Multi-level approach for the integrated assessment of polar organic micropollutants in an international lake catchment: the example of Lake Constance.
Polar organic micropollutants (MPs) can have ecotoxicological effects on aquatic ecosystems and their occurrence in drinking water is a threat to public health. An extensive exposure assessment of MPs in large river and lake catchments is a necessary but challenging proposition for researchers and regulators. To get a complete picture of MP exposure in a large catchment, we employed a novel integrated strategy including MP measurement in the international catchment of Lake Constance and mass-flux modeling. A comprehensive screening of 252 MPs in the lake water by high-resolution mass spectrometry was used to identify the most commonly present MPs for the study site. It was found that the wastewater borne MPs diclofenac, carbamazepine, sulfamethoxazole, acesulfame, sucralose, benzotriazole, and methylbenzotriazole accounted for the most frequent and prominent findings. The concentration pattern of these compounds in the catchment was calculated based on regionalized inputs from wastewater treatment plants (WWTPs) and substance specific elimination rates. In 52, 8, and 3 of the 112 investigated river locations the concentration exceeded the predicted no-effect levels for diclofenac, sulfamethoxazole and carbamazepine, respectively. By coupling the catchment and lake model the effect of future trends in usage as well as possible mitigation options were evaluated for the tributaries and the lake. The upgrade of the major WWTPs in the catchment with a postozonation step would lead to a load reduction between 32% and 52% for all substances except for sucralose (10%).


Diagnostics barriers and innovations in rural areas: insights from junior medical doctors on the frontlines of rural care in Peru.
Worldwide, rural communities face barriers when accessing health services. In response, numerous initiatives have focused on fostering technological innovations, new management approaches and health policies. Research suggests that the most successful innovations are those involving stakeholders at all levels. However, there is little evidence exploring the opinions of local health providers that could contribute with further innovation development and research. The aims of this study were to explore the perspectives of medical doctors (MDs) working in rural areas of Peru, regarding the barriers impacting the diagnostic process, and ideas for diagnostic innovations that could assist them. Data gathered through three focus group discussions (FGG) and 18 individual semi-structured interviews (SSI) with MDs who had completed their medical service in rural areas of Peru in the last two years were analyzed using thematic analysis. Three types of barriers emerged. The first barrier was the limited access to point of care (POC) diagnostic tools. Tests were needed for: i) the differential diagnosis of malaria vs. pneumonia, ii) dengue vs. leptospirosis, iii) tuberculosis, iv) vaginal infections and cervical cancer, v) neurocysticercosis, and vi) heavy metal toxicity. Ultrasound was needed for the diagnosis of obstetric and intra-abdominal conditions. There were also health system-related barriers such as limited funding for diagnostic services, shortage of specialists, limited laboratory services and access to telecommunications, and lack of institutional support. Finally, the third type of barriers included patient related-barriers to follow through with diagnostic referrals. Ideas for innovations proposed included POC equipment and tests, and telemedicine. MDs at primary health facilities in rural Peru face diagnostic challenges that are difficult to overcome due to a limited access to diagnostic tools. Referrals to specialized facilities are constrained by deficiencies in the organization of health services and by barriers that impede the patients' travel to distant health facilities. Technological innovations suggested by the participants such as POC diagnostic tools and mobile-health (m-health) applications could help address part of the problem. However, other types of innovation to address social, adaptation and policy issues should not be dismissed.


Current treatment options for monogenic periodic fever syndromes - the role of interleukin 1 inhibitors.
Monogenic periodic fever syndromes are heterogeneous group of autoinflammatory diseases including distinct syndromes, such as cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor alpha receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). Individual diseases differ in pathogenesis, clinical manifestations, and severity. However, cytokines from the interleukin 1 (IL-1) family play a key role in all of them. Inhibition of these cytokines, especially IL-1, thus plays a crucial role in their treatment. At present, we have a wide range of drugs that differ in structure, mechanism of action, efficacy, and spectrum of side effects. The most available are anakinra, canakinumab and rilonacept. Moreover, several clinical trials are currently underway with other very promising drugs, such as gevokizumab, tadekinig alfa or tranilast. In the following review, we provide a new perspective on the efficacy and safety of IL-1 inhibitors that have provided the novel results coming from recently published clinical trials.


Use of Screening Tests for Colorectal Cancer Among Gynecologists in Puerto Rico.
To determine the use of screening tests for colorectal cancer (CRC) among Gynecologists in Puerto Rico. This study evaluates the screening practices used by Gynecologists in PR to diagnose CRC and adherence to screening guidelines. A self-administered anonymous questionnaire was mailed to 440 practicing gynecologists through the College of Physicians and Surgeons of PR. The questionnaire included general and specific questions. Response rate was 23.2% (102/440). Of this group of gynecologists, 77.5% referred screening patients, while 22.5% did not. The majority (28.4%) use Fecal Occult Blood Test (FOBT) as a first screening test, while 27.5% use Colonoscopy. Screening is started by 49% at age 50. Only 7% stop screening at 75 years and 31% never stop screening. CRC Screening performed by participants were: 35% screen annually, 6% screen 2-3 years, 10% screen every 5 years, 6% screen every 10 years and 6% screen 5-10 years. Data for CRC Screening reveals 7% gynecologists comply with all the guidelines; 49% comply with the recommendations regarding the start screening age and 7% stop screening as per guidelines. The recommendations are not followed by most of the gynecologists in PR that participated in the study, Further research should be directed towards the reasons for not complying and how to educatethemedical population to achieve adequate screening in the PR female population.


Autoimmunity to sperm antigens in vasectomized men.
Sera from vasectomized men were tested for the presence of antibodies directed against sperm antigens. A high percentage (about 55%) of the vasectomized men developed agglutinating antibodies. A lower percentage (22%) also developed low titres of antibodies to human protamine, as detected in the indirect IFT on swollen sperm heads and 22% developed cytotoxic antibodies. A correlation was found between the presence of anti-protamine antibodies and the presence of agglutinating and of cytotoxic antibodies. This correlation, and also the fact that they developed after vasectomy, indicates that the formation of antibodies against human protamine is a result of an autoimmune response to spermatozoa. The indirect IFT was also performed on 'normal' unswollen spermatozoa. All the sera were positive at least on one of the sperm antigens located in the acrosome, equator, or post-nuclear region, but no increase nor decrease in titre was found after vasectomy.


Prescribing privileges: grail for some practitioners, potential calamity for interprofessional collaboration in mental health.
The focus of this article is the probable consequences, in the event psychologists aggressively pursue prescription privileges (RxP), upon collaboration between psychologists and physicians. The case for RxP is briefly and critically summarized and the current state of collaboration between psychologists and medical professionals is reviewed. Data are presented from a recent small survey of clinical psychologists that support the following hypotheses: (1) psychiatrists and other medical professional receive a consequential volume of referrals from psychologists which would be diminished by RxP; (2) psychologists receive referrals for psychosocial services from medical professionals which would be diminished by RxP; (3) psychologists anticipate an adverse effect upon collaboration from RxP; and (4) contrary to some claims, psychologists are at best divided over RxP. Implications of these findings upon interprofessional collaboration are discussed.


Antibodies to HSP-70 in normal donors and autoimmune hearing loss patients.
To evaluate serum antibody to heat shock protein (HSP) 70 as a marker for autoimmune sensorineural hearing loss (AISNHL). Sera from 20 patients with rapidly progressive sensorineural HL and 20 control volunteers without HL were tested for antibody reactivity against multiple HSP 70 substrates. Substrates included recombinant human HSP (rHuHSP) 72, purified bovine brain heat shock cognate (HSC) 73 and HSP 72, as well as heat-shocked and non-heat-shocked protein extracts from bovine kidney (MDBK) cells. All serum donors were previously tested for antibody to guinea pig inner ear supporting cells; 17 of 20 patients but none (0 of 20) of the controls were positive. Sera were tested using Western blots. Reactivity with rHuHSP 70 was observed in 16 patients and 17 controls. Similarly, 15 of 20 patients and 17 of 20 controls stained for both HSP 72 and HSC 73 from the bovine brain. When tested against the heat-shock-induced and control MDBK extracts, six patients and nine controls had greater reactivity with the induced HSP 72. The frequency of antibodies to HSP substrates did not differ in patients and controls. Prior studies reported that HSP 72 is the 68 kD antigen commonly detected by AISNHL sera. However, we show that HSP 72 antibodies are no more prevalent in patients than in normal controls. Thus, it is unlikely that the 68 kD protein is HSP 72. Therefore, HSPs are not appropriate substrates for serodiagnosis of AISNHL.


Reduced Lateral Confinement and Its Effect on Stability in Patterned Strong Polyelectrolyte Brushes.
The stability of strong polyelectrolyte brushes (PEBs) was studied in bulk and in patterned structures. Thick PEBs of poly([(2-methacryloyloxy)ethyl]trimethylammonium chloride) with thicknesses >100 nm were synthesized using single electron transfer living radical polymerization. Brush patterning was identified using deep-ultraviolet photolithography by means of either a top-down (TD) or bottom-up (BU) method, with features as small as 200 nm. The brushes were soaked in water under a range of pH or temperature conditions, and the hydrolysis was monitored through dry-state ellipsometry and atomic force microscopy measurements. BU patterns showed reduced degrafting for smaller patterns, which was attributed to increased stress relaxation at such dimensions. In contrast to the already relaxed BU-patterned brush, a TD-patterned brush possesses perpendicular structures that result from the use of orthogonal lithography. It was found that the TD process induces cross-linking on the sidewall, which subsequently fortifies the sidewall materials. This modification of the polymer brushes hindered the stress relaxation of the patterns, and the degrafting trends became irrelevant to the pattern sizes. With proper tuning, the cross-linking on the sidewall was minimized and the degrafting trends were again relaxation-dependent.


[Renal peripelvic multicystic lymphangiectasia: is echographic diagnosis possible?].
We describe the role of US, in the diagnosis of LMPR and in differentiating LMPR from other renal disease, such as hydronephrosis and parapelvic cysts. In 10 patients mild to moderate hydronephrosis showed at the US, bilateral in 8 cases, was not confirmed at IVP and CT scan evaluation. Instead, compression of the collecting system by multiple cysts arising from the renal sinus was revealed by CT scan in 8 cases and by IVP in 2. At the U.S. the profile of the calices appeared irregular, differing from the features of hydronephrosis; furthermore calices were adjacent each other, separated only by a thin membrane. All patients were asymptomatic. The examination of the cystic liquor and wall, obtained percutaneously or during surgical procedures, showed the lymphatic origin of them. We cannot provide definitive data regarding how to differentiate LMPR from hydronephrosis at U.S.. In asymptomatic patients the U.S. evidence of dilated calices with irregular profile and thin membrane separating each other, can strongly suggest the diagnosis of LMPR.


