Wafer-scale production of highly uniform two-dimensional MoS2 by metal-organic chemical vapor deposition.
Semiconducting two-dimensional (2D) materials, particularly extremely thin molybdenum disulfide (MoS2) films, are attracting considerable attention from academia and industry owing to their distinctive optical and electrical properties. Here, we present the direct growth of a MoS2 monolayer with unprecedented spatial and structural uniformity across an entire 8 inch SiO2/Si wafer. The influences of growth pressure, ambient gases (Ar, H2), and S/Mo molar flow ratio on the MoS2 layered growth were explored by considering the domain size, nucleation sites, morphology, and impurity incorporation. Monolayer MoS2-based field effect transistors achieve an electron mobility of 0.47 cm2 V-1 s-1 and on/off current ratio of 5.4 × 104. This work demonstrates the potential for reliable wafer-scale production of 2D MoS2 for practical applications in next-generation electronic and optical devices.


Attitudes and beliefs about domestic violence: results of a public opinion survey: II. Beliefs about causes.
This report presents findings from a public opinion survey designed to measure beliefs about the causes of domestic violence (DV) based on telephone interviews with 1,200 residents across six New York State communities. Findings reveal substantial diversity and complexity among beliefs and interesting similarities and differences across open- and close-ended questions regarding explanations for partner abuse. Most respondents think about the causes of violence in the context of individual problems, relationships, and families, not as a problem with roots in our society or culture. Few believe that women are the cause of their own abuse, one fourth still believe that some women want to be abused, and most believe that women can end abusive relationships. Secondhand experiences with DV were associated with some beliefs about causes of abuse, and gender, age, education, and race were associated with certain beliefs in predictable ways.


Lissencephaly with agenesis of corpus callosum and rudimentary dysplastic cerebellum: a subtype of lissencephaly with cerebellar hypoplasia.
Lissencephaly with agenesis of the corpus callosum and rudimentary dysplastic cerebellum may represent a subset of lissencephaly with cerebellar hypoplasia (LCH) of unknown etiology, one that is distinct from other types of LCH. We present a detailed neuropathological description of an autopsy brain from a 7-day-old neonate born at 38-gestational weeks, presenting with this malformation. The brain was severely hydrocephalic and totally agyric. The corpus callosum was absent and deep gray matter structures indistinct. A rudimentary dysplastic cerebellum, dysplastic olivary nuclei and nearly complete absence of corticospinal tracts were also noted. Microscopic examination revealed various types of dysplastic and malformative features throughout the brain in addition to the classic four-layered neocortical structure characteristic of type I lissencephaly. Unique features in the present case were (1) bilateral periventricular undulating cortical ribbon-like structures mimicking fused gyri and sulci, associated with aberrant reelin expression, (2) large dysplastic neocortical neurons positive for phosphorylated neurofilament, calbindin-D28K, tuberin, hamartin, doublecortin, LIS1, reelin and Dab1, (3) derangement of radial glial fibers, and (4) disorganized cerebellar cortex and heterotopic gray matter composed exclusively of granule cells in the cerebellar deep white matter. The clinicopathological features in the present case are suggestive of a distinct category of lissencephaly with cerebellar involvement. We suggest a possible classification of this unique case among the LCH syndromes.


[Metabolic parameters of CAPD and CCPD in diabetics with terminal renal insufficiency].
The effects of continuous ambulant (CAPD) and continuous cyclic peritoneal dialysis (CCPD) on a series of laboratory parameters in the blood and dialysate were assessed in two groups of nine juvenile diabetics each, suffering from terminal renal failure. The CCPD patients showed higher urea and creatinine levels in serum and, as a result of lower protein loss via the dialysate, also higher total protein and transferrin concentrations than the CAPD patients. The glucose absorption of the CCPD patients was about 50% lower than of the CAPD patients. Control of diabetes was equally successful with both procedures, the HbA1 values were less than 10%. The triglycerides were lowered by both CAPD and CCPD on the condition that the absorbed glucose amounts were included in the calculation of the dietary adjustment. Cholesterol and HDL-cholesterol remained unchanged. Thus CCPD appears to have advantages over CAPD, especially with respect to the lowering of the glucose absorption and the protein loss. The wider application of both methods will be, however, less influenced by the metabolic parameters than by other factors such as reduction of the risk of peritonitis.


Post-pandemic self-reported mental health of mental healthcare professionals in the Netherlands compared to during the pandemic - an online longitudinal follow-up study.
The mental health of professionals was under pressure during- and post-pandemic. Initially, the focus was mainly on the health workers in the hospitals, but over time the pressure shifted to other sectors, including mental health care. An increase in workload and decrease in mental health of healthcare professionals in mental health care can lead to a decrease in the available care capacity. In an earlier online survey of mental health professionals, 1,300 professionals from a large number of mental healthcare institutions were involved. In this study, conducted in September 2021, about half of the respondents reported increased levels of stress. Feelings of anxiety, anger, and sadness were also increasingly experienced due to the COVID-19 pandemic. Furthermore, 4.2% replied that they were considering resigning their jobs. One of the recommendations of this previous study was to monitor these professionals repeatedly to be able to make an estimate of the stress and vision of work during the course of the pandemic and afterwards. Following this recommendation, the online survey was repeated. The aim of the current online longitudinal follow-up study was to re-evaluated mental status of healthcare workers. 510 healthcare workers participated in this follow-up survey. The reported mental health complaints were significantly higher during compared to post-pandemic. Respondents were less able to maintain work/life balance during the pandemic and even reported a shift to work. However, the majority of respondents indicated that they had restored this balance post-pandemic. Moreover, more sick leave was reported post-pandemic than during the pandemic and more frequent absences post-pandemic. This highlights the importance of focusing on resilience over training and career.


Size-dependent conformational change in halogen-π interaction: from benzene to graphene.
Diatomic halogen molecules X2 (X = Cl/Br) favor the edge-to-face conformation on benzene with significant electrostatic interaction via halogen bonding. In contrast, they favor the stacked conformation on graphene with negligible electrostatic interaction. As the aromatic ring expands, the inner facial side becomes almost electrostatically neutral. On coronene, the two conformations are compatible.


Density Functional Theory Study on the Complexation of NOTA as a Bifunctional Chelator with Radiometal Ions.
1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) is a key bifunctional chelator utilized for the complexation of metal ions in radiopharmaceutical applications; the ability of these chelators depends on the strength of their binding with ions. The focus of the present work is to evaluate the complexation of Cu2+, Ga3+, Sc3+, and In3+ radiometal ions with NOTA using density functional theory (B3LYP functional) and 6-311+G(2d,2p)/DGDZVP basis sets. The significant role of ion-water interactions in the chelation interaction energies in solution reflects the competition between ion-water and NOTA-ion interaction in the chelation process. There is reasonable agreement between experimental and theoretical binding constants, geometries, and 1H NMR chemical shifts. Chelation interaction energies, Gibbs free energies, and entropies in solution show that the NOTA-Ga3+ and NOTA-Cu2+ are the most and least stable complexes, respectively. The natural atomic charges and second order perturbation analysis reveal charge transfer between NOTA and radiometal ions. The theoretical 1H NMR chemical shifts of NOTA are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. Global scalar properties such as EHOMO/ELUMO, ΔELUMO-HOMO, and chemical hardness/softness confirm that the NOTA-Cu2+ complex, which has a singly occupied molecular orbital, has the lowest ΔELUMO-HOMO value, the least chemical hardness, and the highest chemical softness. The significant variation of the hardness and ΔELUMO-HOMO values of the complexes can be attributed to the different positions of the metal ions on the periodic table. This study affirms that, among the radiometal ions, Ga3+ can be used to effectively radiolabel NOTA chelator for radiopharmaceutical usage as it binds most stably with NOTA.


Flute and Shank Dimensions of Reciprocating Instruments before and after Simulated Root Canal shaping.
This study analyzed the effect of the dimensions of the flute and shank in the first 4 mm of instrument tips on the deformation and dimensional changes of reciprocating instruments after root canal shaping (RCS). The reciprocating instruments used were Reciproc® R25, R40, and R50; WaveOne® Small, Primary, and Large; and Unicone® #20, #25, and #40. Scanning electron microscopy images of the first 4 mm of the tip were acquired at 30× magnification before and after simulated curved root canals were shaped. Each instrument was used only once. The images were transferred to the AxioVision® software to measure the flute area (μm2), shank area (μm2), flute length (μm), and cross-sectional diameter (μm). Student's t test for paired samples was used to compare differences before and after RCS, and analysis of variance followed by the Tukey test, to compare differences between instruments of similar sizes. The instruments were classified according to deformations after RCS. Reciproc® instruments had larger flutes and smaller shanks. The Reciproc® R40 had significant differences in cross-sectional diameter at 0.5 mm from the tip. Reciproc® had no plastic deformations. Unicone® #20 instruments had significant differences in cross-sectional diameter at 1.5 and 3.0 mm from the tip, and #25 instruments had differences at 1.5 and 3.0 mm and in length of the second and third flutes. One #20 and three #40 instruments had plastic deformations. The differences in length of the first and fourth flutes of WaveOne® Primary and in cross-sectional diameter at 2.0 mm from the tip of WaveOne® Large were significant. Two of three WaveOne® Large instruments had plastic deformations. Reciproc® instruments had greater flute areas and lengths and smaller shanks than Unicone® and WaveOne® instruments of similar sizes. Reciproc® instruments had a greater flute-to-shank ratio. WaveOne® instruments had the lowest flute-to-shank ratio. Unicone® instruments had the most plastic deformations. Instruments with larger flutes and smaller shanks had fewer plastic deformations after curved RCS. The knowledge of mechanical behavior before choosing the endodontic instrument may avoid fracture, regardless of the clinical condition, and it is essential to the success of root canal treatment.


