Camel-related injuries in the pediatric age group.
Road traffic accidents continue to be a major cause of morbidity and mortality among children. Domestic animal-related injuries in general, camel-related in particular, have not been given much attention, and very little is written about them. The medical records of all children admitted to our hospital with camel-related injuries were retrospectively reviewed for age, sex, mechanism of injury, type of injuries, treatment, and outcome. Seventy-eight children with camel-related injuries were seen at our hospital. Most of them were camel jockeys. All were males, and their ages ranged from 4 to 15 years (mean, 8.6 years). In 74, the cause of injury was a fall from a racing camel, 2 were kicked by a camel, and 1 had a camel bite. Forty-four (56.4%) had head injury, which was moderate to severe in 17, and 6 of them had associated skull fractures, whereas 3 had intracranial hematomas. Twenty-five (32.1%) had fractures of various bones, and 14 of them had fracture of the tibia. One child had L2 and L3 dislocation, with displacement and compression fracture of L2. Two sustained thoracic injuries, whereas 9 had intraabdominal injuries, including liver injury (3), splenic injury (1), renal injury (3), and bowel injury (2). One had a camel bite leading to a fractured mandible, injury to his ear, and intimal tear of the left common carotid artery. Camels are a potential cause of serious injuries and a major public health problem for children in this part of the world. This is especially so for camel jockeys. Every effort should be made to prevent such injuries, including limiting camel racing to older children as well as providing adequate protective measures and public education about the proper and compassionate handling of domestic animals.


Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration.
Age-related macular degeneration, Stargardt disease, and their Abca4-/- mouse model are characterized by accelerated accumulation of the pigment lipofuscin, derived from photoreceptor disc turnover in the retinal pigment epithelium (RPE); lipofuscin accumulation and retinal degeneration both occur earlier in albino mice. Intravitreal injection of superoxide (O2•-) generators reverses lipofuscin accumulation and rescues retinal pathology, but neither the target nor mechanism is known. Here we show that RPE contains thin multi-lamellar membranes (TLMs) resembling photoreceptor discs, which associate with melanolipofuscin granules in pigmented mice but in albinos are 10-fold more abundant and reside in vacuoles. Genetically over-expressing tyrosinase in albinos generates melanosomes and decreases TLM-related lipofuscin. Intravitreal injection of generators of O2•- or nitric oxide (•NO) decreases TLM-related lipofuscin in melanolipofuscin granules of pigmented mice by ~50% in 2 d, but not in albinos. Prompted by evidence that O2•- plus •NO creates a dioxetane on melanin that excites its electrons to a high-energy state (termed "chemiexcitation"), we show that exciting electrons directly using a synthetic dioxetane reverses TLM-related lipofuscin even in albinos; quenching the excited-electron energy blocks this reversal. Melanin chemiexcitation assists in safe photoreceptor disc turnover.


Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane.
Adreno-cortical carcinoma (ACC) is a rare cancer with poor prognosis. Complete surgical resection of the primary tumor and, when feasible, of the local and distant metastases offers the best prospects for long-term survival; conversely, the role of systemic therapy in patients developing unresectable metastatic disease is unclear. We describe the case of a young female patient (36 yr) who presented with an androgen-releasing metastatic ACC. Treatment consisted of five courses of chemotherapy with etoposide, doxorubicin and cisplatin (EDP scheme) plus oral mitotane, which caused the complete disappearance of distant metastases and reduction of the primary tumor, as documented by serial computed tomography (CT) scans of the chest and the abdomen. Moreover, during treatment, clinical and biochemical resolution of the hypersecretory status occurred. The left adrenal gland was then removed and histopathological examination showed extensive tumor necrosis and the absence of viable cancer cells. The patient is currently alive without evidence of recurrence 3 yr after surgery. This report shows that chemotherapy plus mitotane could result in complete pathological remission, which may be a surrogate for long-term progression- free survival in metastatic ACC patients.


Are nonemergent cardiac operations performed during off-time associated with worse outcome?
With the implementation of value-based health care, it is of increasing interest to understand whether performing elective surgeries during off-time impacts surgical outcomes. The objective of this study was to evaluate the impact of start times on nonemergent cardiac operations. The institutional Society of Thoracic Surgeons was used to identify all adult nonemergent cardiac operations performed between January 2008 and December 2015 at our institution. "Off-time" is defined as either operation "late starts," that is, an incision time after 3 PM and before 7 AM, or procedures occurring during the weekends. Univariate and multivariate logistic regression analyses were performed to examine its impact on in-hospital mortality and major adverse events. Available cost data were directly obtained from the departmental BIOME database. Of the 3406 cardiac operations included in the study, 2933 (86.1%) were normal-start and 473 (13.9%) were off-time-start operations. After adjusting for patient and operative characteristics, late operating room start times were not associated with increased in-hospital mortality (P = 0.28, confidence interval [CI] 95% = 0.99-1.03), readmissions (P = 0.21, CI 95% = 0.99-1.07), or major adverse events (P = 0.07, CI 95% = 1.00-1.12). In addition, there was no significant impact on total hospital cost (9.0% increase, P = 0.07). These findings suggest that late operating room start times are not associated with increased mortality or other complications in a tertiary-care academic medical center. Our findings should be considered during operative scheduling to optimize resource distribution and patient care strategies.


Data on phase and chemical compositions of black sands from "El Ostional" beach situated in Mompiche, Ecuador.
Data revealing the phase and chemical compositions of natural black sands from "El Ostional" beach, located in the northern Ecuadorian Pacific coast have been presented. The samples were collected from six points over the shore area of approximately 500 × 40 m2. The data on crystalline phases (iron titanium oxide, orthoclase feldspar and zircon) were determined by X-ray powder diffraction (XRPD), while semi-quantitative chemical analyses of major (Fe and Ti) and trace elements were obtained by X-ray fluorescence spectroscopy (XRF). The phase composition was verified by scanning electron microscopy (SEM), using backscattered electron (BSE) mode and energy dispersive spectroscopy (EDS). These comprehensive data are a contribution to valorize ilmenite-hematite solid solutions from natural resources towards the identification of novel technological applications.


Early stage breast cancer follow-up in real-world clinical practice: the added value of cell free circulating tumor DNA.
Physical examinations and annual mammography (minimal follow-up) are as effective as laboratory/imaging tests (intensive follow-up) in detecting breast cancer (BC) recurrence. This statement is now challenged by the availability of new diagnostic tools for asymptomatic cases. Herein, we analyzed current practices and circulating tumor DNA (ctDNA) in monitoring high-risk BC patients treated with curative intent in a comprehensive cancer center. Forty-two consecutive triple negative BC patients undergoing neoadjuvant therapy and surgery were prospectively enrolled. Data from plasma samples and surveillance procedures were analyzed to report the diagnostic pattern of relapsed cases, i.e., by symptoms, follow-up procedures and ctDNA. Besides minimal follow-up, 97% and 79% of patients had at least 1 non-recommended imaging and laboratory tests for surveillance purposes. During a median follow-up of 5.1(IQR, 4.1-5.9) years, 13 events occurred (1 contralateral BC, 1 loco-regional recurrence, 10 metastases, and 1 death). Five recurrent cases were diagnosed by intensive follow-up, 5 by symptoms, and 2 incidentally. ctDNA antedated disseminated disease in all evaluable cases excepted two with bone-only and single liver metastases. The mean time from ctDNA detection to suspicious findings at follow-up imaging was 3.81(SD, 2.68), and to definitive recurrence diagnosis 8(SD, 2.98) months. ctDNA was undetectable in the absence of disease and in two suspected cases not subsequently confirmed. Some relapses are still symptomatic despite the extensive use of intensive follow-up. ctDNA is a specific test, sensitive enough to detect recurrence before other methods, suitable for clarifying equivocal imaging, and exploitable for salvage therapy in asymptomatic BC survivors.


TAM receptors: A phosphatidylserine receptor family and its implications in viral infections.
Phosphatidylserine (PS) is an anionic phospholipid that is usually localized in the inner leaflets of the plasma membrane. However, the enzyme scramblase catalyzes the externalization of PS on the outer leaflet of the plasma membrane during apoptosis or cellular stress. This event prompts the recognition of PS displaying cells by phagocytes leading to "apoptotic clearance." Multiple PS receptors (PSRs) mediate this process including members from the TAM (Tyro3, Axl, Mertk) receptor Tyrosine kinases (RTKs) by interacting with PS via bridging proteins like Gas6 and ProS1. Ironically, this network (PS/TAM) that evolved for boosting cellular health through clearance of apoptotic and necrotic cells, has been manoeuvred by pathogens and tumor cells using "apoptotic mimicry." Enveloped viruses, responsible for most of the lethal epidemics and pandemics including the current SARS-CoV2 outbreak, have employed apoptotic mimicry to their advantage. In the current chapter, we summarize the existing knowledge regarding the involvement of PS/Gas6, ProS1/TAM in facilitating infectivity in a diverse set of cell lines, animals as well as organoids. This network executes a largely proviral role in facilitating infection as seen with Zika, Ebola, Influenza and Dengue viruses. However, this response varies with strains and the cells infected, and in some cases, this same signaling displays an antiviral function. We also report multiple studies that have used neutralizing antibodies and small molecule inhibitors in successfully reducing viral replication and ameliorating pathogenicity. Knowledge about this unique signaling pathway and measures that can be taken to inhibit it is most valuable now given how enveloped viruses lead to plagues on the entire globe.