Direct Functionalization of Poly(spirophosphazene)s via the Regioselective Lithiation of the Aromatic Rings Using a Cooperative Superbase.
The direct chemical functionalization of poly(spirophosphazene) [NP(O2 C12 H8 )]n (1) can be performed by the lithiation of the aromatic rings at low temperature using Schlosser's base (Lit Bu/KOt Bu or "superbase"), and the subsequent reaction with various electrophiles such as ClSiMe3 , ClPPh2 , or MeOB(O2 C6 H12 ) (MeOBpin). The functionalized polymers, isolated in very high yields (>90%) and without degradation of the polymeric chains, have an average degree of substitution per repeat unit ranging from 0.3 (random copolymers) to a maximum of 1.0, which corresponds to the homopolymers [NP(O2 C12 H7 FG)]n (FG (functional group) =SiMe3 , PPh2 , and Bpin). NMR studies, including bidimensional high temperature experiments on silylated and deuterated polymers, show that the substitution is regioselectively occurring at the C3 carbon of the aromatic rings due to the coordination of the lithium cations to the nitrogen of the polyphosphazene chain. The introduction of functional groups on the aromatic rings leads to significant changes in the solubility (silylated polymers), Tg , and electronic properties of the material, showing how the change of substituents in the aromatic rings can lead to polyphosphazenes with properties markedly different from those of the precursor polymer.


[Charcot's disease and juvenile amyotrophic lateral sclerosis].
The authors studied 102 clinical observations of patients presenting the symptoms of amyotrophic lateral sclerosis (Charcot's disease). Two distinct groups were discerned from an analysis of the ages of onset: the first group, comprising 20 patients, represents the juvenile form, with onset before the age of 30. The second group (82 patients) represents the classic form of Charcot's disease. Generally speaking, the adult group is identical to that reported in the literature since Charcot first described amyotrophic lateral sclerosis. The incidence is greater in males. Hyperproteinorachia is frequent. No local etiologic cause has been identified. The apparent incidence of the disease in the regions of Tunis and Nabeul is 0,45 per 100 000 inhabitants per year. The juvenile form is characterized by a relative frequency of the familial form (30 p. 100), a possible association with particular sensory symptoms, and a slow evolution. Hypoproteinorachia is relatively frequent. The authors discuss the relations between these two groups of amyotrophic lateral sclerosis. Are they two different expressions of the same disease, or are they two different diseases?


Intracellular marking of identified neurones in the superficial dorsal horn of the cat spinal cord.
Intracellular iontophoresis of horseradish peroxidase has been used to mark identified neurones in the superficial dorsal horn of cats. The cats were anaesthetized with alpha-chloralose and paralysed with gallamine triethodide. Four specific nocireceptive neurones in the marginal zone and seven neurones in the substantia gelatinosa were recovered. One of the former and four of the latter are described in detail and are illustrated as reconstructions from serial sections. The results confirm previous conclusions that the substantia gelatinosa contains neurones classified as 'inverse' and that the nocireceptive neurones of lamina I are Waldeyer Cells.


Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes.
Dravet syndrome (DS) is a severe epileptic encephalopathy mainly caused by haploinsufficiency of the gene SCN1A, which encodes the voltage-gated sodium channel NaV1. 1 in the brain. While SCN1A mutations are known to be the primary cause of DS, other genes that may cause DS are poorly understood. Several genes with pathogenic mutations result in DS or DS-like phenotypes, which may require different drug treatment approaches. Therefore, it is urgent for clinicians, especially epilepsy specialists to fully understand these genes involved in DS in addition to SCN1A. Particularly for healthcare providers, a deep understanding of these pathogenic genes is useful in properly selecting and adjusting drugs in a more effective and timely manner. The purpose of this study was to identify genes other than SCN1A that may also cause DS or DS-like phenotypes. A comprehensive search of relevant Dravet syndrome and severe myoclonic epilepsy in infancy was performed in PubMed, until December 1, 2021. Two independent authors performed the screening for potentially eligible studies. Disagreements were decided by a third, more professional researcher or by all three. The results reported by each study were narratively summarized. A PubMed search yielded 5,064 items, and other sources search 12 records. A total of 29 studies published between 2009 and 2021 met the inclusion criteria. Regarding the included articles, seven studies on PCDH19, three on SCN2A, two on SCN8A, five on SCN1B, two on GABRA1, three on GABRB3, three on GABRG2, and three on STXBP1 were included. Only one study was recorded for CHD2, CPLX1, HCN1 and KCNA2, respectively. It is worth noting that a few articles reported on more than one epilepsy gene. DS is not only identified in variants of SCN1A, but other genes such as PCDH19, SCN2A, SCN8A, SCN1B, GABRA1, GABRB3, GABRG2, KCNA2, CHD2, CPLX1, HCN1A, STXBP1 can also be involved in DS or DS-like phenotypes. As genetic testing becomes more widely available, more genes associated with DS and DS-like phenotypes may be identified and gene-based diagnosis of subtypes of phenotypes in this spectrum may improve the management of these diseases in the future.


What could 'Brexit' mean for vets?
BVA has produced a briefing paper on the possible implications of a British exit from the EU and is inviting vets to have their say via the BVA community, explains BVA policy offer Susie Child.


Outcome of peroral endoscopic myotomy in children with achalasia.
Achalasia cardia is rare in children and optimum endoscopic management options are not well known. Peroral endoscopic myotomy (POEM) is a novel treatment modality for achalasia with excellent results in adult patients. The long-term outcomes of POEM are not well known in children. In this study, we aim to evaluate the outcome of POEM in children with idiopathic achalasia. We analyzed the data of children (≤ 18 years) diagnosed with achalasia from September 2013 to January 2018. Technical success, clinical success, and adverse events were assessed. Post-POEM, gastroesophageal reflux (GER) was assessed with 24-h pH-impedance study and esophagogastroduodenoscopy. A total of 44 children (boys-23, girls-21) with mean age of 14.5 ± 3.41 years (4-18) were diagnosed with achalasia during the study period. Of these, 43 children underwent POEM. The subtypes of achalasia according to Chicago classification were type I-11, type II-29, type III-2, and unclassified-2. Eighteen children (40.9%) had history of prior treatment. POEM was successfully performed in 43 children (technical success-97.72%). Intra-operative adverse events occurred in 11 (25.6%) children including retroperitoneal CO2 (7), capnoperitoneum (3), and mucosal injury (1). Clinical success at 1, 2, 3, and 4 years' follow-up was 92.8%, 94.4%, 92.3%, and 83.3%, respectively. Erosive esophagitis was detected in 55% (11/20) children. On 24-h pH study, GER was detected in 53.8% (7/13) children. POEM is a safe, effective, and durable treatment for achalasia in children. However, GER is a potential concern and should be evaluated in prospective studies before adopting POEM for the management of achalasia in children.


Database mining and transcriptional analysis of genes encoding inulin-modifying enzymes of Aspergillus niger.
As a soil fungus, Aspergillus niger can metabolize a wide variety of carbon sources, employing sets of enzymes able to degrade plant-derived polysaccharides. In this study the genome sequence of A. niger strain CBS 513.88 was surveyed, to analyse the gene/enzyme network involved in utilization of the plant storage polymer inulin, and of sucrose, the substrate for inulin synthesis in plants. In addition to three known activities, encoded by the genes suc1 (invertase activity; designated sucA), inuE (exo-inulinase activity) and inuA/inuB (endo-inulinase activity), two new putative invertase-like proteins were identified. These two putative proteins lack N-terminal signal sequences and therefore are expected to be intracellular enzymes. One of these two genes, designated sucB, is expressed at a low level, and its expression is up-regulated when A. niger is grown on sucrose- or inulin-containing media. Transcriptional analysis of the genes encoding the sucrose- (sucA) and inulin-hydrolysing enzymes (inuA and inuE) indicated that they are similarly regulated and all strongly induced on sucrose and inulin. Analysis of a DeltacreA mutant strain of A. niger revealed that expression of the extracellular inulinolytic enzymes is under control of the catabolite repressor CreA. Expression of the inulinolytic enzymes was not induced by fructose, not even in the DeltacreA background, indicating that fructose did not act as an inducer. Evidence is provided that sucrose, or a sucrose-derived intermediate, but not fructose, acts as an inducer for the expression of inulinolytic genes in A. niger.


CCS-Net: Cascade Detection Network With the Convolution Kernel Switch Block and Statistics Optimal Anchors Block in Hypopharyngeal Cancer MRI.
Magnetic resonance imaging (MRI) is a common diagnostic method for hypopharyngeal cancer (HPC). It is a challenge to automatically detect HPC tumors and swollen lymph nodes (HPC risk areas) from MRI slices because of the small size and irregular shape of HPC risk areas. Herein, we propose a cascade detection network with Convolution Kernel Switch (CKS) Block and Statistics Optimal Anchors (SOA) Block in HPC MRI (CCS-Net). CKS Block can adaptively switch standard convolution to deformable convolution in some appropriate layers to detect irregular objects more efficiently without taking up too much computing resources. SOA Block can automatically generate the optimal anchors based on the size distribution of objects. Compared with other methods, our method achieves splendid detection performance and outperforms other methods on the HPC dataset (more than 1800 T2 MRI slices), achieving the highest AP50 of 78.90%. Experiments show that the proposed network can be the basis of a computer aided diagnosis utility that helps achieve faster and more accurate diagnostic decisions for HPC.


High Efficiency over 15% by Breaking the Theoretical Efficiency Limit of Fluorescent Organic Light-Emitting Diodes with Localized Surface Plasmon Resonance Effects.
The theoretical efficiency limit of fluorescence organic light-emitting diodes (OLEDs) was successfully surpassed by utilizing the localized surface plasmon resonance (LSPR) effect with conventional emissive materials. The interaction between polaritons and plexcitons generated during the LSPR process was also analyzed experimentally. As a result, the external quantum efficiency (EQE) increased dramatically from 6.01 to 15.43%, significantly exceeding the theoretical efficiency limit of fluorescent OLEDs. Additionally, we introduced a new concept of the LSPR effect, called "LSPR sensitizer", which allowed for simultaneous improvement in color conversion and efficiency through cascade transfer of the LSPR effect. To the best of our knowledge, the EQE and the current efficiency of our LSPR-OLED are the highest among LSPR-based fluorescent OLEDs to date.