L-positioned Perforator Propeller Flap for Partial Breast Reconstruction with Axillary Dead Space.
Partial breast reconstruction using perforator flaps harvested from the lateral chest wall has become a well-established surgical technique recently. In the case of a partial mastectomy with an axillary lymph node dissection, there are 2 main defects; one is a partial breast defect and the other is an axillary dead space. To reconstruct the 2 separate defects with local flaps, basically 2 different flaps are needed, and usually, it is rather difficult to harvest 2 different local flaps in the adjacent area. To resolve this problem, we introduce the L-positioned perforator propeller flap (PPF). We used an L-positioned PPF on 2 female patients, aged 46 and 47 years old, who were suffering from breast cancer in the upper outer quadrant. The concept of this flap design is as follows: the partial breast defect is reconstructed with the longer lobe of the L-positioned PPF and the axillary defect is filled with the smaller lobe of the L-positioned PPF at the same time. The reconstruction time was 2 hours and 0 minutes and 1 hour and 46 minutes in each case. The patients were successfully provided with aesthetically acceptable breast reconstruction without postoperative complications. Moreover, both patients had consecutive postoperative radiotherapy on the reconstructed area without complications. With this flap design, it is possible for patients to have safe and aesthetic reconstruction with only 1 local flap and fewer invasive procedures.


Pigmented epithelioid melanocytoma: two case reports.
Because of indolent course without mortality, the term "pigmented epithelioid melanocytoma" has been suggested as a replacement for "equine" or "animal-type" melanoma and for the epithelioid blue nevus of the Carney type, from which they are histologically indistinguishable. This report reviews this concept and recounts in detail two of eighteen cases occurring in residents of the Central Coast of California. This paper also contains clinical photographs of pigmented epithelioid melanocytoma, unlike prior reports.


Malignant pleural mesothelioma with heterologous osteoblastic elements: computed tomography, magnetic resonance, and positron emission tomography imaging characteristics of a rare tumor.
The imaging findings of a rare mixed type of malignant mesothelioma of the pleura with heterologous bone stroma in a patient without a previous history of asbestos exposure are reported. Imaging findings of this type of bone-forming pleural mesothelioma are scarcely reported in the literature, with only a few case reports describing findings on conventional radiography, computed tomography, and magnetic resonance imaging. To the best of our knowledge, no positron emission tomography imaging characteristics of this type of mesothelioma have been previously reported.


Nanocomposite Hydrogels: Advances in Nanofillers Used for Nanomedicine.
The ongoing progress in the development of hydrogel technology has led to the emergence of materials with unique features and applications in medicine. The innovations behind the invention of nanocomposite hydrogels include new approaches towards synthesizing and modifying the hydrogels using diverse nanofillers synergistically with conventional polymeric hydrogel matrices. The present review focuses on the unique features of various important nanofillers used to develop nanocomposite hydrogels and the ongoing development of newly hydrogel systems designed using these nanofillers. This article gives an insight in the advancement of nanocomposite hydrogels for nanomedicine.


Rapid and Efficient Method for the Detection of Microplastic in the Gastrointestinal Tract of Fishes.
The rising evidence of microplastic pollution impacts on aquatic organisms in both marine and freshwater ecosystems highlights a pressing need for adequate and comparable detection methods. Available tissue digestion protocols are time-consuming (>10 h) and/or require several procedural steps, during which materials can be lost and contaminants introduced. This novel approach comprises an accelerated digestion step using sodium hydroxide and nitric acid in combination to digest all organic material within 1 h plus an additional separation step using sodium iodide which can be used to reduce mineral residues in samples where necessary. This method yielded a microplastic recovery rate of ≥95%, and all tested polymer types were recovered with only minor changes in weight, size, and color with the exception of polyamide. The method was also shown to be effective on field samples from two benthic freshwater fish species, revealing a microplastic burden comparable to that indicated in the literature. As a consequence, the present method saves time, minimizes the loss of material and the risk of contamination, and facilitates the identification of plastic particles and fibers, thus providing an efficient method to detect and quantify microplastics in the gastrointestinal tract of fishes.


Rapid targeted somatic mutation analysis of solid tumors in routine clinical diagnostics.
Tumor genotyping is an essential step in routine clinical practice and pathology laboratories face a major challenge in being able to provide rapid, sensitive and updated molecular tests. We developed a novel mass spectrometry multiplexed genotyping platform named PentaPanel to concurrently assess single nucleotide polymorphisms in 56 hotspots of the 5 most clinically relevant cancer genes, KRAS, NRAS, BRAF, EGFR and PIK3CA for a total of 221 detectable mutations. To both evaluate and validate the PentaPanel performance, we investigated 1025 tumor specimens of 6 different cancer types (carcinomas of colon, lung, breast, pancreas, and biliary tract, and melanomas), systematically addressing sensitivity, specificity, and reproducibility of our platform. Sanger sequencing was also performed for all the study samples. Our data showed that PentaPanel is a high throughput and robust tool, allowing genotyping for targeted therapy selection of 10 patients in the same run, with a practical turnaround time of 2 working days. Importantly, it was successfully used to interrogate different DNAs isolated from routinely processed specimens (formalin-fixed paraffin embedded, frozen, and cytological samples), covering all the requirements of clinical tests. In conclusion, the PentaPanel platform can provide an immediate, accurate and cost effective multiplex approach for clinically relevant gene mutation analysis in many solid tumors and its utility across many diseases can be particularly relevant in multiple clinical trials, including the new basket trial approach, aiming to identify appropriate targeted drug combination strategies.


[Otoscopic pitfall : the congenital cholesteatoma].
The congenital cholesteatoma is a rare benign tumor whose diagnosis is mainly made during childhood. Otoscopic examination shows a white retrotympanic collection with or without hearing loss. In case of a late diagnosis, the disease will spread to the surrounding structures, leading to ossicules destruction, facial palsy, sensorineural hearing loss and vestibular dysfunction. Surgery is the therapeutic gold-standard, with different techniques chosen based on the cholesteatoma's extension. Patient should benefit from a long term medical and radiological (MRI) follow-up.


Related strains of African swine fever virus with different virulence: genome comparison and analysis.
Two strains of African swine fever virus (ASFV), the high-virulence Lisboa60 (L60) and the low-virulence NH/P68 (NHV), which have previously been used in effective immunization/protection studies, were sequenced. Both were isolated in Portugal during the 11-year period after the introduction of ASFV to the European Continent in 1957. The predicted proteins coded by both strains were compared, and where differences were found these were also compared to other strains of known virulence. This highlighted several genes with significant alterations in low-virulence strains of ASFV that may constitute virulence factors, several of which are still uncharacterized regarding their function. Phylogenetic analysis grouped L60 and NHV closest to other P72 genotype I ASFV strains from Europe and West Africa, consistent with the assumed West African origin of all European strains. Interestingly, a relatively lower genomic identity exists between L60 and NHV, both isolated in a similar geographical location 8 years apart, than with other European and west African strains isolated subsequently and in more distant locations. This may reflect the intensive passage in tissue culture, during the early 1960s, of a Portuguese isolate to obtain an attenuated vaccine, which may have led to NHV. This study contributes to a better understanding of the evolution of ASFV, and defines additional potential virulence genes for future studies of pathogenesis towards the development of effective vaccines.


BabblePlay: An app for infants, controlled by infants, to improve early language outcomes.
This project set out to develop an app for infants under one year of age that responds in real time to language-like infant utterances with attractive images on an iPad screen. Language-like vocalisations were defined as voiced utterances which were not high pitched squeals, nor shouts. The app, BabblePlay, was intended for use in psycholinguistic research to investigate the possible causal relationship between early canonical babble and early onset of word production. It is also designed for a clinical setting, (1) to illustrate the importance of feedback as a way to encourage infant vocalisations, and (2) to provide consonant production practice for infant populations that do not vocalise enough or who vocalise in an atypical way, specifically, autistic infants (once they have begun to produce consonants). This paper describes the development and testing of BabblePlay, which responds to an infant's vocalisations with colourful moving shapes on the screen that are analogous to some features of the infant's vocalization including loudness and duration. Validation testing showed high correlation between the app and two human judges in identifying vocalisations in 200 min of BabblePlay recordings, and a feasibility study conducted with 60 infants indicates that they can learn the contingency between their vocalisations and the appearance of shapes on the screen in one five minute BabblePlay session. BabblePlay meets the specification of being a simple and easy-to-use app. It has been shown to be a promising tool for research on infant language development that could lead to its use in home and professional environments to demonstrate the importance of immediate reward for vocal utterances to increase vocalisations in infants.


Pancreatic islet transplantation prevents the impaired healing of intestinal anastomoses in Lewis rats with streptozotocin-induced diabetes.
Pancreatic islet transplantation may prevent secondary complications of diabetes mellitus, but its potential benefits on early complications have been incompletely examined. The objective of this study was to investigate whether preoperative islet transplantation would normalize impaired healing of intestinal anastomoses in diabetic rats. Male Lewis rats were divided into a control group (I), an uncontrolled diabetic group (II), and a transplant group (III). Nine days before surgery, groups II and III were rendered diabetic by injection of streptozotocin. Two days before surgery, group III received an intrahepatic isogenic two-donor islet graft, whereas groups I and II underwent sham transplantation. On day 0, all animals underwent resection and anastomosis of both ileum and colon. Half of the animals in each group were killed on day 3 and the other half were killed on day 7. Blood glucose levels in group II rats remained over 20 mmol/L throughout the experiment, whereas in group III rats they were normalized within 24 hours after transplantation. At death, group II rats, but not groups I and III rats, showed a high incidence of anastomotic abscesses. Uncontrolled diabetes lowered anastomotic strength, and transplantation prevented this reduction. For instance, anastomotic bursting pressure in the ileum on day 3 was 11.9 +/- 4.8 kPa in group I rats, 3.3 +/- 3.0 kPa in group II rats, and 11.1 +/- 4.3 kPa in group III rats. Rupture on day 3 always occurred within the anastomosis, whereas on day 7 intra-anastomotic ruptures were only observed in group II rats. No differences between the groups were found for either anastomotic hydroxyproline concentration or content. However, the acid solubility of anastomotic collagen was significantly higher in group II rats than in groups I and III rats. Thus, uncontrolled diabetes lowers anastomotic strength without affecting anastomotic collagen content. Defective repair is prevented by pancreatic islet transplantation before surgery.


