Role of Amylin in Type 1 and Type 2 Diabetes.
The pathophysiology of diabetes has historically focused on alterations in insulin secretion and function; however, diabetes involves multiple hormonal alterations, including abnormal regulation of amylin. This review discusses the physiologic functions of amylin in glucose homeostasis and the rationale for amylin replacement in type 1 and 2 diabetes. The use of pramlintide, a synthetic amylin analog, is also discussed. Amylin, formed primarily in pancreatic islet β cells, is cosecreted with insulin in response to caloric intake. Patients with type 1 diabetes have lower baseline amylin serum concentrations, and amylin response to caloric intake is absent. Patients with type 2 diabetes requiring insulin also have a diminished amylin response to caloric intake, potentially related to the degree of β-cell impairment. Key physiologic functions of amylin in maintaining glucose homeostasis include suppressing glucagon release in response to caloric intake, delaying the rate of gastric emptying, and stimulating the satiety center in the brain to limit caloric intake. Pramlintide is indicated for adults with type 1 and 2 diabetes who have not achieved adequate glucose control despite optimal insulin therapy. As an adjunct to insulin therapy, pramlintide demonstrated significant reductions in A1C in patients with type 1 and 2 diabetes, with favorable effects on body weight. It is administered subcutaneously before each major meal. There is an increased risk of hypoglycemia with insulin when used in combination with pramlintide. Other adverse effects may include nausea, vomiting, anorexia, reduced appetite, and headache. Proper patient selection and education are essential to successful pramlintide use.


Carotid sinus syndrome. Report of five cases and review of the literature.
Five cases of carotid sinus syndrome are presented. The syndrome is defined by spontaneous attacks of dizziness and fainting which can be reproduced by graded pressure on one carotid sinus. Three forms of the clinical syndrome, cardioinhibitory, vasodepressor, and cerebral, are discussed. The hyperactive carotid sinsu reflex, in which there is ventricular asystole lasting at least 3 seconds or a decrease of more than 50 mm Hg in systolic and diastolic blood pressure, should be differentiated from this syndrome. Treatment modalities include reassurance, drugs, radiotherapy, cardiac pacemakers, and surgical approaches. Carotid sinus syndrome should be considered in the differential diagnosis of unexplained syncope, arteriovenous block, or inappropriate sinus bradycardia.


Comparison of Insulin Dose Adjustments by Primary Care Physicians and Endocrinologists.
IN BRIEF Insulin dose adjustment decisions in 20 simulated patients by nine primary care physicians (PCPs) and nine endocrinologists were compared to the algorithms used in a diabetes program in a large safety-net clinic. The number of dose changes was similar in the PCP and endocrinologist groups; however, the amounts of the dose changes in the PCP group were significantly closer to the diabetes program algorithms than the amounts in the endocrinologist group. Time constraints, rather than lack of ability, seem to be the major barrier to PCPs treating patients with insulin.


Macroscopic and histological changes of the ileum HLA-B27 related diseases: therapeutic consequences.
Ileocolonoscopy and microscopic examination of ileum biopsies have been performed on patients with reactive synovitis, ankylosing spondylitis (AS) and on a control group. Histological signs of gut inflammation were present in practically all patients with reactive synovitis, with the exception of the patients with sexually-acquired disease. In the AS group, inflammation of the ileum was observed in the HLA-B27 negative patients and in AS B27 positive patients with peripheral joint involvement. Occasionally, changes of the ileum were seen in the B27 positive AS patients without peripheral joint involvement. Signs of gut inflammation were absent in all controls. These data suggest that chronic inflammation of the ileum could be implicated in the pathogenesis of some cases of reactive synovitis and even in the peripheral joint involvement frequently seen in ankylosing spondylitis. In the second part of the study, sulfasalazine (Salazopyrin) was administered to 15 HLA-B27 positive patients with reactive synovitis, who had failed to respond to non-steroidal anti-inflammatory drugs. In 11 of the 15 patients, a clinical and biological remission occurred 3 to 11 months after the start of sulfasalazine treatment. The frequency of spontaneous remissions in reactive synovitis calls for confirmation of these encouraging results in double-blind controlled studies.


Aphaenogaster gamagumayaa sp. nov.: the first troglobiotic ant from Japan (Hymenoptera: Formicidae: Myrmicinae).
Aphaenogaster gamagumayaa sp. nov., a new troglobiotic (true cave-dwelling) ant species, from a limestone cave on the island of Okinawa (Okinawa-jima), Ryukyu Archipelago, Japan is described. This is the first discovery of a troglobiotic ant in Japan and the second verified record worldwide. This species has only been found in a cave area with heavy guano deposits, and some worker ants were observed carrying guano. The evidence for categorizing this new species as troglobiont is discussed.


Fractal analysis of the structural complexity of the connective tissue in human carotid bodies.
The carotid body (CB) may undergo different structural changes during perinatal development, aging, or in response to environmental stimuli. In the previous literature, morphometric approaches to evaluate these changes have considered quantitative first order parameters, such as volumes or densities, while changes in spatial disposition and/or complexity of structural components have not yet been considered. In the present study, different strategies for addressing morphological complexity of CB, apart from the overall amount of each tissue component, were evaluated and compared. In particular, we considered the spatial distribution of connective tissue in the carotid bodies of young control subjects, young opiate-related deaths and aged subjects, through analysis of dispersion (Morisita's index), gray level co-occurrence matrix (entropy, angular second moment, variance, correlation), and fractal analysis (fractal dimension, lacunarity). Opiate-related deaths and aged subjects showed a comparable increase in connective tissue with respect to young controls. However, the Morisita's index (p < 0.05), angular second moment (p < 0.05), fractal dimension (p < 0.01), and lacunarity (p < 0.01) permitted to identify significant differences in the disposition of the connective tissue between these two series. A receiver operating characteristic (ROC) curve was also calculated to evaluate the efficiency of each parameter. The fractal dimension and lacunarity, with areas under the ROC curve of 0.9651 (excellent accuracy) and 0.8835 (good accuracy), respectively, showed the highest discriminatory power. They evidenced higher level of structural complexity in the carotid bodies of opiate-related deaths than old controls, due to more complex branching of intralobular connective tissue. Further analyses will have to consider the suitability of these approaches to address other morphological features of the CB, such as different cell populations, vascularization, and innervation.


Preclinical efficacy of sepantronium bromide (YM155) in multiple myeloma is conferred by down regulation of Mcl-1.
The inhibitor-of-apoptosis family member survivin has been reported to inhibit apoptosis and regulate mitosis and cytokinesis. In multiple myeloma, survivin has been described to be involved in downstream sequelae of various therapeutic agents. We assessed 1093 samples from previously untreated patients, including two independent cohorts of 392 and 701 patients, respectively. Survivin expression was associated with cell proliferation, adverse prognostic markers, and inferior event-free and overall survival, supporting the evaluation of survivin as a therapeutic target in myeloma. The small molecule suppressant of survivin--YM155--is in clinical development for the treatment of solid tumors. YM155 potently inhibited proliferation and induced apoptosis in primary myeloma cells and cell lines. Gene expression and protein profiling revealed the critical roles of IL6/STAT3-signaling and the unfolded protein response in the efficacy of YM155. Both pathways converged to down regulate anti-apoptotic Mcl-1 in myeloma cells. Conversely, growth inhibition and apoptotic cell death by YM155 was rescued by ectopic expression of Mcl-1 but not survivin, identifying Mcl-1 as the pivotal downstream target of YM155 in multiple myeloma. Mcl-1 expression was likewise associated with adverse prognostic markers, and inferior survival. Our results strongly support the clinical evaluation of YM155 in patients with multiple myeloma.


[Primary hyperreninemia. An unusual cause of secondary arterial hypertension].
In 1975, scintigraphy revealed a 6.5 x 5 cm tumour in the region of the left adrenal in a 36-year-old man with known hypertension for 5 years (systolic pressure up to 250 mm Hg, diastolic up to 130 mm Hg). A laparotomy was performed for a suspected phaeochromocytoma. A tumour was located in the upper pole of the kidney and removed together with the kidney. The blood pressure quickly returned to normal after the operation: it remained stable for the following 17 years (between 130/80 to 150/90 mm Hg). Originally the tumour could not be clearly classified either clinically or histologically. But recently the paraffin-imbedded tumour specimen was re-examined by immunohistochemistry and in-situ hybridization. This identified a renin-producing tumour so that primary reninism was the cause of the arterial hypertension.


Posttransplant cyclophosphamide versus antithymocyte globulin in patients with acute lymphoblastic leukemia treated with allogeneic hematopoietic cell transplantation from matched unrelated donors: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
The aim of this study was to compare two immunosuppressive strategies, based on the use of either rabbit antithymocyte globulin (ATG) or posttransplant cyclophosphamide (PTCY), as a prophylaxis of graft-versus-host disease (GVHD) for patients with acute lymphoblastic leukemia (ALL) in first complete remission who underwent hematopoietic cells transplantation from matched unrelated donors. Overall, 117 and 779 adult patients who received PTCY and ATG, respectively, between the years 2015 and 2020 were included in this retrospective study. The median patient age was 40 and 43 years in the PTCY and ATG groups, respectively, and 37% and 35% of patients, respectively, had Philadelphia chromosome-positive ALL. In univariate analysis, the cumulative incidence of acute and chronic GVHD did not differ significantly between the study groups. The cumulative incidence of relapse at 2 years was reduced in the PTCY group (18% vs. 25%; p = .046) without a significant impact on nonrelapse mortality (11% vs. 16% in the ATG group; p = .29). The rates of leukemia-free survival (LFS) and overall survival were 71% versus 59%, respectively (p = .01), and 82% versus 74%, respectively (p = .08). In multivariate analysis, the receipt of ATG compared with PTCY was associated with a reduced risk of extensive chronic GVHD (hazard ratio, 0.54; 95% confidence interval, 0.3-0.98; p = .04) and an increased risk of low LFS (hazard ratio, 1.57; 95% confidence interval, 1.01-2.45; p = .045). The receipt of ATG compared with PTCY, despite the reduced risk of extensive chronic GVHD, is associated with inferior LFS in adults with ALL who undergo hematopoietic cell transplantation from 10/10 human leukocyte antigen-matched unrelated donors. These findings warrant verification in prospective trials.


Esophageal varices: treatment and implications.
The purpose of this article is to present an overview of esophageal varices. The causes of esophageal varices and the current treatments are examined. Information is provided regarding surgical and nonsurgical forms of treatment. Various aspects of nursing care are discussed, including the implications involved in the emergency setting, psychological needs, and education for patients and their families.