[Usefulness of multiple burr-hole operation for child Moyamoya disease].
Excellent results of multiple burr-hole operation (MBHO) for child moyamoya disease are reported in this study. Three patients of moyamoya disease had MBHO. After MBHO, transient, ischemic attacks disappeared in a patient despite progressing stenosis of the major cerebral arteries, and remarkable neurological improvement was recognized in a patient who had encephaloduroarteriosynangiosis. Another patient slowly improved and became able to go to junior high school. N-isopropyl-p-[123I] iodoamphetamine (IMPSPECT) findings also improved in all patients. There was no mortality or morbidity, and no new neurological deficits or bleedings developed during the follow up period. The authors recommend the MBHO as the surgical treatment of choice for not only adult but also child moyamoya disease because of its safety and effectiveness, and also report the usefulness of MBHO for the patients who have already received other bypass operations.


[The effect of immunofan on the immunity system characteristics and lipid peroxidation parameters upon acute chemical poisoning].
The results of experiments on Wistar rats under conditions of acute poisoning with 0.75 LD50 of zarin (isopropylmethyl fluorophosphonate), luisite (beta-chlorovinyl dichloroarsine), arsenic chloride, and dichloroethane showed that a four-day treatment with immunofan in a dose of 10 microg/kg restored the immune status characteristics (antibody formation to T-dependent antigen, antibody-dependent cell-mediated cytotoxicity, natural killer cell activity, and delayed type hypersensitivity) and the related LPO parameters.


Stochastic re-calibration: contextual effects on perceived tilt.
The human visual system exaggerates the difference between the tilts of adjacent lines or grating patches. In addition to this tilt illusion, we found that oblique flanks reduced acuity for small changes of tilt in the centre of the visual field. However, no flanks--regardless of their tilts--decreased sensitivity to contrast. Thus, the foveal tilt illusion should not be attributed to orientation-selective lateral inhibition. Nor is it similar to conventional crowding, which typically does not impair letter recognition in the fovea. Our observers behaved as though the reference orientation (horizontal) had a small tilt in the direction of the flanks. We suggest that the extent of this re-calibration varies randomly over trials, and we demonstrate that this stochastic re-calibration can explain flank-induced acuity loss in the fovea.


Risk Indicators and Prevention of Implant Soft-Tissue Complications: Interproximal Papillae Loss and Midfacial Implant Mucosal Recessions.
Achieving a long-term esthetic implant restoration in the maxillary anterior area is sometimes unpredictable. This article reviews several risk indicators of implant mucosal recession and loss of interproximal papillae, and how to prevent these risks. Results obtained from the literature suggest that the following factors are strongly related to implant soft-tissue complications: buccally positioned implant placement, a thin gingival biotype, lack of an adequate amount of keratinized mucosa, implant placement after ridge augmentation procedures, an increased distance of tooth bone peak to the contact point, and an inadequate horizontal implant-tooth distance. Factors that have been shown to favor longterm stability and improve implant esthetic outcomes include implant placement in an ideal 3-dimensional position, use of platform-switching implant/abutment designs, and performing soft-tissue grafting. Careful assessment of the above factors and adoption of suggested guidelines are critical to executing successful implant placement with favorable esthetic outcomes while minimizing soft-tissue complications.


A non-cytotoxic suppressor of immunoglobulin synthesis and secretion by B cells of normal humans and patients with rheumatoid arthritis and systemic lupus erythematosus.
A factor secreted by thymocytes of immunized rabbits totally suppressed both the initiation of, and ongoing synthesis and secretion of, lectin (PWM)-induced synthesis of IgM and IgG immunoglobulins by the circulating B lymphocytes of normal humans, and of twenty consecutive patients with rheumatoid arthritis and twelve consecutive patients with systemic lupus erythematosus. The suppressor factor, referred to as human Ig synthesis/secretion suppressor factor or HISSF, is not HLA restricted in its activity and is not cytotoxic to the circulating human mononuclear cells (B cells, T cells, Null cells and monocytes). It was demonstrated that T cells precultured with HISSF were transformed into suppressor cells which, when added to fresh cultures of autologous B cells, suppressed the synthesis and secretion of IgM and IgG. On the basis of its suppressive and non-cytotoxic properties in vitro, HISSF may be an effective immunosuppressant in the treatment of patients with autoimmune diseases.


The effect of foam surface properties on postural stability assessment while standing.
A common assessment of postural control often involves subjects standing on a compliant surface, such as a foam block, to make balance tests more challenging. However, the physical properties of the foam block used by different researchers can vary considerably. The objective of this study was to provide an initial approach for investigating whether two of the foam properties, i.e. density and elastic modulus, influenced recorded anteroposterior and lateral torque variance with eyes open and eyes closed. Thirty healthy adults (mean age 22.5 years) were assessed with posturography using three different types of foam block placed on a force platform. These blocks were categorised: firm foam, medium foam and soft foam by their elastic modulus. To investigate the spectral characteristics of recorded body movements, variance values were calculated for total movements, movements <0.1Hz and movements >0.1Hz. Results showed that anteroposterior and lateral torque variances >0.1Hz were larger when standing on the firm foam compared with medium and soft foam and in turn were larger on the medium foam compared with the soft foam with eyes closed. Moreover, GLM and correlation analysis demonstrated that the properties of the foam blocks affected anteroposterior torque variance >0.1Hz and lateral torque variance in all frequency ranges. In addition, the stabilising effect of vision in the anteroposterior direction had a greater influence when the subjects' stability was increasingly challenged by the support surface, as illustrated by the higher torque variance values. In conclusion, caution should be taken when analysing balance deficits with foam test setups, because the foam properties may influence the recorded body movements.


Natural history of hepatocellular carcinoma including fibrolamellar and hepato-cholangiocarcinoma variants.
The natural history of hepatocellular carcinoma (HCC) varies greatly with the global region, because the carcinogenic factors are not the same among countries. Besides the clinicopathological factors such as tumor characteristics, sex, and age, background liver disease is a major determinant of prognosis. Hepatocellular carcinoma, mainly associated with chemical carcinogens such as aflatoxin, does not have severe background cirrhosis, and grows quickly, whereas HCC developing in association with a virus in a cirrhotic liver generally grows more slowly, and the severity of cirrhosis is the major prognostic factor. The median survival of untreated sub-Saharan African patients is less than 1 month from diagnosis, contrasted by an average survival of 4 months in virus-induced HCC associated with cirrhosis. Tumor characteristics, such as size, number, and growth speed, which vary considerably from case to case, affect the prognosis. Vascular (portal) invasion portends a poor prognosis, and alpha-fetoprotein levels also correlate with prognosis. Several distinct clinical types of HCC occur, namely diffuse-type HCC caused by rapid portal spread of cancer cells, febrile-type caused by poorly differentiated sarcomatoid cancer cells, and cholestatic HCC caused by intraductal invasion; all have a short survival. There are several histological variant forms: combined hepato-cholangiocarcinoma behaves like HCC, with a poorer prognosis because of more frequent lymph node metastases; fibromellar carcinoma, which is relatively common in young Caucasian adults, has a good prognosis if diagnosed early, permitting resection; and cholangiolocellular carcinoma, which derives from the canalicular epithelium, is indistinguishable from HCC, with a similar prognosis.


Nurse Manager Core Competencies: A Proposal in the Spanish Health System.
Nurses who are capable of developing their competencies appropriately in the field of management are considered fundamental to the sustainability and improvement of health outcomes. These core competencies are the critical competencies to be developed in specific areas. There are different core competencies for nurse managers, but none in the Spanish health system. The objective of this research is to identify the core competencies needed for nurse managers in the Spanish health system. The research was carried out using the Delphi method to reach a consensus on the core competencies and a Principal Component Analysis (PCA) to determine construct validity, reducing the dimensionality of a dataset by finding the causes of variability in the set and organizing them by importance. A panel of 50 experts in management and healthcare engaged in a four-round Delphi study with Likert scored surveys. We identified eight core competencies from an initial list of 51: decision making, relationship management, communication skills, listening, Leadership, conflict management, ethical principles, collaboration and team management skills. PCA indicated the structural validity of the core competencies by saturation into three components (α Cronbach >0.613): communication, leadership and decision making. The research shows that eight competencies must be developed by the nursing managers in the Spanish health system. Nurse managers can use these core competencies as criteria to develop and plan their professional career. These core competencies can serve as a guideline for the design of nurse managers' development programs in Spain.


Older People Living Alone: A Predictive Model of Fall Risk.
Falls in older people are a result of a combination of multiple risk factors. There are few studies involving predictive models in a community context. The aim of this study was to determine the validation of a new model for predicting fall risk in older adults (65+) living alone in community dwellings (n = 186; n = 117) with a test-retest reliability study. We consider in the predictive model the significant factors emerged from the bivariate analysis: age, zone, social community resources, physical exercise, self-perception of health, difficulty to keep standing, difficulty to sit and get up from a chair, strain to see, use of technical devices, hypertension and number of medications. The final model explained 28.5% of the risk of falling in older adults living alone in community dwellings. The AUC = 0.660 (se = 0.065, IC 95% 0.533-0.787, p = 0.017). The predictive model developed revealed a satisfactory discriminatory performance of the model and can contribute to clinical practice, with respect to the evaluation of risk of falling in this frailty group and preventing falls.


Relationship between the UPLC-Q-TOF-MS fingerprinted constituents from Daphne genkwa and their anti-inflammatory, anti-oxidant activities.
Daphne genkwa Sieb.et Zucc. is a well-known medicinal plant. This study was designed to apply the ultra-high performance liquid chromatography system to establish a quality control method for D. genkwa. Data revealed that there were 15 common peaks in 10 batches of D. genkwa Sieb. Et Zucc. (Thymelaeaceae) from different provinces of China. On this basis, the fingerprint chromatogram was established to provide references for quality control. Afterwards, the chemical constitutions of these common peaks were analyzed using the UPLC-Q-TOF-MS system and nine of them were identified. In addition, LPS-stimulated RAW264.7 murine macrophages and DPPH assay were used to study the anti-inflammatory and anti-oxidation effects of D. genkwa. Then the fingerprint-efficacy relationships between UPLC fingerprints and pharmacodynamic data were studied with canonical correlation analysis. Analysis results indicated that the anti-inflammatory and anti-oxidation effects differed among the 10 D. genkwa samples owing to their inherent differences of chemical compositions. Taken together, this research established a fingerprint-efficacy relationship model of D. genkwa plant by combining the UPLC analytic technique and pharmacological research, which provided references for the detection of the principal components of traditional Chinese medicine on bioactivity.


