The hospital data presented herein suggest that prospective reimbursement such as with DRGs in Germany and the United States encourages preadmission testing, more ambulatory care procedures, shorter average lengths of stay, and a greater number of employee hours per discharge. Payment on the basis of total patient days, such as in Canada, results in more acute care beds and more total days per 1000 persons, longer average lengths of stay, and less intensive use of personnel. But even when nations provide universal access, for various reasons those with mental illness and those who are indigent, poorly educated, and nonwhite use less healthcare services.


Reformation of the pattern of neuromuscular connections in the regenerated axolotl hindlimb.
Retrograde neuronal tracing with horseradish peroxidase (HRP) was used to determine the position in the spinal cord of motor neurone pools innervating muscles in the regenerated axolotl hindlimb. This method allows a detailed analysis of the accuracy of reformation of neuromuscular connections. The results show that regenerated distal limb muscles are reinnervated by motor neurones in the same region of the cord as those that innervate normal control distal limb muscles but that proximal muscles are innervated by a mixture of motor neurones in a normal position and motor neurones in a region of the spinal cord that normally supplies innervation to distal limb muscles. This difference between the reinnervation of proximal and distal limb muscles suggests that axons destined for proximal muscles may not enter distal limb territory during reinnervation of the regenerated limb.


Analytical model of the optical response of periodically structured metallic films.
In this paper we investigate the optical response of periodically structured metallic films constituted of sub-wavelength apertures. Our approach consists in studying the diffraction of transverse magnetic polarized electromagnetic waves by a one-dimensional grating. The method that we use is the Rigorous Coupled Waves Analysis allowing us to obtain an analytical model to calculate the diffraction efficiencies. The zero and first order terms allow determining the transmission, reflectivity and absorption of symmetric or asymmetric nanostructures surrounded either by identical or different dielectric media. For both type of nanostructures the spectral shape of the enhanced resonant transmission associated to surface plasmons displays a Fano profile. In the case of symmetric nanostructures, we study the conditions of formation of coupled surface plasmon-polaritons as well as their effect on the optical response of the modulated structure. For asymmetric nanostructures, we discuss the non-reciprocity of the reflectivity and we investigate the spectral dependency of the enhanced resonant transmission on the refractive index of the dielectric surrounding the metal film.


Prospective study of a single-incision sling versus a transobturator sling in women with stress urinary incontinence: 3-year results.
Long-term safety and efficacy data on use of single-incision slings in stress urinary incontinence are limited. To determine whether the single-incision sling Solyx (Boston Scientific, Marlborough, MA) is noninferior to the transobturator sling Obtryx II (Boston Scientific) in efficacy and safety for treatment of stress urinary incontinence. This 522 post-market surveillance study has been designed in response to a Food and Drug Administration request to evaluate improvement in stress urinary incontinence at 36 months following single-incision sling compared with baseline, as well as provide an assessment of mesh-related complications and subject-reported outcomes, relative to the transobturator sling control. This prospective, nonrandomized, parallel cohort, multicenter postapproval study enrolled subjects to receive single-incision sling or transobturator sling. Study sites were assigned to a cohort group based on documented competency with the cohort device. Patient follow-up was 36 months to compare efficacy and adverse events for noninferiority. Inclusion criteria included stress predominant urinary incontinence, a positive cough stress test, and post-void residual ≤150 cc. Participants were ineligible if they had undergone previous stress urinary incontinence surgery or had a previous mesh complication. Primary endpoint was treatment success defined by composite negative cough stress test and subjective improvement in stress urinary incontinence using Patient Global Impression of Improvement at 36 months. Secondary endpoints included adverse events and indications for retreatment. Noninferiority margins of 15% and 10% were prespecified for the primary efficacy and safety endpoints. Data analysis was performed using intent-to-treat and per-protocol methods. Due to the observational nature of the study, a propensity score methodology was applied to account for differences in patient and surgeon characteristics between treatment groups. The study design and variables to be included in the propensity score model were reviewed and approved by Food and Drug Administration reviewers before outcome analyses were performed. No evidence of imbalance in baseline characteristics was observed between groups after propensity score stratification in the 281 subjects. EBL (72.3±92 vs 73.1±63.9 mL, P=.786), time to spontaneous void (1.1±2 vs 0.8±2.8 days, P=.998), and time to discharge (0.7±0.7 vs 0.6±0.6 days, P=.524) were similar between groups. At 36 months, treatment success was 90.4% in the single-incision sling group and 88.9% in the transobturator sling group (P=.93). At 36 months, mesh-related complications were similar between groups (mesh exposure: 2.8% vs 5.0%, P=.38). Serious adverse events including pain during intercourse (0.7% vs 0%, P=1.00), pelvic pain (0.7% vs 0%, P=1.00), and urinary retention (2.8% vs 4.3%, P=.54) were similar between groups. Single-incision sling was not inferior to transobturator sling for long-term treatment success of stress urinary incontinence. The rates of serious adverse events were acceptably low and similar between groups.


A call for safer utilization of radio frequency identification in the e-health era.
The main purpose of this study was to investigate the perceptions of the electromagnetic interference (EMI) caused by radio frequency identification (RFID) with medical devices among hospitals as well as to call the attention of medical institutions to the development of RFID applications. A survey sponsored by the Department of Health of Taiwan was conducted and the target subjects were every hospital in Taiwan (486 in total). The survey topics included testing of RFID interference with medical devices and perceptions of safety issues of RFID. The main targets of the survey were the Chief Information Officers (CIOs) or the main person responsible for RFID systems in each hospital. Of the original 486 questionnaires mailed, 273 were returned. A return rate of 56.17% was obtained. The survey results revealed that only six hospitals had carried out tests on interference by RFID with medical devices, and the results of these tests indicated that RFID does not interfere with medical devices. A majority of hospitals understood that RFID may interfere with medical devices but did not think that this would seriously harm patients. The application of RFID in the healthcare industry is certainly promising; however, EMI issues must be appropriately handled. This study asserts that most hospitals do not understand or pay insufficient attention to the issue of RFID interference with patient safety or medical devices. In addition, most hospitals believe that the problem of RFID should be resolved by RFID vendors. Therefore, this study argues that medical institutions should develop more understanding of RFID issues and that more attention should be given to the potential problems of RFID interference when developing RFID applications.