Morphologic, immunophenotypic, molecular genetic, and clinical characterization in patients with SRSF2-mutated acute myeloid leukemia.
SRSF2 mutations are known to be associated with poor outcomes in myelodysplastic neoplasm, but studies on their prognostic impact on acute myeloid leukemia (AML) remain limited. In this retrospective study, we analyzed clinical and pathologic characteristics of patients with AML and correlated the outcomes with SRSF2 mutations. We characterized the morphologic, immunophenotypic, molecular, and clinical findings in AML with mutated SRSF2 and compared them with SRSF2 wild-type (WT) myeloid neoplasms (MNs). Using next-generation sequencing, we identified 134 patients with MNs and SRSF2 mutations (85 with AML and 49 with MNs) in addition to 342 SRSF2-WT AMLs. Fifty-two (62%) patients with altered SRSF2 demonstrated a variable degree of morphologic dysplasia. The most frequent immunophenotypic aberrancies in SRSF2-mutant AML included diminished CD33 expression and overexpression of CD7, CD56, or CD123, similar to WT AML. More IDH1/2 (P = .015) and NPM1 (P = .002) mutations were seen in SRSF2-mutant AML than in SRSF2-mutant non-AML. Further, more IDH1/2, ASXL1, RUNX1, and STAG2 mutations were observed in SRSF2-mutant AML than in SRSF2-WT AML (P < .0001 to P = .001). Finally, patients with SRSF2-mutant AML showed a significantly worse overall survival (OS) than patients with SRSF2-WT AML (P < .0001), but this worse OS appeared to be rescued by allogeneic stem cell transplant (allo-SCT). Acute myeloid leukemia with altered SRSF2 shows a variable degree of morphologic dysplasia without uniform immunophenotypic aberrancies. SRSF2 mutations appear to be independent poor prognostic factors, but allo-SCT has improved the clinical outcomes in patients with SRSF2-mutant AML.


Reports of the decline of empathy during medical education are greatly exaggerated: a reexamination of the research.
Research is said to show that empathy declines during medical school and residency training. These studies and their results were examined to determine the extent of the decline and the plausibility of any alternative explanations. Eleven studies published from 2000 to 2008 which reported empathy at various stages of physician training were reexamined. Their results were transformed back to the original units of the rating scales to make results more interpretable by reporting them in the metric of the original anchors. Next, the relationship between empathy ratings and response rates were examined to see whether response bias was a plausible threat to the validity of the empathy decline conclusion. The changes in mean empathy ranged across the 11 studies from a 0.1-point increase in empathy to a 0.5-point decrease, with an average of a 0.2-point decline for the 11 studies (ratings were on 5-point, 7-point, and 9-point scales). Mean ratings were similar in medical school and residency. Response rates were low and-where reported-declined on average about 26 percentage points. Reexamination revealed that the evidence does not warrant the strong, disturbing conclusion that empathy declines during medical education. Results show a very weak decline in mean ratings, and even the weak decline is questionable because of the low and varying response rates. Moreover, the empathy instruments are self-reports, and it isn't clear what they measure-or whether what they measure is indicative of patients' perceptions and the effectiveness of patient care.


Amino acid derivatives from the marine sponge Jaspis digonoxea.
Six heterocycles, bengamide A [1], bengamide B [2], cyclo(L-trans-(4-hydroxyprolinyl)-L-phenylalanine) [4], the functionalized nonene lactone 5, the novel digonazole [6] and cyclo(L-prolinyl-L-tyrosine) [7], previously unreported from marine origin have been isolated from the South African sponge Jaspis digonoxea. The structures of the known compounds and the new digonazole [6] were elucidated primarily by nmr spectroscopy.


Gnathostome phylogenomics utilizing lungfish EST sequences.
The relationship between the Chondrichthyes (cartilaginous fishes), the Actinopterygii (ray-finned fishes), and the piscine Sarcopterygii (lobe-finned fishes) and how the Tetrapoda (four-limbed terrestrial vertebrates) are related to these has been a contentious issue for more than a century. A general consensus about the relationship of these vertebrate clades has gradually emerged among morphologists, but no molecular study has yet provided conclusive evidence for any specific hypothesis. In order to examine these relationships on the basis of more extensive sequence data, we have produced almost 1,000,000 bp of expressed sequence tags (ESTs) from the African marbled lungfish, Protopterus aethiopicus. This new data set yielded 771 transcribed nuclear sequences that had not been previously described. The lungfish EST sequences were combined with EST data from two cartilaginous fishes and whole genome data from an agnathan, four ray-finned fishes, and four tetrapods. Phylogenomic analysis of these data yielded, for the first time, significant maximum likelihood support for a traditional gnathostome tree with a split between the Chondrichthyes and remaining (bone) gnathostomes. Also, the sister group relationship between Dipnoi (lungfishes) and Tetrapoda received conclusive support. Previously proposed hypotheses, such as the monophyly of fishes, could be rejected significantly. The divergence time between lungfishes and tetrapods was estimated to 382-388 Ma by the current data set and six calibration points.


Subcutaneous dermatofibroma.
Dermatofibroma (DF) is usually confined to the dermis and the overlying epidermis is usually hyperplastic. Although DF with deep subcutaneous extension is commonly encountered, purely subcutaneous DF is uncommon. In this review, we describe a case of a 41-year-old male patient who presented with a painless, subcutaneous, hard papule on the left thigh. After the skin had been incised the lesion was totally removed, and histopathology revealed a subcutaneous dermatofibroma.


Endoscopic Ultrasound Staging of Upper Gastrointestinal Malignancies.
Since 1980, endoscopic ultrasound (EUS) has been used as an important tool for the evaluation of malignant diseases in hollow viscus and bilio-pancreas, as well as sub-epithelial tumors. The high-resolution capacity and low penetration depth of EUS make it possible to obtain highly detailed images of the gastrointestinal wall and immediate surroundings to a depth of 4-5 cm. Thus, over the past 35 years, EUS succeeded to modify management in significant number of cases and is now considered a gold standard tool for many gastrointestinal diseases, especially in the pancreatico-biliary tract, and adjuvant needle insertion now allows access to remote lesions that were difficult to reach in the past. With the growing spectrum of indications, tissue sampling for diagnostic purposes has become common. In this review, we aim to highlight the expanding spectrum of EUS indications and uses in staging of upper gastrointestinal malignancies, especially esophageal, gastric and ampullary tumors.


Tracking development assistance and government health expenditures for 35 malaria-eliminating countries: 1990-2017.
Donor financing for malaria has declined since 2010 and this trend is projected to continue for the foreseeable future. These reductions have a significant impact on lower burden countries actively pursuing elimination, which are usually a lesser priority for donors. While domestic spending on malaria has been growing, it varies substantially in speed and magnitude across countries. A clear understanding of spending patterns and trends in donor and domestic financing is needed to uncover critical investment gaps and opportunities. Building on the Institute for Health Metrics and Evaluation's annual Financing Global Health research, data were collected from organizations that channel development assistance for health to the 35 countries actively pursuing malaria elimination. Where possible, development assistance for health (DAH) was categorized by spend on malaria intervention. A diverse set of data points were used to estimate government health budgets expenditure on malaria, including World Malaria Reports and government reports when available. Projections were done using regression analyses taking recipient country averages and earmarked funding into account. Since 2010, DAH for malaria has been declining for the 35 countries actively pursuing malaria elimination (from $176 million in 2010 to $62 million in 2013). The Global Fund is the largest external financier for malaria, providing 96% of the total external funding for malaria in 2013, with vector control interventions being the highest cost driver in all regions. Government expenditure on malaria, while increasing, has not kept pace with diminishing DAH or rising national GDP rates, leading to a potential gap in service delivery needed to attain elimination. Despite past gains, total financing available for malaria in elimination settings is declining. Health financing trends suggest that substantive policy interventions will be needed to ensure that malaria elimination is adequately financed and that available financing is effectively targeted to interventions that provide the best value for money.


Sclerosing encapsulating peritonitis in a liver transplant patient: a case report.
We report a patient with HBV-related hepatocellular carcinoma (HCC) and refractory ascites who had received a peritoneal-venous shunt (PVS) 1 year before liver transplantation. Urgent surgical intervention following bowel obstruction and failure of immunosuppression therapy. No intestinal obstruction was found during an initial PVS. However, intestinal obstruction developed 2 wk after liver transplantation; and a cocoon abdomen was found upon exploration. This is the first reported case of cocoon abdomen caused by PVS and exacerbated by liver transplantation.


Effect of antithymocyte globulin on histocompatibility antigen recognition in man.
Nonmajor histocompatibility complex (non-MHC) antigens are important targets of graft rejection and graft-versus-host disease in clinical transplantation. Little is known regarding immunity to non-MHC antigens. To study this problem we evaluated the effect of antihuman thymocyte globulin (ATG) on reactivity in autologous and allogeneic mixed lymphocyte cultures and activity in a model of immunity to non-MHC antigens, the response to trinitrophenyl (TNP)-modified autologous cells. Primary proliferative responses to autologous B lymphocytes, allogeneic cells, and TNP-modified autologous cells were all inhibited by ATG treatment. Secondary proliferative responses and cytotoxicity to TNP-modified autologous cells were also inhibited as was cross-reactive cytotoxicity to TNP-modified allogeneic cells. These data indicate that both MHC-restricted and MHC-nonrestricted immune responses to modified self-antigens and possibly to non-MHC antigens are sensitive to ATG treatment. ATG may be useful in clinical situations where the objective of immunosuppression is to inhibit immunity to non-MHC antigens such as after HLA-matched kidney grafting or bone marrow transplantation.


Unconfirmed penicillin allergy labels in the paediatric outpatient setting: A call for research and quality improvement initiatives.
Over the last 10 years, the electronic medical record has redefined medical documentation, and physicians rely on accurate records to make clinical decisions. Penicillin allergy labels (PALs) are important pieces of the medical history that guide physicians in selecting specific antibiotic classes for the treatment of infectious diseases. However, most children labelled as penicillin-allergic do not have an IgE-mediated (immediate) allergic reaction to penicillin or its derivatives. In the absence of confirmatory penicillin allergy testing or additional history, these children receive alternative, often broad-spectrum and second-line, antibiotics. Addressing unconfirmed PALs requires an understanding of how and why labels get added to the electronic medical record. This viewpoint highlights the knowledge gaps in paediatric outpatient penicillin allergy labelling and proposes an acronym ('LABEL') that primary care providers and antimicrobial stewards can utilise when designing initiatives to address unconfirmed PALs in the community.