Protective effects of marrubiin improve endometriosis through suppression of the expression of RANTES.
Marrubiin can improve blood and lymph microcirculation disturbance, and has pharmacological effects in myocardial protection, anti‑inflammation and anti‑oxidation. The aim of the present study was to evaluate the protective effects of marrubiin on endometriosis through suppression of the expression of regulated on activation, normal T cell expressed and secreted (RANTES). Endometriotic cells were implanted into the peritoneal cavity of mice, and these mice were injected estradiol benzoate (30 µg/kg) once each day for 14 days. The mice with endometriosis were then treated with 12, 25 or 50 mg/kg marrubiin. Reverse transcription‑quantitative polymerase chain reaction was used to assess the mRNA expression of RANTES, and western blot analysis was used to analyze the protein expression of RANTES, TNF‑α and PGE2. Inflammation factors were measured by ELISA. Treatment with marrubiin effectively improved lesion regression and inhibited toxicity in the mouse model of endometriosis. Marrubiin significantly inhibited endometrial lesions and monocyte chemotaxis in the mice with endometriosis, and reduced U937 cell migration. Calcium mobilization, levels of tumor necrosis factor‑α and the secretion of RANTES were effectively suppressed by marrubiin treatment. The calcium levels were effectively induced, whereas the protein expression of prostaglandin E2 (PGE2) and formation of thromboxane B2 (TXB2) were effectively inhibited by marrubiin treatment. These findings indicated that the protective effect of marrubiin improved endometriosis in the mice through the suppression of inflammation and downregulation of the expression of RANTES, followed by mediation of the levels of calcium, PGE2 and TXB2.


CDK4 phosphorylation status and a linked gene expression profile predict sensitivity to palbociclib.
Cyclin D-CDK4/6 are the first CDK complexes to be activated in the G1 phase in response to oncogenic pathways. The specific CDK4/6 inhibitor PD0332991 (palbociclib) was recently approved by the FDA and EMA for treatment of advanced ER-positive breast tumors. Unfortunately, no reliable predictive tools are available for identifying potentially responsive or insensitive tumors. We had shown that the activating T172 phosphorylation of CDK4 is the central rate-limiting event that initiates the cell cycle decision and signals the presence of active CDK4. Here, we report that the profile of post-translational modification including T172 phosphorylation of CDK4 differs among breast tumors and associates with their subtypes and risk. A gene expression signature faithfully predicted CDK4 modification profiles in tumors and cell lines. Moreover, in breast cancer cell lines, the CDK4 T172 phosphorylation best correlated with sensitivity to PD0332991. This gene expression signature identifies tumors that are unlikely to respond to CDK4/6 inhibitors and could help to select a subset of patients with HER2-positive and basal-like tumors for clinical studies on this class of drugs.


Methods for nano-particle based vaccine formulation and evaluation of their immunogenicity.
Nano- and microparticles have long been used for the delivery of drugs and are currently being evaluated as vaccine delivery systems. Particulates can elicit potent immune responses, either by direct immuno-stimulation of antigen presenting cells (APC) or/and by delivering antigen to specific cellular compartments and promoting antigen uptake by appropriate stimulatory cell types. Herein, we describe a detailed method for the preparation of a novel nanoparticle-based antigen delivery system which induces strong cellular and humoral immune responses in mice and sheep. This simple system is based on the use of 40 nanometer (nm) inert solid carrier beads to which antigen is covalently coupled before injection. Covalent conjugation of antigen to the nanobeads, assessment of conjugation efficiency, characterisation and measurement of in vivo immunogenicity by cytokine ELISPOT (to measure antigen-specific T-cell responses) and ELISA (to measure antibody titers), are described. Emphasis is placed on providing trouble-shooting advice to enable the reproducible production of soluble nano-size formulations that do not suffer from common problems such as aggregation, as well as understanding the causes and thus avoiding a range of prevalent technical problems that occur when using immune response detection assays, such as the cytokine ELISPOT assay and ELISA.


How coenzyme B12-dependent ethanolamine ammonia-lyase deals with both enantiomers of 2-amino-1-propanol as substrates: structure-based rationalization.
Coenzyme B(12)-dependent ethanolamine ammonia-lyase acts on both enantiomers of the substrate 2-amino-1-propanol [Diziol, P., et al. (1980) Eur. J. Biochem. 106, 211-224]. To rationalize this apparent lack of stereospecificity and the enantiomer-specific stereochemical courses of the deamination, we analyzed the X-ray structures of enantiomer-bound forms of the enzyme-cyanocobalamin complex. The lower affinity for the (R)-enantiomer may be due to the conformational change of the Valα326 side chain of the enzyme. In a manner consistent with the reported experimental results, we can predict that the pro-S hydrogen atom on C1 is abstracted by the adenosyl radical from both enantiomeric substrates, because it is the nearest one in both enantiomer-bound forms. We also predicted that the NH(2) group migrates from C2 to C1 by a suprafacial shift, with inversion of configuration at C1 for both enantiomeric substrates, although the absolute configuration of the 1-amino-1-propanol intermediate is not yet known. Reported labeling experiments demonstrate that (R)-2-amino-1-propanol is deaminated by the enzyme with inversion of configuration at C2, whereas the (S)-enantiomer is deaminated with retention. By taking these results into consideration, we can predict the rotameric radical intermediate from the (S)-enantiomer undergoes flipping to the rotamer from the (R)-enantiomer before the hydrogen back-abstraction. This suggests the preference of the enzyme active site for the rotamer from the (R)-enantiomer in equilibration. This preference might be explained in terms of the steric repulsion of the (S)-enantiomer-derived product radical at C3 with the Pheα329 and Leuα402 residues.


Continuity of care with physicians and risk of subsequent hospitalization and end-stage renal disease in newly diagnosed type 2 diabetes mellitus patients.
Effective management for type 2 diabetes mellitus (DM) can slow the progression of kidney outcomes and reduce hospital admissions. Better continuity of care (COC) was found to improve patients' adherence and self-management. This study examined the associations between COC, hospitalization, and end-stage renal disease (ESRD) in DM patients. In the cohort study, data from 1996 to 2012 were retrieved from the Longitudinal Health Insurance Database, using inverse probability weighted analysis. A total of 26,063 patients with newly diagnosed type 2 DM who had been treated with antihyperglycemic agents were included. COC is to assess the extent to which a DM patient visited the same physician during the study period. This study categorized COC into 3 groups - low, intermediate, and high, - according to the distribution of scores in our sample. The number of ESRD patients in the high, intermediate, and low COC groups were 92 (22.33%), 130 (31.55%), and 190 (46.12%), respectively, and the mean follow-up periods for the 3 groups were 7.13, 7.12, and 7.27 years, respectively. After using inverse probability weighting, the intermediate and low COC groups were significantly associated with an increased risk of ESRD compared with the high COC group (adjusted hazard ratio (aHR) 1.36 [95% CI, 1.03-1.80] and aHR 1.76 [95% CI, 1.35-2.30], respectively). The intermediate and low COC groups were also significantly associated with the subsequent hospitalization compared with the high COC group (aHR 1.15 [95% CI, 0.99-1.33] and aHR 1.72 [95% CI, 1.50-1.97], respectively). COC is related to ESRD onset and subsequent hospitalization among patients with DM. This study suggested that when DM patients keep visiting the same physician for managing their diseases, the progression of renal disease can be prevented.


An antigen expressed by cells of the myelo-monocytic lineage.
We describe an antigen(s) characterized by a heteroantiserum raised in rabbits against mature human granulocytes. This antigen was found on neutrophils, monocytes, platelets, acute and chronic myelocytic leukemia cells and on granulocyte-macrophage progenitor cells grown in agar. It was not found on lymphocytes, eosinophils, erythrocytes, or erythroid progenitor cells. On the basis of tissue distribution and absorption studies, the antigen (tentatively designated the "myelo-monocytic" antigen) is distinct from antigens previously identified on human neutrophils. Restriction of the "myelo-monocytic" antigen to normal and malignant cells of the myelo-monocytic series suggests that it may represent a normal differentiation antigen of the myelo-monocytic lineage.


Identification of molecular subtypes and immune infiltration in endometriosis: a novel bioinformatics analysis and In vitro validation.
Endometriosis is a worldwide gynacological diseases, affecting in 6-10% of women of reproductive age. The aim of this study was to investigate the gene network and potential signatures of immune infiltration in endometriosis. The expression profiles of GSE51981, GSE6364, and GSE7305 were obtained from the Gene Expression Omnibus (GEO) database. Core modules and central genes related to immune characteristics were identified using a weighted gene coexpression network analysis. Bioinformatics analysis was performed to identify central genes in immune infiltration. Protein-protein interaction (PPI) network was used to identify the hub genes. We then constructed subtypes of endometriosis samples and calculated their correlation with hub genes. qRTPCR and Western blotting were used to verify our findings. We identified 10 candidate hub genes (GZMB, PRF1, KIR2DL1, KIR2DL3, KIR3DL1, KIR2DL4, FGB, IGFBP1, RBP4, and PROK1) that were significantly correlated with immune infiltration. Our study established a detailed immune network and systematically elucidated the molecular mechanism underlying endometriosis from the aspect of immune infiltration. Our study provides comprehensive insights into the immunology involved in endometriosis and might contribute to the development of immunotherapy for endometriosis. Furthermore, our study sheds light on the underlying molecular mechanism of endometriosis and might help improve the diagnosis and treatment of this condition.