Surgical Treatment and Outcome of Patients with De Novo Lung Cancer After Liver Transplantation.
De novo malignancy, including primary lung cancer, is one of the limitations to long-term survival after liver transplantation. The purpose of this study was to describe patients who developed de novo lung cancer after living-donor liver transplantation (LDLT) and investigate their clinicopathological features as well as the feasibility of surgical resection. We investigated 554 patients who underwent LDLT. De novo lung cancer after LDLT was observed in five (0.9%) out of 554 studied patients: four men and one woman, aged 61-78 years (mean=67 years). All four men had a smoking history. Clinical stages of de novo lung cancer were stage IA in three patients, and stage IB and IV in one patient each. Three out of five patients underwent pulmonary lobectomy and pathological stage was IA in two patients and IIA in one. All patients who underwent surgery stopped immunosuppressive therapy 1 day preoperatively and restarted on postoperative day 1. There were no serious postoperative complications. All three patients are still alive without any recurrence, with survival ranging from 8 to 29 months, with an average of 16.3 months after diagnosis of lung cancer. Although the study population was small, these results suggest that pulmonary lobectomy of de novo lung cancer after LDLT, even under immunosuppressive conditions, is a feasible procedure and may yield a survival benefit.


A process approach to describing mathematics difficulties in girls with Turner syndrome.
To expand on previous reports of mathematics difficulty in girls with Turner syndrome (TS). Mathematics performance was examined by evaluating the types of errors made on mathematics achievement subtests by 29 girls with TS, 26 girls with fragile X syndrome (another genetic condition associated with mathematics difficulty), and 41 girls with neither disorder. Correlations between mathematics achievement scores and measures of IQ, attention, and visuospatial skills were also examined. Relatively low mathematics achievement was evident in girls with TS before 10 years of age, and a higher percentage of girls with TS made operation (57%) and alignment (48%) errors on a mathematics calculations test than did girls with fragile X syndrome (19% and 14%, respectively). No group differences were found for procedural or multiplication table errors. Girls with TS attempted more "unfamiliar" problems than did girls with fragile X syndrome or girls in the comparison group. Mathematics achievement scores in girls with TS were positively correlated with Judgment of Line Orientation and Wechsler Intelligence Scale for Children-Revised Third Factor scores; these correlations differed from those in the other groups. The qualitative group differences observed further support the concept of specificity of the TS phenotype and illustrate the importance of a process approach to assessment.


Effects of vitamin E treatment on peroxisome proliferator-activated receptor-alpha expression and insulin resistance in patients with non-alcoholic steatohepatitis: results of a pilot study.
Insulin resistance (IR) is commonly associated with non-alcoholic steatohepatitis (NASH). Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) may also play a role in the pathogenesis of NASH. A pivotal role in NASH pathogenesis depends on the hypothesis of increased oxidative stress. The aim of our study was to evaluate the effects of supplemental oral vitamin E, a potent antioxidant, on liver functions, PPAR-alpha expression and IR in patients with NASH. Nine patients with biopsy-proven NASH were given oral vitamin E 800 mg daily for 24 weeks. Liver functions, lipid parameters, IR index with homeostatic metabolic assessment and liver histology and PPAR-alpha staining index in biopsy specimens were detected before and after the treatment. Seven patients (78%) had IR initially. After 6 months of therapy in nine patients, fasting insulin improved (P = 0.01), but serum cholesterol, triglyceride, fasting blood glucose levels and body mass index remained unchanged. Aspartate aminotransferase and alanine aminotransferase levels decreased (P = 0.01 and P = 0.01, respectively). IR index with homeostatic metabolic assessment resistance improved (P = 0.01), but PPAR-alpha staining index did not change (P = 0.37). Although the histological grade of steatosis decreased (P = 0.01), necroinflammation and fibrosis remained unchanged. In seven patients with IR, however, necroinflammation and PPAR-alpha staining index were improved (P = 0.04 and P = 0.02). Vitamin E treatment, in addition to its previously shown beneficial effect by suppressing oxidative stress, may also achieve improvement by reducing IR and PPAR-alpha expression in NASH.


Analysis of lower limb bradykinesia in Parkinson's disease patients.
Bradykinesia of the lower limb is an important limiting factor of the quality of life in parkinsonian patients. This study aims to develop quantitative measures of bradykinesia and to investigate the possible dissociation of amplitude and velocity measures and their dependence on movement direction during toe-tapping. Subjects included 39 patients with PD, as well as 14 healthy control subjects. A gyrosensor on the dorsum of a foot was used to measure ankle joint movement during toe-tapping. Four representations (root-mean square, mean peak, coefficient of variation in peaks, peak in the last 5 s) for each of amplitude and velocity and for each of plantar flexion and dorsiflexion movement of toe-tapping were investigated. Outcome measures were compared between patients and controls, and their correlations with clinical scores were investigated. Category distributions of outcome measures in patients were analyzed. All outcome measures were smaller in patients than in controls (P < 0.001) and correlated well with clinical scores (P < 0.01). The mean peak of plantar-flexion velocity and variation of dorsiflexion velocity best represented the clinical toe-tapping score (r = 0.72-0.81). All clinical scores showed better correlation with velocity than with amplitude, and velocity was more affected (dispersed from the performance of controls) than amplitude. Movement directions had a slight effect on the results; specifically, the magnitude measures better correlated during plantar flexion and the variation measure better correlated during dorsiflexion. The suggested measures represented clinical scores well and are expected to be helpful in clinical diagnosis of lower limb bradykinesia. Possible dissociations of amplitude and speed impairments and of movement directions in PD deserve further investigation.