Adrenal response to corticotropin during therapy with itraconazole.
Itraconazole is a triazole with a mechanism of action similar to that of ketoconazole. Endocrine side effects of ketoconazole, including impaired cortisol synthesis, have been well documented (A. Pont, J. R. Graybill, P. C. Craven, J. N. Galgiani, W. E. Dismukes, R. E. Reitz, and D. A. Stevens, Arch. Intern. Med. 144:2150-2153, 1984). We examined the adrenal response to corticotropin in 10 patients being treated with itraconazole. No impairment of cortisol synthesis could be demonstrated.


Formation of CdS nanoparticle necklaces with functionalized dendronized polymers.
A one-dimensional assembly of cadmium sulfide (CdS) nanoparticles was prepared by using functionalized polymers with pendant Fréchet-type dendritic wedges of different generation. The novel dendronized polymers acted as both nanoreactors for the formation of CdS nanoparticles and a template to arrange the nanoparticles into a necklace. The polymers of different dendron generation were applied to stabilize CdS particles and the effect of dendron size was observed. CdS nanoparticle necklaces were obtained successfully when polymers bearing second-generation dendrons were applied.


Contralaterally controlled functional electrical stimulation immediately improves hand function.
Murata S, Koike Y, Kasukawa Y, Saito K, Okada K, Kudo D, Shimada Y, Miyakoshi N. Contralaterally controlled functional electrical stimulation immediately improves hand function. Jpn J Compr Rehabil Sci 2022; 13: 26-30. The purpose of this study was to investigate the immediate effects of contralaterally controlled functional electrical stimulation (CCFES) on upper limb function in stroke patients. CCFES and mirror therapy (MT) exercises were conducted for 13 stroke patients at least 4 weeks post-onset. A sufficient interval of at least 24 hours was left between the two types of rehabilitation exercises. Before treatment and immediately after each training session, grip strength, Fugl-Meyer Assessment for Upper Extremity (FMA-UE) score and FMA-UE subscores for the shoulder/elbow/forearm, wrist, hand, and coordination were evaluated. Grip strength, FMA-UE and FMA-UE shoulder/elbow/forearm, wrist, and coordination did not differ significantly after CCFES and MT compared to before therapy. FMA-UE hand did not change significantly after MT compared to before therapy, but it improved significantly after CCFES (p = 0.013). CCFES for the upper extremities immediately improves hand function and may be effective in maintaining and improving patients' motivation for rehabilitation treatment.


Randomized double-blinded pilot clinical study of the antidiabetic activity of Balanites aegyptiaca and UPLC-ESI-MS/MS identification of its metabolites.
Balanites aegyptiaca Del. (Zygophyllaceae) fruits are traditionally known for the treatment of hyperglycaemia. Several in vitro and in vivo studies proposed some mechanisms of action. However, clinical trials in human beings were never reported to date. To investigate the antidiabetic efficacy of the 70% ethanol extract of the pericarps of B. aegyptiaca (BE) within a nutritional intervention in elderly people. Ultra-performance electrospray ionization-mass spectroscopy (UPLC-ESI-MS/MS) analysis was used for metabolic profiling of BE which was incorporated in hard gelatine capsules (400 mg/day) and tested on 30 type 2 diabetes (T2D) Egyptian patients for 8 weeks. According to sex, age and body mass index participants were divided into two equivalent groups, placebo and treatment. Thirteen compounds were identified in BE using UPLC-ESI-MS/MS analysis among which five steroidal saponins, seven phenolic compounds and a sterol glucoside. At the end of the 8-week treatment, the treated group showed 26.88% decrease in 2 h postprandial plasma glucose relative to 2.6% increase in the placebo group, while fasting plasma glucose was reduced to 10.3%. Treatment with BE capsules for 8 weeks produced significant reduction in the plasma triglyceride, total cholesterol and low-density lipoprotein cholesterol by 9.0, 12.76 and 21.35%, respectively, with 29.8% increase in the high-density lipoprotein cholesterol. Plasma alanine transaminase and aspartate transaminase were reduced by 42.6 and 43.3%, respectively. Administration of the BE capsules to T2D resulted in significant improvements in the glycaemic markers and the lipid profile, without adverse effects or hypoglycaemia.


Smart Bacteria-Responsive Drug Delivery Systems in Medical Implants.
With the rapid development of implantable biomaterials, the rising risk of bacterial infections has drawn widespread concern. Due to the high recurrence rate of bacterial infections and the issue of antibiotic resistance, the common treatments of peri-implant infections cannot meet the demand. In this context, stimuli-responsive biomaterials have attracted attention because of their great potential to spontaneously modulate the drug releasing rate. Numerous smart bacteria-responsive drug delivery systems (DDSs) have, therefore, been designed to temporally and spatially release antibacterial agents from the implants in an autonomous manner at the infected sites. In this review, we summarized recent advances in bacteria-responsive DDSs used for combating bacterial infections, mainly according to the different trigger modes, including physical stimuli-responsive, virulence-factor-responsive, host-immune-response responsive and their combinations. It is believed that the smart bacteria-responsive DDSs will become the next generation of mainstream antibacterial therapies.


[Integrated effect of incorporation with different organic manures on CH4 and N2O emissions from rice paddy].
Field experiment was conducted in 2001 rice growing season to understand the effect of organic manure application on CH4 and N2O emissions. Five treatments of fertilizer including urea and NH4HCO3 used as chemical fertilizer (CF), chemical fertilizer + pig manure (CF + PM), chemical fertilizer + cow manure (CF + CM), chemical fertilizer + rapeseed cake (CF + RC) and chemical fertilizer + wheat straw (CF + WS) were dedicated to this experiment. Results from the field observations indicated that application of the organic manure did not change the seasonal pattern of CH4 and N2O emissions but significantly affected the seasonal amounts. Seasonal amount of CH4 emission from the treatments of CF + CM, CF + RC and CF + WS was respectively 45%, 252% and 250% higher than that from the treatment of CF, but the application of pig manure (CF + PM) did not significantly influence the CH4 emission. The N2O emissions, on the other hand, were reduced by 18%, 21% and 18% for the treatments of CF + PM, CF + CM and CF + WS, respectively. Incorporation of rapeseed cake enhanced the N2O emission, yielding an increment of 22%. On a time scale of 20-year period, the integrated global warming potential (GWP) of CH4 + N2O released during the rice growing season for the treatments of CF + RC, CF + WS and CF + CM was respectively 154%, 136% and 17% higher than that for the CF treatment, while a reduction of 10% was obtained for the CF + PM treatment. The calculation of the GWP per unit rice grain yield suggested that the application of pig manure took the slight advantages not only in reducing the GWP but also in improving the grain yield.


Human-biometeorological conditions and thermal perception in a Mediterranean coastal park.
This study looks at the interrelation of human-biometeorological conditions, physiological thermal stress and subjective thermal perception in the design and use of a new waterfront park in Tel-Aviv, Israel. Our initial assumption was that the park's design would embody a comprehensive response to the area's ever-increasing heat stress and water shortage. However, almost half of it is covered by grass lawns, irrigated with fresh water, while the remaining area is mainly covered with concrete paving, with minimal shading and sparse trees. We hypothesized that stressful thermal conditions would prevail in the park in the summer season and would be expressed in a high discomfort perception of its users. Thermo-physiological stress conditions in a typical summer month were compared with the subjective comfort perceptions of pedestrians surveyed in the park. It was found that even during mid-day hours, the level of thermal stress tends to be relatively mild, owing largely to the strong sea breeze and despite the high intensity of solar radiation. Moreover, it appears that the largely favorable perception of comfort among individuals may also result from socio-cultural aspects related to their satisfaction with the park's aesthetic attractiveness and in fact its very existence. Adaptive planning is proposed for such vulnerable regions, which are expected to experience further aggravation in thermal comfort due to global as well as localized warming trends.


Simplifying Breast Imaging Reporting and Data System classification of mammograms with pure suspicious calcifications.
Objectives To investigate the risk of malignancy following stereotactic breast biopsy of calcifications classified as Breast Imaging Reporting and Data System (BI-RADS) 3, 4, and 5. Methods The study included women with pure calcifications (not associated with masses or architectural distortions) who underwent stereotactic breast biopsy at the Dutch Cancer Institute between January 2011 and October 2013. Suspicious calcifications (Breast Imaging Reporting and Data System 3, 4, or 5) detected on mammography were biopsied. All lesions were assessed by breast radiologists and classified according to the BI-RADS lexicon. Results Overall, 473 patients underwent 497 stereotactic breast biopsies. Sixty-six percent (326/497) of calcifications were classified B4, 30% (148/497) B3, and 4% (23/497) B5. Of the 226 (45%) malignant lesions, there were 182 pure ductal carcinoma in situ, 22 mixed ductal carcinoma in situ and invasive carcinomas (ductal or lobular), 21 pure invasive carcinomas, and one angiosarcoma. Malignancy was found in 32% (95% confidence interval [CI] 0.24 to 0.39) of B3, 49% (95% CI 0.43 to 0.54) of B4, and 83% (95% CI 0.61 to 0.95) of B5 calcifications. Conclusions Considering the high predictive value for malignancy in B3 calcifications, we propose that these lesions should be classified as suspicious (B4), especially in a screening setting.


Identification and characterization of lumpy skin disease virus isolated from cattle in the Republic of North Ossetia-Alania in 2015.
The first notifications of the unknown disease of cattle appeared in September-October 2015 in North Caucasus region of Russia (Republic of North Ossetia-Alania). The clinical signs included watery discharge from eyes, apathy, loss of appetite, salivation, lameness and nodular skin lesions. Capripoxvirus genome was detected by real-time PCR in the tissue samples of sick animals. The aetiological agent was isolated in the primary cell cultures of lamb testis and goat testis, as well as in the continuous MDBK cell culture. Further sequencing of the GPCR gene and phylogenetic analysis showed the close genetic relationship of isolated capripoxvirus with a group of lumpy skin disease virus. Koch's postulates were fulfilled by the experimental infection of four calves with a suspension of tissue samples from sick animals.