Heparanase Overexpresses in Keratoconic Cornea and Tears Depending on the Pathologic Grade.
Keratoconus has classically been defined as a noninflammatory disorder, although recent studies show elevated levels of inflammatory markers suggesting that keratoconus could be, at least in part, an inflammatory condition. Heparanase upregulation has been described in multiple inflammatory disorders. In this article, we study the differential expression of heparanase in cornea and tears from keratoconus patients and healthy controls. A transcriptomic approach was used employing quantitative polymerase chain reaction to analyze the expression of heparanase and heparanase 2 in stromal and epithelial corneal cells. The protein expression was analyzed by immunohistochemistry in corneal sections. Enzymatic activity in tears was measured using [3H]-labeled heparan sulfate as substrate. Heparanase transcription was detected in stromal and epithelial cells and appeared upregulated in keratoconus. Overexpression of the enzyme was also detected by immunohistochemistry. Corneal expression of heparanase 2 was detected in some cases. Heparanase catalytic activity was found in tears and displayed a positive correlation with the degree of keratoconus. Heparanase overexpresses in keratoconic corneas, possibly reinforcing the inflammatory condition of the pathology. The presence of heparanase activity in tears allows us to propose its use as a biomarker for the diagnosis of the disorder.


Cancer pain: you can help!
Pain exists because electrical impulses travel along a series of nerves from "where it hurts" through the gate in the spinal cord and through the thalamus to the areas of the brain where thinking, feeling, and action are controlled. Along this path are several "switches" that can adjust the pain, or turn it down as one would the volume of a radio. Figure 5 summarizes the interventions that have been discussed in this article in relation to these four switches. One can use a moderate to large amount of a single intervention (such as medication) to shut off the pain; or one can use small to moderate amounts of a combination of interventions to accomplish the same or greater level of comfort. In most situations, a combined approach provides the patient with better control of pain, a more active role in his care, fewer side effects, and less dependence on others.


Vernonia kotschyana roots: therapeutic potential via antioxidant activity.
The roots of Vernonia kotschyana Sch. Bip. ex Walp. (Asteraceae) are used in Malian traditional medicine in the treatment of gastroduodenal ulcers and gastritis. Since oxidative stress is involved in gastric ulceration, the aim of this study was to screen the root extracts for their in vitro antioxidant activity and phenolic content. The roots were extracted successively with chloroform, ethyl acetate, ethanol and water. The antioxidant activity of root extracts was evaluated in both cell-free and cell-based assays. Their chemical characterization was performed by Fourier transform infrared spectroscopy (FT-IR) whereas the total phenolic content was determined by the Folin-Ciocalteu method. The ethyl acetate extract displayed the highest phenolic content and was found to be the most active in the free radical scavenging and lipid peroxidation inhibition assays; it also showed a high antioxidant activity in MCF-12F cells. This study suggests a potential use of the ethyl acetate extract of Vernonia kotschyana not only as an antioxidant agent in gastroduodenal ulcers and gastritis, but also in other disorders characterized by high levels of oxidative stress.


Biochemical and physiological bases for utilization of dietary amino acids by young Pigs.
Protein is quantitatively the most expensive nutrient in swine diets. Hence it is imperative to understand the physiological roles played by amino acids in growth, development, lactation, reproduction, and health of pigs to improve their protein nutrition and reduce the costs of pork production. Due to incomplete knowledge of amino acid biochemistry and nutrition, it was traditionally assumed that neonatal, post-weaning, growing-finishing, and gestating pigs could synthesize sufficient amounts of all "nutritionally nonessential amino acids" (NEAA) to support maximum production performance. Therefore, over the past 50 years, much emphasis has been placed on dietary requirements of nutritionally essential amino acids as building blocks for tissue proteins. However, a large body of literature shows that NEAA, particularly glutamine, glutamate, arginine and proline regulate physiological functions via cell signaling pathways, such as mammalian target of rapamycin, AMP-activated protein kinase, extracellular signal-related kinase, Jun kinase, mitogen-activated protein kinase, and NEAA-derived gaseous molecules (e.g., nitric oxide, carbon monoxide, and hydrogen sulfide). Available evidence shows that under current feeding programs, only 70% and 55% of dietary amino acids are deposited as tissue proteins in 14-day-old sow-reared piglets and in 30-day-old pigs weaned at 21 days of age, respectively. Therefore, there is an urgent need to understand the roles and dietary requirements of NEAA in swine nutrition. This review highlights the basic biochemistry and physiology of absorption and utilization of amino acids in young pigs to enhance the efficacy of utilization of dietary protein and to minimize excretion of nitrogenous wastes from the body.


Regression of long standing anorexia nervosa following acute renal failure caused by gentamicin intoxication.
A female patient aged 22 with fully developed symptoms of anorexia nervosa presented the following metabolic disturbances: persistent hyperuricemia, hyponatruria, (sometimes with sodium lack in urine) as well as frequent hyponatremia and hyper-uricosuria. The patient's low arterial blood pressure (70/40 mm Hg on average) was not improved by pharmacological treatment, and only high oral doses of table salt (20-70 g/24 h) did prove effective in the therapy. The subject passed seven renal calculi composed of sodium urate and uric acid. Numerous urinalyses did not reveal any changes, and bacterial cultures of the urine were also negative. After 14 years of anorexia nervosa, the patient was treated for pneumonia with gentamicin at doses of 2 x 80 mg/24 h. Following third dose of the antibiotic, the patient developed acute renal failure and was treated by haemodialysis for six weeks. The renal function came gradually to the norm. Simultaneously, all the anorexia nervosa symptoms subsided along with sodium metabolism disturbances, while purine metabolism disorders got considerably alleviated. The patient started to have her menstrual cycles again, gained 12 kg in body weight, and one year afterwards bore a son. A further 10-year follow-up period was free of any pathological changes except for a slight hyperuricemia. To the best of our knowledge, the similar case has not been reported in the medical literature and electronic data bases.


Helium leak test for sterility assurance of a sealed bag. I: Relationship of helium leak and pinhole diameter.
Described herein is an attempt to establish a simpler, more reliable method to maintain the aseptic condition of bulk materials of drug substances. The method would be used in the manufacturing process of our "double-bag" kit system for infusion, which has two compartments, one for the infusion liquid and another for the drug product. To manufacture the kit system, we used a flexible inner container to enclose the bulk under aseptic conditions and a method for ensuring sterility of the container. We used an aluminum laminate bag as the inner container, which was then enclosed in a polyethylene bag. To detect tears or pinholes in the bag, a helium leak test was evaluated. First, a simple experimental model of helium leakage from bags was established. In the model, a pinhole was made in a film disk of the aluminum laminate or polyethylene material used for the inner and outer bags. A helium leak detector was used to measure the escape of helium through the pinhole, and the leak could be detected from a pinhole from 10 microns in diameter. As the bulk product was doubly sealed in an aluminum bag and a polyethylene bag in the manufacturing process to maintain an aseptic condition, we also checked for helium leak from pinholes of film disks after connecting two film disks. The results showed that helium leak was detectable when the pinhole diameters of both film disks were more than 20 microns. Clearly, helium leak is strongly affected by pinhole diameter in both experimental models. We have calculated, for the pinhole geometries studied, helium leak rates by using the Poiseuille Equation. Calculated values were in agreement with experimental values.


Isolation of a novel peroxisomal catalase gene from sugarcane, which is responsive to biotic and abiotic stresses.
Catalase is an iron porphyrin enzyme, which serves as an efficient scavenger of reactive oxygen species (ROS) to avoid oxidative damage. In sugarcane, the enzymatic activity of catalase in a variety (Yacheng05-179) resistant to the smut pathogen Sporisorium scitamineum was always higher than that of the susceptible variety (Liucheng03-182), suggesting that catalase activity may have a positive correlation with smut resistance in sugarcane. To understand the function of catalase at the molecular level, a cDNA sequence of ScCAT1 (GenBank Accession No. KF664183), was isolated from sugarcane infected by S. scitamineum. ScCAT1 was predicted to encode 492 amino acid residues, and its deduced amino acid sequence shared a high degree of homology with other plant catalases. Enhanced growth of ScCAT1 in recombinant Escherichia coli Rosetta cells under the stresses of CuCl2, CdCl2 and NaCl indicated its high tolerance. Q-PCR results showed that ScCAT1 was expressed at relatively high levels in the bud, whereas expression was moderate in stem epidermis and stem pith. Different kinds of stresses, including S. scitamineum challenge, plant hormones (SA, MeJA and ABA) treatments, oxidative (H2O2) stress, heavy metal (CuCl2) and hyper-osmotic (PEG and NaCl) stresses, triggered a significant induction of ScCAT1. The ScCAT1 protein appeared to localize in plasma membrane and cytoplasm. Furthermore, histochemical assays using DAB and trypan blue staining, as well as conductivity measurement, indicated that ScCAT1 may confer the sugarcane immunity. In conclusion, the positive response of ScCAT1 to biotic and abiotic stresses suggests that ScCAT1 is involved in protection of sugarcane against reactive oxidant-related environmental stimuli.


Information and counselling for patients approaching end-stage renal failure in selected centres across Europe.
The EDTNA/ERCA survey of the provision of pre-ESRF information, education and counselling in renal care was the third project organised through the Collaborative Research Programme (CRP). Data was collected from 35 participating centres in 10 countries. The majority of participating centres had a structured pre-ESRF programme. Advice and education received by patients in these centres was usually provided by a multidisciplinary team and was coordinated by nurses in half of the centres. Programmes in all countries had similar content in that normal kidney function, medication, diet, haemodialysis, peritoneal dialysis and transplantation were routinely discussed and that issues such as employment, importance of leisure activities, holidays and Kidney Patient Associations were also on the agenda for discussion. Educational material produced by companies was widely used. Policy differences did emerge in attitudes to discussing the "no-treatment" option with patients accepted for dialysis and in the treatment that would be offered to patients with specific co-morbidities and life-style.


Model-Based Approach for Optimizing Study Design and Clinical Drug Performances of Extended-Release Formulations of Methylphenidate for the Treatment of ADHD.
Methylphenidate (MPH) is currently used to treat children with attention deficit hyperactivity disorder (ADHD). Several extended-release (ER) formulations characterized by a dual release process were developed to improve efficacy over an extended duration. In this study, a model-based approach using literature data was developed to: 1) evaluate the most efficient pharmacokinetic (PK) model to characterize the complex PK profile of MPH ER formulations; 2) provide PK endpoint metrics for comparing ER formulations; 3) define criteria for optimizing development of ER formulations using a convolution-based model linking in vitro release, in vivo release, and hour-by-hour behavioral ratings of ADHD symptoms; and 4) define an optimized trial design for assessing the activity of MPH in pediatric populations. The convolution-based model accurately described the complex PK profiles of a variety of ER MPH products, providing a natural framework for establishing an in vitro/in vivo correlation and for defining criteria for assessing comparative bioequivalence of MPH ER products.


