Eczematoid graft-vs-host disease: a novel form of chronic cutaneous graft-vs-host disease and its response to psoralen UV-A therapy.
Chronic cutaneous graft-vs-host disease (GVHD) is generally classified by whether lesions have a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the features of dermatomyositis and lupus erythematosus. Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed. We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5 months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk factors for chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the histologic features of GVHD coexisting with the changes of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six patients also received psoralen-UV-A. Four patients achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia. The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that we named eczematoid GVHD. Eczematoid GVHD is an aggressive, chronic dermatosis that requires substantial immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be transmitted to an individual from a hematopoietic stem cell transplant, none of the donors in this series gave a history of an atopic disorder. Therefore, other factors must be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic graft-vs-host activity.


PD1/PD-L1 pathway in psoriasis and psoriatic arthritis: a review.
Programmed-death 1 (PD-1) is a co-receptor that inhibits the inflammatory response, and thus helps in maintenance of peripheral immunotolerance. Impairment in the PD-1/PD-L1 pathway is believed to play an important role in many immune-mediated diseases, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis and autoimmune hepatitis, and, as emphasized recently, in psoriasis and psoriatic arthritis. Biologic drugs targeting immune checkpoint regulators may be associated with new-onset psoriasis or exacerbations of pre-existing dermatosis. In this review we discuss the role of PD-1/PD-L1 pathway in psoriasis basing on data published to date.


Low-dose quinine is effective in the treatment of chloroquine-resistant Plasmodium falciparum malaria in eastern Sudan.
In November-December 2002, 98 patients presented at the Elhara Eloula health centre, in the New Halfa area of eastern Sudan, with Plasmodium falciparum malaria that had failed to respond to chloroquine treatment. After informed consent was obtained, 93 of these patients were randomly allocated to one of three regimens for quinine treatment, being given the drug, orally and sometimes intravenously, for 7 days, at doses of 10 mg/kg thrice daily (32 patients), 10 mg/kg twice daily (31 patients) or 15 mg/kg once daily (30 patients). All the patients were followed daily until day 7 and then weekly until day 28. There was no significant difference in the parasite-clearance times observed in the three groups. Parasitaemias re-occurred by day 28 in 12 patients: two (6.3%) of the patients treated thrice daily, five (16.1%) of those treated twice daily, and five (16.7%) of those treated once daily (P > 0.05). Genotyping indicated that in nine of these 12 patients the parasitaemias that developed post-treatment represented true recrudescences and not re-infections. In the treatment of chloroquine-resistant, P. falciparum malaria in Sudan, once-daily treatment with quinine, in a relatively low daily dose (15 mg/kg. day), appears as effective as the thrice-daily treatment (at 30 mg/kg. day) often recommended.


Phenotypic variability in familial prion diseases due to the D178N mutation.
Between January 1993 and December 2003, 19 patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2,100,000 inhabitants. Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.


Antirheumatic treatment is associated with reduced serum Syndecan-1 in Rheumatoid Arthritis.
The endothelial glycocalyx (EG) is essential for proper function of the endothelium and for vascular integrity, but its role in premature atherogenesis in rheumatoid arthritis (RA) has not been studied yet. EG impairment can play a role in pathogenesis of vascular disease, and one of its characteristics is shedding of syndecan-1 from endothelial cells. Syndecan-1 shedding is mediated by matrix metalloproteinase-9 (MMP-9) and counteracted by tissue inhibitor of metalloproteinases (TIMP)-1. Cardiovascular disease risk in RA is reversible by disease modifying antirheumatic drugs (DMARDs), but the exact modes of action are still unclear. Therefore, we examined effects of DMARDs on syndecan-1, MMP-9 and TIMP-1 in RA patients, and searched for associations between these parameters and inflammatory activity. From the observational PSARA study, we examined 39 patients starting with methotrexate (MTX) monotherapy (in MTX naïve patients, n = 19) or tumor necrosis factor inhibitors (TNFi) in combination with MTX (in MTX non-responders, n = 20) due to active RA. Serum syndecan-1, MMP-9 and TIMP-1 were measured at baseline and after six weeks of treatment. Serum syndecan-1 (p = 0.008) and TIMP-1 (p<0.001) levels decreased after six weeks of anti-rheumatic treatment. Levels of MMP-9 also decreased, but the difference was not statistically significant. The improvement in syndecan-1 levels were independent of changes in inflammatory activity. There was no significant difference in changes in syndecan-1 levels from baseline to 6 weeks between the MTX and TNFi groups, however the change was significant within the MTX group. Six weeks of antirheumatic treatment was associated with reduction in serum levels of syndecan-1, which might reflect reduced syndecan-1 shedding from EG. Thus, it is possible that EG-preserving properties of DMARDs might contribute to their cardioprotective effects. These effects may be at least partly independent of their anti-inflammatory actions. Our findings do not support the notion that syndecan-1 shedding in RA is mediated mainly by increased MMP-9 or decreased TIMP-9 serum concentration.


Delivery of anticancer drugs via isolated hepatic perfusion: a promising strategy in the treatment of irresectable liver metastases?
The prognosis of patients with irresectable liver metastases derived from colorectal cancer is invariably poor; unfortunately, these tumours show only minor responses to conventional anticancer agents. The best responses have been obtained by fluoropyrimidines delivered as continuous infusion into the hepatic artery (HAI): their rapid uptake and detoxification by liver cells results in relatively low systemic drugs levels. This approach increases mean survival duration from 17 to 26 months and, in few patients, causes "down-staging" that may result in resectability. To improve opportunities for chemotherapy, the technique of 1-hour recirculating perfusion of the vascularly isolated liver (isolated hepatic perfusion, IHP) was developed. If leakage to the systemic circulation is negligible-and the compounds used do not readily cause hepatotoxicity-IHP allows usage of drug doses that would be fatal if delivered systemically. Because alkylating agents generally have steep dose-response curves, mitomycin C (MMC) and melphalan (L-PAM) entered phase I/II studies on IHP. Using these drugs, IHP was performed in principle as a single procedure in 60 otherwise untreated patients at our institution. However, despite preliminary data that indicate impressive clinical responses are obtained, improvement over HAI will probably be minor. Because IHP is a complicated way of drug delivery, one could argue that its use is justified only when it has the potential to kill all tumour cells in the liver. We critically discuss the possibilities of IHP and/or the use of gene therapy in an IHP setting.


[New-generation proton pump inhibitors: progress in the treatment of peptic acid diseases?].
EFFECTS AND INCONVENIENCIES OF THE OLDER PRODUCTS: The proton pump inhibitors (PPIs) are now universally considered the treatment of choice for management of gastric-acid-related diseases, mainly gastro-oesophageal reflux disease (GERD). These drugs share similar properties: general structure, acid-activation step, covalent binding to the proton pump of the gastric parietal cell via the production of covalent disulphide bonds, relatively stable inhibition of H+,K+-ATPase. However, the older PPIs (omeprazole, lansoprazole et pantoprazole) have notable limitations. These drugs exhibit substantial interpatient variability and may have significant interactions with other drugs. These first-generation PPIs also do not achieve a rapid and sustained suppression of gastric acid, leading to the development of new acid-pump antagonists. The new-generation PPIs, esomeprazole and rabeprazole, offer several pharmacokinetic advantages: lower oxidative hepatic metabolism rate via the CYP 2C19 reducing the activity variations due to genetic polymorphisms and decreasing the risk of significant drug-drug interactions (advantages mainly for rabeprazole), lower metabolic clearance of esomeprazole (S-enantiomer of omeprazole) increasing plasma concentrations and acid suppression of this new PPI, higher accumulation of rabeprazole in the parietal cell due to its higher pKa. Gastric pH studies and therapeutic trials have demonstrated significant advantages of esomeprazole and rabeprazole compared with the older PPIs, which omeprazole is the prototype: a greater inhibition of acid secretion, a more rapid onset of action to provide reflux symptoms relief over 24 hours with lower GERD-related cost for rabeprazole, a sustained acid suppression, cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole, reduced potential for clinically significant drug-drug interactions with rabeprazole compared with omeprazole and esomeprazole. Due to their properties, esomeprazole and rabeprazole are the best candidates for "on demand" treatment of GERD.


Age Differences and the Acceptance of Infusion Pump Technology.
Previous studies demonstrate that age and receptiveness to new technologies tend to be negatively correlated. Using data from a sample of 311 nurses in a large teaching hospital in the midwestern United States, this study sought to determine whether age predicted satisfaction perceptions of infusion pump technology. Hierarchical regression indicated that the relationship between age and infusion pump satisfaction was not statistically significant, but it also revealed interesting moderation effects. When perceived support for infusion pump use was low, age was negatively related to infusion pump satisfaction. However, when perceived support was high, age was positively related to infusion pump satisfaction.


Opposite effects of total lymphoid irradiation on T cell-dependent and T cell-independent antibody responses.
The effect of total lymphoid irradiation (TLI) on the primary antibody response to the dinitrophenylated heterologous protein, keyhole limpet hemocyanin (DNP-KLH), in complete Freund's adjuvant (CFA), and to the trinitrophenylated polysaccharide antigen, Brucella abortus (TNP-BA), was studied in BALB/c mice. The antibody response to both antigens was diminished in comparison with nonirradiated mice when antigens were injected within 3 days after TLI. When the mice were immunized 30 days after completion of TLI the antibody response to DNP-KLH in CFA was still diminished, but the antibody response to TNP-BA was enhanced 5- to 10-fold as compared with that of control animals. The opposite effect of TLI on the two antibody responses was also observed in a syngeneic primary adoptive transfer system.


Scaphoid fracture non-union: a systematic review of the arthroscopic management.
There is no consensus regarding the most appropriate treatment of scaphoid nonunion. This systematic review aimed to investigate whether wrist arthroscopy exerts a positive influence on bone union and clinical outcomes. We searched the literature on Medline (PubMed), Web of Science, Embase and Scopus databases using the combined keywords "scaphoid" AND "arthroscopy" AND "pseudoarthrosis" OR "nonunion". Eighteen studies were finally included in our review. The quality of the studies was assessed using the Coleman Methodological Score. Our systematic review has shown that arthroscopic management of scaphoid nonunion achieves a high rate of union and satisfactory clinical outcomes with minimal complications. There is need to perform randomized controlled trials reporting on the use of arthroscopy. In addition, the different pattern of pseudoarthrosis should be better classified to manage the patients who will benefit after the management.