Incidence and epidemiology of cerebral venous thrombosis.
Cerebral venous sinus thrombosis is a disorder whose epidemiology has changed over the past few decades. It is no longer regarded as a uniformly fatal disease. CVST is not a rare disorder. It may have a differential geographic distribution with a higher incidence in the Asian world. It is a disease of neonates, younger women and men, often a hypercoagulable state, either acquired (e.g., cancer) or a genetic prothrombotic condition may be present. Outcome is not uniformly dismal and prognostic criteria that detect patients with a poor outcome have become available from prospective studies. There is a paucity of well designed large scale epidemiologic studies focused on venous thrombosis from regions where it is relatively frequent (South Asia, Middle East). The newer epidemiologic data derived from a Caucasian database; suggest a better overall prognosis, younger age at distribution than arterial stroke.


Validation of the International Classification of Functioning, Disability and Health (ICF) core set for Diabetes Mellitus from nurses' perspective using the Delphi method.
To explore content validity of the ICF core set for Diabetes Mellitus from nurses' perspective. A two-round Delphi study was conducted with nurses specialized in diabetes care, who were recruited by purposive sampling. Level of agreement on relevance of ICF categories was calculated using Item-level Content Validity Index. Twenty-seven nurses judged 147 second-level ICF categories on relevance for people with Diabetes Mellitus. Agreement was reached on 65 (44.2%) categories, of which 46 were from the ICF core set for Diabetes Mellitus, 17 were from previous validation studies, and two were additional categories that were mentioned as relevant. Forty-six out of the 65 categories were derived from the component body functions and structures. No agreement was reached on 82 (55.8%) categories, of which 33 were derived from the component environmental factors. Content validity of the ICF core set for Diabetes Mellitus was partially supported by specialized nurses. Agreement was predominantly reached on biomedical categories. Content validity of categories derived from environmental factors received little support. The nursing profession should be aware of a gap between the current biomedical focus and the desired biopsychosocial approach; the latter of which is recommended in chronic care.IMPLICATIONS FOR REHABILITATIONThe International Classification of Functioning, Disability and Health (ICF) encourages a biopsychosocial approach in health care, and ICF core sets, such as the core set for Diabetes Mellitus, are useful in identifying the needs of patients.Content validity of the ICF core set for Diabetes Mellitus was partially supported by nurses specialized in diabetes care; agreement was predominantly reached on biomedical categories.The nursing profession should be aware of a potential gap between the current biomedical focus and a desired biopsychosocial approach, which is particularly recommended in chronic care.It is recommended that nurses take part in future revisions of ICF core sets; a multidisciplinary approach enables members to learn from each other's perspectives, including from those of patients.


[Synchronous tumor of the upper urinary tract with bladder cancer. Opportunity for nephroureterectomy and block-cystectomy].
One of the basic characteristics of urothelial carcinoma is its tendency to synchronous or metachronous multifocality. Thus the need to explore the entire urinary tract of patients with urothelial neoformations. The aim of this article is to study the tumors of the upper urinary tract that appear synchronously with infiltrating carcinoma of the bladder. The clinicopathological characteristics and the morbidity and mortality of en bloc surgery of both tumors are analyzed. A retrospective study was carried out on 170 radical cystectomies for infiltrating bladder tumor performed in our department over a 13-year period. Patient history, clinicopathological characteristics, complementary tests, type of surgery performed, postoperative complications and follow-up were analyzed. Tumor of the upper urinary tract appeared in 14 (1 bilateral) of these patients and were synchronous in 10 cases. All patients were male; mean age 63 years. Three were localized in the pelvis, 2 in the proximal ureter and 6 in the distal third. Diagnosis was made by IVP in 6 patients and by US and antegrade pyelography in the other 4 patients. Nephroureterectomy and radical cystectomy were performed en bloc in 8 cases; 6 had a Bricker procedure and 2 ileal substitution. Salvage radical cystectomy + distal ureterectomy were performed in the other two patients. Two patients submitted to en bloc surgery had postoperative complications; one presented prolonged ileua and the other required surgery for retroperitoneal hemorrhage. The two patients submitted to palliative surgery died of and sepsis during the postoperative period. At 33 months' mean follow-up, 3 patients have shown tumor progression. There is a high proportion of synchronous tumor of the upper urinary tract in our series of patients with infiltrating carcinoma of the bladder undergoing radical cystectomy, therefore we consider it necessary to explore the entire urinary system. Surgical removal of both tumors en bloc does not increase the morbidity and mortality.


Interaction between Filler and Polymeric Matrix in Nanocomposites: Magnetic Approach and Applications.
In recent years, polymer nanocomposites produced by combining nanofillers and a polymeric matrix are emerging as interesting materials. Polymeric composites have a wide range of applications due to the outstanding and enhanced properties that are obtained thanks to the introduction of nanoparticles. Therefore, understanding the filler-matrix relationship is an important factor in the continued growth of this scientific area and the development of new materials with desired properties and specific applications. Due to their performance in response to a magnetic field magnetic nanocomposites represent an important class of functional nanocomposites. Due to their properties, magnetic nanocomposites have found numerous applications in biomedical applications such as drug delivery, theranostics, etc. This article aims to provide an overview of the filler-polymeric matrix relationship, with a special focus on magnetic nanocomposites and their potential applications in the biomedical field.


Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS.
The inwardly rectifying K+ channel subtype Kir5.1 is only functional as a heteromeric channel with Kir4.1. In the CNS, Kir4.1 is localised to astrocytes and is the molecular basis of their strongly negative membrane potential. Oligodendrocytes are the specialised myelinating glia of the CNS and their resting membrane potential provides the driving force for ion and water transport that is essential for myelination. However, little is known about the ion channel profile of mature myelinating oligodendrocytes. Here, we identify for the first time colocalization of Kir5.1 with Kir4.1 in oligodendrocytes in white matter. Immunolocalization with membrane-bound Na+/K+-ATPase and western blot of the plasma membrane fraction of the optic nerve, a typical CNS white matter tract containing axons and the oligodendrocytes that myelinate them, demonstrates that Kir4.1 and Kir5.1 are colocalized on oligodendrocyte cell membranes. Co-immunoprecipitation provides evidence that oligodendrocytes and astrocytes express a combination of homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels. Genetic knock-out and shRNA to ablate Kir4.1 indicates plasmalemmal expression of Kir5.1 in glia is largely dependent on Kir4.1 and the plasmalemmal anchoring protein PSD-95. The results demonstrate that, in addition to astrocytes, oligodendrocytes express both homomeric Kir4.1 and heteromeric Kir4.1/Kir5.1 channels. In astrocytes, these channels are essential to their key functions of K+ uptake and CO2/H+ chemosensation. We propose Kir4.1/Kir5.1 channels have equivalent functions in oligodendrocytes, maintaining myelin integrity in the face of large ionic shifts associated with action potential propagation along myelinated axons.


Spinal Muscular Atrophy.
This article provides an overview of the pathophysiology and clinical presentations of spinal muscular atrophy (SMA) and reviews therapeutic developments, including US Food and Drug Administration (FDA)-approved gene-targeted therapies and mainstays of supportive SMA care. Over the past decades, an understanding of the role of SMN protein in the development and maintenance of the motor unit and the intricate genetics underlying SMA has led to striking developments in therapeutics with three FDA-approved treatments for SMA, one targeting SMN1 gene replacement (onasemnogene abeparvovec-xioi) and two others enhancing SMN protein production from the SMN2 gene (nusinersen and risdiplam). These therapies are most effective in infants treated at younger ages, and improvement is most striking in babies treated as neonates. Despite improvements in motor function, patients (especially those treated at older ages) continue to experience significant weakness and require continued close monitoring of respiratory and orthopedic symptoms. Striking therapeutic advancements have changed the clinical course of SMA dramatically, although supportive care continues to play an important role in patient care.


Economic impact of redundant antimicrobial therapy in US hospitals.
Overutilization of antimicrobial therapy places patients at risk for harm and contributes to antimicrobial resistance and escalating healthcare costs. Focusing on redundant or duplicate antimicrobial therapy is 1 recommended strategy to reduce overutilization and its attendant effects on patient safety and hospital costs. This study explored the incidence and economic impact of potentially redundant antimicrobial therapy. We conducted a retrospective analysis of inpatient administrative data drawn from 505 nonfederal US hospitals. All hospitalized patients discharged between January 1, 2008, and December 31, 2011, were eligible for study inclusion. Potentially redundant antimicrobial therapy was identified from pharmacy records and was defined as patients receiving treatment with overlapping antibiotic spectra for 2 or more consecutive days. We found evidence of potentially inappropriate, redundant antimicrobial coverage for 23 different antimicrobial combinations in 394 of the 505 (78%) hospitals, representing a total of 32,507 cases. High-frequency redundancies were observed in 3 antianaerobic regimens, accounting for 22,701 (70%) of the cases. Of these, metronidazole and piperacillin-tazobactam accounted for 53% (n = 17,326) of all potentially redundant cases. Days of redundant therapy totaled 148,589, representing greater than $12 million in potentially avoidable healthcare costs. Our study suggests that there may be pervasive use of redundant antimicrobial therapy within US hospitals. Appropriate use of antimicrobials may reduce the risk of harm to patients and lower healthcare costs.


Temperature-sensitive variants for saturation density and anchorage dependencey of a simian virus 40-transformed human X mouse hybrid cell line.
Several variant clones temperature sensitive for some parameters of transformation from a hybrid cell line containing a stable diploid mouse genome and two human chromosomes 7 carrying an integrated defective simian virus 40 have been isolated. Like the wild-type (wt) cells, at the permissive temperature the temperature-sensitive (ts) clones grew to high saturation densities and readily formed colonies in methyl cellulose. In contrast to the wt cells, at the nonpermissive temperature they had variable but always lower saturation densities and were unable to form colonies in methyl cellulose. The fraction of cells that synthesized DNA decreased at both temperatures when the cells reached saturation density, but it represented always at least 20% of the total population. All of the ts clones so far tested had a near triploid chromosome number, contained from one to three human chromosomes 7, and were T-antigen-positive both at the permissive and nonpermissive temperatures. The ts clones maintained low saturation density at the nonpermissive temperature because of a decrease in the number of cells that were actively proliferating and because of the shedding of cells into the medium. Temperature downshifts and refeeding allowed for expression of the permissive phenotype. In most of the isolated clones anchorage independency was not correlated with unrestricted cell proliferation. These variant clones may provide useful systems for a better understanding of the number of interdependent pathways involved in the expression of the phenotype of a transformed cell and elucidate the molecular mechanism required for the maintenance of a normal state in a cell population.