Insights into left ventricular function from the time course of regional and global rotation by speckle tracking echocardiography.
Description and quantification of regional left ventricular (LV) rotation and the time course of LV rotation might provide further insight into LV function. The study comprised 60 healthy volunteers (age 39 +/- 15 years, 31 men) in whom complete global and regional LV rotation could be assessed at both the basal and apical LV level with speckle tracking echocardiography, using QLAB advanced quantification software version 6.0 (Philips, Best, The Netherlands). At the LV basal level, a brief counterclockwise rotation from aortic valve opening until 25% ejection was seen in the anterior segments (anterior, anteroseptal, anterolateral) only. Clockwise rotation in the anterior segments at the basal level was decreased as compared to the posterior segments (inferior, inferoseptal, inferolateral) from 25% ejection until aortic valve closure. At the LV apical level, all segments showed a brief clockwise rotation during the isovolumic contraction phase. Also, at this level there were no differences in regional LV rotation at any other moment during the cardiac cycle. There was a marked de-rotation from the moment of maximal rotation until E-peak at the LV basal level (79 +/- 18%) whereas de-rotation during this interval was less pronounced at the LV apical level (55 +/- 21%). Only at the LV basal level significant linear relationships were seen between the E/A ratio and de-rotation extent and velocity from mitral valve opening until E-peak (R(2)= 0.42 and R(2)= 0.40, respectively, both P < 0.001). In the normal human heart significant regional differences in LV rotation and de-rotation exist.


Osteoporotic thoracolumbar junctional fracture accompanied by spinous process fracture without posterior ligament injury: its clinical and radiologic significances.
To assess the clinical and radiologic outcome of osteoporotic thoracolumbar junctional fracture accompanied by spinous process fracture (SPF) without posterior ligament injury. A total of 391 patients with single-level osteoporotic thoracolumbar junctional (T10-L2) fracture were selectively enrolled. The patients were divided into two groups by absence (group I) or presence (group II) of SPF. Clinical and radiologic parameters were compared between the two groups. Group I comprised of 332 patients with only vertebral body fracture, and group II comprised of 59 patients with both vertebral body and SPFs. In all cases of group II, SPFs were located just one level above the fractured vertebral body, and the injury of the posterior ligament was not found. At the time of injury, group II patients showed worse outcomes in anterior vertebral body compression percentage, kyphotic Cobb angle, cranial disk status, and the rate of the initial neurologic injury. Kyphotic alignment changes during 1-year follow-up were compared between the conservative subgroups of groups I and II. At the time of injury, there were no statistical differences in anterior vertebral body compression percentage and Cobb angle between the two conservative subgroups. However, the difference was significant after 1-year follow-up. Comparison of kyphotic alignment change at 12 months after diagnosis within group II was done according to the treatment method. Vertebroplasty subgroup in group II did not show benefit even in preventing such kyphotic alignment change, whereas instrumentation subgroup in group II showed lordotic alignment restoration despite more severe kyphotic alignment at the time of injury. Osteoporotic thoracolumbar junctional fracture accompanied by spinous process fracture without posterior ligament injury represented more severe injury with flexion forces on the anterior column and tensile forces on the posterior column, and was related with more severe posttraumatic kyphotic changes during the 12-month follow-up.


Theory-based intervention for dementia behaviors: a within-person analysis over time.
The historic "black-box" approach to treatment effectiveness research has hampered the development of effective activity interventions for persons with dementia. The purpose of this case study is to test the effectiveness of activities derived from the Need-Driven Dementia-Compromised Behavior Model. Activities that matched skill level and personality style of interest resulted in a pattern of greater time on task (p =.0012), participation (p =.004), and positive mood (p =.0001) and fewer dementia-related behaviors (p =.009) compared with activities matched to skill level only. Practitioners may improve behavioral outcomes for persons with dementia by prescribing activities based on an assessment of skill level and style of interest.


Craniofacial osseointegration.
Craniofacial osseointegration has been hailed as the most significant advance in maxillofacial prosthetic restoration over 25 years. It provides a particularly unfortunate group of patients, who previously may have had few treatment options, with new reconstructive opportunities. This paper outlines the surgical and prosthetic techniques of craniofacial osseointegration. Treatment outcomes in terms of individual implant success rates are described and the role of hyperbaric oxygen is considered. The need for future avenues of development are also discussed. Craniofacial implants have become an integral part of the treatment options available for head and neck reconstruction. It is important that this care is provided within a multidisciplinary clinical-research environment.


In vivo Electroporation of Skeletal Muscle Fibers in Mice.
In vitro models are essential for investigating the molecular, biochemical, and cell-biological aspects of skeletal muscle. Still, models that utilize cell lines or embryonic cells do not fully recapitulate mature muscle fibers in vivo. Protein function is best studied in mature differentiated tissue, where biological context is maintained, but this is often difficult when reliable detection reagents, such as antibodies, are not commercially available. Exogenous expression of tagged proteins in vivo solves some of these problems, but this approach can be technically challenging because either a mouse must be engineered for each protein of interest or viral vectors are required for adequate levels of expression. While viral vectors can infect target cells following local administration, they carry the risk of genome integration that may interfere with downstream analyses. Plasmids are another accessible expression system, but they require ancillary means of cell penetration; electroporation is a simple physical method for this purpose that requires minimal training or specialized equipment. Here, we describe a method for in vivo plasmid expression in a foot muscle following electroporation.


Determination of biological species and analysis of genetic variability by RAPD of isolates of Pleurotus subgenus Coremiopleurotus.
Isolates of Pleurotus cystidiosus and P. smithii were studied to verifie the occurrence of P. cystidiosus instead of P. smithii in South America. The two species are mainly separated by the growth rate of the anamorph in culture, the morphology of the anamorph and teleomorph, intercompatibility tests, and genetic variability. In order to see if the isolate found in Brazil and previously identified as Antromycopsis macrocarpa (the anamorph of P. cystidiosus) belongs to P. cystidiosus, a species with a world wide distribution, or to P. smithii which is restricted to Mexico and South America, or if P. cyistidiosus and P. smithii are the same species, isolates of different geographic origins were studied. Growth rate in culture, mono-dikaryotic matings, and genetic variability determined by RADP were investigated. The results show that the criteria used to separate the two species are unsatisfactory, and that P. smithii should be considered a synonym of P. cystidiosus; this extends the distribution of this later species to Central and South America.


Family economic pressure and adolescent suicidal ideation: application of the family stress model.
This study used a sample of 501 families from the Mississippi Delta region to examine the feasibility of the Family Stress Model for understanding adolescent suicidal ideation. The results indicated that family economic pressure was related to parental depressive symptoms, which, in turn, was related to parental hostile behavior and physical abuse. These parental behaviors were related to adolescent self-esteem and depressive symptoms, which, in turn, were related to adolescent suicidal ideation. Therefore, family economic pressure and parental depressive symptoms and behaviors were indirectly related to adolescent suicidal ideation. The results indicate the applicability of the Family Stress Model for understanding adolescent suicidal ideation.


The atypical receptor CCRL2 is required for CXCR2-dependent neutrophil recruitment and tissue damage.
CCRL2 is a 7-transmembrane domain receptor that shares structural and functional similarities with the family of atypical chemokine receptors (ACKRs). CCRL2 is upregulated by inflammatory signals and, unlike other ACKRs, it is not a chemoattractant-scavenging receptor, does not activate β-arrestins, and is widely expressed by many leukocyte subsets. Therefore, the biological role of CCRL2 in immunity is still unclear. We report that CCRL2-deficient mice have a defect in neutrophil recruitment and are protected in 2 models of inflammatory arthritis. In vitro, CCRL2 was found to constitutively form homodimers and heterodimers with CXCR2, a main neutrophil chemotactic receptor. By heterodimerization, CCRL2 could regulate membrane expression and promote CXCR2 functions, including the activation of β2-integrins. Therefore, upregulation of CCRL2 observed under inflammatory conditions is functional to finely tune CXCR2-mediated neutrophil recruitment at sites of inflammation.


Treatment of Traumatic Esophagopleural Fistula Using the Over-the-Scope-Clip System.
Esophagopleural fistula (EPF) is a rare condition that is usually accompanied by severe infection and life-threatening morbidity. Here, we report the successful treatment of an EPF by closing an esophageal orifice using the over-the-scope-clip (OTSC) system without postprocedural complications. A 41-year-old man had serious thoracic and abdominal trauma due to a traffic accident. Computed tomography revealed findings suggestive of esophageal rupture due to Boerhaave syndrome. An emergent explorative operation was performed for primary repair with the insertion of a vacuum-assisted closure device. A postoperative upper gastrointestinal series revealed an EPF tract connecting the left pleural space and distal esophagus. We performed an endoscopic procedure using the "traumatic-type"OTSC to seal the EPF, and the esophageal orifice was completely healed 2 weeks postoperatively. The OTSC system might represent a safe and feasible modality for the treatment of EPF.