Tumor cell implantation following neodymium-YAG bladder injury: a comparison to electrocautery injury.
Recent clinical experience using the neodymium-YAG laser for the ablation of superficial bladder carcinoma seems to indicate a decreased local and second-site recurrence rate when compared to standard electrosurgical methods. Altered tumor cell implantation has been suggested as a mechanism explaining this phenomenon. The purpose of this study was to compare the effects of laser ablation and standard electrosurgical resection on tumor implantation. Each of three requisite steps in tumor cell implantation was assayed in an animal model system. The number of viable tumor cells liberated during ablation of a standardized lesion was 620% greater in the electrosurgically resected group compared to the laser irradiated group. No difference was observed in the qualitative or quantitative patterns of cellular adherence to a fulguration bladder injury compared to a laser bladder injury. The number of cells adhering to an injury site was shown to increase as a function of the cell concentration to which it was exposed. There was no difference between groups in occurrence of tumor at the injury site following exposure to an equal number of tumor cells. This study has demonstrated marked differences between electroresection and laser ablation in terms of the number of viable cells released during the course of tumor removal. This data, together with the absence of injury site differences, suggests it may play a role in the clinically observed differences in tumor recurrence rates.


The effects of stress on periodontal treatment: a longitudinal investigation using clinical and biological markers.
To investigate the effects of psychosocial stress on the outcome of non-surgical periodontal treatment (NPT). Patients were categorized as stressed or unstressed, and the degree of stress was measured. One deep bleeding and one deep non-bleeding site ≥6 mm were selected in each patient for detailed investigation, and the clinical parameters were recorded before and at 6 months after NPT. Elastase and C-terminal teleopeptide of type I collagen (ICTP) were measured in gingival crevicular fluid (GCF) samples at both intervals. The baseline, clinical parameters and biological markers were similar in both stressed and unstressed groups, other than for GCF elastase levels, which were significantly higher in the stressed group of patients (p < 0.05). The effect of stress on the changes for clinical measurements and elastase levels in GCF was statistically significant for deep bleeding sites, with the response to treatment being poorer in the stressed group. The effects of smoking and the degree of stress were not statistically significant for any of the clinical or biological parameters (p > 0.05). Patients under psychosocial stress had a poorer outcome following NPT. The assessment of psychosocial stress may be valuable in the holistic management of periodontal disease.


The influence of time on dynamic signature: An exploratory data analysis.
Dynamic signatures are a digitalized form of handwritten signatures. Their use has seen a steep increase for important transactions, such as life insurance and telecommunication contracts, sales and banking operations. A dynamic signature can be disputed and a forensic handwriting examiner may be hired to help determine whether it is genuine or not. Such a conflict may emerge years after the questioned signature has been affixed. Since reference material contemporary to the relevant period may not be made available to the expert, it can be questioned whether time influences dynamic signature data, which could affect the expert's results. This study was designed to explore this possible influence. Dynamic signatures of three participants were collected over a duration of 18 months, during 44 acquisition sessions. Based on this sample, the goals of describing variation of dynamic features over short and longer time periods, defining adequate sample collection strategies and sampling time frames, as well as laying down the foundation for using the time information for comparative analysis of dynamic signatures, were pursued. Both the relative stability and the slow 'drift' of signatures over time were illustrated by our results. The findings of this study lead to recommendations for sampling in casework, validate statements previously made by forensic scientist through an empirical investigation on dynamic signatures and strengthen the statistical basis for forensic signature comparison.


Annotation of differential protein expression in the hypothalami of layer-type Taiwan country chickens in response to acute heat stress.
The hypothalamus is the coordinating center for maintaining temperature homeostasis. In this study, global protein expression in the hypothalami of layer-type Taiwan country chickens in response to acute heat stress was investigated. Twelve 30-week-old female TCCs were divided into three acute heat-stressed groups, namely acute heat stress at 36 °C for 4 h with 0 h (without recovery, H4R0), 2 h (H4R2), or 6 h (H4R6) of recovery. A control group was maintained at 25 °C. Hypothalamus samples were collected at the end of each time point for proteomic analysis. The analysis results revealed that 134 protein spots representing 118 distinct proteins exhibited differential expressions after acute heat stress treatment. Results of gene ontology analysis showed that most of the differentially expressed proteins are involved in carbohydrate metabolism, cellular processes, actin cytoskeleton organization, and responses to stimuli. Functional pathway analysis results suggested that the proteins are associated with networks of carbon metabolism, glycolysis, and gluconeogenesis. Upregulation of the expression of triosephosphate isomerase, phosphoglycerate kinase, pyruvate kinase, alpha-enolase, glycogen phosphorylase (brain form), phosphoglucomutase, L-lactate dehydrogenase A chain and downregulation of 6-phosphogluconolactonase expression indicated an increase in the glycolytic activity and glucose supply for ATP production in the hypothalami in response to heat stress. By contrast, upregulated expressions of heat shock protein 90 alpha, glutathione S-transferase 2s, peroxiredoxin-1, and dihydropyrimidinase-like 2 suggested that acute heat stress adversely affects the hypothalamus; thus, it induces mechanisms that prevent oxidative damage and endoplasmic reticulum stress. In conclusion, acute heat stress induces differential protein expression in the hypothalami of the L2 strain Taiwan country chickens, which may manifest detrimental effects. Furthermore, differential expression is a critical response in the hypothalamus for the regulation of thermotolerance.


Sensory processing issues associated with Asperger syndrome: a preliminary investigation.
The purpose of this study was to identify the sensory processing patterns of children with Asperger syndrome. Researchers compared the performance of 42 children with Asperger syndrome and 42 children without disabilities on section and factor scores of the Sensory Profile. As reported by parents on the Sensory Profile, the children with Asperger syndrome were significantly different from children without disabilities on 22 of 23 items. This result was obtained with good power estimates (.997-1.00) and large effect sizes (02 = .267-.732). Both groups of children performed the same on modulation of visual input affecting emotional responses and activity level. This study provides initial evidence that clear differences exist in the sensory processing patterns of children with Asperger syndrome when compared with peers without disabilities.


Myocardial extraction of cyclic AMP during pacing-induced angina.
The application of cyclic AMP as a marker of myocardial ischemia in humans with coronary artery disease has been investigated during pacing-induced angina. Cyclic AMP was determined by a radioimmunoassay. In 15 patients myocardial lactate extraction at rest (20 +/- 12%) converted to production levels (-30 +/- 23%) during angina (p less than 0.0005). Insignificant changes occurred in coronary venous plasma cyclic-AMP levels. The mean myocardial cyclic-AMP extraction at rest (0.3 +/- 8.7%) converted to small release values (-6.0 +/-11%) during angina (= n.s.). No significant correlation was found between myocardial lactate and cyclic-AMP uptake or release. Therefore, cyclic AMP is an insensitive marker in the evaluation of myocardial ischemia.


Examining the Association of Socioeconomic Position with Microcephaly and Delayed Childhood Neurodevelopment among Children with Prenatal Zika Virus Exposure.
Increased rates of Zika virus have been identified in economically deprived areas in Brazil at the population level; yet, the implications of the interaction between socioeconomic position and prenatal Zika virus exposure on adverse neurodevelopmental outcomes remains insufficiently evaluated at the individual level. Using data collected between September 2015 and September 2019 from 163 children with qRT-PCR and/or IgM-confirmed prenatal exposure to Zika virus participating in a prospective cohort study in Rio de Janeiro, Brazil (NCT03255369), this study evaluated the relationships of socioeconomic indicators with microcephaly at birth and Bayley-III neurodevelopmental scores during the early life course. Adjusted logistic regression models indicated increased odds of microcephaly in children born to families with lower household income (OR, 95% CI: 3.85, 1.43 to 10.37) and higher household crowding (OR, 95% CI: 1.83, 1.16 to 2.91), while maternal secondary and higher education appeared to have a protective effect for microcephaly compared to primary education (OR, 95% CI: 0.33, 0.11 to 0.98 and 0.10, 0.03 to 0.36, respectively). Consistent with these findings, adjusted linear regression models indicated lower composite language (-10.78, 95% CI: -19.87 to -1.69), motor (-10.45, 95% CI: -19.22 to -1.69), and cognitive (-17.20, 95% CI: -26.13 to -8.28) scores in children whose families participated in the Bolsa Família social protection programme. As such, the results from this investigation further emphasise the detrimental effects of childhood disadvantage on human health and development by providing novel evidence on the link between individual level socioeconomic indicators and microcephaly and delayed early life neurodevelopment following prenatal Zika virus exposure.


Steroid-induced alterations of mood and behavior in children during treatment for acute lymphoblastic leukemia.
Despite their therapeutic utility, children may experience emotional and behavioral side effects from steroids during treatment for leukemia. However, clinical manifestations and treatment options have rarely been described in the pediatric literature. The aim of this current paper is to address this knowledge gap via four brief case examples and a review of the literature. In addition, we review recent data to indicate how concurrent use of antifolates may place these children at particular risk for adverse psychological reactions.


The SOS-function-inducing activity of chemical mutagens in Escherichia coli.
The SOS-function-inducing activities of 42 chemical mutagens were investigated in Escherichia coli K12. The induction of the SOS function was assayed by monitoring the beta-galactosidase activity in the sulA::lacZ fusion strain PQ37 . To correct for the inhibitory effects of test chemicals on mRNA or protein synthesis, the level of the constitutive alkaline phosphatase was assayed in parallel. Most of the mutagens reported to be mutagenic to the Ames' Salmonella tester strains showed the SOS-function-inducing activity. The inducible SOS repair may be responsible for not only base-change mutations but also frameshift mutations. However, 9-aminoacridine, ethidium bromide and 4-nitro-o-phenylenediamine did not induce the SOS function, suggesting that the mutagenesis induced by these mutagens may occur independently of SOS repair. Present results support the SOS mutagenesis model that error-prone SOS repair plays an important role in mutagenesis induced by most chemical mutagens.


Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver.
To determine whether 1) hepatic ceramide and diacylglycerol concentrations, 2) SCD1 activity, and 3) hepatic lipogenic index are increased in the human nonalcoholic fatty liver. We studied 16 subjects with (n = 8) and without (n = 8) histologically determined nonalcoholic fatty liver (NAFL(+) and NAFL(-)) matched for age, sex, and BMI. Hepatic concentrations of lipids and fatty acids were quantitated using ultra-performance liquid chromatography coupled to mass spectrometry and gas chromatography. The absolute (nmol/mg) hepatic concentrations of diacylglycerols but not ceramides were increased in the NAFL(+) group compared with the NAFL(-) group. The livers of the NAFL(+) group contained proportionally less long-chain polyunsaturated fatty acids as compared with the NAFL(-) group. Liver fat percent was positively related to hepatic stearoyl-CoA desaturase 1 (SCD1) activity index (r = 0.70, P = 0.003) and the hepatic lipogenic index (r = 0.54, P = 0.030). Hepatic SCD1 activity index was positively related to the concentrations of diacylglycerols (r = 0.71, P = 0.002) but not ceramides (r = 0.07, NS). We conclude that diacylglycerols but not ceramides are increased in NAFL. The human fatty liver is also characterized by depletion of long polyunsaturated fatty acids in the liver and increases in hepatic SCD1 and lipogenic activities.


[Uncommon case of paraganglioma syndrome in combination with malignant paraganglioma].
Combination of paraganglioma syndrome and malignant paraganglioma is an uncommon disease worldwide. We report the case of a 69-year old man with a jugular-tympanal paraganglioma, who underwent surgery. Histopathological examination revealed a malignant paraganglioma. An other contralateral carotid-body and a tumor in the thyroid gland had been discovered during staging. The molecular results confirmed the existence of a paraganglioma syndrome. A malignant paraganglioma based on a hereditary paraganglioma syndrome is a rare described case in literature. On the background of the literature we discuss the pathology, pathogenesis, diagnostic and therapy of this disease.


Severe Impairment of TNF Post-transcriptional Regulation Leads to Embryonic Death.
Post-transcriptional regulation mechanisms control mRNA stability or translational efficiency via ribosomes, and recent evidence indicates that it is a major determinant of the accurate levels of cytokine mRNAs. Transcriptional regulation of Tnf has been well studied and found to be important for the rapid induction of Tnf mRNA and regulation of the acute phase of inflammation, whereas study of its post-transcriptional regulation has been largely limited to the role of the AU-rich element (ARE), and to a lesser extent, to that of the constitutive decay element (CDE). We have identified another regulatory element (NRE) in the 3' UTR of Tnf and demonstrate that ARE, CDE, and NRE cooperate in vivo to efficiently downregulate Tnf expression and prevent autoimmune inflammatory diseases. We also show that excessive TNF may lead to embryonic death.


Complex genomic interactions in the dynamic regulation of transcription by the glucocorticoid receptor.
The glucocorticoid receptor regulates transcriptional output through complex interactions with the genome. These events require continuous remodeling of chromatin, interactions of the glucocorticoid receptor with chaperones and other accessory factors, and recycling of the receptor by the proteasome. Therefore, the cohort of factors expressed in a particular cell type can determine the physiological outcome upon treatment with glucocorticoid hormones. In addition, circadian and ultradian cycling of hormones can also affect GR response. Here we will discuss revision of the classical static model of GR binding to response elements to incorporate recent findings from single cell and genome-wide analyses of GR regulation. We will highlight how these studies have changed our views on the dynamics of GR recruitment and its modulation of gene expression.


Neurosurgical experience with tumours of the pineal region at Clinica Puerta de Hierro.
The clinicopathological experience with 50 cases of pineal region tumours at Clinica Puerta de Hierro is presented. In this series, 88% of the patients were evaluated by CT-scan. Pineal region tumours make up approximately 0.7% of the intracranial expansive processes in the Spanish population. The largest group of lesions appearing in this localization is that of the germinomas (38%), followed by nontumoural lesions (20%) and tumours generally considered to be of the vicinity, such as meningiomas, gliomas and metastases (18%), tumours of the pineal parenchyma (14%), and non-germinoma germinal tumours (10%). In our series, in addition to an intracranial hypertension syndrome, an ophthalmological and, to a minor degree, an endocrinological syndrome predominate in germ-cell tumours, with a cerebellar syndrome appearing in gliomas of the pineal region. All the patients in the series diagnosed as having a germinoma and treated by irradiation are alive, and free of disease, after follow-up ranging from 2 to 20 years (mean: 8 years). The experience obtained with the present series supports the opinion that, in radiosensitive tumours, surgical resection adds no therapeutic benefit to treatment with radiotherapy alone. We suggest that when dealing with a tumour of the pineal region, CT-scan and clinical assessment now permit an initial selection of patients susceptible to surgery as a first therapeutic option, indicating those patients who, because they are considered to have either a "probable germinoma" or a "tumour of uncertain diagnosis", should undergo stereotaxic biopsy or trial radiotherapy and, only when this has proved a failure, should be subjected to open surgery.


Procalcitonin as a useful marker to decide upon intervention for urinary tract infection.
Because the use of procalcitonin has been advocated as a marker of bacterial infection, this study was carried out to determine the usefulness of serum PCT as an early marker to decide upon intervention for urinary tract infection. The subjects were 68 patients with urinary tract infection (UTI) in whom we measured serum procalcitonin concentration at the start of treatment. There were 47 patients with nonobstructed UTI and 21 with obstructed UTI. All patients with obstructed UTI were subjected to intervention. There were significant differences in procalcitonin, white blood cells, and creatinine levels between patients with nonobstructed and obstructed UTI (P < 0.05). Although this retrospective study comprised a small number of patients, we found that procalcitonin was a useful marker to decide upon urinary intervention.


A case report on anesthetic challenges in the post-Covid complication of active mucormycosis: Patient preparedness for family physicians.
Mucormycosis is a well-known yet complicated illness that seems benign but behaves malignantly. This article discusses the anesthesia challenges in providing care for a 49-year-old male who presented with post-Covid pneumonia and uncontrolled diabetes along with active mucormycosis and scheduled for functional endoscope sinus surgery (FESS) and debridement of necrotic tissue. We want to illustrate the importance of anticipated difficult airway, while highlighting the toxicity of intravenous amphotericin-B and its combination against anesthesia drugs.


[Grading of intrahepatic cholestasis of pregnancy].
This study was to evaluate the grading of intrahepatic cholestasis of pregnancy (ICP). All 278 ICP cases were collected in the First Affiliated Hospital of Chongqing Medical University between Jan 1999 and May 2003. They were graded into mild ICP and severe ICP based on liver function test. Outcome of pregnancy and perinatal mortality were assessed. One hundred and ninety two cases were diagnosed as mild ICP while 86 cases were as severe ICP. There was significant difference in the average time of expectant therapy (10.3 +/- 4.8 vs 19.1 +/- 6.4 days) and gestational weeks (35.8 +/- 1.6 vs 37.7 +/- 1.9) between severe ICP and mild ICP groups (P < 0.01 and P < 0.001). The incidences of meconium passage, newborn asphyxia and admissions to neonatal intensive care unit in severe ICP were significantly higher than that in mild ICP. These were 38.4% vs 9.4%, 12.8% vs 4.2%, and 30.2% vs 9.4%, respectively. The difference of perinatal mortality between the patients with ICP diagnosed by using and not using the grading system (0.7% - 1.2% vs 3.9% - 6.0%) was statistically significant (P < 0.01). Grading of ICP based on liver function test may improve perinatal prognosis.


Potentially-implantable, amperometric glucose sensors with mediated electron transfer: improving the operating stability.
The major problems with existing amperometric enzyme electrodes for glucose sensing are oxygen sensitivity and output drift. The recently described miniature glucose sensors using immobilised ferrocene (dicyclopentadienyl iron) to mediate electron transfer from glucose oxidase to a base electrode are oxygen-independent but are often unstable. In this study, we test the hypothesis that the stability of ferrocene-based sensors can be markedly improved by better retention of the enzyme at the electrode. Sensors with graphite foil as the base electrode, dimethylferrocene as the mediator and carbodiimide/glutaraldehyde for enzyme immobilisation lost most of their activity when calibration curves were compared before and after 18 h operation in vitro at 37 degrees C (mean current decrease at 20 mmol/litre glucose was 91%). This sensor type with a covering cellulose membrane also lost activity (mean current decrease of 40% after 18 h). Electrodes in which the base sensor was platinum and the enzyme was covalently attached to agarose lost no activity when operated either at 700 mV without mediator (as a hydrogen peroxide detector) or at 160 mV with mediator. We conclude that both ferrocene-mediated and hydrogen peroxide-detecting amperometric glucose sensors with a high density of covalently-linked enzyme have an operating stability in vitro which may render them suitable for clinical use as, for example, an overnight hypoglycaemia alarm.


Management of peritonsillar abscess: needle aspiration versus incision and drainage versus tonsillectomy.
Peritonsillar abscess is the most common deep infection of the head and neck. This article focuses on the different methods to manage this infection. Efficacy, cost-effectiveness, patient discomfort, recovery time, and possibility of recurrence are the issues considered to determine the best treatment option.