Does the morphology of cutaneous melanoma help to explain the international differences in survival? Results from 1 578 482 adults diagnosed during 2000-2014 in 59 countries (CONCORD-3).
CONCORD-3 highlighted wide disparities in population-based 5-year net survival for cutaneous melanoma during 2000-2014. Clinical evidence suggests marked international differences in the proportion of lethal acral and nodular subtypes of cutaneous melanoma. We aimed to assess whether the differences in morphology may explain global variation in survival. Patients with melanoma were grouped into the following seven morphological categories: malignant melanoma, not otherwise specified (International Classification of Diseases for Oncology, third revision morphology code 8720), superficial spreading melanoma (8743), lentigo maligna melanoma (8742), nodular melanoma (8721), acral lentiginous melanoma (8744), desmoplastic melanoma (8745) and other morphologies (8722-8723, 8726-8727, 8730, 8740-8741, 8746, 8761, 8770-8774, 8780). We estimated net survival using the nonparametric Pohar Perme estimator, correcting for background mortality by single year of age, sex and calendar year in each country or region. All-ages survival estimates were standardized using the International Cancer Survival Standard weights. We fitted a flexible parametric model to estimate the effect of morphology on the hazard of death. Worldwide, the proportion of nodular melanoma ranged between 7% and 13%. Acral lentiginous melanoma accounted for less than 2% of all registrations but was more common in Asia (6%) and Central and South America (7%). Overall, 36% of tumours were classified as superficial spreading melanoma. During 2010-2014, age-standardized 5-year net survival for superficial spreading melanoma was 95% or higher in Oceania, North America and most European countries, but was only 71% in Taiwan. Survival for acral lentiginous melanoma ranged between 66% and 95%. Nodular melanoma had the poorest prognosis in all countries. The multivariable analysis of data from registries with complete information on stage and morphology found that sex, age and stage at diagnosis only partially explain the higher risk of death for nodular and acral lentiginous subtypes. This study provides the broadest picture of distribution and population-based survival trends for the main morphological subtypes of cutaneous melanoma in 59 countries. The poorer prognosis for nodular and acral lentiginous melanomas, more frequent in Asia and Latin America, suggests the need for health policies aimed at specific populations to improve awareness, early diagnosis and access to treatment. What is already known about this topic? The histopathological features of cutaneous melanoma vary markedly worldwide. The proportion of melanomas with the more aggressive acral lentiginous or nodular histological subtypes is higher in populations with predominantly dark skin than in populations with predominantly fair skin. What does this study add? We aimed to assess the extent to which these differences in morphology may explain international variation in survival when all histological subtypes are combined. This study provides, for the first time, international comparisons of population-based survival at 5 years for the main histological subtypes of melanoma for over 1.5 million adults diagnosed during 2000-2014. This study highlights the less favourable distribution of histological subtypes in Asia and Central and South America, and the poorer prognosis for nodular and acral lentiginous melanomas. We found that later stage at diagnosis does not fully explain the higher excess risk of death for nodular and acral lentiginous melanoma compared with superficial spreading melanoma.


Multiple non-odontogenic cysts--a case report.
Nonodontogenic cysts have been identified at various locations in oral cavity. These occur primarily in relation to fusion of maxillary process either with its counterpart or different portions of nasal part of frontonasal process. Usually solitary, these primarily affect maxilla alone; can rarely be seen in ramus of mandible. We present a case of multiple non-odontogenic cysts involving both maxilla and mandible.


Pedestrian head impact conditions depending on the vehicle front shape and its construction--full model simulation.
For the evaluation of pedestrian protection, the European Enhanced Vehicle-Safety Committee Working Group 17 report is now commonly used. In the evaluation of head injuries, the report takes into account only the hood area of the vehicle. But recent pedestrian accident data has shown the injury source for head injury changing to the windshield and A-pillar from the hood. The head contact points are considered to fall on a parallel to the front shape of the vehicle along the lateral direction, but the rigidity of the outer side construction is different from the center area. The purpose of this study is to consider the reason for the change in injury source for recent vehicle models. The head contact points and contact conditions, speed and angle, are thought to be influenced not only by the vehicle's geometry, but also its construction (rigidity). In this study, vehicle-pedestrian impact simulations were calculated with a finite element model for several hitting positions, including the outer side areas. Full dummy sled tests were conducted to confirm the simulation results. These results show that, for impacts at the outer sides of the vehicle, the head contact points are more rearward than at the vehicle center. In addition, the speed and angle of the head contact were found to be influenced by the pedestrian height.


B-type natriuretic peptide: issues for the intensivist and pulmonologist.
B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), although promising as biomarkers for heart failure, are affected by multiple confounders. The purpose of this article is to review the literature on the utility of BNP and NT-proBNP as biomarkers, with a focus on their role in critical illness and pulmonary diseases. Published articles on BNP and NT-proBNP. Multiple disorders in the intensive care unit cause elevated BNP and NT-proBNP levels, including cardiac diseases, shock, pulmonary hypertension, acute respiratory distress syndrome, acute pulmonary embolism, chronic obstructive pulmonary disease, renal failure, and other conditions. Intensivists and pulmonologists should understand that BNP and NT-proBNP levels might be raised to different degrees not only in heart failure but also in critical illness and various pulmonary diseases; in these situations, BNP and NT-proBNP may also serve as markers of severity and prognosis.


A simultaneous modulation of reactive and proactive inhibition processes by anodal tDCS on the right inferior frontal cortex.
Proactive and reactive inhibitory processes are a fundamental part of executive functions, allowing a person to stop inappropriate responses when necessary and to adjust performance in in a long term in accordance to the goals of a task. In the current study, we manipulate, in a single task, both reactive and proactive inhibition mechanisms, and we investigate the within-subjects effect of increasing, by means of anodal transcranial direct current stimulation (tDCS), the involvement of the right inferior frontal cortex (rIFC). Our results show a simultaneous enhancement of these two cognitive mechanisms when modulating the neural activity of rIFC. Thus, the application of anodal tDCS increased reaction times on Go trials, indicating a possible increase in proactive inhibition. Concurrently, the stop-signal reaction time, as a covert index of the inhibitory process, was reduced, demonstrating an improvement in reactive inhibition. In summary, the current pattern of results validates the engagement of the rIFC in these two forms of inhibitory processes, proactive and reactive inhibition and it provides evidence that both processes can operate concurrently in the brain.


Simulation of the hydraulic performance of highway filter drains through laboratory models and stormwater management tools.
Road drainage is one of the most relevant assets in transport infrastructure due to its inherent influence on traffic management and road safety. Highway filter drains (HFDs), also known as "French Drains", are the main drainage system currently in use in the UK, throughout 7000 km of its strategic road network. Despite being a widespread technique across the whole country, little research has been completed on their design considerations and their subsequent impact on their hydraulic performance, representing a gap in the field. Laboratory experiments have been proven to be a reliable indicator for the simulation of the hydraulic performance of stormwater best management practices (BMPs). In addition to this, stormwater management tools (SMT) have been preferentially chosen as a design tool for BMPs by practitioners from all over the world. In this context, this research aims to investigate the hydraulic performance of HFDs by comparing the results from laboratory simulation and two widely used SMT such as the US EPA's stormwater management model (SWMM) and MicroDrainage®. Statistical analyses were applied to a series of rainfall scenarios simulated, showing a high level of accuracy between the results obtained in laboratory and using SMT as indicated by the high and low values of the Nash-Sutcliffe and R 2 coefficients and root-mean-square error (RMSE) reached, which validated the usefulness of SMT to determine the hydraulic performance of HFDs.


[Determination of five coumarins in toys by high performance liquid chromatography-tandem mass spectrometry].
A rapid analytical method for the determination of five coumarins (coumarin, 7-methoxycoumarin, dihydrocoumarin, 7-methyl coumarin and 7-ethoxy-4-methyl coumarin) in toys by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) has been developed. After ultrasonic extraction in tetrahydrofuran, the samples were analyzed by HPLC-MS/MS in multi-reaction monitoring (MRM) mode. Acetonitrile and 0.1% acetic acid were used as the mobile phases with gradient elution. The linear ranges of calibration curves were 10 - 1 000 microg/L, and the limits of quantification (LOQ) (S/N > 10) were 2.0 microg/L for all the analytes, except that the LOQ for dihydrocoumarin was 5.0 microg/L. The recoveries of the five coumarins spiked in three types of samples were in the ranges of 93.2% - 105.8%, 97.3% - 103.2% and 96.8% - 102.9%, with the relative standard deviations in the ranges of 4.35% - 8.27%, 3.65% - 6.73% and 4.03% - 6.45%, respectively. The method was applied in the determination of 12 toy samples. The five analytes were found in 9 samples, and in some cases, the presence of quite high concentrations of these coumarins in the toys should be a matter of concern.


[The value of SpO2 measurement in young infants in the primary care setting].
Hypoxia can be an early sign of infection, respiratory or circulatory pathology in infants. Since it is difficult to properly judge oxygen saturation solely by skin discoloration, it is preferable to objectify this parameter via pulse oximetry (PO). PO in young infants has shown to be feasible in the primary care setting. Even though PO is broadly used by general practitioners (GPs) in older children and adults, it is rarely performed in young infants. We present three patients, aged 0 to 6 months, who were seen in primary care, where PO was an important factor in determining the level of illness. These patients illustrate the value of PO in infants by GPs in estimating illness severity, need for referral and mode of transport to the emergency department. We therefore advocate for GPs to obtain adequate equipment for PO in infants.


Plasmodium falciparum malaria associated with mefloquine failure in Gambia.
A 25-year-old Caucasian man developed Plasmodium falciparum malaria after traveling to Gambia, despite having received chemoprophylaxis with mefloquine. The patient was hospitalized after returning to the United States. He received a 3-day course of atovaquone-proguanil and made a complete recovery. This case illustrates the potential role of pharmacists in the pharmaceutical care of travelers and underscores the importance of using current recommendations for preventing and treating malaria.