[Serum prohepcidin and other iron metabolism parameters in healthy adults].
Hepcidin is a newly discovered iron metabolism regulator. It decreases iron absorption from the duodenal enterocytes and inhibits its release from the reticuloendothelial macrophages. The experiments on hepcidin and its precursor--prohepcidin seem very promising and underline the need to establish the reference intervals for these proteins and define the effects of age and sex on their concentrations. The aim of this study was to assess the impact of age and sex on serum prohepcidin concentration in healthy adults. The study group consisted of 79 healthy volunteers (F-29, M-50) between 18 to 88 years of age. Healthy adults were divided into three groups according to age: group 1-33 healthy volunteers aged between 18-36, group 2-20 healthy volunteers aged between 38-53, group 3- 26 healthy volunteers aged between 58-88. Prohepcidin and ferritin concentrations were determined by enzyme-linked immunosorbent assays (ELISA). Serum iron concentration was measured on Architect c8000 System. In this work, we demonstrated that prohepcidin concentrations were significantly higher in group 3 (Me = 292,2 ng/ ml) in comparison with group 1 (Me = 150.7 ng/ml; p < 0.000001) or group 2 (Me = 118.1 ng/ml; p < 0.000001). We observed a positive correlation between age and prohepcidin concentration (R = 0.38; p = 0.001). The oldest group of volunteers also revealed significantly higher levels of ferritin and lower levels of serum iron in comparison with two groups of younger adults. Females showed significantly higher level of prohepcidin (Me = 226.51 ng/ml) than males (Me = 142.6 ng/ml; p = 0.01). We observed that females under 50 years of age had significantly higher levels of prohepcidin (Me = 290.9 ng/ml) in comparison with younger females (Me = 150.7 ng/ml; p = 0.0001), similar correlation was noticed in males (212.3 ng/ml vs 128.3 ng/ml; p = 0.007). Prohepcidin concentration increased significantly with age and was significantly higher in women than men. The results of our study show that serum prohepcidin concentration is age and sex dependent.


Cytokine absorption in critically ill old COVID-19 patients with renal failure: A retrospective analysis of 503 intensive care unit patients.
COVID-19 is associated with cytokine release in critical disease states. Thus, cytokine absorption has been proposed as a therapeutic option. This study investigated the influence of cytokine absorption on mortality in old critical patients with COVID-19 and renal failure admitted to intensive care units (ICU). This retrospective analysis of a prospective international observation study (the COVIP study) analysed ICU patients≥70 years with COVID-19. Data on Sequential Organ Failure Assessment (SOFA) score, clinical frailty scale (CFS), ICU therapy details including renal replacement therapy (RRT) with/without cytokine absorption were collected. The cytokine absorption group was compared to patients receiving RRT without cytokine absorptionRESULTS:Among 3927 patients, 503 received RRT; among them 47 patients were treated with cytokine absorption. Mortality rates were high in both groups with increased rates in the cytokine group for ICU mortality and 30-day mortality, but not for 3-month mortality. Logistic regression analysis indicated that SOFA-score, but not cytokine absorption was associated with mortality. Critical COVID-19 patients with renal failure treated with cytokine absorption showed higher short term mortality rates when compared to patients with renal replacement therapy alone. Mortality is associated with disease severity, but not cytokine absorption in a multivariate analysis.


Synchronous primary malignancies of papillary thyroid carcinoma and Hodgkin lymphoma: Interventions and outcome.
Thyroid carcinoma is uncommon. Papillary thyroid carcinoma (PTC) represents the majority of differentiated thyroid carcinoma and is a recognised complication of prior exposure to ionizing radiation. Even more uncommon is the synchronous occurrence of PTC with Hodgkin lymphoma (HL) as multiple primary malignancies. We report a 33-year-old mother of three who developed asymptomatic thyroid nodule for four years, and neck swelling for the recent ten months. She denied constitutional symptoms or B symptoms, and thyroid profiles were normal. Initially, metastatic thyroid cancer was suspected based on ultrasound scan findings of enlarged left thyroid gland and enlarged supraclavicular lymph nodes (LN). However, fine needle aspiration examinations of the thyroid nodule were inconclusive, and the supraclavicular LN was suspicious of HL. Computerised tomography scan detected a large mass at the thyroid glands and lymphadenopathies in the mediastinal, hilar, subcarinal and axilla with dimensions up to 6 cm. Left hemi-thyroidectomy with left supraclavicular LN biopsy revealed PTC in the left thyroid lobe measuring 38 x 25 x 18 mm, and the left supraclavicular LN was not definitive of HL. Completion thyroidectomy on the right side, bilateral central neck dissection and excision biopsy of the right supraclavicular LN revealed the presence of HL in the right supraclavicular LN, and both HL and metastatic PTC in right central LN. After multidisciplinary discussions, the patient received chemotherapy at four weeks postoperatively and achieved complete remission. This report highlights the importance of patient-centered approach and multidisciplinary consensus within lack of established guidelines, given rarity of the case.


Effects of the Hypnotic Alkylphenol Derivative Propofol on Breast Cancer Progression. A Focus on Preclinical and Clinical Studies.
Propofol is a hypnotic alkylphenol derivative with many biological activities. It is predominantly used in anesthesia and is the most used parenteral anesthetic agent in the United States. Accumulating preclinical studies have shown that this compound may inhibit cancer recurrence and metastasis. Nevertheless, other investigations provided evidence that this compound may promote breast cancer cell progression by modulating different molecular pathways. Clinical data on this topic are scarce and derive from retrospective analyses. For this reason, we reviewed and evaluated the available data to reveal insight into this controversial issue. More preclinical and clinical investigations are necessary to determine the potential role of propofol in the proliferation of breast cancer cells.


Esophageal varices in cirrhotic patients: evaluation with liver CT.
The objective of this study was to evaluate the performance of routine helical liver CT in the detection and grading of esophageal varices in cirrhotic patients. A total of 67 consecutive cirrhotic patients who underwent both upper endoscopy and helical liver CT within a 4-week interval were evaluated. The CT protocol included unenhanced, arterial, and portal phases with a collimation of 7-7.5 mm. Two blinded abdominal imagers (6 and 7 years' experience) retrospectively interpreted all CT images to detect the presence of esophageal varices on a 5-point confidence scale and measure the largest varix identified. Receiver operating characteristic (ROC) curve analysis was performed, and the correlation between CT measurements and endoscopic grading, the reference standard, was assessed. The variceal detection rates for the observers was 92% (11/12) and 92% (11/12) for large (i.e., clinically significant) varices, 53% (16/30) and 60% (18/30) for small varices, and 64% (27/42) and 69% (29/42) for all varices. The area under the ROC curve for the detection of esophageal varices of any size was 0.77 (observer 1) and 0.80 (observer 2). CT variceal grading showed a strong correlation with endoscopic grading for both observers (p < or = 0.001). Using a variceal diameter threshold of 3 mm on CT, sensitivity, specificity, and accuracy for distinguishing large esophageal varices from small or no varices were 92% (11/12), 84% (46/55), and 85% (57/67), respectively, for both observers. Liver CT is useful for the detection and grading of esophageal varices. A diameter of 3 mm may be an appropriate screening threshold for large clinically significant varices.


Transcriptome Analysis of Hypothalamic Gene Expression during Daily Torpor in Djungarian Hamsters (Phodopus sungorus).
Animals living at high or temperate latitudes are challenged by extensive changes in environmental conditions over seasons. Djungarian hamsters (Phodopus sungorus) are able to cope with extremely cold ambient temperatures and food scarcity in winter by expressing spontaneous daily torpor. Daily torpor is a circadian controlled voluntary reduction of metabolism that can reduce energy expenditure by up to 65% when used frequently. In the past decades it has become more and more apparent, that the hypothalamus is likely to play a key role in regulating induction and maintenance of daily torpor, but the molecular signals, which lead to the initiation of daily torpor, are still unknown. Here we present the first transcriptomic study of hypothalamic gene expression patterns in Djungarian hamsters during torpor entrance. Based on Illumina sequencing we were able to identify a total number of 284 differentially expressed genes, whereby 181 genes were up- and 103 genes down regulated during torpor entrance. The 20 most up regulated group contained eight genes coding for structure proteins, including five collagen genes, dnha2 and myo15a, as well as the procoagulation factor vwf. In a proximate approach we investigated these genes by quantitative real-time PCR (qPCR) analysis over the circadian cycle in torpid and normothermic animals at times of torpor entrance, mid torpor, arousal and post-torpor. These qPCR data confirmed up regulation of dnah2, myo15a, and vwf during torpor entrance, but a decreased mRNA level for all other investigated time points. This suggests that gene expression of structure genes as well as the procoagulation factor are specifically initiated during the early state of torpor and provides evidence for protective molecular adaptions in the hypothalamus of Djungarian hamsters including changes in structure, transport of biomolecules and coagulation.


Variation of the ribosomal operon 16S-23S gene spacer region in representatives of Salmonella enterica subspecies.
The 16S-23S spacer regions of two ribosomal operons (rrnA and rrnE) have been sequenced in seven representatives of the Salmonella enterica subspecies. Isolated nucleotide substitutions were found at the same sites as in Escherichia coli but the number of polymorphic sites was much larger, as could be expected for a more heterogeneous species. Still, as in E. coli, most of the variation found was due to insertions and/or deletions affecting blocks of nucleotides generally located at equivalent regions of the putative secondary structure for both species. Isolated polymorphic sites generated phylogenetic trees generally consistent with the subspecies structure and the accepted relationships among the subspecies. However, the sequences of rrnE put subspecies I closer to E. coli K-12 than to the other S. enterica subspecies. The distribution of polymorphisms affecting blocks of nucleotides was much more random, and the presence of equivalent sequences in distantly related subspecies, and even in E. coli, could reflect relatively frequent horizontal transfer. The smallest 16S-23S spacers in other genera of the family Enterobacteriaceae were also sequenced. As expected, the level of variation was much larger. Still, the phylogenetic tree inferred is consistent with those of 16S rRNA or housekeeping genes.