Quetiapine-induced frequent premature ventricular contraction.
A 17-year-old female diagnosed with bipolar II disorder was treated for emotional lability with quetiapine. Two-lead electrocardiography revealed frequent monomorphic premature ventricular contraction (PVC) during an electroencephalography examination. Twenty-four-hour Holter electrocardiography revealed 0.6% uniform frequent PVCs and indicated that the readministration and second-time withdrawal of quetiapine markedly increased (7.1%) and decreased the frequency of PVC (1.1%), respectively. This case indicates that quetiapine can cause PVC as a serious side effect.


Catheter-based recanalization techniques for acute ischemic stroke.
Recent advances in endovascular interventional therapies have revolutionized the management of acute ischemic stroke. For patients who present with occluded circle of Willis vessels, timely and successful arterial recanalization is the best predictor of clinical improvement. Diagnostic neuroimaging has advanced noninvasive tools--namely, transcranial Doppler, CT angiography, and MR angiography--to screen individuals with acute neurologic syndromes rapidly for arterial occlusion, and hence to exclude from treatment those who are unlikely to benefit from or could be harmed by arterial recanalization strategies. Intra-arterial thrombolysis has been proven to be of benefit in large clinical trials. Moreover, the US Food and Drug Administration has recently approved the use of a mechanical clot retrieval device for acute embolic stroke, and a number of other similar strategies are under various stages of investigation. This article reviews the diagnostic and interventional approach to the management of large vessel embolic stroke.


Efficacy and safety of live varicella zoster vaccine in diabetes: a randomized, double-blind, placebo-controlled trial.
To elucidate varicella zoster virus (VZV)-specific cell-mediated immunity and humoral immunogenicity against live attenuated Oka varicella zoster vaccine concurrently vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in elderly people with diabetes mellitus. This double-blind randomized controlled single-centre study of 60-70-year-old people with diabetes compared immunity and safety profiles 3 months after one dose of varicella zoster vaccine or placebo. PPSV23 was immunized simultaneously. Primary analysis evaluated cell-mediated immunity using the VZV skin test. Secondary analyses were a VZV interferon-γ enzyme-linked immunospot (ELISPOT) assay and immunoadherence haemagglutination test. Adverse experiences were recorded using diary questionnaires. By intent-to-treat analysis, 27 participants with diabetes who had been administered the vaccine were compared with 27 participants who were given a placebo. Changes in skin test scores were 0.41 ± 0.80 and 0.11 ± 0.93 (P = 0.2155), and geometric mean fold rises of the ELISPOT counts were 1.2 [95% confidence interval (CI) 0.2, 7.9] and 1.2 (95% CI 0.2, 7.3) (P = 0.989) in the vaccine and placebo groups, respectively. The geometric mean titre did not increase 3 months after vaccination in either group. No vaccination-related severe adverse experience was reported and no participant developed herpes zoster. Our previous results demonstrated that varicella zoster vaccine safely enhanced VZV-specific immunity in elderly people with or without diabetes. The results of this study showed that varicella zoster vaccine can be used safely, but it cannot boost virus-specific immunity in elderly people with diabetes when administered with concurrent PPSV23. Alternative strategies are needed to prevent VZV-associated diseases in this population.


Granulocyte elastase release and pulmonary hemodynamics in patients with mitral valvular disease.
In patients with atrial septal defect in whom pulmonary hypertension could develop as a consequence of left-to-right shunt, the extent of neutrophil-mediated lung injury induced by cardiopulmonary bypass (CPB) is related to the degree of increase in the preoperative pulmonary artery pressure. In the present study, we investigated the relationship between levels of granulocyte elastase (GEL) after CPB and preoperative pulmonary hemodynamics or changes in pulmonary function after the operation in patients with mitral valve disease, in whom pulmonary hypertension could develop as a result of pulmonary venous congestion. The plasma levels of GEL were measured before and after CPB in patients who underwent mitral valve replacement. Respiratory index (RI) was evaluated preoperatively and postoperatively. Preoperative pulmonary hemodynamics were determined within one month of the operation. Granulocyte elastase level rose significantly after CPB from baseline (134.3 +/- 44.6 mg/L versus 2042.1 +/- 1215.0 mg/L; p <0.001). Peak level of GEL was significantly correlated with preoperative systolic pulmonary artery pressure (r = 0.71; p = 0.020), mean pulmonary artery pressure (r = 0.64; p = 0.046), pulmonary capillary wedge pressure (r = 0.68; p = 0.032), and pulmonary-to-systemic arterial pressure ratio (r = 0.64; p = 0.045), but not with the hemodynamic variables for pulmonary blood flow or pulmonary resistance. Moreover, the value of (Postoperative RI - Preoperative RI)/Preoperative RI was positively correlated with the peak level of GEL (r = 0.76; p = 0.011). In conclusion, in patients with mitral valvular disease, as in those with atrial septal defect, the increase in GEL level after CPB is proportional to the increase in preoperative pulmonary artery pressure, which may cause the accordant pulmonary vascular damage.


Discrimination of O. viverrini, C. sinensis, H. pumilio and H. taichui using nuclear DNA-based PCR targeting ribosomal DNA ITS regions.
Small liver and minute intestinal flukes are highly prevalent in Southeast Asia, and in mixed infections, their eggs are difficult to differentiate morphologically in fecal samples. PCR assays targeting the ITS regions in ribosomal DNA were designed to identify and differentiate species. The PCR amplicons of Opisthorchis viverrini, Clonorchis sinensis, Haplorchis pumilio, and Haplorchis taichui were 800, 820, 1250, and 930 bp for the ITS1 region, and 380, 390, 380, and 530 bp for ITS2, respectively. The ITS1-region amplicon sizes successfully differentiated 4 species, while only H. taichui were significantly different from the other 3 species in the ITS2 region. PCR assays were employed for preliminary analysis using fecal samples diagnosed as having "small trematode eggs" by modified thick smear, showing 76.2% sensitivity for ITS1 and 95.2% for ITS2.


Transient hyperprolactinemia during cycle stimulation and its influence on oocyte retrieval and fertilization rates.
Prolactin (PRL) has been shown to have inhibitory effect on follicle-stimulating hormone induced aromatase activity and estrogen biosynthesis in human granulosa cells cultured in vitro. To investigate the validity of the hypothesis that transient hyperprolactinemia during controlled ovarian hyperstimulation might influence follicular steroidogenesis and oocyte maturation, we measured serum PRL, estradiol, and progesterone before aspiration of oocytes in women undergoing ovarian stimulation (n = 108) in in vitro fertilization-embryo transfer. No correlation was detected between PRL and total number oocytes, number mature oocytes, fertilization rate, cleavage rate, and pregnancy rate. Transient elevation of PRL was a common finding in patients (57%) but was not associated with a poor clinical outcome.


Monitoring copopulated conformational states during protein folding events using electrospray ionization-ion mobility spectrometry-mass spectrometry.
The precise mechanism of protein folding remains elusive and there is a deficiency of biophysical techniques that are capable of monitoring the individual behavior of copopulated protein conformers during the folding process. Herein, an ion mobility spectrometry (IMS) device integrated with electrospray ionization mass spectrometry (ESI-MS) has been used to successfully separate and analyze protein conformers differing in cross section and/or charge state. In an initial test, an ensemble of folded and partially folded conformers of the protein cytochrome c was separated. A detailed study undertaken on the amyloidogenic protein beta(2)-microglobulin (beta(2)m), which forms fibrils by protein unfolding followed by self-aggregation and is responsible for the disease dialysis-related amyloidosis, has generated important insights into its folding landscape. Initially, a systematic titration of beta(2)m over the pH range 2 to 7 using ESI-IMS-MS allowed individual conformers to be monitored and quantified throughout the acid denaturation process. Furthermore, a comparison of wild-type beta(2)m with single and double amino acid variants with a range of folding stabilities and propensities for amyloid fibril formation has provided illuminating evidence of the role of different conformers in protein stability and amyloidogenic aggregation. The ESI-IMS-MS data presented here not only demonstrate an important and informative further dimension to ESI-MS, but also illustrate the potential of the ESI-IMS-MS technique for unravelling protein folding enigmas in general and studying protein misfolding diseases in particular.


Comparison of endotoxins and cutaneous burn toxin as immunosuppressants.
Endotoxins of E. coli, S. typhosa and Ps. aeruginosa were injected i.p. into mice a few days before administration of the antigen sheep erythrocytes (SE). Antibody-forming cells (AFC) to SE were later enumerated in relation to dose of endotoxin given. In comparison a toxic lipid protein isolated from burned skin (cutaneous burn toxin or CBT) was similarly applied and found to be more inhibitory of the immune response than any of the three endotoxins. Considering the 50 per cent inhibitory doses on a molar basis CBT was found to be 1000 fold more immunosuppressive than the most inhibitory endotoxin. As the immune suppression which follows severe thermal injury involves failure of interleukin 2 (IL2) function, as a critical index of survival, the CBT was tested for its effects on the culture of a human IL2-dependent cell line in the presence of IL2. CBT inhibited the growth of these cells, however, endotoxin had no effect on their proliferation. Thus CBT, which arises by a thermally induced polymerization of skin lipid protein, is specific to burn injury and has a direct inhibitory effect on the immune response.


[Sexual dysfunction associated with psychotropic drugs and treatment options].
Sexual dysfunction associated with psychotropic drugs is a threat to patient quality of life and a major reason for non-compliance. Psychotropic agents can impair the sexual response in different ways due to their neurobiological mode of action. Presentation of the frequencies of sexual functional disorders for selected psychopharmacological groups and the available treatment modalities. Literature search, selection and review of relevant studies. The most relevant groups for impairments are antidepressants and antipsychotics due to the serotonin agonistic and anti-dopaminergic properties as well as the prolactin increasing characteristics. Agents with a favorable side effects profile are now available. All phases of the sexual response are affected. The treatment of psychiatric disorders should follow a comprehensive treatment plan that anticipates a likely sexual dysfunction at the initiation of treatment. The main aim is improvement of the underlying primary disorder. Some limited evidence-based treatment strategies are available.