Following the tracks of AKT1 gene.
The AKT or PKB family of protein kinases is one of the best characterized targets of phosphoinositide 3-kinases or PI3Ks. The AKT/PKB signal transduction pathway regulates many growth and survival mechanisms including transcription, cell cycle progression, metabolism, apoptosis, invasion and metastasis. Recently, Carpten et al. (Nature 2007;448:439-44) reported a very interesting study on the isoform AKT1 (PKBalpha). They described a novel point mutation (E17K) in the pleckstrin homology domain (PHD) of the AKT1 gene in human breast, colorectal and ovarian cancers, and demonstrated that it induces leukemia in mice. Here we give a critical appraisal of this finding and underline its clinical impact. We also discuss possible interventions for therapeutic development of AKT inhibitors to treat human cancer.


Patterns in hospital admissions for adults with congenital heart disease for non-cardiac procedures.
Advances in management of congenital heart disease (CHD) have led to an increasing population of adults with CHD, many of whom require non-cardiac procedures. The objectives of this study were to describe the characteristics of these patients, their distribution among different hospital categories and the characteristics determining this distribution, and mortality rates following noncardiac procedures. We retrospectively analysed 27 state inpatient databases. Encounters with CHD and non-cardiac procedures were included. The location of care was classified into two categories: hospitals with and without cardiac surgical programmes. Variables included were demographics, comorbidity index, mortality. Multivariable logistic regression was used to explore predictors for care in different locations. The cohort consisted of 12 944 encounters in 1206 hospitals. Most patients were cared for in hospitals with a cardiac surgical programme (78.1%). Patients presenting to hospitals with a cardiac surgical programme presented with higher comorbidity index (6 (IQR: 0-19) vs 2 (IQR: -3-14), p<0.001) than patients presenting to hospitals without a cardiac surgical programme. Mortality was higher in hospitals with cardiac surgical programmes compared with hospitals without cardiac surgical programmes (4.0% vs 2.3%, p<0.001). Factors associated with provision of care at a hospital with a cardiac surgical programme were comorbidity index (>7: OR 2.01 (95% CI 1.83 to 2.21), p<0.001; 2-7: OR 1.59 (95% CI 1.41 to 1.79), p<0.001) and age (18-44 years: OR 1.43 (95% CI 1.26 to 1.62), p<0.001; 45-64 years: OR 1.21 (95% CI 1.08 to 1.34), p<0.001). Adults with CHD undergoing non-cardiac procedures are mainly cared for in hospitals with a cardiac surgical programme and have greater comorbidities and higher mortality than those in centres without cardiac surgical programmes. Risk stratification and locoregional accessibility need further assessment to fully understand admission patterns.


Fine structure of the eggs of Haemagogus equinus and Hg. janthinomys (Diptera: Culicidae).
The eggs of Haemagogus equinus Theobald and Hg. janthinomys Dyar, the first of this genus to be examined with a scanning electron microscope, are described from material collected in Trinidad, West Indies. All surfaces of the eggs are described, including both dorsal and ventral surfaces at the anterior and posterior ends as well as the micropyle and associated apparatus. The dorsal surface, normally attached to the substrate, consists of a dense, hairlike mat of filaments formed from numerous, greatly elongated outer chorionic tubercles. These filaments possibly serve to improve anchorage of the egg as a protection against flushing by rain water or physical removal by predators. The outer chorionic cells on the ventral (upper) surfaces are extremely similar to those of two species of the subgenus Finlaya of Aedes, Ae. albolateralis (Theobald) and Ae. melanopterus (Giles), both collected in Taiwan.


Presurgical therapy in metastatic renal cell carcinoma.
The standard approach for managing patients with metastatic renal cell carcinoma consists of a cytoreductive nephrectomy followed by immunotherapy, chemotherapy or a targeted agent. Optimal timing of surgery and systemic therapy is not known, and has not been researched. A number of questions arise. First, in the era of antivascular therapy, is cytoreductive nephrectomy a necessity? Second, is it possible that pretreatment with systemic therapy prior to cytoreductive nephrectomy improves surgical outcome and survival? Third, which agents are best suited for an integration of surgery with systemic therapy, both in the metastatic and the nonmetastatic setting? This review will address each of these questions and summarize ongoing trials that are designed to provide some of the answers.


Functional MRI study of a serial reaction time task in Huntington's disease.
The aim of this study was to investigate pathophysiological changes at an early stage of clinical Huntington's disease (HD) using a functional magnetic resonance imaging (fMRI) study and a serial reaction time task paradigm. Mildly affected and presymptomatic HD subjects (n = 8) and healthy normal controls (NC, n = 12) were studied. A group behavioral effect of implicit learning was seen only in the control population. Individual statistical parametric mapping (SPM) analysis showed more consistent activation of the caudate nucleus and putamen in the NC group. In the HD group, the group average SPM showed significant activation in the right head of caudate nucleus, as well as bilateral thalami, left middle temporal, right superior temporal, right superior frontal, right middle and inferior frontal and right postcentral gyri. In the comparison of between-group differences (NC-HD), reduced activation in the HD group relative to NC was observed in the right middle frontal, left middle occipital, left precuneus, and left middle frontal gyri. The variable striatal activity in the Huntington's group suggests early functional loss possibly associated with previously demonstrated early atrophy of these same neural structures.


The use of minimal preparation computed tomography for the primary investigation of colon cancer in frail or elderly patients.
To assess the place of computed tomography (CT) of the colon in frail or elderly patients with symptoms suggestive of colon cancer. A total of 195 patients (median age 76 years) underwent CT of the abdomen and pelvis following the administration of positive oral contrast medium but no bowel preparation. All had symptoms suggestive of colon cancer. CT findings were classified as normal/diverticular disease (DD), possible colon cancer, definite colon cancer or extracolonic pathology. Accuracy of CT was assessed against patient outcome. Association between symptoms and colon cancer was assessed by chi-squared test. There were 47 deaths and median follow up for those alive was 16 months. Overall sensitivity of CT was 100% and specificity 87% for detection of colon cancer. One hundred and ten normal/DD CT examinations had no significant bowel lesion on follow up. Of 12 cases defined as 'definite cancers' on CT, there were nine colon cancers, two extracolonic cancers, and one normal. Of 23 'possible cancers' on CT, there were two colon cancers, three DD masses and 18 normal/DD. Fifty examinations had extracolonic findings including 33 (17%) cases of significant abdominal disease. CT findings led to a halt in investigations in 115 cases (59%), colonoscopy in 18 (9%) cases and surgery in 16 (8%) cases. None of the symptoms present showed a significant association with colon cancer (all P > 0.05). Minimal preparation CT is a non-invasive and sensitive method for investigating colon cancer in frail or elderly patients. It has a 100% negative predictive value and also detects a large number of extracolonic lesions.


Age incidence of Pityrosporum orbiculare on human skin.
We have investigated the incidence of the lipophilic fungi Pityrosporum orbiculare and P. ovale on clinically normal skin in newborn children and in children at the age of 6 months, 1 year, 5 years, 10 years, and 15 years. P. orbiculare was absent in children of less than 5 years of age. It was present in the highest incidence (93%) in the 15-year-old children, about the same frequency as in adults. The colonization starts during the period when the sebaceous glands become active. P. ovale could not be cultured and this may depend on geographical variations in the distribution of these yeasts.


Rehabilitation of poststroke cognition.
Given the increasing rates of stroke and our aging population, it is critical that we continue to foster innovation in stroke rehabilitation. Although there is evidence supporting cognitive rehabilitation in stroke, the set of cognitive domains effectively addressed to date represents only a small subset of the problems experienced by stroke survivors. Further, a gap remains between investigational treatments and our evolving theories of brain function. These limitations present opportunities for improving the functional impact of stroke rehabilitation. The authors use a case example to encourage the reader to consider the evidence base for cognitive rehabilitation in stroke, focusing on four domains critical to daily life function: (1) speech and language, (2) functional memory, (3) executive function and skilled learned purposive movements, and (4) spatial-motor systems. Ultimately, they attempt to draw neuroscience and practice closer together by using translational reasoning to suggest possible new avenues for treating these disorders.


Description of strongly coupled Yukawa fluids using the variational modified hypernetted chain approach.
The variational modified hypernetted chain approach as proposed by J. Stat. Phys. 42, 437 (1986)] is used to describe strongly coupled Yukawa fluids. The integral equations of interest can be solved using the spherical harmonic oscillator wave functions as a seed. Comparisons are done with simulation results for equation of state and transport coefficients over the entire fluid domain for a wide range of the system parameters.


Molecular cloning and functional expression of the rat 175-kDa hyaluronan receptor for endocytosis.
We recently purified the rat liver hyaluronan receptor for endocytosis (HARE) and found abundant expression of 175- and approximately 300-kDa HARE species in sinusoidal endothelial cells of the liver, spleen, and lymph nodes. We report herein the first cloning and functional expression of the rat 175-kDa HARE. Peptide sequences were obtained from the purified 175-kDa HARE, and degenerate oligonucleotide primers were designed for reverse transcription-polymerase chain reaction and cDNA cloning. Results of 5'-rapid amplification of cDNA ends, Northern analysis, N-terminal sequence, and antibody reactivity analyses indicated the absence of mRNA directly encoding the 175-kDa HARE. This protein is most likely derived from a larger precursor. Accordingly, we constructed an artificial 4.7-kb cDNA encoding the 1431 amino acid 175-kDa HARE. The predicted type I membrane protein has a mass of 156,393 Da and a pI of 7.86. The 175-kDa HARE cDNA, fused to the N-terminal leader sequence of the Ig kappa-chain, was transfected transiently into COS-7 cells and stably into SK-Hep-1 cells, respectively, to assess hyaluronan or hyaluronic acid (HA)-binding activity and endocytosis. In both cases, HARE expression and HA-binding activity were detected. Furthermore, stable SK-175HARE cells demonstrated specific endocytosis of (125)I-HA and receptor recycling. Fluorescence-activated cell sorting analysis confirmed that recombinant HARE was expressed on the cell surface and that fluorescent HA uptake was inhibited by a specific blocking monoclonal antibody against HARE. Additionally, HARE was substantially colocalized with clathrin, but not with internalized HA that was delivered to lysosomes. The results confirm that recombinant 175-kDa HARE is an authentic endocytic receptor for HA and that this receptor can function independently of the approximately 300-kDa HARE. HARE is the first functionally identified member of a protein family that shares a similar organization of Fasciclin, epidermal growth factor-like, Xlink, and transmembrane domains.