The Beneficial Effects of Curcumin on Lipids: Possible Effects on Dyslipidemia-Induced Cardiovascular Complications.
Dyslipidemia and altered lipid metabolism are closely involved in the pathogenesis and clinical manifestation of many metabolic and non-metabolic diseases. Therefore, mitigation of pharmacological and nutritional factors together with lifestyle modifications is paramount. One potential nutraceutical exhibiting cell signaling and lipid-modulating properties implicated in dyslipidemias is curcumin. Specifically, recent evidence suggest that curcumin may improve lipid metabolism and prevent dyslipidemia-induced cardiovascular complications via several pathways. Although the exact molecular mechanisms involved are not well understood, the evidence presented in this review suggests that curcumin can provide significant lipid benefits via modulation of adipogenesis and lipolysis, and prevention or reduction of lipid peroxidation and lipotoxicity via different molecular pathways. Curcumin can also improve the lipid profile and reduce dyslipidemia-dependent cardiovascular problems by impacting important mechanisms of fatty acid oxidation, lipid absorption, and cholesterol metabolism. Although only limited direct supporting evidence is available, in this review we assess the available knowledge regarding the possible nutraceutical effects of curcumin on lipid homeostasis and its possible impacts on dyslipidemic cardiovascular events from a mechanistic viewpoint.


Diffusion tensor MRI of spinal decompression sickness.
In order to develop more sensitive imaging tools for clinical use and basic research of spinal decompression sickness (DCS), we used diffusion tensor MRI (DTI) validated by histology to assess DCS-related tissue injury in sheep spinal cords. DTI is based on the measurement of water diffusion indices, including fractional anisotropy (FA) and mean diffusion (MD) to detect tissue microstructural abnormalities. In this study, we measured FA and MD in white and gray matter spinal cord regions in samples taken from sheep following hyperbaric exposure to 60-132 fsw and 0-180 minutes of oxygen pre-breathing treatment before rapid decompression. The main finding of the study was that decompression from >60 fsw resulted in reduced FA that was associated with cell death and disrupted tissue microstructure in spinal cord white matter tracts. Additionally, animals exposed to prolonged oxygen pre-breathing prior to decompression demonstrated reduced MD in spinal cord gray matter regions regardless of dive depth. To our knowledge, this is the first study to demonstrate the utility of DTI for the investigation of DCS-related injury and to define DTI biomarkers of spinal DCS.


Dock mediates Scar- and WASp-dependent actin polymerization through interaction with cell adhesion molecules in founder cells and fusion-competent myoblasts.
The formation of the larval body wall musculature of Drosophila depends on the asymmetric fusion of two myoblast types, founder cells (FCs) and fusion-competent myoblasts (FCMs). Recent studies have established an essential function of Arp2/3-based actin polymerization during myoblast fusion, formation of a dense actin focus at the site of fusion in FCMs, and a thin sheath of actin in FCs and/or growing muscles. The formation of these actin structures depends on recognition and adhesion of myoblasts that is mediated by cell surface receptors of the immunoglobulin superfamily. However, the connection of the cell surface receptors with Arp2/3-based actin polymerization is poorly understood. To date only the SH2-SH3 adaptor protein Crk has been suggested to link cell adhesion with Arp2/3-based actin polymerization in FCMs. Here, we propose that the SH2-SH3 adaptor protein Dock, like Crk, links cell adhesion with actin polymerization. We show that Dock is expressed in FCs and FCMs and colocalizes with the cell adhesion proteins Sns and Duf at cell-cell contact points. Biochemical data in this study indicate that different domains of Dock are involved in binding the cell adhesion molecules Duf, Rst, Sns and Hbs. We emphasize the importance of these interactions by quantifying the enhanced myoblast fusion defects in duf dock, sns dock and hbs dock double mutants. Additionally, we show that Dock interacts biochemically and genetically with Drosophila Scar, Vrp1 and WASp. Based on these data, we propose that Dock links cell adhesion in FCs and FCMs with either Scar- or Vrp1-WASp-dependent Arp2/3 activation.


The effect of intraoperative rectal washout on local recurrence after rectal cancer surgery: a meta-analysis.
Implantation of exfoliated cancer cells has been suggested as a possible mechanism of local recurrence at the site of colorectal anastomosis. Intraoperative rectal washout has been suggested to eliminate free cancer cells; however, there is no conclusive evidence of a beneficial effect of intraoperative rectal washout on local recurrence after anterior resection of rectal cancer. Studies published through February 2012 evaluating the impact of intraoperative rectal washout for local recurrence or positive cytology from donuts wash were identified by an electronic literature search. A meta-analysis was performed using the DerSimonian-Laird random-effects models to compute risk ratio (RR) along with 95% confidence intervals (CI). Nine studies met the inclusion criteria, yielding a total of 5,395 patients. Eight studies evaluated overall local recurrence, including anastomotic recurrence, and five of the eight studies evaluated anastomotic recurrence separately. Two studies evaluated positive cytology from donuts wash. Local recurrence rate was 5.79% in the washout group and 10.05% in the no washout group-a difference that was statistically significant (RR = 0.57; 95% CI = 0.46-0.71; P < 0.00001). Rectal washout significantly reduced the risk of anastomotic recurrence (RR = 0.3; 95% CI = 0.12-0.71; P = 0.007). No influence of rectal washout was observed on positive cytology from donuts wash. From the results of this meta-analysis, it may be justified to recommend intraoperative rectal washout to prevent local recurrence in rectal cancer surgery.