New pore protein produced in cells lysogenic for Escherichia coli phage HK253hrk.
Outer membrane pore protein OmpC was identified as the receptor for the temperate Escherichia coli phage HK253hrk. The part of OmpC protein recognized by the phage was identified by using hybrid proteins in which parts of OmpC protein are replaced by the corresponding parts of the related PhoE protein. In contrast to other OmpC-specific phages, HK253hrk recognizes a part of OmpC within the C-terminal 50 amino acids of the protein. E. coli strains lysogenic for HK253hrk produce reduced amounts of OmpC protein, and produce a new pore protein instead. Expression of this new protein was temperature-dependent, i.e. low at 30 degrees C. The functioning of this new pore protein was characterized both in vivo by studying the uptake of beta-lactam antibodies and in vitro after reconstitution of the protein in black lipid films. Its effective pore size was larger than that of the OmpF pores of E. coli B. The new porin appears to be cation-selective. A comparison with the selectivity of the known OmpC and OmpF pores of E. coli showed that the new pore has a higher selectivity than OmpF but is less selective than OmpC. The new pore protein appears to function in E. coli K12 lysogens as the receptor for the phages HK187, HK189 and HK332.


Marital instability and its predictors in a representative sample of Mashhadi citizens, Iran, 2014.
Background:High quality and supportive relationships is essential to develop healthy individuals in all aspects of life. This study deals with the marital instability frequency and its predisposing factors and predictors in a representative sample of Mashhad, Iran, in 2014. Methods:In a cross-sectional study, a total number of 583 couples participated. A checklist and the marital instability index (MII) were divided into 2 sections: the first section (part A) focused on the marital instability of couples and the second section (part B) focused on attractions and obstacles in each family, completed via a face-to-face interview. Results:247 (42.2%) participants were male and 338 (57.8%) were female. The median age of participants was 34 years with a maximum of 82. The mean score of the marital instability was 19.97 ± 7.29 and 13.96 ± 3.08 for attractions and obstacles. Age, education, suspicion regarding the partner, history of divorce, the way to get married (personal or by family), socioeconomic concordance with partner, expressing love to partner and partner expressing love, were identified as predictors of marital instability. Sex, addiction, history of divorce, socioeconomic fit, family interfering, violence behavior and love expression regarding the partner, were predictors of attractions and obstacles part. Conclusion:The overall score obtained from the marital instability questionnaire in this study was fair and showed lower levels of marital instability and divorce among our participants. However, it was necessary to inform young couple about the underlying factors of marital instability. Findings could be promising for the policy makers to design specific interventions suited to target population.


Ultrastructure of cementogenesis as affected by growth hormone in the molar periodontium of the hypophysectomized rat.
To document the effect of hypophysectomy and growth hormone replacement on the ultrastructure of cementogenesis in the developing rat third molar, 12 female Wistar rats were randomly allocated to normal control, hypophysectomized or hypophysectomized plus human growth hormone (for 10 days) treatment groups. The results of this study by electron and light microscopy and morphometry have shown that qualitative and quantitative changes occur in the organelles of cementoblasts forming cellular cementum as a result of hypophysectomy and growth hormone replacement. After hypophysectomy, the changes of less prominent nucleoli and nuclear pores, less prominent Golgi apparatuses and decreased endoplasmic reticulum can be interpreted as diminished cementum matrix biosynthesis--an interpretation that can be confirmed morphometrically by less cellular cementum formation. Growth hormone replacement for 10 days reactivates protein synthesis and cementogenesis as evidenced by ultrastructural changes in cementoblasts and a greater production of cementum.


Hypervariable Domain of nsP3 of Eastern Equine Encephalitis Virus Is a Critical Determinant of Viral Virulence.
Eastern equine encephalitis virus (EEEV) is the most pathogenic member of the Alphavirus genus in the Togaviridae family. This virus continues to circulate in the New World and has a potential for deliberate use as a bioweapon. Despite the public health threat, to date no attenuated EEEV variants have been applied as live EEEV vaccines. Our previous studies demonstrated the critical function of the hypervariable domain (HVD) in EEEV nsP3 for the assembly of viral replication complexes (vRCs). EEEV HVD contains short linear motifs that recruit host proteins required for vRC formation and function. In this study, we developed a set of EEEV mutants that contained combinations of deletions in nsP3 HVD and clustered mutations in capsid protein, and tested the effects of these modifications on EEEV infection in vivo These mutations had cumulative negative effects on viral ability to induce meningoencephalitis. The deletions of two critical motifs, which interact with the members of cellular FXR and G3BP protein families, made EEEV cease to be neurovirulent. The additional clustered mutations in capsid protein, which affect its ability to induce transcriptional shutoff, diminished EEEV's ability to develop viremia. Most notably, despite the inability to induce detectable disease, the designed EEEV mutants remained highly immunogenic and, after a single dose, protected mice against subsequent infection with wild-type (wt) EEEV. Thus, alterations of interactions of EEEV HVD and likely HVDs of other alphaviruses with host factors represent an important direction for development of highly attenuated viruses that can be applied as live vaccines.IMPORTANCE Hypervariable domains (HVDs) of alphavirus nsP3 proteins recruit host proteins into viral replication complexes. The sets of HVD-binding host factors are specific for each alphavirus, and we have previously identified those specific for EEEV. The results of this study demonstrate that the deletions of the binding sites of the G3BP and FXR protein families in the nsP3 HVD of EEEV make the virus avirulent for mice. Mutations in the nuclear localization signal in EEEV capsid protein have an additional negative effect on viral replication in vivo Despite the inability to cause a detectable disease, the double HVD and triple HVD/capsid mutants induce high levels of neutralizing antibodies. Single immunization protects mice against infection with the highly pathogenic North American strain of EEEV. High safety, the inability to revert to wild-type phenotype, and high immunogenicity make the designed mutants attractive vaccine candidates for EEEV infection.


Role of SPECT/CT in diagnosis of hepatic hemangiomas.
To investigate the role of SPECT/CT in the diagnosis of hepatic hemangiomas whose anatomical positions are not ideal, situated adjacent to the heart, the inferior cava, hepatic vessels or abdominal aorta, etc. The hepatic perfusion, blood pool, and fusion imaging were carried out using SPECT/CT in 54 patients, who were suspected for hepatic hemangiomas. When the anatomical positions were not ideal, the diagnosis was difficult by SPECT only. So the information of computed tomography (CT) was applied to help in diagnosing. The results were recorded as hemangiomas or not. Of the 54 patients, 31 patients were diagnosed as suffering from hepatic hemangiomas. The anatomical positions of eight patients' hepatic hemangiomas (25.81%) were not ideal. Among these lesions of the eight patients, three patients' hepatic lesions were located near to the abdominal aorta, one to the heart, and four to the inferior cava. In addition, six abnormal radioactivity accumulation regions, adjacent to the heart and inferior cava, with the help of CT, were confirmed to be the imaging of inferior cava other than hepatic hemangiomas. When the anatomical positions of hepatic hemangiomas are not good enough for diagnosis, the fusion imaging of SPECT/CT is a simple and efficient method for differential diagnosis.


The Association of GRM7 Single Nucleotide Polymorphisms with Age-Related Hearing Impairment in a Taiwanese Population.
Age-related hearing impairment (ARHI) is a major disability among the elderly. This study aimed to analyze the association of single nucleotide polymorphisms (SNPs) of metabotropic glutamate receptor 7 (GRM7) gene with ARHI in an elderly population in Taiwan. This was a community-based study performed in a metropolitan hospital. Participants ≥65 years of age were recruited. Participants with a pure tone average (PTA) of speech frequencies in the better ear of >35 decibel hearing level (dBHL) were classified into the case group, whereas those with PTA ≤25 dBHL were classified into the control group. The association of SNPs rs11928865, rs1353828, rs9814809, and rs9880404 with ARHI was analyzed. In 106 cases and 190 controls, alleles of all SNPs were found not to be associated with ARHI. The genotype of rs9880404 was found to be associated with ARHI in a dominant pattern, but the genotypes of rs11928865, rs1353828, and rs9814809 were found not to be associated with ARHI. GRM7 SNPs are associated with susceptibility to ARHI, but the significance of this finding in a Taiwanese population differed from that observed in European studies. Further studies may help to determine Taiwanese (Asian)-specific SNPs associated with ARHI.


Increase of transient lower esophageal sphincter relaxation associated with cascade stomach.
We previously reported that cascade stomach was associated with reflux symptoms and esophagitis. Delayed gastric emptying has been believed to initiate transient lower esophageal sphincter relaxation (TLESR). We hypothesized that cascade stomach may be associated with frequent TLESR with delayed gastric emptying. Eleven subjects with cascade stomach and 11 subjects without cascade stomach were enrolled. Postprandial gastroesophageal manometry and gastric emptying using a continuous 13C breath system were measured simultaneously after a liquid test meal. TLESR events were counted in early period (0-60 min), late period (60-120 min), and total monitoring period. Three parameters of gastric emptying were calculated: the half emptying time, lag time, and gastric emptying coefficient. The median frequency of TLESR events in the cascade stomach and non-cascade stomach groups was 6.0 (median), 4.6 (interquartile range) vs 5.0, 3.0 in the early period, 5.0, 3.2 vs 3.0, 1.8 in the late period, and 10.0, 6.2 vs 8.0, 5.0 in the total monitoring period. TLESR events were significantly more frequent in the cascade stomach group during the late and total monitoring periods. In contrast, gastric emptying parameters showed no significant differences between the two groups. We concluded that TLESR events were significantly more frequent in persons with cascade stomach without delayed gastric emptying.


Conceptual and methodological issues in comparative studies of psychotherapy and pharmacotherapy, II: Nature and timing of treatment effects.
This is the second of two articles on the conceptual and methodological problems involved in comparing the effectiveness of drugs and psychotherapy in the treatment of mental disorders. Part II focuses on differences between psychotherapy and pharmacotherapy in the nature of treatment effects and related goals for treatment, differences in the time course of treatment effects, and potential sources of bias in the research setting. In designing comparative studies of psychotherapy and pharmacotherapy, investigators should address methodological choices explicitly and consider the implications for interpretation of findings.