Dodecylbenzene sulfonate-coated magnetite nanoparticles as a new adsorbent for solid phase extraction-spectrophotometric determination of ultra trace amounts of ammonium in water samples.
A new method was proposed for the determination of ammonium based on the preconcentration with dodecylbenzene sulfonate modified magnetite nanoparticles. Ammonium was oxidized to nitrite by hypobromite and then the nitrite produced was determined spectrophotometrically, using sulfabenzamide and N-(1-naphthyl) ethylenediamine after solid phase extraction. The azo dye produced was desorbed by an appropriate small volume of sodium hydroxide prior to the absorbance measurement. The linear calibration graphs were obtained in the concentration range of 0.03-6.00 ng mL(-1) ammonium. The relative standard deviation and recovery percents were 1.0 and 99.0, respectively, for 1.0 ng mL(-1) ammonium, and the limit of detection was 3.2 ng L(-1) ammonium. The interfering effects of a large number of diverse ions on the determination of ammonium were studied. The method was applied to the determination of ammonium in various types of water resources. The results revealed a high efficiency for the recommended ammonium determination method.


Carotenoid content in tritordeum is not primarily associated with esterification during grain development.
Tritordeums show a significant proportion of lutein esters which increases carotenoid stability and retention throughout the food chain. Esterification is a common means of carotenoid sequestration. A putative association between lutein esters formation acting as a metabolic sink during early stages of grain development and the high carotenoid content of tritordeums is analyzed in this work. Compared to wheat, tritordeums accumulated significantly higher lutein contents from 20 days post anthesis (dpa) but lutein esters were not detected until 36 dpa. Thus esterification is not acting as a metabolific sink before 36 dpa. The presence of lutein esters at late stages of grain development may have a complementary role in carotenoid accumulation by reducing and/or counteracting their catabolism. The differences for lutein esterification among tritordeums suggest the existence of diversity for xanthophyll acyl transferases that could be exploited to increase lutein retention in this cereal and through the food chain.


Maternal and fetal complications associating lupus anticoagulant and its management; three case reports.
Both lupus anticoagulant and anticardiolipin antibody are groups of antiphospholipid antibodies associated with high frequency of thrombosis, fetal loss and thrombocytopenia. The hall marks of their identification is the prolongation of phospholipid-dependant coagulation tests. Much is written in literature about the successful management of lupus anticoagulant during pregnancy, via corticosteroid and acetyl salicylic acid (Aspirin) therapy; however, up to now only little has been mentioned about maternal and fetal complications associating lupus anticoagulant and its management. Here we present three cases with significant complications among patients with lupus anticoagulant managed in Sint Augustinus Hospital over the last 3 years. These complications were secondary to antiphospholipid syndrome or to therapy. Maternal complications included gastritis, atrophy of quadriceps muscle, resistant premature contractions and pre-eclampsia. One of our patients developed small lymphocytic lymphoma 1 year after her last labour. Fetal complications included: prematurity, suprarenal insufficiency (temporary) and delayed neuromuscular development found at the 2 year follow-up. As far as we know, some of these complications have never been mentioned in literature.


Tumor-suppressive function of long noncoding RNA MALAT1 in glioma cells by downregulation of MMP2 and inactivation of ERK/MAPK signaling.
Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a type of long noncoding RNA. It is associated with metastasis and is a favorable prognostic factor for lung cancer. Recent studies have shown that MALAT1 plays an important role in other malignancies. But, little is known about the role of MALAT1 in glioma. In this study, quantitative reverse transcription PCR (qRT-PCR) was used to demonstrate that the expression of MALAT1 was lower than that in normal brain tissues. Stable RNA interference-mediated knockdown of MALAT1 in human glioma cell lines (U87 and U251) significantly promoted the invasion and proliferation of the glioma cells by in vitro assays. Conversely, overexpression of MALAT1 caused significant reduction in cell proliferation and invasion in vitro, and tumorigenicity in both subcutaneous and intracranial human glioma xenograft models. Furthermore, MALAT1-mediated tumor suppression in glioma cells may be via reduction of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling activity and expression of matrix metalloproteinase 2 (MMP2). In conclusion, overall data demonstrated the tumor-suppressive role of MALAT1 in glioma by attenuating ERK/MAPK-mediated growth and MMP2-mediated invasiveness.


Lived Experiences of Mistreatment in a General Surgery Residency.
Explore the lived experiences of General Surgery residents to identify how they perceive, define mistreatment, and which factors can contribute to or mitigate mistreatment within the Clinical Learning Environment. This is a phenomenological study conducted during 2019-2020 using Giorgi's psychological descriptive phenomenology methodology. Researcher bias, trustworthiness, and triangulation were addressed using bracketing, check-ins with program leadership, comparisons to resident survey, and team consensus based on Consensual Qualitative Research. General Surgery Residency program at Long School of Medicine, UT Health San Antonio, Texas. All residents in the general surgery program were invited to participate (n= 66, 43% female and 63% non-Hispanic). Specific demographic and identifying data for each participant was not collected. Approximately 50 (76% of program) residents from General Surgery participated. We were able to identify four themes that helped to delineate the lived experience of residents including program cultural factors, resident internal processing, and perceived effects of mistreatment by the residents. The resulting psychological structure and conceptual framework help clarify the interrelations between the themes and the Clinical Learning Environment. The scenarios discussed were adapted and depersonalized to use as prompts for the Forum Theater intervention. This project set out to explore resident's lived experiences and allow the data to reveal the main outcomes. The data was coded and analyzed following strict guidelines from descriptive psychological phenomenology and Consensual Qualitative Research with the aim of informing a later experiential intervention based on Forum Theater. The lived experience of general surgery residents helped identify cultural factors and behaviors that contribute to and/or mitigate mistreatment providing information to plan interventions at the resident and faculty level. Mitigating or stopping mistreatment can improve the Clinical Learning Environment and hence, the quality of training.


Performance evaluation of public non-profit hospitals using a BP artificial neural network: the case of Hubei Province in China.
To provide a reference for evaluating public non-profit hospitals in the new environment of medical reform, we established a performance evaluation system for public non-profit hospitals. The new "input-output" performance model for public non-profit hospitals is based on four primary indexes (input, process, output and effect) that include 11 sub-indexes and 41 items. The indicator weights were determined using the analytic hierarchy process (AHP) and entropy weight method. The BP neural network was applied to evaluate the performance of 14 level-3 public non-profit hospitals located in Hubei Province. The most stable BP neural network was produced by comparing different numbers of neurons in the hidden layer and using the "Leave-one-out" Cross Validation method. The performance evaluation system we established for public non-profit hospitals could reflect the basic goal of the new medical health system reform in China. Compared with PLSR, the result indicated that the BP neural network could be used effectively for evaluating the performance public non-profit hospitals.


Hospital Frailty Risk Score (HFRS) Predicts Adverse Outcomes Among Hospitalized Patients with Chronic Pancreatitis.
The prevalence of frailty among patients with chronic pancreatitis (CP) and its impact on clinical outcomes is unclear. We report the impact of frailty on mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the United States. We extracted data on patients hospitalized with a primary or secondary diagnosis of CP from the Nationwide Readmissions Database 2019. We applied a previously validated hospital frailty risk scoring system to classify CP patients into frail and non-frail on index hospitalization and compared the characteristics of frail and non-frail patients. We studied the impact of frailty on mortality, readmission, and healthcare utilization. Of 56,072 patients with CP, 40.78% of patients were classified as frail. Frail patients experienced a higher rate of unplanned and preventable hospitalizations. Almost two-thirds of frail patients were younger than 65, and one-third had no or only single comorbidity. On multivariate analysis, frailty was independently associated with two times higher mortality risk (adjusted hazard ratio [aHR], 2.05; 95% CI 1.7-2.5). Frailty was also associated with a higher risk of all-cause readmission with an aHR of 1.07; (95% CI 1.03-1.1). Frail patients experienced a longer length of stay, higher hospitalization costs, and hospitalization charges. Infectious causes were the most common cause of readmission among frail patients compared to acute pancreatitis among non-frail patients. Frailty is independently associated with higher mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the US.


Meta-analysis of Randomized Controlled Trials Assessing the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies on Mortality and Cardiovascular Outcomes.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition by monoclonal antibodies has been shown to reduce low density lipoprotein (LDL-C) but its effects on cardiovascular (CV) outcomes have not been fully described. The aim of this study is to assess the impact of PCSK9 inhibition on mortality and CV outcomes by pooling data from all available randomized clinical trials (RCT) of PCSK9 inhibitors. We conducted a comprehensive search of electronic databases, up to December 1, 2018, for all RCTs comparing PCSK9 inhibition to placebo or ezetimibe in patients with hypercholesterolemia or coronary artery disease receiving maximally tolerated statin for primary or secondary prevention of mortality and cardiovascular outcomes. We used random-effects meta-analyses to summarize the studies. We retained 23 RCTs having included 88,041 patients in primary and secondary prevention. The follow-up ranged from 6 to 36 months. PCSK9 inhibition was not significantly associated with reductions in total mortality (odds ratio [OR] 0.91, 95% confidence interval [CI] 078 to 1.06; p = 0.22) and CV mortality (OR 0.95, 95% CI 0.84 to 1.07; p = 0.37). In contrast, PCSK9 inhibition was associated with reductions in myocardial infarction (OR 0.80, 95% CI 0.71 to 0.91; p <0.0001), stroke (OR 0.75, 95% CI 0.65 to 0.85; p <0.0001), and coronary revascularization (OR 0.82, 95% CI 0.77 to 0.88; p <0.0001). In conclusion, PCSK9 inhibition was associated with reductions in myocardial infarction, stroke, and coronary revascularization. Future analyses may identify high-risk patients who may benefit more from these agents and longer follow-up of current or new trials may show a mortality benefit.