Transcription of the beta-galactoside alpha 2,6-sialyltransferase gene in B lymphocytes is directed by a separate and distinct promoter.
A single human gene, SIAT1, encodes the beta-galactoside alpha 2,6-sialyltransferase from which multiple mRNA isoforms are generated. In rat, expression of the hepatic mRNA isoform (Form 1) has been defined with respect to the transcriptional initiation site and promoter region. We show here that a similar hepatic SIAT1 mRNA isoform exists in human. Another human mRNA isoform, a mature B-cell-specific mRNA isoform (Form 2), was previously reported. Here, we used 5'-RACE and S1 nuclease protection analysis to define the 5'-untranslated region of Form 2 human SIAT1 mRNA. We demonstrate conclusively that Form 2 mRNA is initiated from a point completely distinct from that of Form 1 mRNA. A number of cis-acting regulatory elements residing immediately 5'of the Form 2 initiation site includes AP-1, AP-2, NF-kappa B, NF-IL6, C/EBP, and CREB. A TATAA box is also present 29 bp 5' of the transcriptional initiation site. CAT reporter gene expression from serially-truncated segments of the 5'-flanking region of the Form 2 initiation site indicates that the segment between -784 and +125 was sufficient to promote high level CAT expression in Louckes, a mature B-cell line. The 5'-flanking region to the human Form 1 initiation site is competent in expression of CAT upon transfection of the fusion construct into HepG2, a human hepatoma cell line. Cellular specificity of expression is apparently retained. Louckes cells expressed CAT efficiently from Form 2 promoter but only marginally from the Form 1 promoter. In contrast, CAT expression from Form 1 promoter is more efficient than from the Form 2 promoter in HepG2 cells.


Total hip arthroplasty with the Lord prosthesis. A long-term follow-up study.
The Lord prosthesis has been used rather extensively for total hip arthroplasty. In 1981, we began a prospective study for the purpose of determining the long-term results associated with the use of this prosthesis. In the present report, we describe the results for the living patients after a mean duration of follow-up of 17.5 years (range, fifteen to twenty years). One hundred and two patients (116 hips) with a mean age of sixty-two years at the time of the index arthroplasty were included in the study. Eighty-nine hips were in women, and twenty-seven were in men. The Lord femoral prosthesis (with a 32-mm head) and the Lord threaded cup were used in all patients. The protocol included radiographic analysis, recording of complications, and a clinical evaluation. The patients were evaluated at one to four years, five to nine years, and fifteen to twenty years. One patient (one hip) refused to participate and forty-two patients (forty-five hips) died with the femoral component in place, leaving fifty-nine patients (seventy hips) available for clinical assessment. One femoral component was revised because of mechanical loosening, and one was revised because of a stem fracture. One stem appeared to be loose radiographically. Kaplan-Meier survivorship analysis with revision of the femoral component because of mechanical loosening, stem fracture, or radiographic loosening as the end point revealed a cumulative survival rate of 98% (95% confidence interval, 95.3% to 100.7%) (with twenty-eight hips at risk) at 17.5 years. Seventeen acetabular components were revised because of mechanical loosening, and sixteen were considered to be radiographically loose. Kaplan-Meier survivorship analysis with revision of the acetabular component because of mechanical or radiographic loosening as the end point revealed a cumulative survival rate of 65% (95% confidence interval, 53% to 72%) (with twenty-two hips at risk) at 17.5 years. We believe that the survival rate of the Lord femoral component after 17.5 years of follow-up was excellent. However, there was a substantial rate of proximal femoral bone loss. The results associated with the threaded cup were rather poor, and many patients had a loose implant but few symptoms. We recommend that patients with these implants be followed closely so that revision can be performed before substantial destruction of the acetabulum has occurred. Therapeutic study, Level II-1 (prospective cohort study). See Instructions to Authors for a complete description of levels of evidence.


Regional biosynthetic markers in the early amphibian embryo.
A search has been made for regional differences in macromolecular synthesis in the axolotl embryo at a stage when the principal regions have become determined but terminal differentiation has not yet begun. The epidermis of the neurula makes a number of abundant proteins which are not made elsewhere. Some of these are identified by immunoprecipitation as cytokeratins (relative molecular masses (Mr) 62,59,54,51 and 46 X 10(3)). At the same stage a network of tonofilaments becomes visible by electron microscopy and is also confined to the epidermis. There is no significant incorporation of 3H-sugars into glycoproteins before neurulation. During neurulation specific species begin to be made by the notochord (Mr 265 and 185 X 10(3)), the mesoderm (315 X 10(3)) and the epidermis (170 X 10(3)). The latter species is water soluble, has a native Mr of 470 X 10(3), is somewhat resistant to trypsin and has a high sugar content. Since these characteristics do not relate to any known glycoprotein it has been given a new name: epimucin. Several neutral glycolipids and gangliosides are present in the early embryo, the most abundant of which is identified as galactocerebroside. Synthesis occurs from fertilization onwards, however even by the neurula stage the qualitative pattern is the same in all parts except for the epidermis which shows two substantial enhancements and one reduction compared to other regions. The differences reported probably relate to physiological functions rather than to the mechanism of determination itself, so their chief importance is as markers of early embryo regions in experiments on induction.