TriDFusion (3DF) image viewer.
An open-source, extensible medical viewing platform is described, called the TriDFusion image viewer (3DF). The 3DF addresses many broad unmet needs in nuclear medicine research; it provides a viewer with several tools not available in commercial nuclear medicine workstations, yet invaluable for imaging in research studies. The 3DF includes an image integration platform to register images from multiple imaging modalities together with delineated volumes of interest (VOIs), structures and dose distributions. It can process images from different vendors' systems and is therefore vendor neutral. The 3DF also provides a convenient tool for performing multi-modality image analysis and fusion. The functional components currently being distributed is open-source code that includes: (1) a high quality viewer that can display axial, coronal, and sagittal tomographic images, maximum intensity projection images, structure contours, and isointensity contour lines or dose colorwash, (2) multi-image fusion allowing multiple images to be fused with VOI and dose distributions, (3) a suite of segmentation tools to edit and/or create tumor and organ VOIs, (4) dosimetry tools for several radioisotopes, (5) clinical tools for correcting acquisition errors, including patient orientation, and (6) the ability to save the resultant image and VOI as DICOM files or to export the numerical results as comma separated values files. Because the code is written in MATLAB™, it is highly readable and is easier for the coder to make changes compared to languages such as C or C++. In what follows, we describe the content of the new TriDFusion (3DF) image viewer software platform using examples of a number of clinical research workflows. Such examples vary in complexity but illustrate the main attributes of the software. In summary, 3DF provides a powerful, convenient, easy-to-use suite of open-source imaging research tools for the nuclear medicine community that allows physicians, medical physicists, and academic researchers to display, manipulate, and analyze images.


E2F1-Induced Overexpression of Long Noncoding RNA SBF2-AS1 Promotes Non-Small-Cell Lung Cancer Metastasis Through Regulating miR-362-3p/GRB2 Axis.
Long noncoding RNA SBF2 antisense RNA 1 (lncRNA SBF2-AS1) has been reported to be involved in non-small-cell lung cancer (NSCLC) tumorigenesis. However, the biological role and regulatory mechanism of lncRNA SBF2-AS1 on NSCLC metastasis remain largely unknown. In this study, the expression level and functional role of SBF2-AS1 were investigated in both NSCLC tissues and cell lines. We found that SBF2-AS1 was upregulated in both NSCLC tissues and cell lines. Patients with high levels of SBF2-AS1 have larger tumors, higher malignancy, and poor prognosis. Knockdown of SBF2-AS1 significantly inhibited tumor growth in vivo and cell proliferation, migration, and invasion in vitro. Moreover, bioinformatics analysis, chromatin immunoprecipitation assay, and luciferase reporter assay proved that the upregulation of SBF2-AS1 was mediated by transcription factor E2F1. Further experiments demonstrated that miR-362-3p had complementary binding site with 3'-UTR of SBF2-AS1. Besides, luciferase reporter assay validated that GRB2 was the target protein of miR-362-3p. Rescue experiments showed that SBF2-AS1 silencing inhibited cell invasion and migration, while cotransfection si-SBF2-AS1 and miR-362-3p inhibitor rescued the effect of si-SBF2-AS1. These results demonstrate that E2F1-induced overexpression of SBF2-AS1 promotes the expression of GRB2 by targeting miR-362-3p to facilitate the metastasis of NSCLC.


Relative genomic stability of adipose tissue derived mesenchymal stem cells: analysis of ploidy, H19 long non-coding RNA and p53 activity.
Mesenchymal stem cells (MSCs) are multipotent and have been derived from various tissues. Although MSCs share many basic features, they often display subtle tissue specific differences. We previously demonstrated that bone marrow (BM) MSCs frequently become polyploid in culture. This tendency was mediated by a reduction in the expression of H19 long non-coding RNA during the transition from a diploid to a polyploid state. MSCs were derived from both BM and adipose tissue of mice and expanded under normoxic and hypoxic culture conditions. Cells were stained by propidium iodide and their ploidy was evaluated by FACS. Gene expression of independent MSC preparations was compared by quantitative real time PCR and protein expression levels by Western blot analysis. p53 silencing in MSCs was performed by a specific small hairpin RNA (shRNA). We set to examine whether genomic instability is common to MSCs originating from different tissues. It is demonstrated that adipose derived MSCs (ASCs) tend to remain diploid during culture while a vast majority of BM MSCs become polyploid. The diploid phenotype of ASCs is correlated with reduced H19 expression compared to BM MSCs. Under hypoxic conditions (3% oxygen) both ASCs and BM MSCs demonstrate increased RNA expression of H19 and Vascular endothelial growth factor A. Importantly, ASC gene expression is significantly less variable than BM MSCs under both oxygen conditions, indicating to their superior homogeneity. Gene expression analysis revealed that p53 target genes, often induced by DNA damage, are up-regulated in ASCs under basal conditions. However, p53 activation following treatment with DNA damaging agents was strongly elevated in BM MSCs compared to ASCs. We found that p53 is involved in maintaining the stable diploid state of ASCs as p53 shRNA induced ploidy changes in ASCs but not in BM MSCs. The increased genomic stability of murine ASCs together with their lower H19 expression and relative homogeneity suggest a tissue specific higher stability of ASCs compared to BM MSCs, possibly due to higher activity of p53. The tissue specific differences between MSCs from a different tissue source may have important consequences on the use of various MSCs both in vitro and in vivo.


The bursa of Fabricius: the evolution of a discovery.
It has been a joy these past 40 yr to have traveled the "Bursal Road"--a road we helped construct and whose route allowed us to make a variety of observations that contributed either to basic science or indirectly or directly to the role of the bursa of Fabricius in the B cell repertoire. The chicken's bursa of Fabricius introduced me to endocrine, heritability, and growth studies, which allowed serendipity to occur and the revelation of the classical and modification of the classical theses of bursal function. The modification of the classical thesis, presence of immunoglobulin in the absence of the bursa, raised questions that directed us to study hypothalamic control of behavior, which was not directly related to bursal function. This forced us to learn various techniques, e.g., autoradiography, cell labeling, and electron microscopy, that made it possible to study long- and short-lived lymphocytes, lymphokines, labeled cells, and the fine structure and function of the bursa of Fabricius, cecal tonsil, Harderian gland, lymph nodes, Meckel's diverticulum, Pineal gland, and spleen. In an attempt to use cyclophosphamide to understand how the spleen acquired the ability to produce antibodies, we revealed a dendritic cell in the bursa, the bursal-secretory dendritic cell (BSDC), and in the spleen, the ellipsoid-associated cell (EAC). The BSDC is a novel cell in the bursal microenvironment and may be involved in an interaction with prebursal or bursal stem cells, leading to the differentiation or selection of the B cell repertoire of the chicken.


A one-mutation mathematical model can explain the age incidence of acute myeloid leukemia with mutated nucleophosmin (NPM1).
Acute myeloid leukemia with mutated NPM1 gene and aberrant cytoplasmic expression of nucleophosmin (NPMc(+) acute myeloid leukemia) shows distinctive biological and clinical features. Experimental evidence of the oncogenic potential of the nucleophosmin mutant is, however, still lacking, and it is unclear whether other genetic lesion(s), e.g. FLT3 internal tandem duplication, cooperate with NPM1 mutations in acute myeloid leukemia development. An analysis of age-specific incidence, together with mathematical modeling of acute myeloid leukemia epidemiology, can help to uncover the number of genetic events needed to cause leukemia. We collected data on age at diagnosis of acute myeloid leukemia patients from five European Centers in Germany, The Netherlands and Italy, and determined the age-specific incidence of AML with mutated NPM1 (a total of 1,444 cases) for each country. Linear regression of the curves representing age-specific rates of diagnosis per year showed similar slopes of about 4 on a double logarithmic scale. We then adapted a previously designed mathematical model of hematopoietic tumorigenesis to analyze the age incidence of acute myeloid leukemia with mutated NPM1 and found that a one-mutation model can explain the incidence curve of this leukemia entity. This model fits with the hypothesis that NPMc(+) acute myeloid leukemia arises from an NPM1 mutation with haploinsufficiency of the wild-type NPM1 allele.


Free radical reductive degradation of vic-dibromoalkanes and reaction of bromine atoms with polyunsaturated fatty acids: possible involvement of Br(.) in the 1,2-dibromoethane-induced lipid peroxidation.
Bromine atoms generated upon reductive degradation of 1,2-dibromoethane and various other vic-dibromoalkanes have been shown to react with polyunsaturated fatty acids via both abstraction of bisallylic hydrogen and addition to the double bonds. The abstraction process occurs with 53, 68, and 77% efficiency from linoleic (18:2), linolenic (18:3), and arachidonic acid (20:4), respectively. The corresponding absolute rate constants have been evaluated to be 1.2 x 10(9), 1.8 x 10(9), and 5.1 x 10(9) M-1 s-1 for these three polyunsaturated fatty acids (PUFAs). The rate constants for the bromine atom addition reaction appear to be very similar for all PUFAs and have been determined to (1.2 +/- 0.3) x 10(9) M-1 s-1. Absolute rate constants in the order of 10(5)-10(6) s-1 have also been measured for the bromine atom elimination from various beta-bromoalkyl radicals. The results render bromine atoms a potential initiator for lipid peroxidation, and their reactions may well provide an important chemical basis for the overall toxic action of 1,2-dibromoethane and related substrates.