A Clinical Trial of a Program for Pain Management and Opioid Reduction During Pregnancy.
A substantial proportion of pregnant women use prescription opioids. However, the lack of efficacy of chronic prescription opioid use for pain, combined with an increased risk of these medications in general and during pregnancy, suggests that the risks of these medications may outweigh the benefits of continued use. Though research has not evaluated non-pharmacological approaches to treat chronic pain during pregnancy, research conducted with the general population outside of pregnancy suggests that cognitive behavioral therapy (CBT) is an effective, non-pharmacological treatment. Therefore, the purpose of this study was to evaluate the effectiveness of CBT for chronic pain paired with shared decision-making for prescription opioid dose reduction among pregnant women with prescription opioid misuse. The study was an open-label, 8-week clinical trial of CBT for chronic pain and shared decision-making for prescription opioid dose reduction. Participants included a clinical sample of 20 pregnant women between the ages of 18 and 45 years who were misusing opioids but did not meet DSM-IV criteria for an opioid use disorder or other substance use disorder. Compared to baseline, at 8 weeks, participants had significant reductions in average prescription opioid morphine equivalent dose, prescription opioid misuse, worst pain ratings, and pain interference in general activity and at work. They did not report improvement in other pain ratings or areas of functioning. This study provides valuable information regarding the preliminary efficacy of CBT for chronic pain paired with shared decision-making among pregnant women misusing prescription opioids. ClinicalTrials.gov: NCT02804152.


Deciphering the Acute Cellular Phosphoproteome Response to Irradiation with X-rays, Protons and Carbon Ions.
Radiotherapy is a cornerstone of cancer therapy. The recently established particle therapy with raster-scanning protons and carbon ions landmarks a new era in the field of high-precision cancer medicine. However, molecular mechanisms governing radiation induced intracellular signaling remain elusive. Here, we present the first comprehensive proteomic and phosphoproteomic study applying stable isotope labeling by amino acids in cell culture (SILAC) in combination with high-resolution mass spectrometry to decipher cellular response to irradiation with X-rays, protons and carbon ions. At protein expression level limited alterations were observed 2 h post irradiation of human lung adenocarcinoma cells. In contrast, 181 phosphorylation sites were found to be differentially regulated out of which 151 sites were not hitherto attributed to radiation response as revealed by crosscheck with the PhosphoSitePlus database.Radiation-induced phosphorylation of the p(S/T)Q motif was the prevailing regulation pattern affecting proteins involved in DNA damage response signaling. Because radiation doses were selected to produce same level of cell kill and DNA double-strand breakage for each radiation quality, DNA damage responsive phosphorylation sites were regulated to same extent. However, differential phosphorylation between radiation qualities was observed for 55 phosphorylation sites indicating the existence of distinct signaling circuitries induced by X-ray versus particle (proton/carbon) irradiation beyond the canonical DNA damage response. This unexpected finding was confirmed in targeted spike-in experiments using synthetic isotope labeled phosphopeptides. Herewith, we successfully validated uniform DNA damage response signaling coexisting with altered signaling involved in apoptosis and metabolic processes induced by X-ray and particle based treatments.In summary, the comprehensive insight into the radiation-induced phosphoproteome landscape is instructive for the design of functional studies aiming to decipher cellular signaling processes in response to radiotherapy, space radiation or ionizing radiation per se Further, our data will have a significant impact on the ongoing debate about patient treatment modalities.


Environmental and biotic controls on the evolutionary history of insect body size.
Giant insects, with wingspans as large as 70 cm, ruled the Carboniferous and Permian skies. Gigantism has been linked to hyperoxic conditions because oxygen concentration is a key physiological control on body size, particularly in groups like flying insects that have high metabolic oxygen demands. Here we show, using a dataset of more than 10,500 fossil insect wing lengths, that size tracked atmospheric oxygen concentrations only for the first 150 Myr of insect evolution. The data are best explained by a model relating maximum size to atmospheric environmental oxygen concentration (pO(2)) until the end of the Jurassic, and then at constant sizes, independent of oxygen fluctuations, during the Cretaceous and, at a smaller size, the Cenozoic. Maximum insect size decreased even as atmospheric pO(2) rose in the Early Cretaceous following the evolution and radiation of early birds, particularly as birds acquired adaptations that allowed more agile flight. A further decrease in maximum size during the Cenozoic may relate to the evolution of bats, the Cretaceous mass extinction, or further specialization of flying birds. The decoupling of insect size and atmospheric pO(2) coincident with the radiation of birds suggests that biotic interactions, such as predation and competition, superseded oxygen as the most important constraint on maximum body size of the largest insects.


The role of decision analytic modeling in the health economic assessment of spinal intervention.
Narrative review. To review the common tenets, strengths, and weaknesses of decision modeling for health economic assessment and to review the use of decision modeling in the spine literature to date. For the majority of spinal interventions, well-designed prospective, randomized, pragmatic cost-effectiveness studies that address the specific decision-in-need are lacking. Decision analytic modeling allows for the estimation of cost-effectiveness based on data available to date. Given the rising demands for proven value in spine care, the use of decision analytic modeling is rapidly increasing by clinicians and policy makers. This narrative review discusses the general components of decision analytic models, how decision analytic models are populated and the trade-offs entailed, makes recommendations for how users of spine intervention decision models might go about appraising the models, and presents an overview of published spine economic models. A proper, integrated, clinical, and economic critical appraisal is necessary in the evaluation of the strength of evidence provided by a modeling evaluation. As is the case with clinical research, all options for collecting health economic or value data are not without their limitations and flaws. There is substantial heterogeneity across the 20 spine intervention health economic modeling studies summarized with respect to study design, models used, reporting, and general quality. There is sparse evidence for populating spine intervention models. Results mostly showed that interventions were cost-effective based on $100,000/quality-adjusted life-year threshold. Spine care providers, as partners with their health economic colleagues, have unique clinical expertise and perspectives that are critical to interpret the strengths and weaknesses of health economic models. Health economic models must be critically appraised for both clinical validity and economic quality before altering health care policy, payment strategies, or patient care decisions. 4.


Fluorescent staining of human chromosomes: identification of some common aberrations.
With the development of fluorescent staining techniques and their application to human chromosomes, identification of the entire human karyotype is now possible. Of considerable value are the elimination of the guesswork in the pairing of the C group and sex chromosomes and the recognition and characterization of the translocation chromosomes in mongolism.


Biological Aspects of the Tongue and Oropharyngeal Cavity of the Eurasian Collared Dove (Streptopelia decaocto, Columbiformes, Columbidae): Anatomical, Histochemical, and Ultrastructure Study.
We characterized the morphological and anatomical adaptations of the lingual microstructures of the Eurasian collared dove and discussed their implications for its dietary niche. We analyzed tongues of nine S. decaocto using histological, histochemical, stereomicroscopic, and scanning electron microscopic techniques. Our findings showed that the tongue is relatively short with a tapered apex that carries a terminal lingual nail. However, the lingual body has median scales and is bordered laterally by filiform papillae. Further, the tongue body bears a distinctive papillary crest. The tongue root is nonpapillate and infiltered with orifices of the posterior salivary glands. The bulky laryngeal mound has a circular glottic fissure, carrying a single row of papillae at the rear edge. Concurrently, our histological and histochemical findings demonstrate that the tongue has taste buds, anterior and posterior salivary glands, along with an elongated entoglossum that extends from lingual apex to root. Besides, ovoid and globular mucous glands displayed intense alcianophilic reactions. More substantially, the palate is made up of three palatine ridges with a caudal choanal cleft that was bounded by two rows of palatine papillae. Our data indicate multiple and novel structural variations for the lingual and palatal sculptures coopted for their feeding style.


High Expression of EphA4 Predicted Lesser Degree of Tumor Regression after Neoadjuvant Chemoradiotherapy in Rectal Cancer.
Background: Numerous transmembrane receptor tyrosine kinase pathways have been found to play an important role in tumor progression in some cancers. This study was aimed to evaluate the clinical impact of Eph receptor A4 (EphA4) in patients with rectal cancer treated with neoadjuvant concurrent chemoradiotherapy (CCRT) combined with mesorectal excision, with special emphasis on tumor regression. Methods: Analysis of the publicly available expression profiling dataset of rectal cancer disclosed that EphA4 was the top-ranking, significantly upregulated, transmembrane receptor tyrosine kinase pathway-associated gene in the non-responders to CCRT, compared with the responders. Immunohistochemical study was conducted to assess the EphA4 expression in pre-treatment biopsy specimens from 172 rectal cancer patients without distant metastasis. The relationships between EphA4 expression and various clinicopathological factors or survival were statistically analyzed. Results: EphA4 expression was significantly associated with vascular invasion (P=0.015), post-treatment depth of tumor invasion (P=0.006), pre-treatment and post-treatment lymph node metastasis (P=0.004 and P=0.011, respectively). More importantly, high EphA4 expression was significantly predictive for lesser degree of tumor regression after CCRT (P=0.031). At univariate analysis, high EphA4 expression was a negative prognosticator for disease-specific survival (P=0.0009) and metastasis-free survival (P=0.0001). At multivariate analysis, high expression of EphA4 still served as an independent adverse prognostic factor for disease-specific survival (HR, 2.528; 95% CI, 1.131-5.651; P=0.024) and metastasis-free survival (HR, 3.908; 95% CI, 1.590-9.601; P=0.003). Conclusion: High expression of EphA4 predicted lesser degree of tumor regression after CCRT and served as an independent negative prognostic factor in patients with rectal cancer.