Clinically important improvement thresholds for Harris Hip Score and its ability to predict revision risk after primary total hip arthroplasty.
Some aspects of validity are missing for the Harris Hip Score (HHS). Our objective was to examine the clinically meaningful change thresholds, responsiveness and the predictive ability of the HHS questionnaire. We included a cohort of patients who underwent primary total hip arthroplasty (THA) and responded to the HHS preoperatively and at 2- or 5-year post-THA (change score) to examine the clinically meaningful change thresholds (Minimal clinically important improvement, MCII; and moderate improvement), responsiveness (effect size (ES) and standardized response mean (SRM)) based on pre- to post-operative change and the predictive ability of change score or absolute postoperative score at 2- and 5-years post-THA for future revision. Two thousand six hundred sixty-seven patients with a mean age of 64 years completed baseline HHS; 1036 completed both baseline and 2-year HHS and 669 both baseline and 5-year HHS. MCII and moderate improvement thresholds ranged 15.9-18 points and 39.6-40.1 points, respectively. ES was 3.12 and 3.02 at 2- and 5-years; respective SRM was 2.73 and 2.52. There were 3195 hips with HHS scores at 2-years and 2699 hips with HHS scores at 5-years (regardless of the completion of baseline HHS; absolute postoperative scores). Compared to patients with absolute HHS scores of 81-100 (score range, 0-100), patients with scores <55 at 2- and 5-years had higher hazards (95 % confidence interval) of subsequent revision, 4.34 (2.14, 7.95; p < 0.001) and 3.08 (1.45, 5.84; p = 0.002), respectively. Compared to HHS score improvement of >50 points from preoperative to 2-years post-THA, lack of improvement/worsening or 1-20 point improvement were associated with increased hazards of revision, 18.10 (1.41, 234.83; p = 0.02); and 6.21 (0.81, 60.73; p = 0.10), respectively. HHS is a valid measure of THA outcomes and is responsive to change. Both absolute HHS postoperative scores and HHS score change postoperatively are predictive of revision risk post-primary THA. We defined MCID and moderate improvement thresholds for HHS in this study.


Effect of ORF119 gene deletion on the replication and virulence of orf virus.
Orf is a severe infectious disease of sheep and goats caused by orf virus (ORFV). To investigate the role of ORF119 gene of ORFV, we constructed ORFV with deleted ORF119 gene and LacZ as reporter gene (ORFV-Δ119-LacZ) via homologous recombination. The results showed that wild-type ORF-SHZ1 and ORFV-Δ119-LacZ deletion viruses replicated in Vero cells to similar titers. Relative transcriptional levels of virulence genes OVIFNR, GIF, VEGF and VIL-10 of ORFV-Δ119-LacZ deletion virus were slightly but not significantly lower after 24 hr compared with the wtORF-SHZ1 virus. In vivo experiments showed that 2-month-old lambs inoculated with ORFV-Δ119-LacZ deletion virus exhibited a similar total clinical score compared with those inoculated with wtORF-SHZ1 virus. Based on these results, we conclude that deletion of the ORF119 gene has no significant effect on ORFV replication and virulence.


Quantitative analysis for detection and grading of hepatocellular carcinoma: Comparison of diffusion kurtosis imaging, intravoxel incoherent motion and conventional diffusion-weighted imaging.
The aim of the present study was to compare the diagnostic performance of the main parameters derived from diffusion kurtosis imaging (DKI), intravoxel incoherent motion (IVIM) and diffusion-weighted imaging (DWI) regarding the detection and grading of hepatocellular carcinoma (HCC). A total of 78 patients diagnosed with HCC by biopsy were prospectively enrolled in the present study, and underwent routine magnetic resonance imaging (MRI), DWI, IVIM, DKI and contrast-enhanced MRI prior to surgery. Measurements, including mean diffusivity (MD), mean diffusional kurtosis (MK), true diffusion coefficient (D), pseudo-diffusion coefficient (D*), perfusion fraction (f) and apparent diffusion coefficient (ADC), were compared with grading HCC using one-way ANOVA followed by the Student-Neuman-Keuls-q post-hoc test. Spearman's correlation coefficient was used to analyze the correlation between each parameter and pathological grade, while the diagnostic efficiency was evaluated using a receiver operating characteristic (ROC) curve. The 78 patients enrolled in the present study were grouped into highly (n=22), moderately (n=41) or poorly (n=15) differentiated HCC groups according to the criteria of Pathology and Genetics Tumors of the Digestive System. MK values differed significantly between different grades and decreased gradually with the degree of tumor differentiation. The MD, D and ADC values in the highly differentiated HCC group were significantly higher than those in the moderately or poorly differentiated HCC groups (all P<0.001), whereas no significant differences were observed in D* or f (P=0.502 and P=0.853, respectively). A significant correlation was observed between MK, MD, D and ADC, and HCC grades (r=0.705, r=0.570, r=0.423 and r=0.687, respectively). The comparison of the ROC curves of MK, MD, D, ADC, D* and f values for predicting highly differentiated HCC suggested that MK and D were the best indicators for predicting highly differentiated HCC, as the area under the ROC curve (AUC) of MK and D was significantly higher than that of ADC (Z=2.247 and 2.428, P=0.025 and 0.016, respectively), whereas non-statistically significant differences were observed in the AUC values between MK and D (Z=0.072; P=0.942). The DKI-derived MK and IVIM-derived D values had a similar diagnostic performance and were superior to ADC in discriminating the histological grade of HCC. In addition, the combination of MK and D values exhibited an improved diagnostic performance.


XFab-α4-1BB/CD40L fusion protein activates dendritic cells, improves expansion of antigen-specific T cells, and exhibits antitumour efficacy in multiple solid tumour models.
Additional immunotherapies are still warranted for non-responders to checkpoint inhibitors with refractory or relapsing cancers, especially for patients with "cold" tumours lacking significant immune infiltration at treatment onset. We developed XFab-α4-1BB/CD40L, a bispecific antibody targeting 4-1BB and CD40 for dendritic cell activation and priming of tumour-reactive T cells to inhibit tumours. XFab-α4-1BB/CD40L was developed by engineering an anti-4-1BB Fab arm into a CD40L trimer based on XFab® platform. Characterisation of the bispecific antibody was performed by cell-based reporter assays, maturation of dendritic cell assays, and mixed lymphocyte reactions. The abilities of antigen-specific T-cell expansion and antitumour efficacy were assessed in syngeneic mouse tumour models. Toxicological and pharmacodynamic profiles were investigated in non-human primates. XFab-α4-1BB/CD40L demonstrated independent CD40 agonistic activity and conditional 4-1BB activity mediated by CD40 crosslinking, leading to dendritic cell maturation and T-cell proliferation in vitro. We confirmed the expansion of antigen-specific T cells in the vaccination model and potent tumour regression induced by the bispecific antibody alone or in combination with gemcitabine in vivo, concomitant with improved tumour-reactive T-cell infiltration. XFab-α4-1BB/CD40L showed no signs of liver toxicity at doses up to 51 mg/kg in a repeated-dose regimen in non-human primates. XFab-α4-1BB/CD40L is capable of enhancing antitumour immunity by modulating dendritic cell and T-cell functions via targeting 4-1BB agonism to areas of CD40 expression. The focused, potent, and safe immune response induced by the bispecific antibody supports further clinical investigations for the treatment of solid tumours.


Magneto-Optics of Excitons Interacting with Magnetic Ions in CdSe/CdMnS Colloidal Nanoplatelets.
Excitons in diluted magnetic semiconductors represent excellent probes for studying the magnetic properties of these materials. Various magneto-optical effects, which depend sensitively on the exchange interaction of the excitons with the localized spins of the magnetic ions can be used for probing. Here, we study core/shell CdSe/(Cd,Mn)S colloidal nanoplatelets hosting diluted magnetic semiconductor layers. The inclusion of the magnetic Mn2+ ions is evidenced by three magneto-optical techniques using high magnetic fields up to 15 T: polarized photoluminescence, optically detected magnetic resonance, and spin-flip Raman scattering. We show that the holes in the excitons play the dominant role in exchange interaction with magnetic ions. We suggest and test an approach for evaluation of the Mn2+ concentration based on the spin-lattice relaxation dynamics of the Mn2+ spin system.


Molecular characterization of PK-LR gene in pyruvate kinase-deficient Italian patients.
We studied the PK-LR gene in 15 unrelated Italian patients with congenital hemolytic anemia associated with erythrocyte pyruvate kinase (PK) deficiency. Fourteen different mutations were detected among 26 mutated alleles identified: a five-nucleotide (nt) deletion (227 to 231), two splice-site (1269C and IVS3(-2)c), 10 missense (514C, 787T, 823A, 993A, 994A, 1168A, 1456T, 1529A, 1552A, and 1594T) and one nonsense mutation(s) (721T). Eight of these (deletion 227-231, 1269C, IVS3(-2)c, 514C, 787T, 823A, 1168A, and 1552A) were novel. Moreover, a new polymorphic site was detected in the 3' untranslated region of the mRNA (C/T, nucleotide 1738). The deletion 227-231 causes a stop codon after amino acid 77, probably resulting in an unstable gene product. Mutations 1269C and IVS3(-2)c lead to an alteration of the 5' and 3' splice-site consensus sequence, respectively; cDNA analysis failed to reveal any abnormal transcript, suggesting that these mutations generate an unstable mRNA that is rapidly degraded. Of the five new missense mutations, 823A (Gly275-Arg) and 1168A (Asp390-Asn) involve highly conserved amino acids, 514C (Glu172-Gln) and 1552A (Arg518-Ser), although found in less conserved regions, affect the balance of the electric charges of the protein. Mutation 787T (Gly263-Trp) is likely to determine strong modifications in the local structure of the molecule. The most frequent mutation in Italy appears to be 1456T (seven of 30 alleles), followed by 1529A (three of 30) and 994A (three of 30). A correlation was found between mutations, biochemical characteristics of the enzyme, and clinical course of the disease.


Lessons from the Tc-99m shortage: implications of substituting Tl-201 for Tc-99m single-photon emission computed tomography.
In 2009, the Chalk River nuclear reactor closed for repairs that led to a critical shortage of technetium-99m (Tc-99m). Several centers used thallium-201 (Tl-201) as an alternative radiotracer for myocardial perfusion imaging. Because Tl-201 is considered by many as a suboptimal radiotracer, we sought to understand the impact of using Tl-201 (during the Tc-99m shortage) on downstream resource utilization. We performed a retrospective study at the Ottawa Heart Institute of 7402 patients (60% men; mean age, 62.6 ± 11.8 years), patients were referred for myocardial perfusion imaging between May 2008 and January 2011 (PRE_Tc-99m [2938 patients]), during (DURING_Tl-201 [2959 patients]), and after (POST_Tc-99m [1505 patients]) the Tc-99m shortage. Patients were followed for 6 months after their index myocardial perfusion imaging to determine subsequent rates of cardiac catheterization or noninvasive imaging. More downstream testing was seen in the Tl-201 cohort (639 [21.4%] patients) than the Tc-99m cohort (537 [12.1%] patients; P<0.001). After adjustment using propensity scores, differences in downstream referral rates were maintained. The downstream investigations resulted in an estimated increase in per-patient costs ($165.22; 95% confidence interval, 153.00-177.42) in the DURING_Tl-201 cohort compared with the Tc-99m cohort ($90.97; 95% confidence interval, 83.42-98.90; P<0.001). As well, the mean effective radiation dose per-patient was higher in DURING_Tl-201 (23.57 mSv; 95% confidence interval, 23.16-23.96) than in Tc-99m (12.92 mSv; 95% confidence interval, 12.55-13.40; P<0.001). In this single-center study, the use of Tl-201 during the Tc-99m shortage was associated with an increase in downstream testing, cost, and patient radiation exposure, but these findings may not be generalizable to other centers. Although Tl-201 provided a short-term solution to the unexpected Tc-99m shortage, long-term cost-effective solutions should be areas of future study.