The organization and evolution of the Responder satellite in species of the Drosophila melanogaster group: dynamic evolution of a target of meiotic drive.
Satellite DNA can make up a substantial fraction of eukaryotic genomes and has roles in genome structure and chromosome segregation. The rapid evolution of satellite DNA can contribute to genomic instability and genetic incompatibilities between species. Despite its ubiquity and its contribution to genome evolution, we currently know little about the dynamics of satellite DNA evolution. The Responder (Rsp) satellite DNA family is found in the pericentric heterochromatin of chromosome 2 of Drosophila melanogaster. Rsp is well-known for being the target of Segregation Distorter (SD)- an autosomal meiotic drive system in D. melanogaster. I present an evolutionary genetic analysis of the Rsp family of repeats in D. melanogaster and its closely-related species in the melanogaster group (D. simulans, D. sechellia, D. mauritiana, D. erecta, and D. yakuba) using a combination of available BAC sequences, whole genome shotgun Sanger reads, Illumina short read deep sequencing, and fluorescence in situ hybridization. I show that Rsp repeats have euchromatic locations throughout the D. melanogaster genome, that Rsp arrays show evidence for concerted evolution, and that Rsp repeats exist outside of D. melanogaster, in the melanogaster group. The repeats in these species are considerably diverged at the sequence level compared to D. melanogaster, and have a strikingly different genomic distribution, even between closely-related sister taxa. The genomic organization of the Rsp repeat in the D. melanogaster genome is complex-it exists of large blocks of tandem repeats in the heterochromatin and small blocks of tandem repeats in the euchromatin. My discovery of heterochromatic Rsp-like sequences outside of D. melanogaster suggests that SD evolved after its target satellite and that the evolution of the Rsp satellite family is highly dynamic over a short evolutionary time scale (<240,000 years).


Behavior, Neural Structure, and Metabolism in Adult Male Mice Exposed to Environmentally Relevant Doses of Di(2-ethylhexyl) Phthalate Alone or in a Phthalate Mixture.
We have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced down-regulation of the androgen receptor (AR) in the neural circuitry controlling this behavior. The cellular mechanisms induced by chronic exposure of adult male mice to low doses of DEHP alone or in an environmental phthalate mixture were studied. Two-month-old C57BL/6J males were exposed orally for 8 wk to DEHP alone (0, 5, or 50μg/kg/d) or to DEHP (50μg/kg/d) in a phthalate mixture. Behavior, dendritic density per 50-μm length, pre-/postsynaptic markers, synapse ultrastructure, and bioenergetic activity were analyzed. Mice exposed to DEHP either alone or in a phthalate mixture differed in mating, emission of ultrasonic vocalizations, and the ability to attract receptive females in urinary preference tests from control mice. Analyses in the medial preoptic area, the key hypothalamic region involved in male sexual behavior, showed lower dendritic spine density and protein levels of glutamate receptors and differences in other postsynaptic components and presynaptic markers between the treated groups. Ultrastructural observation of dendritic synapses by electron microscopy showed comparable morphology between the treated groups. Metabolic analyses highlighted differences in hypothalamic metabolites of males exposed to DEHP alone or in a phthalate mixture compared to control mice. These differences included lower tryptophan and higher NAD+ levels, respectively, a precursor and end product of the kynurenine pathway of tryptophan metabolism. The protein amounts of the xenobiotic aryl hydrocarbon receptor, one of the targets of this metabolic pathway and known negative regulator of the AR, were higher in the medial preoptic area of exposed male mice. Differences in behavior of male mice exposed to environmental doses of phthalates were associated with differences in neural structure and metabolism, with possibly a key role of the kynurenine pathway of tryptophan metabolism in the effects mediated by these substances. https://doi.org/10.1289/EHP11514.


Aspiration lung disorders in bovines: a case report and review.
Lung aspiration disorders in bovines are invariably diagnosed as infectious aspiration pneumonias. There is a distinct differentiation between aspiration pneumonia and aspiration pneumonitis in humans that can be applied to bovines. The nature and quantity of the aspirate can result in differing pathogeneses which can require differing therapeutic approaches. Whilst blood gases were important in detecting and prognosticating lung problems, changes in barometric pressure with altitude have to be considered when interpreting partial pressures of oxygen. Anatomical differences in the lungs of bovines can explain why this species is more prone to certain pneumonic problems. Pulmonary physiotherapy is important in treating lung disorders in humans and should be considered as an adjunct therapy in bovine respiratory conditions. A case work-up was used to highlight some of the points discussed in this article.


Contribution of the toxic advanced glycation end-products-receptor axis in nonalcoholic steatohepatitis-related hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. The main etiologies of HCC are hepatitis B virus and hepatitis C virus (HCV), and non-hepatitis B/non-hepatitis C HCC (NBNC-HCC) has also been identified as an etiological factor. Although the incidence of HCV-related HCC in Japan has decreased slightly in recent years, that of NBNC-HCC has increased. The onset mechanism of NBNC-HCC, which has various etiologies, remains unclear; however, nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is known to be an important risk factor for NBNC-HCC. Among the different advanced glycation end-products (AGEs) formed by the Maillard reaction, glyceraldehyde-derived AGEs, the predominant components of toxic AGEs (TAGE), have been associated with NASH and NBNC-HCC, including NASH-related HCC. Furthermore, the expression of the receptor for AGEs (RAGE) has been correlated with the malignant progression of HCC. Therefore, TAGE induce oxidative stress by binding with RAGE may, in turn, lead to adverse effects, such as fibrosis and malignant transformation, in hepatic stellate cells and tumor cells during NASH or NASH-related HCC progression. The aim of this review was to examine the contribution of the TAGE-RAGE axis in NASH-related HCC.


Evaluation of antibacterial activities of cephalosporin antibiotics: cefazolin, cephaloridine, cephalothin, and cephalexin.
The antibacterial activities of 4 cephalosporin antibiotics, cefazolin, cephaloridine, cephalothin and cephalexin, against 330 isolates of bacteria from patients at National Taiwan University Hospital, were determined by an agar plate dilution technique. Cephalosporins possess strong antibacterial activity against gram-positive bacteria except Enterococci. Staphylococcus aureus is the most susceptible among the organisms tested. More than 90% of Staphylococcus aureus strains are suppressed by cefazolin, cephaloridine and cephalothin at the concentrations of 3.13 mug/ml or less, except that 49.1% are suppressed by cephalexin. The relative potency of cephalosporins against Staphylococcus aureus in decreasing order is cephaloridine, cephalothin, cefazolin, and cephalexin. The gram-negative bacilli, Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis are less susceptible to cephalosporins than the gram-positive cocci. Among the cephalosporins, cefazolin is the most active against the gram-negative pathogens tested. The relative potency of antibacterial activity of cephalosporins against E. coli in decreasing order is cefazolin, cephaloridine, cephalexin, and cephalothin. One hour after the intramuscular injection of 500 mg of cefazolin, the maximum concentration of 33.3 mug/ml is reached in the serum. The sufficient high levels are sustained for 8 hours. Very high concentrations of cefazolin are also found in the urine.


Facilitated by nature and agriculture: performance of a specialist herbivore improves with host-plant life history evolution, domestication, and breeding.
Plant defenses against herbivores are predicted to change as plant lineages diversify, and with domestication and subsequent selection and breeding in the case of crop plants. We addressed whether defense against a specialist herbivore declined coincidently with life history evolution, domestication, and breeding within the grass genus Zea (Poaceae). For this, we assessed performance of corn leafhopper (Dalbulus maidis) following colonization of one of four Zea species containing three successive transitions: the evolutionary transition from perennial to annual life cycle, the agricultural transition from wild annual grass to primitive crop cultivar, and the agronomic transition from primitive to modern crop cultivar. Performance of corn leafhopper was measured through seven variables relevant to development speed, survivorship, fecundity, and body size. The plants included in our study were perennial teosinte (Zea diploperennis), Balsas teosinte (Zea mays parviglumis), a landrace maize (Zea mays mays), and a hybrid maize. Perennial teosinte is a perennial, iteroparous species, and is basal in Zea; Balsas teosinte is an annual species, and the progenitor of maize; the landrace maize is a primitive, genetically diverse cultivar, and is ancestral to the hybrid maize; and, the hybrid maize is a highly inbred, modern cultivar. Performance of corn leafhopper was poorest on perennial teosinte, intermediate on Balsas teosinte and landrace maize, and best on hybrid maize, consistent with our expectation of declining defense from perennial teosinte to hybrid maize. Overall, our results indicated that corn leafhopper performance increased most with the agronomic transition, followed by the life history transition, and least with the domestication transition.


Biomechanical analysis of fixation strength at different nailing angles for femoral neck fracture with insufficient reduction.
To analyze the fixation strength of cannulated screws fixation in the treatment of femoral neck fracture with posterior tilt due to insufficient reduction. Two sets of digital models of anatomical reduction and 15° tilting reduction were established by CT data. Each group of models was modeled with two different fixation methods. One fixation method was fixed according to the standard cannulated screws recommended by AO. Another fixation method is to tilt the screw posterior tilt 15°. The final four groups of models were obtained: AO principle nailing posterior tilt model (Group A), posterior direction nailing posterior tilt model (Group B), AO principle nailing anatomic reduction model (Group C) and posterior direction nailing anatomic reduction model (Group D). The maximum displacement of the fracture end, the maximum Von-Mises stress and the stress distribution of the internal fixation were compared among the four groups. Four groups of models were established on artificial bone by 3D printing guide plate technology. The 600 N pressure test and yield test were performed on a biomechanical machine. The finite element and biomechanical models showed that groups B and C were more stable than groups A and D. The stability of group B was not worse than that of group C. When the femoral neck fracture produces a posterior tilt, a posterior reduction is allowed. The change of AO screw to posterior tilting screw fixation has more powerful advantages. No posterior tilt or posterior reduction, AO screw placement is still required.


Reverse 3,3',5'-triiodothyronine suppresses increase in free fatty acids in chickens elicited by dexamethasone or adrenaline.
Reverse triiodothyronine (rT3) displays hypometabolic properties and antagonizes the hypermetabolic effect of 3,5,3'-triiodothyronine (T3). Previous experiments revealed that exogenous rT3 enhanced free fatty acids (FFA) in heat-stressed pullets and in chickens infected with lipopolysaccharide from Escherichia coli. To gain more data concerning the action of rT3, its effect on lipaemia produced by two main stress hormones: glucocorticoids and catecholamines, has been investigated. Synthetic glucocorticoid [dexamethasone (Dex)] and adrenaline (Adr) were used in two experiments. The experiments differed in duration, i.e. 24 h (Dex) or 150 min (Adr), and frequency of rT3 injections, i.e. two (Dex) or single (Adr) injections. The doses of hormones were as follows: rT3: 14 microg 100 g body weight/ injection (subcutaneously): Dex: 5 mg/animal (subcutaneously) and Adr: 1 mg/animal (intramuscularly). Maximal increases in FFA of 230.5 and 227.5% were noted after 1.5 and 3 h, respectively, in birds treated with Dex. Reverse T3 almost completely suppressed the rise of plasma FFA elicited by Dex. The increase in Dex + rT3-treated fowl was only 30.4% (not significant in comparison to control). Adr increased FFA by a maximum of 89.1 % and treatment with rT3 (Adr + rT3 group) suppressed this FFA increase to 42.5%. The data obtained demonstrate that rT3 suppresses lipaemia induced by an exogenous glucocorticoid and adrenaline. This suppression was more pronounced in glucocorticoid-treated birds, where Dex produced a higher lipolytic response than Adr.