Platelet to lymphocyte ratio is associated with the severity of coronary artery disease and clinical outcomes of percutaneous coronary intervention in the Chinese Han population.
The aim of the present study was to evaluate whether the ratio of the absolute number of platelets to the number of lymphocytes (PLR) correlates with the severity of coronary artery disease (CAD) and major adverse cardiovascular disease (CVD) events in Chinese patients with CAD. PLR was calculated as follows: PLR=platelet count/lymphocyte count, using the complete blood counts of 854 Chinese Han subjects. CAD severity was determined using angiographic evidence by cardiologists unaware of the study aims. The association between PLR and CAD severity was analyzed by logistic regression. Clinical endpoints were evaluated during a median follow-up period of 42 months. The association between PLR and CVD events was assessed using Cox regression models. Patients with PLR>171 exhibited more severe coronary artery stenosis [odds ratio, 2.393; 95% confidence intervals (CI), 1.394-4.108; P=0.002] and worse prognoses, with a higher rate of major adverse CVD events during five years of follow-up (hazard ratio, 1.982; 95% CI, 1.329-2.957; P=0.001). A Kaplan-Meier curve demonstrated that the CVD event rate of 34.27% in patients with PLR>171 was significantly higher than that in patients with PLR<100 (P<0.001). These findings suggest that PLR is independently associated with CAD severity and long-term major adverse CVD events; therefore, high PLR may predict poor prognosis of CAD in the Chinese Han population.


Rare liver diseases are not rare in China.
Rare diseases, also known as orphan diseases, are a group of diseases that affect a relatively small number of people. Low incidence rates, atypical symptoms, imperfect diagnosis criteria and few treatment options impose medical, psychological and financial stress on the local healthcare system. The spectrum of liver diseases in China has changed in the past decades due to successful control of once highly prevalent viral hepatitis B and C. Furthermore, the increased awareness and improved availability of specific laboratory tests have also facilitated the diagnosis of rare diseases such as autoimmune, cholestatic and genetic liver diseases. Finally, considering the huge population, the total number of many rare liver diseases in China is not as rare as once deemed. In this mini-review article, we will outline the current clinical and epidemiological profiles of some rare liver diseases that are no longer rare in China.


Rheumatology university faculty opinion on coronavirus disease-19 (COVID-19) vaccines: the vaXurvey study from Egypt.
The aim of the present work was to explore the perspectives of Egyptian Rheumatology staff members as regards the coronavirus disease-19 (COVID-19) vaccine. The survey is composed of 25 questions. Some questions were adapted from the global rheumatology alliance COVID-19 survey for patients. 187 rheumatology staff members across Egypt from 18 universities and authorizations actively participated with a valid response. The mean time needed to complete the survey was 17.7 ± 13 min. Participants were 159 (85%) females (F:M 5.7:1). One-third agreed that they will be vaccinated once available, 24.6% have already received at least one dose, 29.4% are unsure while 16% will not take it. Furthermore, 70.1% agreed that they will recommend it to the rheumatic diseases (RD) patients once available, 24.1% are not sure while 5.9% will not recommend it. RD priority to be vaccinated against COVID-19 in descending order include SLE (82.9%), RA (55.1%), vasculitis (51.3%), systemic sclerosis (39.6%), MCTD (31.6%), Behcet's disease (28.3%). The most common drugs to be avoided before vaccination included biologics (71.7%), DMARDs (44.4%), biosimilars (26.7%), IVIg (17.1%) and NSAIDs (9.1%). The results of the study and specifically the low rate of acceptability are alarming to Egyptian health authorities and should stir further interventions to reduce the levels of vaccine hesitancy. As rheumatic disease patients in Egypt were not systematically provided with the vaccine till present, making the vaccine available could as well enhance vaccine acceptance. Further studies to investigate any possible side effects, on a large scale of RD patients are warranted.


Prostaglandin E2 modulates TNF-alpha-induced MCP-1 synthesis in pancreatic acinar cells in a PKA-dependent manner.
Cyclooxygenase (COX)-2 is increased in human chronic pancreatitis. We recently demonstrated in a model of chronic pancreatitis (WBN/Kob rat) that inhibition of COX-2 activity reduces and delays pancreatic inflammation and fibrosis. Monocyte chemoattractant protein (MCP)-1 mRNA and PGE(2) were significantly reduced, correlating with a decreased infiltration of macrophages. MCP-1 plays an important role in the recruitment of macrophages to the site of tissue injury. The aim of our study is to identify mechanisms by which macrophages and acinar cells maintain an inflammatory reaction. The expression profile of E prostanoid receptors EP(1-4) and MCP-1 was analyzed by RT-PCR from pancreatic specimens and AR42J cells. MCP-1 secretion was detected by ELISA from rat pancreatic lobuli. We determined EP(1-4) mRNA levels in WBN/Kob rats with chronic pancreatic inflammation. Individual isoforms were highly increased in rat pancreas, concurrent with MCP-1 mRNA expression. In supernatants of pancreatic lobuli and AR42J cells, MCP-1 was detectable by ELISA. In the presence of TNF-alpha, MCP-1 was upregulated. Coincubation with PGE(2) enhanced the TNF-alpha-induced MCP-1 synthesis significantly. Similarly, TNF-alpha mRNA was synergistically upregulated by TNF-alpha and PGE(2). Furthermore, the synergistic effect of TNF-alpha and PGE(2) was abolished by inhibition of PKA but not of PKC. We conclude that EP receptors are upregulated during chronic pancreatic inflammation. PGE(2) modulates the TNF-alpha-induced MCP-1 synthesis and secretion from acinar cells. This synergistic effect is controlled by PKA. This mechanism might explain the COX-2-dependent propagation of pancreatic inflammation.


Delayed Effects of Acute Radiation Exposure in a Murine Model of the H-ARS: Multiple-Organ Injury Consequent to <10 Gy Total Body Irradiation.
The threat of radiation exposure from warfare or radiation accidents raises the need for appropriate animal models to study the acute and chronic effects of high dose rate radiation exposure. The goal of this study was to assess the late development of fibrosis in multiple organs (kidney, heart, and lung) in survivors of the C57BL/6 mouse model of the hematopoietic-acute radiation syndrome (H-ARS). Separate groups of mice for histological and functional studies were exposed to a single uniform total body dose between 8.53 and 8.72 Gy of gamma radiation from a Cs radiation source and studied 1-21 mo later. Blood urea nitrogen levels were elevated significantly in the irradiated mice at 9 and 21 mo (from ∼22 to 34 ± 3.8 and 69 ± 6.0 mg dL, p < 0.01 vs. non-irradiated controls) and correlated with glomerosclerosis (29 ± 1.8% vs. 64 ± 9.7% of total glomeruli, p < 0.01 vs. non-irradiated controls). Glomerular tubularization and hypertrophy and tubular atrophy were also observed at 21 mo post-total body irradiation (TBI). An increase in interstitial, perivascular, pericardial and peribronchial fibrosis/collagen deposition was observed from ∼9-21 mo post-TBI in kidney, heart, and lung of irradiated mice relative to age-matched controls. Echocardiography suggested decreased ventricular volumes with a compensatory increase in the left ventricular ejection fraction. The results indicate that significant delayed effects of acute radiation exposure occur in kidney, heart, and lung in survivors of the murine H-ARS TBI model, which mirrors pathology detected in larger species and humans at higher radiation doses focused on specific organs.


Genipin enhances the mechanical properties of tissue-engineered cartilage and protects against inflammatory degradation when used as a medium supplement.
Genipin is a naturally-derived biocompatible cross-linking agent commonly used to generate three dimensional tissue-engineered scaffolds or to fix biologically derived scaffolds prior to implantation. Here we propose a novel use for genipin as a long-term culture medium supplement to promote cross-linking of de novo cell products that are produced in engineered cartilage. We hypothesize that the application of genipin will stabilize the extracellular matrix components and increase the mechanical properties of developing engineered cartilage. Chondrocytes encapsulated in agarose hydrogel (a neutrally charged polysaccharide scaffold that is unaffected by genipin cross-linking) were cultured in a chemically-defined growth medium that was supplemented with varying concentrations of genipin (22 microM, 220 microM, 2200 microM) for various durations (continuous or intermittent). Tissues developed significantly higher mechanical properties (+28% dynamic modulus and +20% Young's modulus) by day 42 with genipin treatment compared to untreated controls. These increases were not immediate, but presented over culture time after genipin treatment. The genipin treated groups were also more resistant to cytokine-induced degradation with interleukin-1alpha; maintaining an E(Y) (+218%), G* (+390%) and glycosaminoglycan (GAG) content (+477%) over genipin-untreated constructs subjected to interleukin. We hypothesize two mechanisms through which the physical enhancement of tissue properties may be fostered: (1) by cross-link mediated reorganization and enhanced retention of cell-elaborated extracellular matrix components, and (2) through reduction of the loss of extracellular matrix components by increasing their resilience to catabolic degradation. These studies demonstrate a potential use of genipin as a medium supplement to develop enhanced engineered cartilage.


Efficacy and safety of short duration radiotherapy combined with chemotherapy for advanced rectal cancer.
Radiotherapy or chemoradiotherapy is widely used for the treatment of rectal cancer preoperatively. Although the combination of radiotherapy and chemotherapy as an established preoperative neoadjuvant therapy shows high efficacy in the treatment of rectal cancer, some patients experience a response of poor tolerance and outcomes due to the long duration radiotherapy. The study compared short duration radiotherapy plus chemotherapy vs long duration radiotherapy plus chemotherapy for rectal cancer to determine whether short duration radiation treatment should be considered to diminish complications, reduce risk of recurrence and improve survival in patients with rectal cancer. To evaluate the efficacy and safety of short duration radiotherapy combined with chemotherapy for the treatment of advanced rectal cancer. One hundred patients with stage IIIB or higher severe rectal cancer were selected as the study subjects at The First Affiliated Hospital of Hebei North University between December 2018 and December 2019. The patients were assigned to different groups based on the treatment regimens. Fifty patients who received preoperative short durations of radiotherapy plus chemotherapy were enrolled in an observation group and fifty patients who received conventional radiotherapy and chemotherapy were enrolled in a control group. Colonoscopic biopsy was performed for all patients with pathological diagnosis of rectal cancer. The expression of tumor-related factors such as RUNX3 and Ki-67 was quantitatively analyzed using immunohistochemistry in the tissues of the patients before and after treatment. Moreover, the duration of procedure, the amount of bleeding during the operation, the anus-conserving rate, the incidence of postoperative complications (wound infection, anastomotic leakage, postoperative intestinal obstruction, etc.) and postoperative pathology were compared between the two groups. The overall survival rate, recurrence rate and distant metastasis rate were also compared through postoperative reexamination and regular follow-up. There was no significant difference in the positive expression rate of RUNX3 and Ki-67 between the two groups before the treatment (P > 0.05). Compared with the pretreatment value, the positive rate of RUNX3 was increased and the positive rate of Ki-67 was decreased in both groups after the treatment (all P < 0.05). The incidence of leukopenia, thrombocytopenia, neutropenia and diarrhea were higher in the observation group than in the control group (all P < 0.05). There was no significant difference in the incidence of anemia, fatigue, neurotoxicity and nausea and vomiting between the two groups (all P > 0.05). No significant difference was observed in the duration of procedure, intraoperative bleeding, the anus-conserving rate and the incidence of postoperative complications between the two groups (P > 0.05). After 1 year of follow-up, the 1-yr survival rate was 80.0% in the observation group and 68.0% in the control group, the recurrence rate was 8.0% in the observation group and 10.0% in the control group, the distant metastasis rate was 6.0% in the observation group and 8.0% in the control group difference (all P < 0.05). Short duration radiotherapy combined with chemotherapy can improve the cure rate, prolong the survival time and reduce the incidence of complications in patients with advanced rectal cancer.