[Surgical reconstruction of post-cholecistectomy cicatricial biliary stenosis].
To evaluate a series of cases of cicatricial stenosis of the biliary tract after cholecystectomy undergoing surgical reconstruction. We conducted a retrospective study with 27 patients who underwent surgical reconstruction of the biliary tree for cicatricial stenosis. We analyzed the type of cholecystectomy that resulted in injury, age, gender, signs and symptoms, time of diagnosis, early or late, presence of previous surgery in an attempt to reconstruct the biliary tree, classification of stenosis and type of operation used for treatment of the injury. Twenty-six injuries occurred during a laparotomy and one during laparoscopy. Sixteen (59%) lesions were diagnosed intraoperatively or within the first postoperative day, seven (26%) havinh been submitted to reoperation at the local hospital, with poor results; nine patients in this group (33%) had no reoperation. Eleven patients (41%) had the classic form of cicatricial stenosis, without apparent intraoperative accidents and late development of biliary obstruction. All patients underwent Roux-en-Y hepatic-jejunal anastomosis; in two cases the right and left hepatic ducts were implanted separately in the excluded jejunal loop. Twenty-six patients (96.3%) had no early complications; one patient had biliary fistula and died. One patient presented with stenosis recurrence, secondary cirrhosis and is awaiting liver transplantation. Most injuries were diagnosed during cholecystectomy within the first postoperative days; seven patients had been reoperated in an attempt to reconstruct the biliary tract. Roux-en-Y hepaticojejunostomy proved safe and effective in draining the bile duct in the short and long term.


Safety of Rapid Daratumumab Infusion: A Retrospective, Multicenter, Real-Life Analysis on 134 Patients With Multiple Myeloma.
The anti-CD38 monoclonal antibody daratumumab is the backbone of most anti-multiple myeloma (MM) regimens. To mitigate the risk of infusion-related reactions (IRRs), intravenous daratumumab administration requires 7 hours for the first infusion and 3.5-4 hours thereafter, thus making daratumumab-containing regimens burdensome for patients and health care resources. Preliminary data suggest that a rapid (90-minute) infusion of daratumumab is safe and does not increase IRRs. The rapid schedule was adopted by our centers since 2019. We conducted an observational multi-center, real-life study to assess the safety of rapid daratumumab infusion protocol from the third administration in relapsed MM patients receiving daratumumab alone or in combination with lenalidomide-dexamethasone or bortezomib-dexamethasone. The primary endpoint was the safety of the rapid infusion protocol, particularly in terms of IRRs. A total of 134 MM patients were enrolled. IRRs occurred in 7 (5%) patients and were mostly mild (6/7 of grade 1-2), with only 1 patient experiencing a grade 3 IRR. Due to the IRRs, 5 (3.7%) patients discontinued the rapid infusions and resumed daratumumab at the standard infusion rate, while 1 patient permanently discontinued daratumumab. In 4/7 patients (57%), IRRs occurred while resuming rapid daratumumab infusions after a temporary interruption (2-4 months). No other adverse event was considered related to the rapid infusion protocol. Our findings confirmed the safety of rapid daratumumab infusions starting from the third administration. In case of prolonged daratumumab interruption, it is advisable to resume infusions at the standard rate (3.5 hours) before switching to the rapid infusion.


Comparison of contact patterns relevant for transmission of respiratory pathogens in Thailand and The Netherlands using respondent-driven sampling.
Understanding infection dynamics of respiratory diseases requires the identification and quantification of behavioural, social and environmental factors that permit the transmission of these infections between humans. Little empirical information is available about contact patterns within real-world social networks, let alone on differences in these contact networks between populations that differ considerably on a socio-cultural level. Here we compared contact network data that were collected in The Netherlands and Thailand using a similar online respondent-driven method. By asking participants to recruit contact persons we studied network links relevant for the transmission of respiratory infections. We studied correlations between recruiter and recruited contacts to investigate mixing patterns in the observed social network components. In both countries, mixing patterns were assortative by demographic variables and random by total numbers of contacts. However, in Thailand participants reported overall more contacts which resulted in higher effective contact rates. Our findings provide new insights on numbers of contacts and mixing patterns in two different populations. These data could be used to improve parameterisation of mathematical models used to design control strategies. Although the spread of infections through populations depends on more factors, found similarities suggest that spread may be similar in The Netherlands and Thailand.


The HNF4A-CHPF pathway promotes proliferation and invasion through interactions with MAD1L1 in glioma.
Chondroitin polymerizing factor (CHPF) is an important glycosyltransferases that participates in the biosynthesis of chondroitin sulfate (CS). Our previous study showed that silencing CHPF expression inhibited glioma cell proliferation in vitro, but the molecular mechanisms by which CHPF contributes to development of glioma have not been characterized. In this study, we found that CHPF was up-regulated in glioma tissues and was positively correlated with malignant clinical pathological characteristics of patients with glioma. Silencing CHPF expression inhibited proliferation, colony formation, migration, and cell cycle of glioma cells. Moreover, silencing CHPF suppressed glioma malignance in vivo. Immunoprecipitation, co-immunoprecipitation, GST pulldown, and liquid chromatography-mass spectrometry (LC-MS/MS) assays were used to verify the interaction between CHPF and Mitotic arrest deficient 1-like 1 (MAD1L1). In addition, Chromatin Immunoprecipitation (ChIP)-PCR analysis showed that HNF4A bound to the CHPF promoter region, which indicated that the transcription factor hepatocyte nuclear factor 4A (HNF4A) could regulate the expression of CHPF in glioma cells.


[Nursing participation in the coordination of organ transplants].
The significant growth and development in the field of transplantation has enabled people who suffer from a terminal disease to live longer and with a better quality of life. However, there is still a lack of sensibility for organ/tissue donation in our society. The list of people waiting for an organ grows every day, but not the list of donors. The truth is that without a donor, there is no transplant. Nurses play an important role in this process. They have the knowledge, clinical experience, and management skills to collaborate, organize, and implement specific activities in the transplant process. These activities will be explained in this article. Transplant Coordinator Nurses have the potential to develop their skills in different areas of nursing: patient care, research, teaching and humanism.


Separation of the effects of pH and polymer concentration on the swelling pressure and elastic modulus of a pH-responsive hydrogel.
The elastic shear modulus G and swelling pressure ω are studied for a basic, pH-responsive hydrogel synthesized by crosslinking copolymerization of co-monomers hydroxypropyl methacrylate and N,N-dimethylaminoethyl methacrylate with crosslinker tetraethylene glycol dimethacrylate. Under normal conditions of use as a "smart" material, hydrogel swelling ratio Q and pH vary simultaneously, but here G and ω values are presented as a function of pH with Q held constant and vice-versa. At fixed pH, G decreases with increase in Q in a power law dependence, as predicted by the Flory-Rehner model. However, at fixed Q, G increases with decrease in pH (i.e, increase in degree of ionization). The pH effect is more pronounced than the volume effect, thus the hydrogel stiffens as it swells in response to pH change. At high pH, ω values of the uncharged hydrogel obey the Flory-Rehner model, whereas explicit ionic contributions can be identified at lower pH values.


Rodent models in depression research: classical strategies and new directions.
Depression, among other mood disorders, represents one of the most common health problems worldwide, with steadily increasing incidence and major socio-economic consequences. However, since the knowledge about the underlying pathophysiological principles is still very scanty, depression and other mood disorders are currently diagnosed solely on clinical grounds. Currently used treatment modalities would therefore benefit enormously from the development of alternative therapeutic interventions. The implementation of proper animal models is a prerequisite for increasing the understanding of the neurobiological basis of mood disorders and is paving the way for the discovery of novel therapeutic targets. In the past thirty years, since the seminal description of the Forced Swim Test as a system to probe antidepressant activity in rodents, the use of animals to model depression and antidepressant activity has come a long way. In this review we describe some of the most commonly used strategies, ranging from screening procedures, such as the Forced Swim Test and the Tail Suspension Test and animal models, such as those based upon chronic stress procedures, to genetic approaches. Finally we also discuss some of the inherent limitations and caveats that need to be considered when using animals as models for mental disorders in basic research.


The role of fasciae in Civinini-Morton's syndrome.
This study evaluates the pathogenetic role of the perineural connective tissue and foot fasciae in Civinini-Morton's neuroma. Eleven feet (seven male, four female; mean age: 70.9 years) were dissected to analyse the anatomy of inter-metatarsal space, particularly the dorsal and plantar fasciae and metatarsal transverse ligament (DMTL). The macrosections were prepared for microscopic analysis. Ten Civinini-Morton neuromas obtained from surgery were also analysed. Magnetic resonance images (MRIs) from 40 patients and 29 controls were compared. Dissections showed that the width of the inter-metatarsal space is established by two fibrous structures: the dorsal foot fascia and the DMTL, which, together, connect the metatarsal bones and resist their splaying. Interosseous muscles spread out into the dorsal fascia of the foot, defining its basal tension. The common digital plantar nerve (CDPN) is encased in concentric layers of fibrous and loose connective tissue, continuous with the vascular sheath and deep foot fascia. Outside this sheath, fibroelastic septa, from DMTL to plantar fascia, and little fat lobules are present, further protecting the nerve against compressive stress. The MRI study revealed high inter-individual variability in the forefoot structures, although only the thickness of the dorsal fascia represented a statistically significant difference between cases and controls. It was hypothesized that alterations in foot support and altered biomechanics act on the interosseous muscles, increasing the stiffness of the dorsal fascia, particularly at the points where these muscles are inserted. Chronic rigidity of this fascia increases the stiffness of the inter-metatarsal space, leading to entrapment of the CDPN.