A lipopeptide-encoding sequence upstream from the lysA gene of Pseudomonas aeruginosa.
An open reading frame (ORF) of 141 bp was observed upstream from the Pseudomonas aeruginosa lysA gene. The translation product of this ORF contains a signal peptide with a lipoprotein box, Ile-Ala-Ala-Cys, at the predicted signal peptidase cleavage site. The Escherichia coli phoA gene without its signal sequence was fused in frame to this ORF in a broad host-range plasmid. The resulting construct expressed a hybrid protein exhibiting alkaline phosphatase activity in phoA mutants of both E. coli and P. aeruginosa. This indicates that the ORF encodes a peptide, part of which acts as an export signal. The hybrid peptide was identified by immunoblotting with alkaline phosphatase antiserum. The accumulation of a precursor form was observed when P. aeruginosa cells carrying this gene fusion on a plasmid were treated with globomycin. Moreover, the mature form could be labelled with 2-[3H]-glycerol, indicating that lipidic residues may be linked to the hybrid protein. Taken together, these results strongly suggest that the ORF encodes a lipopeptide. We propose that the gene is called IppL.


Evaluation of motor learning in predictable loading task using a force sense presentation device.
Neural circuits connecting the cerebellum with the cerebral cortex are important for both motor and cognitive functions. Therefore, assessment of cerebellar function is clinically important for patients with various motor and cognitive dysfunctions. Cerebellum-dependent motor learning has been studied using various tasks. The most widely used tasks are visuomotor adaptation tasks, in which subjects are required to make movements in two dimensions. Studies using simpler tasks of one-dimensional movement, which are easier for patients with motor problems to perform, have suggested that anticipatory responses in these tasks are useful to evaluate cerebellum-dependent motor control or motor learning. In this study, we examined whether the motor learning process can be evaluated in a simple loading task. Using space interface device for artificial reality (SPIDAR), a constant downward force was loaded to subjects' hands in a predictable condition, and the vertical movement of the hand was recorded. The hand deflection from the initial position was displayed on a screen for visual feedback information. We examined effects of repeated loading task training (90 times) on hand movements, by analyzing a small upward movement just before loading (anticipatory response) and a large downward movement after loading in each trial. We found that the repeated training lowered the time constant of upward movement and reduced the amplitude and time-to-peak of downward movement. These training effects were maintained into the next day. Furthermore, we found that loading task training with eyes closed was also effective, which indicates that proprioceptive information is enough for improvement of performance.


Unbinding force of a single motor molecule of muscle measured using optical tweezers.
The unbinding and rebinding of motor proteins and their substrate filaments are the main components of sliding movement. We have measured the unbinding force between an actin filament and a single motor molecule of muscle, myosin, in the absence of ATP, by pulling the filament with optical tweezers. The unbinding force could be measured repeatedly on the same molecule, and was independent of the number of measurements and the direction of the imposed loads within a range of +/- 90 degrees. The average unbinding force was 9.2 +/- 4.4 pN, only a few times larger than the sliding force but an order of magnitude smaller than other intermolecular forces. From its kinetics we suggest that unbinding occurs sequentially at the molecular interface, which is an inherent property of motor molecules.


Dopamine and serotonin in rat striatum during in vivo hypoxic-hypoxia.
Dopamine and serotonin were determined in extracellular fluid of rat striatum by semiderivative in vivo voltammetry during normoxia and a single or repeated exposure to 15% O2 (i.e., mild hypoxia) or 12.5% O2 (i.e., moderate hypoxia). A single exposure to 15% oxygen increased extracellular dopamine 76%. With reintroduction of air to the animals, dopamine values returned to baseline. During a second episode of 15% oxygen, dopamine increased 63% and remained elevated even during a final exposure to air. On the other hand, serotonin was unaffected by 15% oxygen. Moderate hypoxia (12.5% oxygen) increased dopamine (79%) and serotonin (26%) and both remained elevated even after the initial reintroduction of air. These studies demonstrate that in vivo hypoxia increases rat striatal extracellular dopamine and, to a lesser extent, extracellular serotonin. Furthermore, after repeated, mild hypoxic episodes or moderate hypoxia, the increases in rat striatal extracellular dopamine and serotonin continue even during normoxia. These studies further support a role for dopamine and serotonin in hypoxic-induced changes in brain function. The hypoxic-induced elevation of these two neurotransmitters during normoxia may be important in the production of hypoxic/ischemic-induced cell damage.


Didanosine compared with continued zidovudine therapy for HIV-infected patients with 200 to 500 CD4 cells/mm3. A double-blind, randomized, controlled trial. Canadian HIV Trials Network Protocol 002 Study Group.
To compare the safety and efficacy of didanosine with that of continued zidovudine therapy in persons with human immunodeficiency virus (HIV) infection who had received zidovudine for at least 6 months and had CD4 cell counts of 200 to 500 CD4 cells/mm3. Double-blind, randomized controlled trial. 10 Canadian university-affiliated specialty clinics. 246 patients were assigned to receive standard doses of either zidovudine or didanosine. The primary clinical end point was the occurrence of a new, previously undiagnosed acquired immunodeficiency syndrome (AIDS)-defining illness or death. 245 of 246 patients were eligible (118 receiving didanosine and 127 receiving zidovudine). Sixty-six percent were asymptomatic, 30% had AIDS-related complex, and 4% had AIDS. The median baseline CD4 count was 320 cells/mm3. The median previous duration of zidovudine therapy was 471 days. Nine new AIDS-defining illnesses developed during the study; all but one were in the zidovudine group (relative risk, 7.9 [95% CI, 1.0 to 63.3; P = 0.02]). A change to didanosine led to a statistically significant increase in CD4 counts by week 2 that persisted until the end of the study at week 48 (P < or = 0.01). Viral sensitivity studies (done in 102 patients) showed that 28% of the zidovudine group and 21% of the didanosine group had high-level in vitro resistance to zidovudine (50% inhibitory concentration greater than 0.8 microM) at baseline (P = 0.49). Only one patient in the didanosine group developed high-level resistance to zidovudine during the study. In the zidovudine group, the cumulative probability of developing high-level resistance to zidovudine was 59% at 1 year (P = 0.01). Abdominal pain, leukopenia, and neutropenia were more frequent in the zidovudine group, and hyperuricemia was more frequent in the didanosine group (P < 0.05). In clinically stable patients with 200 to 500 CD4 cells/mm3 who had tolerated zidovudine for at least 6 months, a change to didanosine led to a decrease in the rate of disease progression, a sustained increase in CD4 counts, and a decrease in the chances of developing high-level resistance to zidovudine. Both drugs were generally well tolerated.


Sales data of a supermarket--a tool for monitoring nutrition interventions.
The aim of the study was to examine the daily variations in sales data for individual food items in a supermarket and to assess the usefulness of the computerized sales data of supermarkets for reliable monitoring and evaluation of shopping behaviour. Longitudinal observational study. The study was carried out in one supermarket in Mikkeli, Finland. Seventy-nine packed food items from food groups important for salt and fat intake were monitored. In all food groups both 'healthier' and 'reference' products were included for assessment of both direct sales and proportional sales. The sales data were collected daily for 2 months in May and September 1996 by reading the European Article Numbering (EAN) codes of the packed foods. The proportional sales turned out to be a more stable and useful measure than the direct sales data and the variation remained the same when the monitoring time was increased from 1 week to 1 month. Proportional sales data are proposed as a tool for measuring the effect of nutrition interventions and also as a possible indirect assessment for population salt and fat intake.


Promoting Sustainable Nursing Leadership: The Nightingale Legacy.
The year 2020 features the 200th anniversary of Florence Nightingale's birth. Her legacy is often recalled as simply being "the lady with the lamp" who cared for sick and wounded British soldiers; however, her impact on the nursing profession includes serving as a role model for many leadership behaviors and strategies that have positively impacted the health of communities and populations around the world. Through her tireless endeavors, Nightingale exemplified many leadership roles, including advocate, change agent, interprofessional collaborator, and visionary. The development of effective skills in these leadership roles remains important for all levels of nursing leaders in today's health-care environment. This article showcases Nightingale's leadership in selected leadership roles, and demonstrates her continued impact on contemporary nurses.


Synthesis of Extra-Large Pore, Large Pore and Medium Pore Zeolites Using a Small Imidazolium Cation as the Organic Structure-Directing Agent.
One common strategy in the search for new zeolites is the use of organic structure-directing agents (OSDA). Typically, one seeks to achieve a high specificity in the structure-directing effect of the OSDA. This study shows, however, that an OSDA lacking strong specificity towards any particular zeolite may provide opportunities for discovery when other synthesis parameters are systematically screened. Thus, 1-methyl-2-ethyl-3-n-propylimidazolium has allowed to crystallize the new large/medium pore zeolite HPM-16 as well as the recently reported extra-large pore -SYT and the medium/small pore and chiral STW. The sophisticated OSDA originally affording -SYT and the new simple OSDA have very little in common, both in terms of size, shape and flexibility, while both may still direct the synthesis of the same zeolite. In fact, molecular simulations show that the new OSDA is located in three different positions of the -SYT structure, including the discrete 8MR where the original organic could not fit.