A major 125-kd membrane glycoprotein of Saccharomyces cerevisiae is attached to the lipid bilayer through an inositol-containing phospholipid.
A number of plasma membrane glycoproteins of mammalian and protozoan origin are released from cells by phosphatidylinositol-specific phospholipase C. Some of these proteins have been shown to be attached to the lipid bilayer via a covalently linked, structurally complex glycophospholipid. Here we establish the existence of similarly linked glycoproteins in the yeast Saccharomyces cerevisiae. The most abundant of these is a tightly membrane-bound glycoprotein of 125 kd. The detergent-binding moiety of this protein can be removed by phosphatidylinositol-specific phospholipase C of bacterial origin or from Trypanosoma brucei. Metabolic labeling indicates that the protein contains covalently attached fatty acid and inositol. It also contains the cross-reacting determinant (CRD), an antigen found previously on the glycophospholipid anchor of protozoan and mammalian origin. Treatment of the protein with endoglycosidases F and H results in a 95-kd species. In the secretion mutant sec18, grown at 37 degrees C, the vesicular transport of glycoproteins is reversibly blocked between the rough endoplasmic reticulum and the Golgi apparatus. We find that sec18 cells, when grown at 37 degrees C, do add phospholipid anchors to newly synthesized glycoproteins. This indicates that these anchors are added in the rough endoplasmic reticulum.


Inhibition of the von Willebrand (VWF)-collagen interaction by an antihuman VWF monoclonal antibody results in abolition of in vivo arterial platelet thrombus formation in baboons.
The interaction between collagen, von Willebrand factor (VWF), and glycoprotein Ib is the first step in hemostasis and thrombosis especially under high shear conditions. We studied the inhibition of the VWF-collagen interaction by using an antihuman VWF monoclonal antibody 82D6A3 to prevent arterial thrombosis in baboons to develop a new kind of antithrombotic strategy and determine for the first time experimental in vivo data concerning the importance of the collagen-VWF interaction. We used a modified Folts model to study the antithrombotic efficacy of 82D6A3, where cyclic flow reductions (CFRs) were measured in the femoral artery. Administering a dose of 100, 300, and 600 microg/kg resulted in a 58.3%, 100%, and 100% reduction in the CFRs, respectively. When 100 microg/kg 82D6A3 was infused into the baboons, 80% of VWF-A3 domain was occupied, corresponding to 30% to 36% ex vivo inhibition of VWF binding to collagen, with no prolongation of the bleeding time. The bleeding time was also not significantly prolonged when the CFRs were abolished at doses of 300 microg/kg and 600 microg/kg. At these doses 100% of VWF was occupied by the antibody and 100% ex vivo inhibition of the VWF-collagen binding was observed. 82D6A3 has a high affinity for VWF; after 48 hours still 68% VWF (300 microg/kg) was occupied with a pharmacologic effect up to 5 hours after administration (80%-100% occupancy). In conclusion, these results clearly indicate that the VWF-collagen interaction is important in vivo in thrombosis under high shear conditions and thus might be a new target for preventing arterial thrombosis.


Efficacy of chloroquine in the treatment of Plasmodium vivax malaria in Turkey.
In most regions of the world, chloroquine (CQ) has been the standard treatment for Plasmodium vivax malaria for more than 40 years. Recently, however, CQ-resistant P. vivax has been reported from Oceania, several parts of Asia, and South America. The therapeutic efficacy of CQ in the treatment of acute, P. vivax malaria has now been assessed in two areas of the Turkish province of Sanliurfa: the towns of Karacadag and Sekerli. On admission and on days 2, 3, 7, 14, 21, and 28, all 112 patients investigated were examined clinically and blood samples were collected and smeared. Treatment consisted of 10 mg CQ/kg on day 0, the same dose on day 1, and 5 mg CQ/mg on day 2, each dose being supervised. Worryingly, 14.7% of the patients from Karacadag and 10.3% of those from Sekerli showed apparent treatment failure between days 3 and 28. In Sanliurfa province, in south-eastern Turkey, there therefore seems to be a high risk of therapeutic failure in patients given CQ to cure P. vivax malaria, probably because of CQ resistance.


Theory of the topological anderson insulator.
We present an effective medium theory that explains the disorder-induced transition into a phase of quantized conductance, discovered in computer simulations of HgTe quantum wells. It is the combination of a random potential and quadratic corrections proportional to p2 sigma(z) to the Dirac Hamiltonian that can drive an ordinary band insulator into a topological insulator (having an inverted band gap). We calculate the location of the phase boundary at weak disorder and show that it corresponds to the crossing of a band edge rather than a mobility edge. Our mechanism for the formation of a topological Anderson insulator is generic, and would apply as well to three-dimensional semiconductors with strong spin-orbit coupling.


Prognostic Significance of Neutrophil-to-lymphocyte Ratio in Luminal Breast Cancers With Low Levels of Tumour-infiltrating Lymphocytes.
This study aimed to improve the prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and tumour-infiltrating lymphocytes (TILs). In this retrospective study, NLR and TIL data from 677 operated breast cancer patients were analysed. The cut-off value of NLR was set at 2.72, and TIL levels were classified as low (<10%), intermediate (≥10 to <50%), and high (≥50%). Recurrence-free survival (RFS) was significantly longer in patients with low NLR (n=459) than in those with high NLR (n=218) (p=0.0383). In ER-positive/HER2-negative and TIL-low breast cancers, there were significant associations between NLR levels and RFS (p=0.0129) or overall survival (OS) (p=0.0046). On multivariate analysis, NLR was a significant and independent factor for OS (hazard ratio=3.78; 95% confidence interval=1.21-14.17; p=0.022). These data may be useful for predicting patient prognosis and understanding the clinical significance of immune status in breast cancers.


Suggested Mechanisms of Tracheal Occlusion Mediated Accelerated Fetal Lung Growth: A Case for Heterogeneous Topological Zones.
In this article, we report an up-to-date summary on tracheal occlusion (TO) as an approach to drive accelerated lung growth and strive to review the different maternal- and fetal-derived local and systemic signals and mechanisms that may play a significant biological role in lung growth and formation of heterogeneous topological zones following TO. Pulmonary hypoplasia is a condition whereby branching morphogenesis and embryonic pulmonary vascular development are globally affected and is classically seen in congenital diaphragmatic hernia. TO is an innovative approach aimed at driving accelerated lung growth in the most severe forms of diaphragmatic hernia and has been shown to result in improved neonatal outcomes. Currently, most research on mechanisms of TO-induced lung growth is focused on mechanical forces and is viewed from the perspective of homogeneous changes within the lung. We suggest that the key principle in understanding changes in fetal lungs after TO is taking into account formation of unique variable topological zones. Following TO, fetal lungs might temporarily look like a dynamically changing topologic mosaic with varying proliferation rates, dissimilar scale of vasculogenesis, diverse patterns of lung tissue damage, variable metabolic landscape, and different structures. The reasons for this dynamic topological mosaic pattern may include distinct degree of increased hydrostatic pressure in different parts of the lung, dissimilar degree of tissue stress/damage and responses to this damage, and incomparable patterns of altered lung zones with variable response to systemic maternal and fetal factors, among others. The local interaction between these factors and their accompanying processes in addition to the potential role of other systemic factors might lead to formation of a common vector of biological response unique to each zone. The study of the interaction between various networks formed after TO (action of mechanical forces, activation of mucosal mast cells, production and secretion of damage-associated molecular pattern substances, low-grade local pulmonary inflammation, and cardiac contraction-induced periodic agitation of lung tissue, among others) will bring us closer to an appreciation of the biological phenomenon of topological heterogeneity within the fetal lungs.


Pain management: a practical approach to nursing education.
This article describes a program that provides a practical approach to educating staff nurses in pain management. The content is appropriate for adult patients across all clinical specialties. Pain assessment and commonly used analgesic and adjuvant medications are provided in nine educational sessions lasting 10 to 20 minute. Each presentation topic is prepared in Microsoft Power Point in three versions: slides, notes, and handouts.


Phase II dose-response trials: A simulation study to compare analysis method performance under design considerations.
Phase II trials are intended to provide information about the dose-response relationship and to support the choice of doses for a pivotal phase III trial. Recently, new analysis methods have been proposed to address these objectives, and guidance is needed to select the most appropriate analysis method in specific situations. We set up a simulation study to evaluate multiple performance measures of one traditional and three more recent dose-finding approaches under four design options and illustrate the investigated analysis methods with an example from clinical practice. Our results reveal no general recommendation for a particular analysis method across all design options and performance measures. However, we also demonstrate that the new analysis methods are worth the effort compared to the traditional ANOVA-based approach.