Gender dimorphism of brain reward system volumes in alcoholism.
The brain's reward network has been reported to be smaller in alcoholic men compared to nonalcoholic men, but little is known about the volumes of reward regions in alcoholic women. Morphometric analyses were performed on magnetic resonance brain scans of 60 long-term chronic alcoholics (ALC; 30 men) and 60 nonalcoholic controls (NC; 29 men). We derived volumes of total brain, and cortical and subcortical reward-related structures including the dorsolateral prefrontal (DLPFC), orbitofrontal, and cingulate cortices, and the temporal pole, insula, amygdala, hippocampus, nucleus accumbens septi (NAc), and ventral diencephalon (VDC). We examined the relationships of the volumetric findings to drinking history. Analyses revealed a significant gender interaction for the association between alcoholism and total reward network volumes, with ALC men having smaller reward volumes than NC men and ALC women having larger reward volumes than NC women. Analyses of a priori subregions revealed a similar pattern of reward volume differences with significant gender interactions for DLPFC and VDC. Overall, the volume of the cerebral ventricles in ALC participants was negatively associated with duration of abstinence, suggesting decline in atrophy with greater length of sobriety.


Liposomal Irinotecan in the Treatment of Refractory Pancreatic Cancer.
Effective therapies against metastatic pancreatic cancer remain limited, and despite treatment, many will ultimately progress. Previously, few options were available for second line therapy in metastatic pancreatic cancer. Liposomal encapsulated irinotecan, in combination with leucovorin-modulated fluorouracil, was found to significantly increase overall survival in patients who have progressed after gemcitabine- based therapy in a large, international, randomized clinical trial (NAPOLI-1). We reviewed the background of systemic therapy for metastatic pancreatic cancer, examined putative mechanisms for the success of encapsulated drugs, and identified recent patent applications on the use of liposomal irinotecan in pancreatic cancer. The landmark NAPOLI-1 trial established a second-line option for those with metastatic pancreatic cancer refractory to gemcitabine chemotherapy, but effective therapies with long duration of response are still lacking. Alternative techniques targeting key driver genes in pancreatic cancer and novel methods of early detection and targeting drugs are currently being explored. How liposomal irinotecan can be integrated into chemotherapy regimens, including neoadjuvant or first line combinations, are currently being tested in clinical trials and covered by several new patent applications.


SlCNGC1 and SlCNGC14 Suppress Xanthomonas oryzae pv. oryzicola-Induced Hypersensitive Response and Non-host Resistance in Tomato.
Mechanisms underlying plant non-host resistance to Xanthomonas oryzae pv. oryzicola (Xoc), the pathogen causing rice leaf streak disease, are largely unknown. Cyclic nucleotide-gated ion channels (CNGCs) are calcium-permeable channels that are involved in various biological processes including plant resistance. In this study, functions of two tomato CNGC genes SlCNGC1 and SlCNGC14 in non-host resistance to Xoc were analyzed. Silencing of SlCNGC1 and SlCNGC14 in tomato significantly enhanced Xoc-induced hypersensitive response (HR) and non-host resistance, demonstrating that both SlCNGC1 and SlCNGC14 negatively regulate non-host resistance related HR and non-host resistance to Xoc in tomato. Silencing of SlCNGC1 and SlCNGC14 strikingly increased Xoc-induced callose deposition and strongly promoted both Xoc-induced and flg22-elicited H2O2, indicating that these two SlCNGCs repress callose deposition and ROS accumulation to attenuate non-host resistance and PAMP-triggered immunity (PTI). Importantly, silencing of SlCNGC1 and SlCNGC14 apparently compromised cytosolic Ca2+ accumulation, implying that SlCNGC1 and SlCNGC14 function as Ca2+ channels and negatively regulate non-host resistance and PTI-related responses through modulating cytosolic Ca2+ accumulation. SlCNGC14 seemed to play a stronger regulatory role in the non-host resistance and PTI compared to SlCNGC1. Our results reveal the contribution of CNGCs and probably also Ca2+ signaling pathway to non-host resistance and PTI.


Probing Protein Dynamics in Neuronal Nitric Oxide Synthase by Quantitative Cross-Linking Mass Spectrometry.
Nitric oxide synthase (NOS) is responsible for the biosynthesis of nitric oxide (NO), an important signaling molecule controlling diverse physiological processes such as neurotransmission and vasodilation. Neuronal NOS (nNOS) is a calmodulin (CaM)-controlled enzyme. In the absence of CaM, several intrinsic control elements, along with NADP+ binding, suppress electron transfer across the NOS domains. CaM binding relieves the inhibitory factors to promote the electron transport required for NO production. The regulatory dynamics of nNOS control elements are critical to governing NO signaling, yet mechanistic questions remain, because the intrinsic dynamics of NOS thwart traditional structural biology approaches. Here, we have employed cross-linking mass spectrometry (XL MS) to probe regulatory dynamics in nNOS, focusing on the CaM-responsive control elements. Quantitative XL MS revealed conformational changes differentiating the nNOS reductase (nNOSred) alone, nNOSred with NADP+, nNOS-CaM, and nNOS-CaM with NADP+. We observed distinct effects of CaM vs NADP+ on cross-linking patterns in nNOSred. CaM induces striking global changes, while the impact of NADP+ is primarily localized to the NADPH-binding subdomain. Moreover, CaM increases the abundance of intra-nNOS cross-links that are related to the formation of the inter-CaM-nNOS cross-links. Taken together, these XL MS results demonstrate that CaM and NADP+ site-specifically alter the nNOS conformational landscape.


A new Lobosceliana Dirsh species (Orthoptera: Pamphagidae: Porthetinae) from coastal Tanzania, East Africa.
A new flightless species of Lobosceliana is described from coastal Tanzania, East Africa. This is the first species within this genus with shortened wings in the male sex. The antennal formula is special in this species as well since it differs from that of other Lobosceliana species, questioning the systematic value of the number of antennal segments in Porthetinae as a useful generic character.


Simultaneous application of lidocaine and ketamine during ambulatory infusion therapy: a retrospective analysis.
Background: Infusions with lidocaine or ketamine have been separately established in the treatment of chronic pain. This study aims to retrospectively evaluate the effect of combined infusions of lidocaine and ketamine. Materials & methods: Patient records were screened for receipt of combined ambulatory infusions of lidocaine and ketamine from 2012 through 2021. A scoring system was designed to assess pain response retrospectively. Results: A total of 319 patients were included. Median pain reduction in days was 10.00 (interquartile range: 13.25). Side effects were limited to the acute phase of infusions. A total of 41.4% of patients who received concomitant pain medication reported a dose reduction. Conclusion: Our data support combined infusions as a safe therapy option, with good short-, medium- and long-term reductions in pain and great heterogeneity in treatment response. Clinical trial registration: ClinicalTrials.gov (NCT05103319).


Perspectives for cancer therapies with cdk2 inhibitors.
Modern anticancer strategies are designed against specific molecular targets with the goal of sparing normal, non-neoplastic tissues. Choosing specific molecular targets, however, is problematic. Cdk2 (Cyclin dependent kinase 2, cell division kinase 2, p33) is an important candidate target for therapeutic intervention. Phosphorylation of retinoblastoma protein (pRb) by Cdk2 is the penultimate step in the transition from G1 to S phase. Inhibition of this step could potentially result in inhibition of proliferation, cytostasis and possibly apoptosis in human tumors. Cdk2 also plays a critical role in the transition through S phase and the S to G2 transition as well. Inhibitors of the cyclin dependent kinases, such as flavopiridol and UCN-01, are currently in clinical trials. While demonstrating clinical activity, neither acts specifically against Cdk2. Other more specific Cdk2 inhibitors are currently in preclinical development. Further studies to explore the therapeutic worth of such agents are warranted.


[Inveterated simultaneous dislocation of the proximal and distal radioulnar joints without an associated fracture].
The authors present an unusual case of the inveterated simultaneous dislocation of the proximal and distal radioulnar joints without an associated fracture in a 55-years-old man. Both dislocations persisted 4 months after injury and primary unsuccessful open reduction of the radial head. The left forearm was fixed in rigid full supination of 90 degrees and no rotational movements of the forearm were possible. Darrach's procedure and radial head resection resulted in 135 degrees of the forearm rotation (from 0 degrees to 90 degrees of supination, from 0 degrees to 45 degrees of pronation) without restriction of the flexion and extension of the elbow and wrist. No significant instability of the elbow and wrist, no valgus deformity of the elbow and no reduction of all daily activities of the patient were present at 6 years follow-up.


Human A53T α-synuclein causes reversible deficits in mitochondrial function and dynamics in primary mouse cortical neurons.
Parkinson's disease (PD) is the second most common neurodegenerative disease. A key pathological feature of PD is Lewy bodies, of which the major protein component is α-synuclein (α-syn). Human genetic studies have shown that mutations (A53T, A30P, E46K) and multiplication of the α-syn gene are linked to familial PD. Mice overexpressing the human A53T mutant α-syn gene develop severe movement disorders. However, the molecular mechanisms of α-syn toxicity are not well understood. Recently, mitochondrial dysfunction has been linked with multiple neurodegenerative diseases including Parkinson's disease. Here we investigated whether mitochondrial motility, dynamics and respiratory function are affected in primary neurons from a mouse model expressing the human A53T mutation. We found that mitochondrial motility was selectively inhibited in A53T neurons while transport of other organelles was not affected. In addition, A53T expressing neurons showed impairment in mitochondrial membrane potential and mitochondrial respiratory function. Furthermore, we found that rapamycin, an autophagy inducer, rescued the decreased mitochondrial mobility. Taken together, these data demonstrate that A53T α-syn impairs mitochondrial function and dynamics and the deficit of mitochondrial transport is reversible, providing further understanding of the disease pathogenesis and a potential therapeutic strategy for PD.


Model for proton transport coupled to protein conformational change: application to proton pumping in the bacteriorhodopsin photocycle.
A modeling method is presented for protein systems in which proton transport is coupled to conformational change, as in proton pumps and in motors driven by the proton-motive force. Previously developed methods for calculating pKa values in proteins using a macroscopic dielectric model are extended beyond the equilibrium case to a master-equation model for the time evolution of the system through states defined by ionization microstate and a discrete set of conformers. The macroscopic dielectric model supplies free energy changes for changes of protonation microstate, while the method for obtaining the energetics of conformational change and the relaxation rates, the other ingredients needed for the master equation, are system dependent. The method is applied to the photoactivated proton pump, bacteriorhodopsin, using conformational free energy differences from experiment and treating relaxation rates through three adjustable parameters. The model is found to pump protons with an efficiency relatively insensitive to parameter choice over a wide range of parameter values, and most of the main features of the known photocycle from very early M to the return to the resting state are reproduced. The boundaries of these parameter ranges are such that short-range proton transfers are faster than longer-range ones, which in turn are faster than conformational changes. No relaxation rates depend on conformation. The results suggest that an "accessibility switch", while not ruled out, is not required and that vectorial proton transport can be achieved through the coupling of the energetics of ionization and conformational states.