Hydrogenation versus transfer hydrogenation of ketones: two established ruthenium systems catalyze both.
The established standard ketone hydrogenation (abbreviated HY herein) precatalyst [Ru(Cl)(2)((S)-tolbinap)[(S,S)-dpen]] ((S),(S,S)-1) has turned out also to be a precatalyst for ketone transfer hydrogenation (abbreviated TRHY herein) as tested on the substrate acetophenone (3) in iPrOH under standard conditions (45 degrees C, 45 bar H(2) or Ar at atmospheric pressure). HY works at a substrate catalyst ratio (s:c) of up to 10(6) and TRHY at s:c<10(4). Both produce (R)-1-phenylethan-1-ol ((R)-4), but the ee in HY are much higher (78-83 %) than in TRHY (4-62 %). In both modes, iPrOK is needed to generate the active catalysts, and the more there is (1-4500 equiv), the faster the catalytic reactions. The ee is about constant in HY and diminishes in TRHY as more iPrOK is added. The ketone TRHY precatalyst [Ru(Cl)(2)((S,S)-cyP(2)(NH)(2))] ((S,S)-2), established at s:c=200, has also turned out to be a ketone HY precatalyst at up to s:c=10(6), again as tested on 3 in iPrOH under standard conditions. The enantioselectivity is opposite in the two modes and only high in TRHY: with (S,S)-2, one obtains (R)-4 in up to 98 % ee in TRHY as reported and (S)-4 in 20-25 % ee in HY. iPrOK is again required to generate the active catalysts in both modes, and again, the more there is, the faster the catalytic reactions. The ee in TRHY are only high when 0.5-1 equivalents iPrOK are used and diminish when more is added, while the (low) ee is again about constant in HY as more iPrOK is added (0-4500 equiv). The new [Ru(H)(Cl)((S,S)-cyP(2)(NH)(2))] isomers (S,S)-9 A and (S,S)-9 B (mixture, exact structures unknown) are also precatalysts for the TRHY and HY of 3 under the same conditions, and (R)-4 is again produced in TRHY and (S)-4 in HY, but the lower ee shows that in TRHY (S,S)-9 A/(S,S)-9 B do not lead to the same catalysts as (S,S)-2. In contrast, the ee are in accord with (S,S)-9 A/(S,S)-9 B leading to the same catalysts as (S,S)-2 in HY. The kinetic rate law for the HY of 3 in iPrOH and in benzene using (S,S)-9 A/(S,S)-9 B/iPrOK or (S,S)-9 A/(S,S)-9 B/tBuOK is consistent with a fast, reversible addition of 3 to a five-coordinate amidohydride (S,S)-11 to give an (S,S)-11-substrate complex, in competition with the rate-determining addition of H(2) to (S,S)-11 to give a dihydride [Ru(H)(2)((S,S)-cyP(2)(NH)(2))] (S,S)-10, which in turn reacts rapidly with 3 to generate (S)-4 and (S,S)-11. The established achiral ketone TRHY precatalyst [Ru(Cl)(2)(ethP(2)(NH)(2))] (12) has turned out to be also a powerful precatalyst for the HY of 3 in iPrOH at s:c=10(6) and of some other substrates. Response to the presence of iPrOK is as before, except that 12 already functions well without it at up to s:c=10(6).


Simultaneous Catheter Replacement for Infectious and Mechanical Complications Without Interruption of Peritoneal Dialysis.
♦ Conventional management for peritoneal dialysis (PD)-related infectious and mechanical complications that fails treatment includes catheter removal and hemodialysis (HD) via a central venous catheter with the end result that the majority of patients will not return to PD. Simultaneous catheter replacement (SCR) can retain patients on PD by avoiding the scenario of staged removal and reinsertion of catheters. The aim of this study was to evaluate a protocol for SCR without interruption of PD. ♦ Clinical outcomes were analyzed for 55 consecutive SCRs performed from 2002 through 2012 and followed through 2013. ♦ Simultaneous catheter replacements were performed for 28 cases of relapsing peritonitis, 12 cases of tunnel infection, and 15 cases of mechanical catheter complications. All cases for peritonitis and tunnel infection and 80% for mechanical complications continued PD on the day of surgery using a low-volume, intermittent automated PD protocol. Systemic antibiotics were continued for 2 weeks postoperatively (up to 4 weeks for Pseudomonas). Simultaneous catheter replacement was performed as an outpatient procedure in 89.1% of cases. Only 1 of 55 procedures was complicated by peritonitis within 8 weeks. No catheter losses occurred during this postoperative timeframe. Long-term, SCR enabled a median technique survival of 5.1 years. ♦ In most instances, SCR can be safely performed without interruption of PD for selected cases of peritonitis and tunnel infection and for mechanical catheter complications. The procedure spares the patient from a central venous catheter, a shift to HD, the psychological ordeal of a change in dialysis modality, and a second surgery to insert a new catheter.


Membrane protein thermodynamic stability may serve as the energy sink for sorting in the periplasm.
Thermodynamic stabilities are pivotal for understanding structure-function relationships of proteins, and yet such determinations are rare for membrane proteins. Moreover, the few measurements that are available have been conducted under very different experimental conditions, which compromises a straightforward extraction of physical principles underlying stability differences. Here, we have overcome this obstacle and provided structure-stability comparisons for multiple membrane proteins. This was enabled by measurements of the free energies of folding and the m values for the transmembrane proteins PhoP/PhoQ-activated gene product (PagP) and outer membrane protein W (OmpW) from Escherichia coli. Our data were collected in the same lipid bilayer and buffer system we previously used to determine those parameters for E. coli outer membrane phospholipase A (OmpLA). Biophysically, our results suggest that the stabilities of these proteins are strongly correlated to the water-to-bilayer transfer free energy of the lipid-facing residues in their transmembrane regions. We further discovered that the sensitivities of these membrane proteins to chemical denaturation, as judged by their m values, was consistent with that previously observed for water-soluble proteins having comparable differences in solvent exposure between their folded and unfolded states. From a biological perspective, our findings suggest that the folding free energies for these membrane proteins may be the thermodynamic sink that establishes an energy gradient across the periplasm, thus driving their sorting by chaperones to the outer membranes in living bacteria. Binding free energies of these outer membrane proteins with periplasmic chaperones support this energy sink hypothesis.


Small Antisense RNA RblR Positively Regulates RuBisCo in Synechocystis sp. PCC 6803.
Small regulatory RNAs (sRNAs) function as transcriptional and post-transcriptional regulators of gene expression in organisms from all domains of life. Cyanobacteria are thought to have developed a complex RNA-based regulatory mechanism. In the current study, by genome-wide analysis of differentially expressed small RNAs in Synechocystis sp. PCC 6803 under high light conditions, we discovered an asRNA (RblR) that is 113nt in length and completely complementary to its target gene rbcL, which encodes the large chain of RuBisCO, the enzyme that catalyzes carbon fixation. Further analysis of the RblR(+)/(-) mutants revealed that RblR acts as a positive regulator of rbcL under various stress conditions; Suppressing RblR adversely affects carbon assimilation and thus the yield, and those phenotypes of both the wild type and the overexpressor could be downgraded to the suppressor level by carbonate depletion, indicated a regulatory role of RblR in CO2 assimilation. In addition, a real-time expression platform in Escherichia coli was setup and which confirmed that RblR promoted the translation of the rbcL mRNA into the RbcL protein. The present study is the first report of a regulatory RNA that targets RbcL in Synechocystis sp. PCC 6803, and provides strong evidence that RblR regulates photosynthesis by positively modulating rbcL expression in Synechocystis.


[Experience of professor LI Yingkun treating tic disorder with acupuncture].
Professor LI Yingkun establishes "scalp acupuncture line" guided by the scalp acupuncture points of international standardization and traditional meridian theory, which can be used to treat tic disorder. With a case, professor LI Yingkun's needling experience for tic disorder is introduced in detail and summarized in order to provide reference for the treatment of the disease.


Effects of recent warm and cold spells on European plant phenology.
Climate change is already altering the magnitude and/or frequency of extreme events which will in turn affect plant fitness more than any change in the average. Although the fingerprint of anthropogenic warming in recent phenological records is well understood, the impacts of extreme events have been largely neglected. Thus, the temperature response of European phenological records to warm and cold spells was studied using the COST725 database. We restricted our analysis to the period 1951-2004 due to better spatial coverage. Warm and cold spells were identified using monthly mean ENSEMBLES temperature data on a 0.5° grid for Europe. Their phenological impact was assessed as anomalies from maps displaying mean onsets for 1930-1939. Our results clearly exhibit continental cold spells predominating in the period 1951-1988, especially during the growing season, whereas the period from 1989 onwards was mainly characterised by warm spells in all seasons. The impacts of these warm/cold spells on the onset of phenological seasons differed strongly depending on species, phase and timing. "False" phases such as the sowing of winter cereals hardly reacted to summer warm/cold spells; only the sowing of summer cereals mirrored spring temperature warm/cold spells. The heading dates of winter cereals did not reveal any consistent results probably due to fewer warm/cold spells identified in the relevant late spring months. Apple flowering and the harvest of winter cereals were the best indicators of warm/cold spells in early spring and summer, also being spatially coherent with the patterns of warm/cold spells.


Structure and Activity Changes of Phytohemagglutinin from Red Kidney Bean (Phaseolus vulgaris) Affected by Ultrahigh-Pressure Treatments.
Phytohemagglutin (PHA), purified from red kidney beans (Phaseolus vulgaris) by Affi-Gel blue affinity chromatography, was subjected to ultrahigh-pressure (UHP) treatment (150, 250, 350, and 450 MPa). The purified PHA lost its hemagglutination activity after 450 MPa treatment and showed less pressure tolerance than crude PHA. However, the saccharide specificity and α-glucosidase inhibition activity of the purified PHA did not change much after UHP treatment. Electrophoresis staining by periodic acid-Schiff (PAS) manifested that the glycone structure of purified PHA remained stable even after 450 MPa pressure treatment. However, electrophoresis staining by Coomassie Blue as well as circular dichroism (CD) and differential scanning calorimetry (DSC) assay proved that the protein unit structure of purified PHA unfolded when treated at 0-250 MPa but reaggregates at 250-450 MPa. Therefore, the hemagglutination activity tends to be affected by the protein unit structure, while the stability of the glycone structure contributed to the remaining α-glucosidase inhibition activity.


V2R mutations and nephrogenic diabetes insipidus.
Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria, with hyposthenuria, and polydipsia are the cardinal clinical manifestations of the disease. Nephrogenic failure to concentrate urine maximally may be due to a defect in vasopressin-induced water permeability of the distal tubules and collecting ducts, to insufficient buildup of the corticopapillary interstitial osmotic gradient, or to a combination of these two factors. Thus, the broadest definition of the term NDI embraces any antidiuretic hormone-resistant urinary-concentrating defect, including medullary disease with low interstitial osmolality, renal failure, and osmotic diuresis. About 90% of patients with congenital NDI are males with X-linked recessive NDI (OMIM 304800)(1) and have mutations in the AVP receptor 2 (AVPR2) gene that codes for the vasopressin V(2) receptor; the gene is located in chromosome region Xq28. In about 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance (OMIM 222000 and 125800)(1). Mutations have been identified in the aquaporin-2 gene (AQP2, OMIM 107777)(1), which is located in chromosome region 12q13 and codes for the vasopressin-sensitive water channel. NDI is clinically distinguishable from neurohypophyseal diabetes insipidus (OMIM 125700(1); also referred to as central or neurogenic diabetes insipidus) by a lack of response to exogenous AVP and by plasma levels of AVP that rise normally with increase in plasma osmolality. Hereditary neurohypophyseal diabetes insipidus is secondary to mutations in the gene encoding AVP (OMIM 192340)(1). Neurohypophyseal diabetes insipidus is also a component of autosomal recessive Wolfram syndrome 1 or DIDMOAD syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) (OMIM 222300)(1), an autosomal recessive disorder. Other inherited disorders with complex polyuro-polydipsic syndrome with loss of water, sodium, chloride, calcium, magnesium, and potassium include Bartter syndrome (OMIM 601678)(1) and cystinosis (OMIM 219800)(1), while long-term lithium administration is the main cause of acquired NDI. Here, we use the gene symbols approved by the HUGO Gene Nomenclature Committee (http://www.gene.ucl.ac.uk/nomenclature) and provide OMIM entry numbers [OMIM (Online Mendelian Inheritance in Man)(1); McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD), 2000; World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim/].