Chronic urticaria--assessment and treatment.
Chronic urticaria is a common condition encountered in general practice and a frequent source of referral to the clinical immunologist, allergist and dermatologist. This article discusses the assessment and management of chronic urticaria in the general practice setting. Chronic urticaria is defined as the occurrence of transient wheals lasting more than 6 weeks in duration. In 80% of cases, a cause is not identified and this is classified as chronic idiopathic urticaria. A physical trigger, vasculitis or systemic disease account for a smaller proportion of cases. Allergic causes are rarely responsible. A detailed history provides the most useful information in determining the presence of chronic urticaria and a possible aetiology. Apart from thyroid function tests and thyroid autoantibodies, other investigations should only be performed if clinically indicated. Second generation antihistamines are the mainstay of treatment and usually twice daily regimens are required for adequate control. H2 antagonists, doxepin and immunomodulation may be necessary in some patients.


Cyclic stretch induces human bladder smooth muscle cell proliferation in vitro through muscarinic receptors.
The present study aimed to investigate whether the cyclic stretch‑induced proliferation of human bladder smooth muscle cells (HBSMCs) is mediated by muscarinic (M) receptors, together with the signal transduction mechanisms involved in this process. HBSMCs seeded onto silicone membranes were subjected to different cyclic stretches (5, 10, 15 and 20%) for 6 and 12 h. As the effect of cyclic stretch on M2 and M3 mRNA expression levels was maximal at 6 h 10% stretch, all subsequent experiments were performed at this stretch. Western blot analysis was used to quantify M2, M3, protein kinase C (PKC) and phosphorylated (p)‑PKC protein expression levels, flow cytometry was employed to examine cell cycle distribution and a 5-bromo‑2-deoxyuridine (BrdU) incorporation assay was used to assess cell proliferation at this stretch. Subsequently, HBSMCs were exposed to different acetylcholine concentrations and/or cyclic stretch, M receptor antagonists [AF-DX16, an M2 receptor antagonist; 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), an M3 receptor antagonist and atropine, a non‑selective antagonist] and GF 109203X, a PKC antagonist, to assess the possible underlying signaling mechanisms. Cyclic stretch was found to increase the proliferation of HBSMCs and the expression levels of M2, M3, PKC and p‑PKC proteins. M receptor and PKC antagonists exerted no apparent effect on nonstretched cells, but reduced the incorporation of BrdU into stretched cells; the most pronounced effects were observed when non‑selective M receptor and PKC antagonists were applied. Notably, 4‑DAMP did not inhibit stretch‑induced PKC activation. These results indicate that the activation of the M3 receptor signaling pathway in stretch‑induced HBSMC proliferation occurs via PKC-independent mechanisms.


Electron microscopy of postmortem autolysis of rat muscle tissue.
To define the progression of ultrastructural changes in normal muscle at post mortem, rat gastrocnemius muscles were studied at various times after storage at +4 degrees C and +22 degrees C. Degeneration of the I-zone (discoid necrosis) and membranous bodies were found to be similar to that seen in muscle diseases, and lamellar formations were seen in mitochondria. At +4 degrees C there was contraction of the sarcomere which vanished in 12 h and inter-filamentous oedema appeared. Z-line degeneration was seen at 24 h and at 4 days all Z-lines had disappeared, and the H-zone showed darkening. In the same samples collapse or ruptures of the I band were seen. At 8 days the H-zones and M-lines were still discernible. In the early stages the mitochondria showed swelling and loss of matrix granules, while later they showed broken cristae and outer membranes, and flocculent densities. At 4 days rearrangement of the cristal material into long pentalaminar "needles" was seen in a few mitochondria. At 4 and 8 days membranous bodies were seen and the T-system and sarcoplasmic reticulum showed ruptures and disintegration into vesicles. The nucleus showed increasing condensation of chromatin at the periphery and clearing of the center. Polysomes and glycogen were reduced at 2 h, and has practically vanished at 24 h. At 22 degrees C the changes were the same but appeared about 4 times as quickly as at +4 degrees C.


CHILDHOOD MALTREATMENT AND THE COURSE OF DEPRESSIVE AND ANXIETY DISORDERS: THE CONTRIBUTION OF PERSONALITY CHARACTERISTICS.
We investigated the effect of childhood maltreatment on predicting the 4-year course of depressive and anxiety disorders and the possible mediating role of personality characteristics in the association between childhood maltreatment and illness course. Longitudinal data in a large sample of participants with baseline depressive and/or anxiety disorders (n = 1,474, 18-65 years) were collected in the Netherlands Study of Depression and Anxiety. At baseline, childhood maltreatment was assessed with a semistructured interview. Personality trait questionnaires (Neuroticism-Extroversion-Openness Five Factor Inventory, Mastery scale, and Leiden Index of Depression Sensitivity), recent stressful life events (List of Threatening Experiences Questionnaire), and psychosocial variables were administered. The Life Chart Interview was used to determine the time to remission of depressive and/or anxiety disorders. At baseline, 846 participants (57.4%) reported any childhood maltreatment. Childhood maltreatment had a negative impact on psychosocial functioning and was predictive of more unfavorable personality characteristics and cognitive reactivity styles (P < 0.001). Childhood maltreatment was a significant predictor of lower likelihood of remission of depressive and/or anxiety disorders (HR = 0.94, P < 0.001). High levels of neuroticism, hopelessness, external locus of control, and low levels of extraversion were mediating the relationship between childhood maltreatment and 4-year remission of depressive and anxiety disorders. Certain personality characteristics are key players in the mechanism linking childhood maltreatment to an adverse illness course of depressive and anxiety disorders. Early interventions--reducing neuroticism and hopelessness, and enhancing extraversion and locus of control--might contribute to a better prognosis in a "high-risk" group of depressive and anxiety disorders.


Random parameter-switching synthesis of a class of hyperbolic attractors.
The parameter perturbation methods (the most known being the OGY method) apply small wisely chosen swift kicks to the system once per cycle, to maintain it near the desired unstable periodic orbit. Thus, one can consider that a new attractor is finally generated. Another class of methods which allow the attractors born, imply small perturbations of the state variable [see, e.g., J. Güémez and M. A. Matías, Phys. Lett. A 181, 29 (1993)]. Whatever technique is utilized, generating any targeted attractor starting from a set of two or more of any kind of attractors (stable or not) of a considered dissipative continuous-time system cannot be achieved with these techniques. This kind of attractor synthesis [introduced in M.-F. Danca, W. K. S. Tang, and G. Chen, Appl. Math. Comput. 201, 650 (2008) and proved analytically in Y. Mao, W. K. S. Tang, and M.-F. Danca, Appl. Math. Comput. (submitted)] which starts from a set of given attractors, allows us, via periodic parameter-switching, to generate any of the set of all possible attractors of a class of continuous-time dissipative dynamical systems, depending linearly on the control parameter. In this paper we extend this technique proving empirically that even random manners for switching can be utilized for this purpose. These parameter-switches schemes are very easy to implement and require only the mathematical model of the underlying dynamical system, a convergent numerical method to integrate the system, and the bifurcation diagram to choose specific attractors. Relatively large parameter switches are admitted. As a main result, these switching algorithms (deterministic or random) offer a new perspective on the set of all attractors of a class of dissipative continuous-time dynamical systems.


The efficacy of inosine pranobex in preventing the acquired immunodeficiency syndrome in patients with human immunodeficiency virus infection. The Scandinavian Isoprinosine Study Group.
We performed a randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of inosine pranobex (Isoprinosine) [corrected] in the treatment of patients with human immunodeficiency virus (HIV) infection but without manifest acquired immunodeficiency syndrome (AIDS). A total of 866 patients were enrolled in 21 centers in Denmark and Sweden. The patients were stratified in three groups according to their CD4+ cell count and randomly assigned to receive either inosine pranobex (1 g three times a day) (n = 429) or matching placebo (n = 437) for 24 weeks. Of the 831 patients who could be evaluated, AIDS developed in 17 in the placebo group as compared with 2 in the inosine pranobex group (P less than 0.001; odds ratio, 8.6 [95 percent confidence limits, 2.2 and 52.6]). There were no significant differences between the groups with respect to changes in CD4+ cell count or the development of other HIV-related conditions, with the exception of thrush, which developed in fewer patients in the inosine pranobex group (P = 0.05). No serious side effects were observed. We conclude that treatment with inosine pranobex delays progression to AIDS in patients with HIV infection. The duration of this beneficial effect, the optimal dose, and the mode of action of inosine pranobex remain to be clarified.


Choleric potencies of some bile acids and their effect on biliary excretion of eosin in the rat.
The effect of bile acids on bile flow and biliary excretion of eosine (80 mg/kg i.v.) has been investigated in anaesthetized (urethane 1.2 g/kg i.p.), bile duct-cannulated female Sprague-Dawley rats weighing 180--220 g. The biliary flow was significantly enhanced by cholic acid, glycocholic acid, taurocholic acid, deoxycholic acid, chenodeoxycholic acid and dehydrocholic acid (each in a dose of 100 mg/kg i.v.). However, it was definitely decreased by lithocholic acid (10o mg/kg i.v.). The biliary excretion of eosine was increased by cholic acid and dehydrocholic acid, whereas it was decreased by chenodeoxycholic acid and lithocholic acid. Deoxycholic acid, glycocholic acid and taurocholic acid had no effect on the biliary excretion rate of eosine. These results suggest that no parallelism exists between the choleretic effect of bile acids and their influence on the biliary excretion of eosin.