In vitro evaluation of the probiotic potential of bacteriocin producer Lactobacillus sakei 1.
Lactobacillus sakei 1 is a food isolate that produces a heat-stable antimicrobial peptide (sakacin 1, a class IIa bacteriocin) inhibitory to the opportunistic pathogen Listeria monocytogenes. Bacterial isolates with antimicrobial activity may be useful for food biopreservation and also for developing probiotics. To evaluate the probiotic potential of L. sakei 1, it was tested for (i) in vitro gastric resistance (with synthetic gastric juice adjusted to pH 2.0, 2.5, or 3.0); (ii) survival and bacteriocin production in the presence of bile salts and commercial prebiotics (inulin and oligofructose); (iii) adhesion to Caco-2 cells; and (iv) effect on the adhesion of L. monocytogenes to Caco-2 cells and invasion of these cells by the organism. The results showed that L. sakei 1 survival in gastric environment varied according to pH, with the maximum survival achieved at pH 3.0, despite a 4-log reduction of the population after 3 h. Regarding the bile salt tolerance and influence of prebiotics, it was observed that L. sakei 1 survival rates were similar (P > 0.05) for all de Man Rogosa Sharpe (MRS) broth formulations when tests were done after 4 h of incubation. However, after incubation for 24 h, the survival of L. sakei 1 in MRS broth was reduced by 1.8 log (P < 0.001), when glucose was replaced by either inulin or oligofructose (without Oxgall). L. sakei 1 was unable to deconjugate bile salts, and there was a significant decrease (1.4 log) of the L. sakei 1 population in regular MRS broth plus Oxgall (P < 0.05). In spite of this, tolerance levels of L. sakei 1 to bile salts were similar in regular MRS broth and in MRS broth with oligofructose. Lower bacteriocin production was observed in MRS broth when inulin (3,200 AU/ml) or oligofructose (2,400 AU/ml) was used instead of glucose (6,400 AU/ml). L. sakei 1 adhered to Caco-2 cells, and its cell-free pH-neutralized supernatant containing sakacin 1 led to a significant reduction of in vitro listerial invasion of human intestinal Caco-2 cells.


Neuropeptide FF modulates neuroendocrine and energy homeostasis through hypothalamic signaling.
Neuropeptide FF (NPFF) is known as a morphine-modulating peptide and was first isolated in 1985. It has been characterized as an RF-amide peptide. The traditional role of NPFF is mediation of the pain response, and it displays both anti-opioid and pro-opioid actions through central nervous system. In the recent decade, additional evidence has revealed some untraditional features of NPFF, such as regulation of the neuroendocrine system, energy homeostasis, anti-inflammation, pain transmission, and peripheral modulation of adipose tissue macrophages. Neuropeptide FF receptor 2 (NPFFR2) is a physiological receptor of NPFF, and the actions of NPFF may occur through downstream NPFFR2 signaling. NPFF and NPFFR2 increase the neuronal activity in various areas of the hypothalamus to modulate the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, food intake, and energy balance. These underlying cellular mechanisms have been explored in the past few years. Here, we review the impact of NPFF and related RF-amide peptides on hypothalamic function. The interaction of NPFF with NPFFR2 in the hypothalamus is emphasized, and NPFF-NPFFR2 system may represent an important therapeutic target in hypothalamic-related disorders in the future.


Positional distribution of isomers of monoenoic fatty acids in animal glycerolipids.
The distributions of the following monoenoic acids were determined [notation: (position of double bond)-(chain length): (no. of double bonds)]: 7-, 9-, and 11-16:1; 7-, 9-, 11-, and 13-18:1; 9-, 11-, and 13-20:1; 9 + 11-22:1 and 13-22:1. As a rule, all isomers of a group show different distribution patterns. In the phospholipids of fish and mammals, the 7- and 13-isomers of 18:1 accumulate in position 1. In triglycerides of mammals fed on fish they accumulate in positions 1 plus 3, and this distribution is shared by 7-16:1 and 11-16:1 and by the groups 20:1 and 22:1. The positional distribution of the acids seems to depend on their structure, the 9-isomers in general accumulating in position 2; but in triglycerides, at least, the origin of the acid also seems to play a directing role, the exogenous acids being incorporated into positions 1 and 3. The variability of the distribution patterns of 9-16:1, 9-18:1, and 11:18:1, which contrasts with the regularity of the patterns for saturated and polyenoic acids, may be connected with the ability of the endogenous monoenoic acids to balance fluctuations in the supply of the exogenous polyenoic acids, and with the role of the fatty acid 9,10-dehydrogenation mechanism in the maintenance of structural and physical properties of phospholipids and triglycerides.


Self-assembled multivalent (SAMul) ligand systems with enhanced stability in the presence of human serum.
Self-assembled cationic micelles are an attractive platform for binding biologically-relevant polyanions such as heparin. This has potential applications in coagulation control, where a synthetic heparin rescue agent could be a useful replacement for protamine, which is in current clinical use. However, micelles can have low stability in human serum and unacceptable toxicity profiles. This paper reports the optimisation of self-assembled multivalent (SAMul) arrays of amphiphilic ligands to bind heparin in competitive conditions. Specifically, modification of the hydrophobic unit kinetically stabilises the self-assembled nanostructures, preventing loss of binding ability in the presence of human serum - cholesterol hydrophobic units significantly outperform systems with a simple aliphatic chain. It is demonstrated that serum albumin disrupts the binding thermodynamics of the latter system. Molecular simulation shows aliphatic lipids can more easily be removed from the self-assembled nanostructures than the cholesterol analogues. This agrees with the experimental observation that the cholesterol-based systems undergo slower disassembly and subsequent degradation via ester hydrolysis. Furthermore, by stabilising the SAMul nanostructures, toxicity towards human cells is decreased and biocompatibility enhanced, with markedly improved survival of human hepatoblastoma cells in an MTT assay.


Serum Phosphorus and Risk of Cardiovascular Disease, All-Cause Mortality, or Graft Failure in Kidney Transplant Recipients: An Ancillary Study of the FAVORIT Trial Cohort.
Mild hyperphosphatemia is a putative risk factor for cardiovascular disease [CVD], loss of kidney function, and mortality. Very limited data are available from sizable multicenter kidney transplant recipient (KTR) cohorts assessing the potential relationships between serum phosphorus levels and the development of CVD outcomes, transplant failure, or all-cause mortality. Cohort study. The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial, a large, multicenter, multiethnic, controlled clinical trial that provided definitive evidence that high-dose vitamin B-based lowering of plasma homocysteine levels did not reduce CVD events, transplant failure, or total mortality in stable KTRs. Serum phosphorus levels were determined in 3,138 FAVORIT trial participants at randomization. During a median follow-up of 4.0 years, the cohort had 436 CVD events, 238 transplant failures, and 348 deaths. Proportional hazards modeling revealed that each 1-mg/dL higher serum phosphorus level was not associated with a significant increase in CVD risk (HR, 1.06; 95% CI, 0.92-1.22), but increased transplant failure (HR, 1.36; 95% CI, 1.15-1.62) and total mortality risk associations (HR, 1.21; 95% CI, 1.04-1.40) when adjusted for treatment allocation, traditional CVD risk factors, kidney measures, type of kidney transplant, transplant vintage, and use of calcineurin inhibitors, steroids, or lipid-lowering drugs. These associations were strengthened in models without kidney measures: CVD (HR, 1.14; 95% CI, 1.00-1.31), transplant failure (HR, 1.72; 95% CI, 1.46-2.01), and mortality (HR, 1.34; 95% CI, 1.15-1.54). We lacked data for concentrations of parathyroid hormone, fibroblast growth factor 23, or vitamin D metabolites. Serum phosphorus level is marginally associated with CVD and more strongly associated with transplant failure and total mortality in long-term KTRs. A randomized controlled clinical trial in KTRs that assesses the potential impact of phosphorus-lowering therapy on these hard outcomes may be warranted.


Spontaneous cervical intradural disc herniation presenting with Brown-Séquard and Horner's syndrome: lesson learned from a very unique case.
Cervical spontaneous intradural disc herniation (IDH) is an extremely rare condition. We describe a unique case of a patient presenting with a Brown-Séquard syndrome (BSS) and Horner's syndrome (HS). This study aimed to report an unusual case of spontaneous cervical intradural disc herniation that presented with Horner's and Brown-Séquard syndrome (BSS) and discuss difficulties in preoperative diagnosis and treatment difficulties of intradural cervical disc. Notes and images review, and analysis of the relevant literature. A 45-year old female presented with acute Horner's syndrome and Brown-Séquard syndrome. The magnetic resonance imaging of cervical spine revealed C4-5 disc extrusion with cord compression. The patient underwent urgent decompression through an anterior cervical corpectomy and fusion. Patient fully recovered 6 months after disease onset. We would like to emphasize that prompt and anterior cervical decompression is the treatment of choice, as it directly address the problem and allows dura repair in spontaneous cervical disc herniation.


Mitochondrial dynamics in chondrocytes and their connection to the mechanical properties of the cytoplasm.
The motion and redistribution of intracellular organelles is a fundamental process in cells. Organelle motion is a complex phenomenon that depends on a large number of variables including the shape of the organelle, the type of motors with which the organelles are associated, and the mechanical properties of the cytoplasm. This paper presents a study that characterizes the diffusive motion of mitochondria in chondrocytes seeded in agarose constructs and what this implies about the mechanical properties of the cytoplasm. Images showing mitochondrial motion in individual cells at 30 s intervals for 15 min were captured with a confocal microscope. Digital image correlation was used to quantify the motion of the mitochondria, and the mean square displacement (MSD) was calculated. Statistical tools for testing whether the characteristic motion of mitochondria varied throughout the cell were developed. Calculations based on statistical mechanics were used to establish connections between the measured MSDs and the mechanical nature of the cytoplasm. The average MSD of the mitochondria varied with time according to a power law with the power term greater than 1, indicating that mitochondrial motion can be viewed as a combination of diffusion and directional motion. Statistical analysis revealed that the motion of the mitochondria was not uniform throughout the cell, and that the diffusion coefficient may vary by over 50%, indicating intracellular heterogeneity. High correlations were found between movements of mitochondria when they were less than 2 microm apart. The correlation is probably due to viscoelastic properties of the cytoplasm. Theoretical analysis based on statistical mechanics suggests that directed diffusion can only occur in a material that behaves like a fluid on large time scales. The study shows that mitochondria in different regions of the cell experience different characteristic motions. This suggests that the cytoplasm is a heterogeneous viscoelastic material. The study provides new insight into the motion of mitochondria in chondrocytes and its connection with the mechanical properties of the cytoplasm.