Reoperative Aortic Valve Replacement for Structural Valve Deterioration through a Lower Hemisternotomy after a Previous Bentall Procedure in a Patient with Tracheostomy.
Patients with tracheostomy who undergo a full sternotomy have an increased risk of mediastinitis and sternal infection. This report describes a reoperative aortic valve replacement (re-AVR) for structural valve deterioration (SVD) through a lower hemisternotomy. This procedure was performed on a 71-year-old man with a tracheostomy who had previously undergone a Bentall procedure with a bioprosthetic valve to replace an enlarged ascending aortic aneurysm. Comorbidities included chronic renal failure requiring hemodialysis. Fourteen months after the Bentall procedure, the patient presented with sudden dyspnea and was transferred to another hospital. Upon suffering acute heart failure, the patient required mechanical ventilation and was transferred to our hospital for intubation. The patient subsequently developed severe pneumonia. As a result of prolonged ventilation, the patient underwent tracheostomy and was administered antibiotic medication (piperacillin/tazobactam) for pneumonia. Echocardiography revealed severe aortic regurgitation caused by SVD. There was a risk that a full sternotomy in a patient with tracheostomy could cause mediastinitis; therefore, we performed a re-AVR through a lower hemisternotomy (second T incision). The re-AVR surgery proceeded without complications, and the bioprosthetic valve was removed while preserving the vascular graft from the previous Bentall procedure. The postoperative course was uneventful, and the patient was discharged from hospital 31 days after the tracheostomy was closed. The success of this procedure demonstrates the viability of re-AVR through a lower hemisternotomy in patients with SVD who are at risk of additional surgical complications.


Twin and dislocation mechanisms in tensile W single crystal with temperature change: a molecular dynamics study.
Molecular dynamics simulations are performed to investigate the orientation and temperature dependence of tensile response in single crystal W. It is found that W single crystal exhibits distinct temperature-dependent deformation behaviors along different orientations. With increasing temperature, the yield strain in the [001] orientation increases, while those in [110] and [111] orientations first increase and then decrease. The tensile deformations along orientations close to [001] are found to be dominated by twinning; the nucleation and growth of twins are accomplished through the nucleation and glide of ⅙111 partial dislocations on {112} planes. In contrast, the deformations along orientations close to [110] and [111] are found to be dominated by the slip of ½111 full dislocations, which move in a stay-and-go fashion. Moreover, intermediate deformation behaviors, which may become unstable at high temperatures, are observed for some intervening orientations. The distinct deformation behaviors of W along different orientations are rationalized based on the twinning-antitwinning asymmetry of ⅙111 partial dislocations on {112} planes.


A feasibility study comparing a web-based intervention to a workshop intervention for caregivers of adults with eating disorders.
To assess for the validity of a future trial, the current feasibility study aimed to compare the feasibility and efficacy of a web- and workshop-based education intervention for caregivers of adults with eating disorders. Psychoeducation was provided to caregivers, who were randomly assigned to a web or workshop condition. Independent samples t tests were conducted to analyse the between-group effect sizes for intervention condition with regard to change over time. A random selection of participants from each intervention provided qualitative feedback about their experiences. Overall, participants reported positive experiences in both education interventions. From baseline to the end of intervention, small between-group effect sizes were observed for changes in caregiver accommodation, problem-solving abilities, the quality of psychological health, and the quality of social relationships, favouring the web-based intervention, and changes in expressed emotion in the family context, caregiver burden, perceived stress, and the quality of the environment, supporting the workshop intervention. There was a difference in initial feasibility of the web intervention. A future large-scale trial of these interventions is supported by the results of this feasibility study.


What are we assessing when we measure food security? A compendium and review of current metrics.
The appropriate measurement of food security is critical for targeting food and economic aid; supporting early famine warning and global monitoring systems; evaluating nutrition, health, and development programs; and informing government policy across many sectors. This important work is complicated by the multiple approaches and tools for assessing food security. In response, we have prepared a compendium and review of food security assessment tools in which we review issues of terminology, measurement, and validation. We begin by describing the evolving definition of food security and use this discussion to frame a review of the current landscape of measurement tools available for assessing food security. We critically assess the purpose/s of these tools, the domains of food security assessed by each, the conceptualizations of food security that underpin each metric, as well as the approaches that have been used to validate these metrics. Specifically, we describe measurement tools that 1) provide national-level estimates of food security, 2) inform global monitoring and early warning systems, 3) assess household food access and acquisition, and 4) measure food consumption and utilization. After describing a number of outstanding measurement challenges that might be addressed in future research, we conclude by offering suggestions to guide the selection of appropriate food security metrics.


Preparedness of outpatient health facilities for ambulatory treatment with all-oral short DR-TB treatment regimens in Zhytomyr, Ukraine: a cross-sectional study.
Ukraine has a high burden of drug-resistant tuberculosis (DR-TB). Mental health problems, including alcohol use disorder, are common co-morbidities. One in five DR-TB patients has human immunodeficiency virus (HIV). As part of health reform, the country is moving from inpatient care to ambulatory primary care for tuberculosis (TB). In Zhytomyr oblast, Médecins Sans Frontières (MSF) is supporting care for DR-TB patients on all-oral short DR-TB regimens. This study describes the preparedness of ambulatory care facilities in Zhytomyr oblast, Ukraine, to provide good quality ambulatory care. This is a retrospective analysis of routinely collected programme data. Before discharge of every patient from the hospital, MSF teams assess services available at outpatient facilities using a standardised questionnaire. The assessment evaluates access, human resources, availability of medicines, infection control measures, laboratory and diagnostic services, and psychosocial support. We visited 68 outpatient facilities in 22 districts between June 2018 and September 2019. Twenty-seven health posts, 24 TB-units, 13 ambulatories, two family doctors and one polyclinic, serving 30% of DR-TB patients in the oblast by September 2019, were included. All facilities provided directly observed treatment, but only seven (10%) provided weekend-services. All facilities had at least one medical staff member, but TB-training was insufficient and mostly limited to TB-doctors. TB-treatment and adequate storage space were available in all facilities, but only five (8%) had ancillary medicines. HIV-positive patients had to visit a separate facility to access HIV-care. Personal protective equipment was unavailable in 32 (55%) facilities. Basic laboratory services were available in TB-units, but only four (17%) performed audiometry. Only ten (42%) TB-units had psychosocial support available, and nine (38%) offered psychiatric support. Outpatient facilities in Zhytomyr oblast are not yet prepared to provide comprehensive care for DR-TB patients. Capacity of all facilities needs strengthening with trainings, infection control measures and infrastructure. Integration of psychosocial services, treatment of co-morbidities and adverse events at the same facility are essential for successful decentralisation. The health reform is an opportunity to establish quality, patient-centred care.