Inhibition of 5-lipoxygenase-activating protein abrogates experimental liver injury: role of Kupffer cells.
Activation of Kupffer cells is a prominent feature of necro-inflammatory liver injury. We have recently demonstrated that 5-lipoxygenase (5-LO) and its accessory protein, 5-LO-activating protein (FLAP), are essential for the survival of Kupffer cells in culture, as their inhibition drives these liver resident macrophages to programmed cell death. In the current study, we explored whether the potent FLAP inhibitor, Bay-X-1005, reduces the number of Kupffer cells in vivo and whether this pharmacological intervention protects the liver from carbon tetrachloride (CCl(4))-induced damage. Rats treated with CCl(4) showed an increased number of Kupffer cells, an effect that was abrogated by the administration of Bay-X-1005 (100 mg/Kg body weight, per oral, daily). Consistent with a role for Kupffer cells in necro-inflammatory liver injury, partial depletion of Kupffer cells following FLAP inhibition was associated with a remarkable hepatoprotective action. Indeed, Bay-X-1005 significantly reduced the intense hepatocyte degeneration and large bridging necrosis induced by CCl(4) treatment. Moreover, Bay-X-1005 induced a reduction in the gelatinolytic activity of matrix metalloproteinase-2 (MMP-2) and a decrease in mRNA expression of tissue inhibitor of MMP-2. The FLAP inhibitor reduced leukotriene (LT)B(4) and cysteinyl LT levels and down-regulated 5-LO and FLAP protein expression in the liver. It is interesting that a significant increase in the hepatic formation of lipoxin A(4), an endogenous, anti-inflammatory lipid mediator involved in the resolution of inflammation, was observed after the administration of Bay-X-1005. These findings support the concept that modulation of the 5-LO pathway by FLAP inhibition may be useful in the prevention of hepatotoxin-induced necro-inflammatory injury.


Wheat containing snowdrop lectin (GNA) does not affect infection of the cereal aphid Metopolophium dirhodum by the fungal natural enemy Pandora neoaphidis.
Studies were carried out to determine if susceptibility of the cereal aphid Metopolophium dirhodum to the fungus Pandora neoaphidis was affected by wheat expressing snowdrop lectin (GNA). Aphid infection did not differ significantly between the transgenic GNA and non-transformed lines (91 and 82%, respectively). Fecundity also did not differ between aphids on the two lines, and was ca. 18 nymphs adult(-1). Time to infection was ca. 5 days for M. dirhodum on both lines in two of three assays. Our results indicate that wheat expressing GNA would not compromise the efficacy of P. neoaphidis as a biocontrol agent.


Fornix transection: discrimination between neuropeptide effects on attention and memory.
Transection of the fornix and the stria terminalis completely blocks the inhibitory action of ACTH 4-10 on extinction of a conditioned avoidance response (CAR), whereas this effect of the vasopressin analogue des-glycinamide-lysine-vasopressin (DG-LVP) is not affected. These data indicate that the behavioral effect of DG-LVP may be localized to certain anatomical substrates, while ACTH 4-10 needs an intact limbic system as a functional substrate for its effect on avoidance behavior. This differential effect of fornicotomy may also be interpreted as a discrimination between the effects of these neuropeptides on attention or on memory consolidation. Additionally, transection of the fornix and the stria terminalis induces an increase in motor responsiveness to an electric footshock (EFS) and a facilitation of acquisition of a CAR.


Non-compliance following renal transplantation in children and adolescents.
Reported frequencies of non-compliance in children with end-stage renal disease range from 8% to 70% with a mean around 40%. Sequelae amount to momentous emotional and financial burdens, including the loss of 7% of transplanted organs. Reasons for non-compliance have too often been attributed selectively to the patients (e.g., emotional, mental, social, or communication problems). Compared with general compliance research, this selective attribution appears to be too simplistic. Selective attribution neglects the patients' experiences within the context of disease and treatment and prevents open communication about non-compliance. Research on personal reasons for non-compliance is scarce. In psychological interviews, a third of our 85 patients with end-stage renal disease (34 boys, 51 girls, mean age 12.7 years, range 7.4-19.3 years) communicated psychologically meaningful reasons for non-compliance, frequently related to interrelational and systemic treatment conditions. Patients indirectly asked for more communication about their subjective reasons for non-compliance.


An Aeromonas veronii biovar sobria infection with disseminated intravascular gas production.
We report a case of Aeromonas veronii biovar sobria infection with disseminated intravascular gas production. The patient was an afebrile 15-year-old girl who had been quite healthy until the onset of the illness. She came to the hospital because of a 6-h history of increasing pain and swelling in her left thigh. On admission, no infection was suspected, and a tentative diagnosis of a ruptured left gracilis muscle was made. Because the pain increased continuously, the treatment concentrated on pain control. Unexpectedly, abrupt death occurred 23 h after her admission. Postmortem computed tomographic (CT) scans showed an abundance of gas in the blood vessels of the entire body. Postmortem investigation revealed disseminated intravascular gas production, marked intravascular hemolysis, and numerous intravascular Gram-negative bacilli in all organs examined. The organisms were identified as A. veronii biovar sobria, and were highly susceptible to third-generation cephalosporins. Regarding therapeutic problems, the early administration of these antibiotics should reduce the fatality rate in such infections. It is critical to keep the possibility of such an infection in mind when a patient complains of severe muscle pain.


Is there a relationship between 'getting up and dressed' and functional and physical outcomes in geriatric rehabilitation inpatients? A quasi-experimental study.
To evaluate the physical and functional outcomes of the 'Ending Pyjama Paralysis' intervention in an inpatient geriatric rehabilitation unit. Quasi-experimental mixed-methods design nested within the 'REStORing health of acutely unwell adulTs' (RESORT) prospective, observational, longitudinal cohort of geriatric rehabilitation inpatients study. Geriatric rehabilitation wards in a major metropolitan public hospital between June 2019 and March 2020. The 'Ending Pyjama Paralysis' movement originated in the UK. Its aim was to encourage patients to 'Get up, Get dressed and Get moving' to reduce hospital-associated functional decline. However, the physical and functional benefits of this campaign have not yet been evaluated. The 'Ending Pyjama Paralysis' was adopted as an integrated intervention on two out of four geriatric rehabilitation wards. The two control wards received usual care. Physical measures included the Short Physical Performance Battery, and functional measures included the Katz Index of Independence in Activities of Daily Living and Lawton and Brody's Instrumental Activities of Daily Living, which were completed on admission and discharge. A linear mixed-effects model was used to analyse the results. A total of 833 admissions were included in this study. Of these, 512 patients were in the control group, and 321 were in the intervention group. There were no significant differences in both physical and functional measures between the intervention and control groups. The 'Ending Pyjama Paralysis' campaign did not result in enhanced functional or physical benefits in geriatric rehabilitation inpatients in this setting when applied in addition to usual care.


Modulators of the human CCR5 receptor. Part 2: SAR of substituted 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides.
SAR and DMPK studies led to the identification of substituted N-alkyl-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-2-phenylacetamides as potent and orally bioavailable ligands for the human CCR5 chemokine receptor.


Proteomic and biochemical analysis of maize anthers after cold pretreatment and induction of androgenesis reveals an important role of anti-oxidative enzymes.
In stress conditions, microspores and young pollen grains can be switched from their normal pollen development toward an embryogenic pathway via a process called androgenesis. Androgenic embryos can produce completely homozygous, haploid or double-haploid plants. This study aimed to investigate changes in the abundance of protein species during cold pretreatment and subsequent cultivation of maize anthers on induction media using gel-based proteomics. Proteins upregulated on the third day of anther induction were identified and discussed here. Simultaneous microscopic observations revealed that the first division occurred in microspores within this period. Using 2-D electrophoresis combined with MALDI TOF/TOF MS/MS analysis 19 unique proteins were identified and classified into 8 functional groups. Proteins closely associated with metabolism, protein synthesis and cell structure were the most abundant ones. Importantly, ascorbate peroxidase, an enzyme decomposing hydrogen peroxide, was also upregulated. Isozyme analysis of peroxidases validated the proteomic data and showed increased peroxidase activities during androgenic induction. Further, the isozyme pattern of SOD revealed increased activity of the MnSOD, which could provide hydrogen peroxide as a substrate for in vivo peroxidase reactions (including ascorbate peroxidase). Together, these data reveal the role of enzymes controlling oxidative stress during induction of maize androgenesis.


Treatment of ventilator-associated pneumonia due to carbapenem-resistant Gram-negative bacteria with novel agents: a contemporary, multidisciplinary ESGCIP perspective.
In the past 15 years, treatment of ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) has represented an intricate challenge for clinicians. In this perspective article, we discuss the available clinical data about novel agents for the treatment of CR-GNB VAP, together with general pharmacokinetic/pharmacodynamic principles for the treatment of VAP, in the attempt to provide some suggestions for optimizing antimicrobial therapy of CR-GNB VAP in the daily clinical practice. Recently, novel β-lactams and β-lactam/β-lactamase inhibitor combinations have become available that have shown potent in vitro activity against CR-GNB and have attracted much interest as novel, less toxic, and possibly more efficacious options for the treatment of CR-GNB VAP compared with previous standard of care. Besides randomized controlled trials, a good solution to enrich our knowledge on how to use these novel agents at best in the near future, while at the same time remaining adherent to current evidence-based guidelines, is to improve our collaboration to conduct larger multinational observational studies to collect sufficiently large populations treated in real life with those novel agents for which guidelines currently do not provide a recommendation (in favor or against) for certain causative organisms.