Body dimensions and carcass measurements of cattle selected for postweaning gain fed two different diets.
Genetic and phenotypic parameters among nine body dimensions and two measures of growth rate were estimated from measurements on 709 Angus and Hereford bulls and heifers born in 1984 and 1985. Height and width at hips, height at withers, body length, girth, head length and width, muzzle width, and cannon bone circumference were measured at weaning and again after 168-d postweaning gain tests. The cattle were from the final two calf crops of a 20-yr study to examine the response to selection for postweaning gain when fed either a high-concentrate diet or an all-hay diet. Sources of variation included year of birth, breed, sire within breed, diet, age of dam, and the linear regression on calf age. Parameter estimates among the body dimensions and carcass measurements were also calculated using a subsample of 318 Hereford and Angus bulls fed until they achieved > or = 7 mm of subcutaneous fat. Yearling measurements from calves fed the high-concentrate diet were larger than those from calves fed the all-hay diet. Sire within breed, age of dam, and the regression on age of calf affected all measurements (P < .001) at both measurement times. Dietary energy concentration influenced all body measurements taken at the end of test. Heritabilities of all body measurements were moderate to high. The highest genetic correlations with gain were for cannon bone circumference, body length, and heart girth. The heritabilities of all body dimensions were sufficient to indicate that selection progress was possible, but the low genetic correlations with gain and carcass traits suggested that this may not be desirable.


Advances in the construction of diverse SuFEx linkers.
Sulfur fluoride exchange (SuFEx), a new generation of click chemistry, was first presented by Sharpless, Dong and co-workers in 2014. Owing to the high stability and yet efficient reactivity of the SVI-F bond, SuFEx has found widespread applications in organic synthesis, materials science, chemical biology and drug discovery. A diverse collection of SuFEx linkers has emerged, involving gaseous SO2F2 and SOF4 hubs; SOF4-derived iminosulfur oxydifluorides; O-, N- and C-attached sulfonyl fluorides and sulfonimidoyl fluorides; and novel sulfondiimidoyl fluorides. This review summarizes the progress of these SuFEx connectors, with an emphasis on analysing the advantages and disadvantages of synthetic strategies of these connectors based on the SuFEx concept, and it is expected to be beneficial to researchers to rapidly and correctly understand this field, thus inspiring further development in SuFEx chemistry.


[Effect of hypoxia/reoxygenation (H/R) on expression of MICA and MICB in human hepatocytes].
It has been found that the human major histocompatibility complex class I chain-related antigen A,B (MICA,B), the ligand for NKG2D (an activating receptor of NK cell, CD8+ cell and gammadelta T cell), could be induced by cellular stress. The purpose of this study is to investigate whether Hypoxia/Reoxygenation could upregulate expression of MICA,B gene in human hepatocytes (HL-7702). The model of cell hypoxia/reoxygenation was used to mimic ischemia/reperfusion injury (IRI) of graft organ. The human hepatocytes were exposed to hypoxic condition for 15 h under 1% O2, 94% N2 and 5% CO2, then reoxygenated for 2 h, 4 h, 6 h, 12 h and 24 h separately under normal condition. The levels of MICA and MICB mRNA were measured by semi-quantitative RT-PCR. The surface expression of MIC were detected by immunofluorescence with a rabbit polyclonal antibody which is recommended for the detection of MICA,B of human origin simultaneously. Hpoxia/Reoxygenation increased the levels of MICA,B in hypoxic hepatocytes. In this article is firstly reported that H/R could increased the levels of MICA,B in human hepatocytes, yet the meachinsm is unknown. The upregulated expression of NKG2D ligand possibly activates NK cells and is hence associated with transplantation.


Hollow thermoresponsive microgels.
Thermoresponsive poly(N-isopropyl acrylamide) (pNIPAm) microgels possessing a hollow structure have been synthesized from core-shell nanoparticles upon oxidation of the particle core, followed by removal of the produced polymer segments by centrifugation. N,N'-(1,2-dihydroxyethylene)bisacrylamide (DHEA) is used as a cross-linker for preparing the degradable core, whereas N,N'-methylenebis(acrylamide) (BIS) is used as a cross-linker to add a nondegradable pNIPAm shell. Addition of NaIO(4) to a suspension of these particles in water leads to controlled degradation of the particle core by cleavage of the 1,2-glycol bond in DHEA. Fluorescence spectroscopy, UV/Vis spectroscopy, and photon correlation spectroscopy are used to characterize the hollow particles produced.


Investigating Brain Network Changes and Their Association With Cognitive Recovery After Traumatic Brain Injury: A Longitudinal Analysis.
Traumatic brain injury (TBI) can result in acute cognitive deficits and diffuse axonal injury reflected in white matter brain network alterations, which may, or may not, later recover. Our objective is to first characterize the ways in which brain networks change after TBI and, second, investigate if those changes are associated with recovery of cognitive deficits. We aim to make initial progress in discerning the relationships between brain network changes, and their (dys)functional correlates. We analyze longitudinally acquired MRI from 23 TBI patients (two time points: 6 days, 12 months post-injury) and cross-sectional data from 28 controls to construct white matter brain networks. Cognitive assessment was also performed. Graph theory and regression analysis were applied to identify changed brain network metrics after injury that are associated with subsequent improvements in cognitive function. Sixteen brain network metrics were found to be discriminative of different post-injury phases. Eleven of those explain 90% (adjusted R 2) of the variability observed in cognitive recovery following TBI. Brain network metrics that had a high contribution to the explained variance were found in frontal and temporal cortex, additional to the anterior cingulate cortex. Our preliminary study suggests that network reorganization may be related to recovery of impaired cognitive function in the first year after a TBI.


Medical leadership is the new black: or is it?
Considerable resources are being invested in healthcare leadership development programs and there is a new requirement for leadership teaching for Australian medical students. The new attention to medical leadership may be a reaction to loss of medical status and power. There is little evidence for return on investment from such programs. It is simply not clear what kind of leadership training is needed for collaborative work to improve healthcare nor what kind of organisational structures enable productive exercise of medical leadership skills. Caution is recommended.


The urgent need for health impact assessment: proposing a transdisciplinary approach to the e-waste crisis in sub-Saharan Africa.
Electronic waste (e-waste) is a growing health and environmental concern in developing countries. In the sub-Saharan African region e-waste is considered a crisis with no end in sight yet; there is lack of structures and regulations to manage the problem. In this article, we discuss the potential of Health Impact Assessment (HIA) in addressing the health, environmental, and social impacts of e-waste in sub-Saharan Africa. We draw from environmental policy, environmental communication, global health policy, and health communication to argue that managing e-waste could be framed as ongoing HIA where all the steps of HIA are performed on a rolling basis with input from local communities. Further, we suggest that HIA should be infused into recycling legislation to help streamline the practice in order to make it safe for health and the environment and to maximize the economic benefits.


Discovery of Radiocesium-bearing Particles in Masks Worn by Members of the Public in Fukushima in Spring 2013.
To investigate the publics' internal exposure by inhalation of radiocesium from the Fukushima Daiichi nuclear disaster in 2011, we examined the activity of radiocesium and radiocesium-bearing particles adhering to nonwoven fabric masks worn daily by members of the public in spring 2013 and 2014. We found a maximum cumulative Cs activity of 4.58 ± 0.15 Bq in 4 wk of spring 2013, which is 20.8% of the activity measured for the same subject in spring 2012 using the same method. This decrease was faster than the physical decay of radiocesium. Radiocesium was detected in 21 of 722 masks in 2013; three of these included type A radiocesium-bearing particles. The activity ratio of the radiocesium-bearing particles on the mask to the total radiocesium was at most approximately 20%. The two radiocesium sources, radiocesium-bearing particles and fugitive dust, are both insoluble particles. The largest internal dose from inhalation was 7.6 μSv in spring 2013, which is negligible compared to the dose limit recommended for members of the public by the International Commission on Radiological Protection.


Discrimination of serous cystadenoma from mucinous cystadenoma in the pancreas with contrast-enhanced ultrasonography: a prospective study in 61 patients.
The preoperative diagnosis between serous cystadenomas (SCAs) and mucinous cystadenomas (MCAs) in pancreas is significant due to their completely different biological behaviors. The purpose of our study was to examine and compare detailed contrast-enhanced ultrasonography (CEUS) images of SCAs and MCAs and to determine whether there are significant findings that can contribute to the discrimination between these two diseases. From April 2015 to June 2016, 61 patients (35 patients with SCAs and 26 patients with MCAs) were enrolled in this study. Forty-three cases were confirmed by surgical pathology and 18 by comprehensive clinical diagnoses. All of the CEUS characteristics of these lesions were recorded: size, location, echogenicity, shape, wall characteristics, septa characteristics, and the presence of a honeycomb pattern or nodules. CEUS examinations were performed by two ultrasound physicians. Location (P=0.003), shape (P=0.000), thickness of the wall (P=0.005), the number of septa (P=0.001), and the honeycomb pattern (P=0.001) were statistically significantly different. A head-neck location, a lobulated shape, an inner regular honeycomb pattern, and a thin wall (<3 mm thick) were significant in diagnosing patients with SCAs. When two of these four findings were combined, we could achieve a sensitivity of 71.4% and a specificity of 80.8% to diagnose SCA; when three of these four findings were combined, the specificity was 100%. A body-tail location, a round/oval shape, 0-2 septa, and a thick wall (≥3 mm thick) were most often detected in patients with MCAs. When two of these four findings were combined, we could achieve a sensitivity of 88.5% and a specificity of 65.7% to diagnose MCA; when three of these four findings were combined, the area under the curve (Az) was highest at 0.832, with a sensitivity of 80.8% and a specificity of 85.7%. The characteristics of tumor location, shape, thickness of the wall, the number of septa, and the honeycomb pattern by CEUS play an important role in the diagnosis of SCAs and MCAs. A combination of these findings can provide better diagnostic performance in the discrimination of SCAs from MCAs.