[A study of coagulation contact factors in hereditary angioneurotic oedema (author's transl)].
Coagulation contact factors were studied in 9 patients with hereditary angioneurotic oedema. After storage of the plasma at O degrees C for 20 hours, activation of prekallikrein and factor VII, together with prekallikrein consumption, were observed. The cold activation, due to deficiency of C1 esterase inhibitor, was not suppressed by polybren in vitro (factor XII activation inhibitor) but was prevented by aprotinins (kallikrein inhibitors). These findings would suggest that patients with hereditary angioneurotic oedema should be investigated for prekallikrein consumption and should be treated with aprotinin as soon as the attack begins.


Effectiveness and safety of Xuefu Zhuyu oral liquid on -stagnation and blood-stasis pattern in patients with stable angina, tension-type headache and primary dysmenorrhea: rationale and design of a master protocol.
We present the rationale and design of a master protocol study that clarifies the effectiveness and safety of Chinese herbal formulas on -stagnation and blood-stasis pattern (QBP). Three randomized controlled trials (RCTs) and real-world observational studies. Based on three registry cohorts of stable angina, tension-type headache and primary dysmenorrhea, patients with QBP will be enrolled in RCTs to receive either Xuefu Zhuyu (, XFZY) oral liquid or a placebo, while patients with non-QBP will be enrolled in the observational studies and experience follow-up. 1414 patients (RCTs: 574; observational studies: 840) will be recruited at seven centers in China over a 3-year period. The primary outcome is the visual analog scale of pain intensity. Adverse events will also be reported. The analysis will be undertaken separately in each sub-study, and then an overall analysis combining multiple subgroups will be performed to comprehensively investigate the effect of XFZY oral liquid. This study will provide high-quality evidence of XFZY oral liquid for QBP patients and show a paradigm of post-marketing evaluation of the effectiveness and safety for Chinese medicine following the notion of the pattern dominating different disease research models.


Late-onset familial amyloid polyneuropathy (FAP) Val30Met without family history.
Familial amyloid polyneuropathy (FAP) is rare and most commonly caused by the Val30Met mutation of the transthyretin (TTR) gene. Beside polyneuropathy, other complications due to amyloid deposits occur, but may vary in phenotype. The mutation tends to occur in endemic clusters. We describe a 65-year-old man from a non-endemic FAPVal30Met area who developed a progressive generalized painless axonal sensorimotor polyneuropathy with mild autonomic involvement and absent FAP symptoms in the family. Nerve biopsy showed amyloid deposits, staining with TTR-antibodies on immunohistochemistry. After DNA-sequencing of the TTR gene, the diagnosis of FAP Val30Met was made. Late-onset FAP Val30Met is a progressive and fatal disorder with varying penetrance, and may occur in non-endemic areas and cases without a family history.


A new form of inherited red-blindness identified in zebrafish.
A red-blind zebrafish mutant, partial optokinetic response b (pob), has been isolated by measuring eye movements of larvae in a three-generation screen for recessive mutations affecting the visual system. pob larvae exhibit eye movements in response to rotating black and white stripes illuminated with white light, but they do not move their eyes when the stripes are illuminated with red light. Physiological, immunohistochemical, and in situ hybridization analyses of pob retinas showed a selective loss of red-sensitive cones at 5 days postfertilization (dpf). At 3 dpf, cells expressing red opsin are present, suggesting that red-sensitive cones form initially but then disappear rapidly, whereas other photoreceptors remain. Linkage analysis indicated that the mutation identified in the pob mutant is not at the red opsin locus. Because red opsin is the only known molecule unique to red cones, these data suggest that a novel gene is required for the maintenance or function of red cones.


Mapping the epitopes of neutralizing anti-human IL-3 monoclonal antibodies. Implications for structure-activity relationship.
The epitopes of neutralizing mAb were mapped in order to identify a receptor binding site on human IL-3 (huIL-3). To initiate this structure and activity analysis, four neutralizing mAb were selected on the basis of preventing rhuIL-3 stimulated proliferation of peripheral blood cells from a patient with chronic myelogenous leukemia (CML). In order to identify continuous epitopes, the neutralizing mAb were assayed in a solid-phase ELISA for their reactivity with either denatured rhuIL-3 or with the peptides generated by digestion of rhuIL-3 by using two different proteinases. Two of the neutralizing mAb recognized single fragments from both digestions. Amino acid (aa) sequence determination showed that these peptides overlap, defining a region of 22 aa (aa 29 to 50 of the mature rhuIL-3 protein). In a competition ELISA, the two continuous epitopes were shown to be linked to one another and to the two discontinuous epitopes, suggesting that all four neutralizing mAb bind to a discrete region of the IL-3 molecule, which might be involved in binding to the IL-3R.


Heat-shock protein 65 and activated gamma/delta T cells in injured arteries.
Because immune mechanisms are implicated in atherogenesis, we investigated the T-lymphocyte subset and factors related to its activation after acute arterial ligation (22 ligated and 13 non-ligated specimens). Ligated arteries produced heat-shock protein 65 (hsp65) and were infiltrated with activated T cells (mostly dendritic, CD3+, CD4-, CD8-, and gamma/delta T-cell-receptor bearing). The protein was found with dendritic T cells, with immunogold-labelled hsp65 beside the dendritic processes. Thus, the immune reaction after acute arterial injury may be associated with binding and recognition of in-situ hsp65 by dendritic gamma/delta T-cells.


Localization of the loosely bound nuclear proteins of rat brain: an immunocytochemical ultrastructural study.
Antibodies against the loosely bound subnuclear protein fraction (0.35 M NaCl-extractable subnuclear fraction) of rat brain were raised in rabbits, and the ultrastructural distribution of the antigenic determinants in rat cerebellum was studied using the unlabeled antibody peroxidase-antiperoxidase (PAP) method. A localization restricted to the nucleus was observed. Both neuronal and neuroglial nuclei exhibited antigens, whereas nuclei of pericytes and endothelial cells did not. The immunoreaction product was homogeneously distributed in dispersed chromatin and was absent from condensed chromatin, suggesting that the antigens were confined to the active regions of the genoma. The outer nuclear membrane and the nucleolus appeared to be free of the antigens, while a perinucleolar ring of immunoreaction was detectable. Liver preparations showed a nuclear reaction markedly weaker than the one for brain nuclei. Adsorption of the serum with isolated liver nuclei nullified the reactivity in liver tissue, whereas a sharp reaction was still observed in the cerebellum, indicating the subcellular reaction under examination to contain antigens specifically concentrated in the nervous system or unique to the brain.


Two new alkaloids from Melodinus suaveolens.
Two new Melodinus-type alkaloids, 15β-hydroxy-14,15-dihydroscandine (1) and 14,15-dihydroscandine (2), together with 6 known ones were isolated from Melodinus suaveolens. The structures of the new compounds were identified from spectroscopic (NMR, UV, IR, CD) and mass spectrometric data and Mosher's method. The new compounds exhibited significant, dose-dependent inhibition of the production of lipopolysaccharide (LPS)-induced NO, IL-6 and IL-8 in mice macrophages.


Prediabetes is associated with loss of appendicular skeletal muscle mass and sarcopenia.
Decreasing mass and metabolism in skeletal muscle are associated with increasing insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The causal relation between sarcopenia and abnormal glucose metabolism may be bidirectional. This investigation is aimed to explore the detailed correlation between pre-diabetes and sarcopenia in United States (US) adults. A total of 22,482 adults aged ≥20 years in the National Health and Nutrition Examination Survey (NHANES) were included. Generalized linear models were conducted to examine associations between diabetes status, serum glucose, glycohemoglobin (HbA1c), and sarcopenia. Generalized additive models and smooth fitting curves were used to examine the non-linear relationship between HbA1c and ASMBMI. Sarcopenia was defined as ASMBMI (appendicular skeletal muscle mass/body mass index) < 0.789 for males, and <0.512 for females based on the cut-off values of the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. After fully adjusting for multiple covariates, sarcopenia was directly correlated with pre-diabetes [OR (95%CI) = 1.230 (1.057, 1.431), p = 0.008] and T2DM [OR (95%CI) = 2.106 (1.625, 2.729), p < 0.001]. In non-T2DM population, HbA1c was negatively correlated with ASMBMI [β (95%CI) = -0.009 (-0.013, -0.005), p < 0.001]. The correlations only persisted in males. Furthermore, in male non-T2DM population, the association of HbA1c and ASMBMI presents an inverted U-shape curve with an inflection point of HbA1c 5.2%. Pre-diabetes is associated with increased risk of sarcopenia. HbA1c is an independent risk factor for loss of appendicular skeletal muscle mass and sarcopenia when HbA1c greater than 5.2% in the male non-T2DM population.


Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing's syndrome.
To evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Retrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference. 469 patients were analyzed [78% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94%); ECS, n=26 (6%)] and 237 patients [228 CD (96%), 9 ECS (4%)]. Both tests were performed in 205 patients (44%). The post-CRH %-increase at 30 minutes of both ACTH (cut-off ≥31%, sensitivity 83%, specificity 85%, AUC 0.81) and cortisol (cut-off ≥12%, sensitivity 82%, specificity 89%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the %-suppression during the 8 mg DST was ≥55% (sensitivity 80%, specificity 78%, AUC 0.75). The CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.


Intestinal bypass surgery for obesity decreases food intake and taste preferences.
Food intake was measured in 22 obese patients before and after jejunioleostomy for obesity. Most of the weight loss could be accounted for by the observed reduction of caloric intake. Malabsorption was also present as indicated by increased loss of fat in the stools, and decreased absorption of D-xylose and vitamin B12. A dislike for sweet tastes developed after surgery in most patients. Preferences for concentrated solutions of sucrose and glucose were reduced after patients showed a depression of food intake by a 440-calorie preload which had not been detected before surgery. These studies show a decrease in food intake after intestinal bypass surgery and suggest a role for taste or other gastrointestinal factors in regulating food intake.