Ba2+ unmasks K+ modulation of the Na+-K+ pump in the frog retinal pigment epithelium.
This paper presents electrophysiological evidence that small changes in [K+]o modulate the activity of the Na+-K+ pump on the apical membrane of the frog retinal pigment epithelium (RPE). This membrane also has a large relative K+ conductance so that lowering [K+]o hyperpolarizes it and therefore increases the transepithelial potential (TEP). Ba2+, a K+ channel blocker, eliminated these normal K+-evoked responses; in their place, lowering [K+]o evoked an apical depolarization and TEP decrease that were blocked by apical ouabain or strophanthidin. These data indicate that Ba2+ blocked the major K+ conductance(s) of the RPE apical membrane and unmasked a slowing of the normally hyperpolarizing electrogenic Na+-K+ pump caused by lowering [K+]o. Evidence is also presented that [K+]o modulates the pump in the isolated RPE under physiological conditions (i.e., without Ba2+). In the intact retina, light decreases subretinal [K+]o and produces the vitreal-positive c-wave of the electroretinogram (ERG) that originates primarily in the RPE from a hyperpolarization of the apical membrane and TEP increase. When Ba2+ was present in the retinal perfusate, the apical membrane depolarized in response to light and the TEP decreased so that the ERG c-wave inverted. The retinal component of the c-wave, slow PIII, was abolished by Ba2+. The effects of Ba2+ were completely reversible. We conclude that Ba2+ unmasks a slowing of the RPE Na+-K+ pump by the light-evoked decrease in [K+]o. Such a response would reduce the amplitude of the normal ERG c-wave.


Evaluation of a Prediction Model for the Development of Atrial Fibrillation in a Repository of Electronic Medical Records.
Atrial fibrillation (AF) contributes to substantial morbidity, mortality, and health care expenditures. Accurate prediction of incident AF would enhance AF management and potentially improve patient outcomes. To validate the AF risk prediction model originally developed by the Cohorts for Heart and Aging Research in Genomic Epidemiology-Atrial Fibrillation (CHARGE-AF) investigators using a large repository of electronic medical records (EMRs). In this prediction model study, deidentified EMRs of 33 494 individuals 40 years or older who were white or African American and had no history of AF were reviewed and analyzed. The participants were followed up in the internal medicine outpatient clinics at Vanderbilt University Medical Center for incident AF from December 31, 2005, until December 31, 2010. Adjusting for differences in baseline hazard, the CHARGE-AF Cox proportional hazards model regression coefficients were applied to the EMR cohort. A simple version of the model with no echocardiographic variables was also evaluated. Data were analyzed from October 31, 2013, to January 31, 2014. Incident AF. Predictors in the model included age, race, height, weight, systolic and diastolic blood pressure, treatment for hypertension, smoking status, type 2 diabetes, heart failure, history of myocardial infarction, left ventricular hypertrophy, and PR interval. Among the 33 494 participants, the median age was 57 (interquartile range, 49-67) years; 57% of patients were women, 43% were men, 85.7% were white, and 14.3% were African American. During the mean (SD) follow-up of 4.8 (0.9) years, 2455 individuals (7.3%) developed AF. Both models had poor calibration in the EMR cohort, with underprediction of AF among low-risk individuals and overprediction of AF among high-risk individuals (10th and 90th percentiles for predicted probability of incident AF, 0.005 and 0.179, respectively). The full CHARGE-AF model had a C index of 0.708 (95% CI, 0.699-0.718) in our cohort. The simple model had similar discrimination (C index, 0.709; 95% CI, 0.699-0.718; P = .70 for difference between models). Despite reasonable discrimination, the CHARGE-AF models showed poor calibration in this EMR cohort. This study highlights the difficulties of applying a risk model derived from prospective cohort studies to an EMR cohort and suggests that these AF risk prediction models be used with caution in the EMR setting. Future risk models may need to be developed and validated within EMR cohorts.


[Immobilization of the human plasmin light chain and analysis of its complexes with streptokinase].
The heavy and light chains of human plasmin were separated by affinity 1-lysin-cellulose column chromatography. The S-carboxymethyl light chain derivative of human plasmin was imobilized by aminogroups by the insoluble matrices. Insoluble derivatives cf plasmin light chain retain an insignificant proteolytic activity, human plasminogen activator activity and capacity to form complexes with streptokinase. The activator activity of the immobilized light chain-streptokinase complex increases 5-10-fold with respect to the human plasminogen. When adding the light chain preparation to immobilized streptokinase its activator activity relative to the human plasminogen is twice as high. The both complexes: immobilized light chain-streptokinase and light chain-immobilized streptokinase are stable and may be reused for plasminogen activation.


Layer-by-layer nano-encapsulation of microbes: controlled cell surface modification and investigation of substrate uptake in bacteria.
LbL nano self-assembly coating of A. vinosum with different polyelectrolyte combinations is presented as an example to investigate substrate uptake in bacteria. The effects of surface charge and the formation of a physical barrier provides new insights in the contact mechanisms between the cell surface and insoluble elemental sulfur. Furthermore, uptake of sulfide by encapsulated cells was investigated. Growth experiments of coated cells showed that surface charge did neither affect sulfide uptake nor the contact formation between the cells and solid sulfur. However, increasing layers slowed or inhibited the uptake of sulfide and elemental sulfur. This work demonstrates how defining surface properties of bacteria has potential for microbiological and biotechnological applications.