A Retrospective Study of the Relationship Between Hypertension and Vestibular Disorders in Middle-Aged Women With and Without HIV.
Patients often conflate the problem of lightheadedness from hypertension (HTN) and vertigo from a vestibular impairment, describing both problems as dizziness. The goal of the study was to learn if there is a relationship between measures of vestibular function and blood pressure. This retrospective study consisted of women who participated in a longitudinal study of the human immunodeficiency virus (HIV) and a control cohort of age-matched women without HIV. We used data from the point in time when participants were tested for vestibular functions with bi-thermal caloric tests and cervical vestibular evoked myogenic potentials; the data also included the blood pressure of the participants. High odds ratios (1.48 to 2.05) suggest a relationship between HTN and vestibular impairment, although the sample size was too small to reach statistical significance. The data suggest that high blood pressure may be related to vestibular impairments. Clinicians whose patients complain of vertigo and balance disorders consistent with vestibular impairments should consider blood pressure as a related problem during the initial visit.


Involvement of Notch1 signaling in malignant progression of A549 cells subjected to prolonged cadmium exposure.
Cadmium exposure is known to increase lung cancer risk, but the underlying molecular mechanisms in cadmium-stimulated progression of malignancy are unclear. Here, we examined the effects of prolonged cadmium exposure on the malignant progression of A549 human lung adenocarcinoma cells and the roles of Notch1, hypoxia-inducible factor 1α (HIF-1α), and insulin-like growth factor 1 receptor (IGF-1R)/Akt/extracellular signal-regulated kinase (ERK)/p70 S6 kinase 1 (S6K1) signaling pathways. Exposing A549 cells to 10 or 20 μm cadmium chloride (CdCl2) for 9-15 weeks induced a high proliferative potential, the epithelial-mesenchymal transition (EMT), stress fiber formation, high cell motility, and resistance to antitumor drugs. Of note, the CdCl2 exposure increased the levels of the Notch1 intracellular domain and of the downstream Notch1 target genes Snail and Slug. Strikingly, siRNA-mediated Notch1 silencing partially suppressed the CdCl2-induced EMT, stress fiber formation, high cell motility, and antitumor drug resistance. In addition, we found that prolonged CdCl2 exposure induced reduction of E-cadherin in BEAS-2B human bronchial epithelial cells and antitumor drug resistance in H1975 human tumor-derived non-small-cell lung cancer cells depending on Notch1 signaling. Moreover, Notch1, HIF-1α, and IGF-1R/Akt/ERK/S6K1 activated each other to induce EMT in the CdCl2-exposed A549 cells. These results suggest that Notch1, along with HIF-1α and IGF-1R/Akt/ERK/S6K1 signaling pathways, promotes malignant progression stimulated by prolonged cadmium exposure in this lung adenocarcinoma model.


Economics of interstitial cystitis in clinical practice.
Urologists may be concerned that treatment of patients with interstitial cystitis (IC) is not economically feasible, and the time spent on these patients could be used for more profitable urologic therapy. However, care of IC patients can provide urologic practices with increased revenue opportunities through a wide range of procedures, including IC evaluation and management, treatment planning, and diagnostic, therapeutic, and even surgical techniques. Current Procedural Terminology (CPT) and evaluation and management (E&M) charge codes are provided for many types, levels, and complexities of IC procedures. Some of these treatments may use physician extenders who generate profits without additional overhead costs. Further, IC therapy may involve the use of many in-office services, such as urodynamics, biofeedback, and peripheral nerve stimulation that can be economically profitable. Rather than being an economic drain, patients with IC can enhance the profitability of a urologic practice while they receive much needed care.


Open Tracheostomy Gastric Acid Aspiration Murine Model of Acute Lung Injury Results in Maximal Acute Nonlethal Lung Injury.
Acid pneumonitis is a major cause of sterile acute lung injury (ALI) in humans. Acid pneumonitis spans the clinical spectrum from asymptomatic to acute respiratory distress syndrome (ARDS), characterized by neutrophilic alveolitis, and injury to both alveolar epithelium and vascular endothelium. Clinically, ARDS is defined by acute onset of hypoxemia, bilateral patchy pulmonary infiltrates and non-cardiogenic pulmonary edema. Human studies have provided us with valuable information about the physiological and inflammatory changes in the lung caused by ARDS, which has led to various hypotheses about the underling mechanisms. Unfortunately, difficulties determining the etiology of ARDS, as well as a wide range of pathophysiology have resulted in a lack of critical information that could be useful in developing therapeutic strategies. Translational animal models are valuable when their pathogenesis and pathophysiology accurately reproduce a concept proven in both in vitro and clinical settings. Although large animal models (e.g., sheep) share characteristics of the anatomy of human trachea-bronchial tree, murine models provide a host of other advantages including: low cost; short reproductive cycle lending itself to greater data acquisition; a well understood immunologic system; and a well characterized genome leading to the availability of a variety of gene deletion and transgenic strains. A robust model of low pH induced ARDS requires a murine ALI that targets mainly the alveolar epithelium, secondarily the vascular endothelium, as well as the small airways leading to the alveoli. Furthermore, a reproducible injury with wide differences between different injurious and non-injurious insults is important. The murine gastric acid aspiration model presented here using hydrochloric acid employs an open tracheostomy and recreates a pathogenic scenario that reproduces the low pH pneumonitis injury in humans. Additionally, this model can be used to examine interaction of a low pH insult with other pulmonary injurious entities (e.g., food particles, pathogenic bacteria).


Underwater auditory localization by a swimming harbor seal (Phoca vitulina).
The underwater sound localization acuity of a swimming harbor seal (Phoca vitulina) was measured in the horizontal plane at 13 different positions. The stimulus was either a double sound (two 6-kHz pure tones lasting 0.5 s separated by an interval of 0.2 s) or a single continuous sound of 1.2 s. Testing was conducted in a 10-m-diam underwater half circle arena with hidden loudspeakers installed at the exterior perimeter. The animal was trained to swim along the diameter of the half circle and to change its course towards the sound source as soon as the signal was given. The seal indicated the sound source by touching its assumed position at the board of the half circle. The deviation of the seals choice from the actual sound source was measured by means of video analysis. In trials with the double sound the seal localized the sound sources with a mean deviation of 2.8 degrees and in trials with the single sound with a mean deviation of 4.5 degrees. In a second experiment minimum audible angles of the stationary animal were found to be 9.8 degrees in front and 9.7 degrees in the back of the seal's head.


Vaccine stockouts around the world: Are essential vaccines always available when needed?
As countries rise to the challenge of implementing the priorities of this "Decade of Vaccine" and their commitments delineated in the Global Vaccine Action Plan (GVAP), many continue to face important challenges of securing a continuous supply of essential vaccine for their national immunization programme. This study provides evidence on the incidence of vaccine stockouts in countries, their root causes and their potential impact on service delivery. Vaccine stockout indicators collected from the WHO-UNICEF Joint Reporting Form (JRF) and UNICEF's Vaccine Forecasting Tool were analysed for the years covering the first half of the GVAP (2011 to 2015) and using 2010 as the baseline year. While the JRF collects annual information on national and subnational stockouts by vaccine, the UNICEF Vaccine Forecasting Tool has the advantage of requesting UNICEF procuring countries to report on the reasons underpinning any stockouts. Every year on average, one in every three WHO Member States experiences at least one stockout of at least one vaccine for at least one month. The incidence is most pronounced in Sub-Saharan Africa where 38% of countries in this area of the world report national-level stockouts. The vaccines most affected are DTP containing vaccines (often combined with HepB and Hib) and BCG. They account for respectively 43% and 31% of stockout events reported. While national level vaccine stockouts occur in countries of all income groups, middle income countries are the most affected. In 80% of cases, national level stockouts were due to reasons internal to countries. More specifically, 39% of stockouts were attributable to government funding delays, 23% were caused by delays in the procurement processes, and poor forecasting and stock management at country level accounted for an additional 18%. When a national level stockout of vaccines occurs, there is an 89% chance that a subnational stockout will occur at district level. More concerning is that if a district level stockout occurs, this will lead to an interruption of vaccination services in 96% of cases. There continues to be important challenges of ensuring a continuous availability of essential vaccines. The global community, together with countries, urgently need to design effective interventions aimed at reducing the frequency and mitigating the impact of stockouts.


Elevator-type mechanisms of membrane transport.
Membrane transporters are integral membrane proteins that mediate the passage of solutes across lipid bilayers. These proteins undergo conformational transitions between outward- and inward-facing states, which lead to alternating access of the substrate-binding site to the aqueous environment on either side of the membrane. Dozens of different transporter families have evolved, providing a wide variety of structural solutions to achieve alternating access. A sub-set of structurally diverse transporters operate by mechanisms that are collectively named 'elevator-type'. These transporters have one common characteristic: they contain a distinct protein domain that slides across the membrane as a rigid body, and in doing so it 'drags" the transported substrate along. Analysis of the global conformational changes that take place in membrane transporters using elevator-type mechanisms reveals that elevator-type movements can be achieved in more than one way. Molecular dynamics simulations and experimental data help to understand how lipid bilayer properties may affect elevator movements and vice versa.


Case report: Thoracic endovascular aortic repair using a non-touch exclusion technique with a custom-made device for the treatment of a large patent ductus arteriosus.
Patent ductus arteriosus (PDA) is a common congenital heart disease affecting roughly one in every 2,000 term births. Although most of the patients are diagnosed and treated during childhood, few cases may persist into adulthood. We presented a 27-year-old male patient with a 20.2 mm diameter PDA who was referred to our hospital with progressive fatigue and exertional dyspnea. Given the potential complications, usual techniques such as coil occlusion and duct occluders were deemed inappropriate for this patient. Thoracic endovascular aortic repair (TEVAR) using a non-touch exclusion technique was successfully performed for this patient. The patient was discharged with no major post-surgical complications. TEVAR could be a new, safe, and effective alternative treatment to other transcatheter procedures for complicated PDAs in some patients.