TULA-2 Deficiency Enhances Platelet Functional Responses to CLEC-2 Agonists.
Platelet activation is essential for hemostasis. Central to platelet activation are the signals transmitted through surface receptors such as glycoprotein VI, the protease-activated receptors, and C-type lectin-like receptor 2 (CLEC-2). CLEC-2 is a HemITAM (hem-immunoreceptor tyrosine activation motif)-bearing receptor that binds podoplanin and signals through spleen tyrosine kinase (Syk). T-cell ubiquitin ligand-2 (TULA-2) is a protein tyrosine phosphatase that is highly expressed in platelets and targets phosphorylated Y352 of Syk. We wanted to determine whether TULA-2 regulates Syk phosphorylation and activity downstream of CLEC-2. To that end, we used TULA-2 knockout mice and wild-type (WT) littermate controls. We found that TULA-2 deficiency enhances the aggregation and secretion response following stimulation with an excitatory CLEC-2 antibody or the CLEC-2 agonist rhodocytin. Consistently, Syk phosphorylation of Y346 is enhanced, as well as phosphorylation of the downstream signaling molecule PLCγ2, in TULA-2 knockout platelets treated with either CLEC-2 antibody or rhodocytin, compared with WT control platelets. Furthermore, the kinetics of Syk phosphorylation, as well as that of PLCγ2 and SLP-76, is enhanced in TULA-2 knockout platelets treated with 2.5-μg/mL CLEC-2 antibody compared with WT platelets. Similarly, thromboxane production was enhanced, in both amount and kinetics, in TULA-2 -/- platelets treated with 2.5-μg/mL CLEC-2 antibody. TULA-2 acts as a negative regulator of CLEC-2 signaling by dephosphorylating Syk on Y346 and restraining subsequent Syk-mediated signaling.


Narratives and Mental Illness: Understanding the Factors That Impact Stigmatizing Attitudes and Behavioral Intentions.
Entertainment television has been explored to reduce stigmatizing attitudes toward mental illness by incorporating positive stories about characters with mental illness. Guided by mediated contact theory and the extended elaboration likelihood model, this study examines whether exposure and engagement with entertainment narratives, featuring characters with mental illnesses of varying levels of public stigma, impacts stigmatizing attitudes and intentions to interact with individuals with mental illness generally. Participants (n = 234) were randomized to one of the three conditions: (1) a more stigmatized mental illness (schizophrenia), (2) a less stigmatized mental illness (depression), or (3) a non-mental illness control (cancer). Participants in the more stigmatized condition reported significantly less identification with characters than those in the less stigmatized condition, and greater identification with the characters were associated with more positive attitudes and behavioral intentions. Narrative counterarguing was associated with less positive attitudes and intentions toward people with mental illness. Implications based on these findings include identifying ways to increase engagement with less familiar mental illnesses to optimize the positive outcomes associated with narrative engagement.


Cytologic changes associated with vaginal pessary use. With special reference to the presence of Actinomyces.
The cytopathology of Papanicolaou smears from 23 postmenopausal women with vaginal pessaries is described. The following alterations, when seen in the smear of an elderly postmenopausal woman, were found to be strongly suggestive of pessary use: cytologic atypia in the form of severe inflammatory changes in squamous cells, atypical metaplasia, and reparative changes with a background pattern of acute inflammation and prominent superficial maturation of the squamous cells. A notable additional finding in 13 of the 23 patients was the presence of filamentous organisms resembling Actinomyces and morphologically similar to organisms recently described and specifically identified as Actinomyces in patients with intrauterine devices.


Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee.
To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA. Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately. The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02). Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.


A molecular, phylogenetic and functional study of the dADAR mRNA truncated isoform during Drosophila embryonic development reveals an editing-independent function.
Adenosine Deaminases Acting on RNA (ADARs) have been studied in many animal phyla, where they have been shown to deaminate specific adenosines into inosines in duplex mRNA regions. In Drosophila, two isoform classes are encoded, designated full-length (contains the editase domain) and truncated (lacks this domain). Much is known about the full-length isoform, which plays a major role in regulating functions of voltage-gated ion channel proteins in the adult brain. In contrast, almost nothing is known about the functional significance of the truncated isoform. In situ hybridization shows that both isoform mRNA classes are maternally derived and transcripts for both localize primarily to the developing central nervous system. Quantitative RT-PCR shows that about 35% of all dADAR mRNA transcripts belong to the truncated class in embryos. 3'-RACE results show that abundance of the truncated isoform class is developmentally regulated, with a longer transcript appearing after the mid-blastula transition. 3'-UTR sequences for the truncated isoform have been determined from diverse Drosophila species and important regulatory regions including stop codons have been mapped. Western analysis shows that both mRNA isoform classes are translated into protein during embryonic development, as full-length variant levels gradually diminish. The truncated protein isoform is present in every Drosophila species studied, extending over a period spanning about 40 × 106 years, implying a conserved function. Previous work has shown that a dADAR protein isoform binds to the evolutionarily conserved rnp-4f pre-mRNA stem-loop located in the 5'-UTR to regulate splicing, while no RNA editing was observed, suggesting the hypothesis that it is the non-catalytic truncated isoform which regulates splicing. To test this hypothesis, we have utilized RNAi technology, the results of which support the hypothesis. These results demonstrate a novel, non-catalytic function for the truncated dADAR protein isoform in Drosophila embryonic development, which is very likely evolutionarily conserved.


Monkey Embryos Cultured to 20 Days.
Gastrulation is a phase in early mammalian development when the three germ layers are generated and body plan is formed. Although well studied in mice, much less is known about gastrulation in humans. Owing to the lack of access to primary human tissue for study and experimental manipulation, as well as legal and ethical constraints surrounding the use of human embryos, a dissection of the molecular and cellular mechanisms that underlie this process in humans has proven elusive. Nonhuman primates, owing to their relatedness to human species, comprise a tantalizing alternative model system for understanding human biology. Two recent studies have established novel systems to study monkey embryos for 20 days, demonstrating landmark events of early primate embryogenesis with possible relevance to human development. Most strikingly, cells grown in the dish closely resembled cells in in vivo embryos, suggesting that embryo development in a dish might actually be equivalent to that which occurs in vivo. In this piece, the author discusses the tremendous potential of these new methods to unveil insights into mechanisms that mediate primate embryo development. Moreover, repurposing the extended monkey embryo culture methods to create human-monkey embryonic chimeras would aid the development of strategies to create human organs inside livestock species. Finally, the ethical and regulatory issues that emerge from reconsideration of extending time limits for human embryo culture beyond 14 days or primitive streak formation are also briefly considered.


Purulent Skin and Soft Tissue Infections, Challenging the Practice of Incision and Drainage: A Scoping Review.
To generate a landscape of the current knowledge in the interventional management and outcomes of purulent skin and soft tissue infections. This study is a scoping review. Electronic searches were undertaken using CINAHL, Medline, Cochrane Library, British Nursing Index, Science Direct, the National Health Service knowledge and library hub, ClinicalTrials.gov, and MedNar. The population, concept, context framework, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews were utilised, supporting a rigorous appraisal and synthesis of literature. Data Sources. The initial search and synthesis of literature were completed in January 2022 with repeat searches completed in March 2022 and July 2023. There were no imposed chronological parameters placed on the returned literature. Nineteen papers were reviewed. Incision and drainage with primary closure, needle aspiration, loop drainage, catheter drainage, and suction drainage are viable adjuncts or alternatives to the traditional surgical management of skin and soft tissue abscesses. Despite the empirically favourable alternatives to the incision and drainage technique demonstrated, this does not appear to be driving a change in clinical practice. Future research must now look to mixed and qualitative evidence to understand the causative mechanisms of incision and drainage and its ritualistic practice. Implications. Ritual surgical practices must be challenged if nurses are to improve the treatment and management of this patient group. This will lead to further practice innovation. Impact: This study explored the challenges posed to patients, clinicians, nurses, and stakeholders, resulting from the ritualistic practice of the incision and drainage technique in purulent skin or soft tissue abscesses. Empirically and holistically viable alternatives were identified, impacting all identified entities and recommending a wider holistic study. Reporting Method. Adherence to EQUATOR guidance was achieved through the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews.


Antibacterial activities and characterization of novel inhibitors of LpxC.
Lipid A is the hydrophobic anchor of lipopolysaccharide (LPS) and forms the major lipid component of the outer monolayer of the outer membrane of gram-negative bacteria. Lipid A is required for bacterial growth and virulence, and inhibition of its biosynthesis is lethal to bacteria. UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) is a metalloenzyme that catalyzes the second step in the biosynthesis of lipid A. Inhibitors of LpxC have previously been shown to have antibiotic activities. We have screened a metalloenzyme inhibitor library for antibacterial activities against an Escherichia coli strain with reduced LpxC activity. From this screen, a series of sulfonamide derivatives of the alpha-(R)-amino hydroxamic acids, exemplified by BB-78484 and BB-78485, have been identified as having potent inhibitory activities against LpxC in an in vitro assay. Leads from this series showed gram-negative selective activities against members of the Enterobacteriaceae, Serratia marcescens, Morganella morganii, Haemophilus influenzae, Moraxella catarrhalis, and Burkholderia cepacia. BB-78484 was bactericidal against E. coli, achieving 3-log killing in 4 h at a concentration 4 times above the MIC, as would be predicted for an inhibitor of lipid A biosynthesis. E. coli mutants with decreased susceptibility to BB-78484 were selected. Analysis of these mutants revealed that resistance arose as a consequence of mutations in the fabZ or lpxC genes. These data confirm the antibacterial target of BB-78484 and BB-78485 and validate LpxC as a target for gram-negative selective antibacterials.


[The integration of hospital policies and educational needs: the description of an experience].
The Educational Office of the Hospital and Health District of Venice offered the nurses completing their degree course in Padua University, a support for the final dissertation. The students were invited to select problems or issues relevant for the Hospital or District and were asked to make their final work available to the hospital and their colleagues. Twenty students were involved in this project. The support offered included the development of the study protocol and the bibliographic search. Four articles were published after the final dissertation and/or presented to local conferences. Two contributions were used to introduce relevant changes in the organization of the Health Department. Moreover, the Health Department can use the bibliographic searches, protocols, nursing guidelines and data produced to improve the training of nurses and the local organization of health services.


Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment.
Lambert-Eaton myasthenic syndrome (LEMS) is a rare pre-synaptic auto-immune disorder of neuromuscular transmission that is characterised by proximal muscle weakness, depressed tendon reflexes and autonomic dysfunction. This review summarises the clinical symptoms, aetiology, diagnosis and treatment options for LEMS. Focus is placed on symptomatic treatment with the potassium channel blocker 3,4-diaminopyridine (3,4-DAP). English-language publications were searched in MEDLINE and EMBASE to retrieve relevant literature on LEMS. The data submitted to obtain regulatory approval of 3,4-DAP phosphate by the European Medicines Agency (EMA) were also used. LEMS is a rare disease with few treatment options which are generally categorised as anti-tumour, immunomodulating or immunosuppressing, and symptomatic treatments. Anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS. While several immunomodulating or immunosuppressing treatments have been identified, these treatments should be initiated when symptomatic treatments are inadequate. As expected, due to the rarity of the disease, few reports of randomised controlled trials (RCTs) exist. Seven RCTs have been conducted to evaluate treatment of patients with LEMS. One RCT evaluated immunomodulating treatment with intravenous immunoglobulin (ivIg), while six evaluated symptomatic treatment with the potassium channel blocker 3,4-DAP. Improvements in LEMS symptoms after ivIg treatment were observed, leading to the recommendation for treatment in patients when symptomatic treatment does not provide satisfactory improvement. Potassium channel blockers evaluated for the treatment of LEMS include guanidine, 4-aminopyridine (4-AP) and 3,4-DAP. However, only 3,4-DAP has been evaluated in RCTs. Results of these RCTs demonstrated that treatment with 3,4-DAP is efficacious in treatment of LEMS and has an acceptable tolerability profile. Hence, 3,4-DAP has been recommended as first-line symptomatic treatment for LEMS by the European Federation of Neurological Societies. While 3,4-DAP base has only been available via named-patient programmes, requiring ad hoc preparations in compounding pharmacies, tablets containing 3,4-DAP phosphate salt, equivalent to 10 mg base, have become available. This formulation has obtained the orphan medicinal product status both in the European Union and in the United States of America, and has received marketing authorisation in Europe as Firdapse*. These tablets have been shown to be essentially bioequivalent with the base preparation. The results of this review show that anti-tumour treatment is recommended for patients with the paraneoplastic form of LEMS and that one RCT has shown that immunomodulating treatments should be initiated when symptomatic treatments do not provide satisfactory results. A number of RCTs have shown that 3,4-DAP is effective in symptomatic treatment of patients with LEMS and has been recommended as first-line symptomatic treatment of patients with LEMS. The 3,4-DAP phosphate salt formulation was shown to be safe and effective in the treatment of LEMS with a positive benefit:risk ratio.


SIRT6: A potential therapeutic target for diabetic cardiomyopathy.
The abnormal lipid metabolism in diabetic cardiomyopathy can cause myocardial mitochondrial dysfunction, lipotoxicity, abnormal death of myocardial cells, and myocardial remodeling. Mitochondrial homeostasis and normal lipid metabolism can effectively slow down the development of diabetic cardiomyopathy. Recent studies have shown that SIRT6 may play an important role in the pathological changes of diabetic cardiomyopathy such as myocardial cell death, myocardial hypertrophy, and myocardial fibrosis by regulating mitochondrial oxidative stress and glucose and lipid metabolism. Therefore, understanding the function of SIRT6 and its role in the pathogenesis of diabetic cardiomyopathy is of great significance for exploring and developing new targets and drugs for the treatment of diabetic cardiomyopathy. This article reviews the latest findings of SIRT6 in the pathogenesis of diabetic cardiomyopathy, focusing on the regulation of mitochondria and lipid metabolism by SIRT6 to explore potential clinical treatments.


Gallium-67 scintigraphy in lymphoma: is there a benefit of image fusion with computed tomography?
The usefulness and complementarity of gallium (67Ga) scintigraphy and computed tomography (CT) in the management of patients with lymphoma have been extensively demonstrated. Owing to a lack of anatomical landmarks and physiological distribution of the tracer, precise localisation of abnormalities on 67Ga scintigraphy can be difficult. As fusion imaging techniques between single-photon emission tomography (SPET) and CT have been developed recently, we investigated whether use of CT/67Ga SPET fusion imaging could help in the interpretation of 67Ga scintigraphy. From November 1999 to May 2001, 52 consecutive fusion studies were performed in 38 patients [22 patients with Hodgkin's disease (HD) and 16 patients with non-Hodgkin's lymphoma (NHL)] as part of pre-treatment staging (n=13), treatment evaluation (n=20) or evaluation of suspected recurrence (n=19). 67Ga scintigraphy was carried out 2 and 6 days following the injection of 185-220 MBq 67Ga citrate. On day 2, 67Ga SPET and CT were performed, focussing on the chest and/or the abdomen/pelvis. Data from each imaging method were co-registered using external markers. 67Ga scintigraphy and CT were initially interpreted independently by nuclear medicine physicians and radiologists. CT/67Ga SPET fusion studies were then jointly interpreted and both practitioners indicated when fusion provided additional information in comparison with CT and 67Ga SPET alone. Image fusion was considered to be of benefit in 12/52 (23%) studies which were performed for initial staging (n=4), treatment evaluation (n=4) or evaluation of suspected recurrence (n=4). In these cases, image fusion allowed either confirmation and/or localisation of pathological gallium uptake (n=10) or detection of lesions not visible on CT scan (n=2). Fusion was relevant for discrimination between osseous lesions and lymph node involvement adjacent to bone, especially in the thoracic and lumbar spine and pelvis. In the abdomen and pelvis, fusion helped to differentiate physiological bowel elimination from abnormal uptake, and assisted in precisely locating uptake in neighbouring viscera of the left hypochondrium, including the spleen, left liver lobe, coeliac area, stomach wall and even the splenic flexure. At the thoracic level, fusion also proved useful for demonstrating clearly the relationships of abnormal foci to the pleura, hepatic dome, mediastinum, ribs or thoracic spine. Clinical management was altered by fusion imaging in one patient (chemotherapy was given instead of radiotherapy) and was potentially affected in three other patients (in that, in conjunction with other factors, the results of fusion imaging had an influence on the decision regarding use of irradiation and especially the treatment volume). In conclusion, CT/67Ga SPET fusion imaging allowed precise localisation of gallium uptake and correct attribution to the involved viscera, thereby altering the diagnosis in 20%-25% of studies in comparison with CT and 67Ga SPET analyses alone. CT/67Ga SPET fusion therefore appears valuable in facilitating the interpretation of 67Ga scintigraphy and we recommend its use in patients with lymphoma when CT and 67Ga scintigraphy are planned.


Not just quantity but also quality of language: Cross-cultural comparisons of maternal mental state talk in New Zealand, Australia, and China.
Western mothers use more mental state talk with children than do Chinese mothers (e.g., "think", "like", "happy"). The present study aimed to examine whether Western mothers not only produced a greater amount of mental state talk, but also used a wider range of mental state terms (i.e., greater lexical variety) compared to Chinese mothers. We compared maternal mental state talk in 271 mother-child dyads from New Zealand, Australia and China, and coded both quantity (i.e., frequency) and quality (i.e., type, variety, valence) of mothers' mental state talk to their 2.5- to 5-year-olds. Western mothers produced more talk about cognitions and emotions, as well as modulations of assertions, but a similar amount of desire talk, compared to Chinese mothers, with the same patterns found in the variety of talk. Western mothers produced an overall higher amount of mental state talk and a greater variety of mental state terms, but crucially, still produced more MS talk after controlling for the variety. Neither the amount nor the variety of maternal MS talk was correlated with children's theory of mind. These findings shed light on the diverse ways that mothers construe and describe mental states in different cultures, and highlight the importance of examining different aspects of maternal mental state talk and their impact on children's theory of mind in future longitudinal studies.


Comparison of an immortalized human corneal epithelial cell line with Vero cells in the isolation of Herpes simplex virus-1 for the laboratory diagnosis of Herpes simplex keratitis.
Herpes simplex keratitis (HSK) is a sight threatening ocular infection often requiring a specific and prompt laboratory diagnosis. Isolation of Herpes simplex virus (HSV-1) in culture provides the most reliable and specific method and is considered as the "Gold Standard" in the laboratory diagnosis of HSK in spite of its low sensitivity. Using "cell lines of corneal origin" for virus isolation may be beneficial under such circumstances, since these cells have been shown to be excellent substrates for the growth of HSV-1 isolated from the cornea. We report a comparative study of a novel human corneal epithelial cell line (HCE) and the Vero cell line in the isolation of HSV-1 from corneal scrapings employing a shell vial assay. Corneal scrapings were obtained from 17 patients with a clinical diagnosis of HSK. All the cases were confirmed by virological investigations (PCR and viral antigen detection positive, n = 15, PCR positive, n = 1, Viral antigen positive, n = 1). Scrapings obtained from 10 patients with infectious keratitis of non-viral origin were included as controls. All the scrapings were simultaneously inoculated into shell vials of HCE and Vero cells. Cultures were terminated at 24 h post-infection. Isolation of HSV-1 was confirmed using an indirect immunofluorescence/ immunoperoxidase assay. Virus could be isolated using both or either of the cell lines in 10/17 (58.82%) patients with HSK. HSV-1 was isolated from 10/17 (58.82%) and 4/17(23.52%) specimens in HCE and Vero cells, respectively (P = 0.036). None of the controls yielded HSV-1. While all the 10 (100%) strains were isolated in HCE, Vero yielded only 4/10 (40%) strains in the shell vial culture (P = 0.014). HCE showed a statistically significant difference in the virus isolation rate with respect to Vero cells. HCE may be an excellent alternative cell line for the isolation of HSV-1, especially from corneal scrapings, for the laboratory diagnosis of HSK.