Features that best define the heterogeneity and homogeneity of autism in preschool-age children: A multisite case-control analysis replicated across two independent samples.
The heterogeneous nature of children with symptoms of autism spectrum disorder (ASD) makes it difficult to identify risk factors and effective treatment options. We sought to identify behavioral and developmental features that best define the heterogeneity and homogeneity in 2-5-year-old children classified with ASD and subthreshold ASD characteristics. Children were enrolled in a multisite case-control study of ASD. Detailed behavioral and developmental data were gathered by maternal telephone interview, parent-administered questionnaires, child cognitive evaluation, and ASD diagnostic measures. Participants with a positive ASD screen score or prior ASD diagnosis were referred for comprehensive evaluation. Children in the ASD group met study criteria based on this evaluation; children who did not meet study criteria were categorized as having subthreshold ASD characteristics. There were 1480 children classified as ASD (81.6% boys) and 594 children classified as having subthreshold ASD characteristics (70.2% boys) in the sample. Factors associated with dysregulation (e.g., aggression, anxiety/depression, sleep problems) followed by developmental abilities (e.g., expressive and receptive language skills) most contributed to heterogeneity in both groups of children. Atypical sensory response contributed to homogeneity in children classified as ASD but not those with subthreshold characteristics. These findings suggest that dysregulation and developmental abilities are clinical features that can impact functioning in children with ASD and other DD, and that documenting these features in pediatric records may help meet the needs of the individual child. Sensory dysfunction could be considered a core feature of ASD and thus used to inform more targeted screening, evaluation, treatment, and research efforts. LAY SUMMARY: The diverse nature of autism spectrum disorder (ASD) makes it difficult to find risk factors and treatment options. We identified the most dissimilar and most similar symptom(s) in children classified as ASD and as having subthreshold ASD characteristics. Factors associated with dysregulation and developmental abilities contributed to diversity in both groups of children. Sensory dysfunction was the most common symptom in children with ASD but not those with subthreshold characteristics. Findings can inform clinical practice and research.


Outbreaks of hospital infection in southwest England caused by gentamicin-resistant Serratia marcescens.
Five geographically separate outbreaks of hospital acquired infection caused by gentamicin-resistant strains of Serratia marcescens occurred in the period October 1977 to January 1980 in southwest England. The patients affected were in wards for general or urological surgery, or in neurosurgical, cardiothoracic or general intensive therapy units. Asymptomatic colonization was more common than symptomatic infection, although deaths and serious infections occurred. Control of spread of the bacteria proved difficult. Most strains were resistant to many currently available antibiotics besides gentamicin; only one strain became resistant to amikacin. Representative isolates where characterized by O serotype, bacteriophage type, antibiotic sensitivity pattern, production of beta-lactamases and amino-glycoside-aminocyclitol (ACAG)-modifying enzymes, and plasmid visualization. Plasmid studies provided information that complemented conventional typing methods in determining epidemiological relationships among the outbreaks.


Maternal nicotine exposure during lactation alters hypothalamic neuropeptides expression in the adult rat progeny.
Maternal exposure to nicotine during lactation causes hyperleptinemia in the pups and, at adulthood, these animals are overweight and hyperleptinemic, while, in their hypothalamus, the leptin signaling pathway is reduced, evidencing a central leptin resistance. Then, we evaluated the expression of pro-opiomelanocortin (POMC), alpha-melanocyte stimulating hormone (α-MSH), cocaine and amphetamine-regulated transcript (CART), neuropeptide Y (NPY), agouti-related peptide (AgRP) and others in different hypothalamic nuclei in order to better understand the mechanisms underlying the obese phenotype observed in these animals at adulthood. On the 2nd postnatal day (P2), dams were subcutaneously implanted with osmotic minipumps releasing nicotine (NIC-6 mg/kg/day) or saline for 14 days. Offspring were killed in P180 and immunohistochemistry and Western blot analysis were carried out. Significance data had p<0.05. Adult NIC offspring showed more intense NPY staining in the paraventricular nucleus (PVN) (+21%) and increased number of POMC-positive cells in the: arcuate nucleus (+33%), as an increase in fiber density of α-MSH in PVN (+85%). However, the number of CART-positive cells was reduced in the PVN (-25%). CRH staining was more intense in NIC offspring (+136%). Orexins and AgRP were not altered. Thus, maternal nicotine exposure changes hypothalamic neuropeptides in the adult progeny that is partially compatible with leptin resistance.


Effects of isokinetic ankle fatigue on the maintenance of balance and postural limits.
To quantify changes in balance parameters and ranges of postural control at the ankle after isokinetic fatigue. Before-after trials, with a 5 x 6 repeated-measures design. General community. Twenty-four men (age, 24.9 +/- 3.92y; height, 177.79 +/- 6.36cm; weight, 80.78 +/- 13.22kg) without ankle trauma within 2 years. Fatigue of the plantarflexors and dorsiflexors was induced by isokinetic contractions. Balance was assessed by using a unilateral test (15-s quiet stance, 10-s lean test) on a force platform immediately before and at 0 (T0), 10 (T10), 20 (T20), and 30 (T30) minutes postfatigue. Mediolateral (ML) and fore-aft (FA) sway as well as ML and FA displacement were analyzed by analysis of variance with repeated measures for time (alpha =.05). In quiet stance, ML sway was greater at T0, whereas total sway increased at all time points postfatigue (P < .05). For the lean test, FA sway increased at T0 and T10, and total sway increased at all time points (P < .05). Both ML and FA displacement significantly differed at T0 (P < .05). All sway parameters returned to baseline within 20 minutes. Isokinetic fatigue of ankle plantarflexors and dorsiflexors significantly influences sway parameters and ranges of postural control in healthy young men. These perturbations are transient, and recovery occurs within 20 minutes.


Assisted conception in women of advanced maternal age.
A delay in childbearing to later in life has increased the number of women of advanced maternal age (AMA) opting for assisted reproduction. Women should be made aware that there are age-related changes to fertility, including a decline in oocyte reserve and quality, in addition to an increase in the number of oocyte chromosomal aberrations. Success rates of assisted reproductive technology (ART) cycles decrease with advanced maternal age. There are different fertility options for women of AMA, including fertility preservation (oocyte or embryo freezing), in vitro fertilisation (IVF treatment) with or without preimplantation genetic screening and oocyte or embryo donation. Detailed counselling needs to be offered to these women with regard to the risks, success rates, ethical and legal implications of these fertility treatment options. Women of AMA should be screened for underlying medical conditions that could have an impact on maternal and neonatal morbidity and mortality.


Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.
Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163·0-464·0) for nivolumab 3 mg/kg, 302 days (IQR not calculable) for nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 361·0 days (273·0-470·0) for nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 260·5 days (248·0-288·0) for nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. An objective response was achieved in ten (10%) of 98 patients receiving nivolumab 3 mg/kg, one (33%) of three patients receiving nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 14 (23%) of 61 receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and ten (19%) of 54 receiving nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) patients in the nivolumab 3 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). No patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event. Six (6%) patients in the nivolumab 3 mg/kg group, seven (11%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg group, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg group discontinued treatment due to treatment-related adverse events. Two patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg died from treatment-related adverse events (myasthenia gravis and worsening of renal failure), and one patient who received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg died from treatment-related pneumonitis. Nivolumab monotherapy and nivolumab plus ipilimumab showed antitumour activity with durable responses and manageable safety profiles in previously treated patients with SCLC. These data suggest a potential new treatment approach for a population of patients with limited treatment options and support the evaluation of nivolumab and nivolumab plus ipilimumab in phase 3 randomised controlled trials in SCLC. Bristol-Myers Squibb.


Renal endothelin system and excretory function in Wistar-Kyoto and Long-Evans rats.
The role of the kidney endothelin system in the renal regulation of fluid and electrolyte excretion was investigated in Wistar-Kyoto (WKY) and Long-Evans (LE) rats in which we found previously marked differences in the renal excretory responses to endothelin A receptor blockade. The selective endothelin A and B receptor antagonists BQ-123 (16.4 nmol kg(-1) min(-1)) and BQ-788 (25 nmol kg(-1) min(-1)) were infused i.v. for 50 min in conscious chronically instrumented WKY and LE rats and their renal function and renal endothelin system were studied. Without effects on glomerular filtration rate or renal blood flow, BQ-123 and BQ-788 decreased by more than 50% (P < 0.01) both urine flow rate and electrolyte excretion in WKY rats but only urine flow rate (P < 0.05) in LE rats. Endothelin-1 content, preproET-1/GPDH mRNA ratio, B(max) and K(d) of total endothelin receptors in renal cortex did not differ between the two strains. In contrast, plasma endothelin-1 concentration (0.58 +/- 0.04 vs. 1.05 +/- 0.01 femtomol mL(-1); P < 0.01), renal papillary ET-1 concentration (68 +/- 5 vs. 478 +/- 62 fmol mg(-1) protein; P < 0.01) and preproET-1/GPDH mRNA ratio (0.65 +/- 0.09 vs. 0.88 +/- 0.05; P < 0.05) as well as total endothelin receptor number in renal papilla (B(max) 5.3 +/- 0.4 vs. and 9.0 +/- 1.2 pmol mg(-1) protein; P < 0.05) were markedly lower in LE than in WKY rats. In vitro studies showed that in both strains ET(B) receptors on renal cortical membranes amounted between 65% and 67% and on papillary membranes between 85% and 88%. The present data show that the selective ET(A) or ET(B) receptor blockade differentially affects tubular water and salt handling, which becomes apparent in conditions of low renal papillary endothelin receptor number and tissue endothelin-1 concentration.


Shifting paradigms in Pseudomonas aeruginosa biofilm research.
Biofilms formed by Pseudomonas aeruginosa have long been recognized as a challenge in clinical settings. Cystic fibrosis, endocarditis, device-related infections, and ventilator-associated pneumonia are some of the diseases that are considerably complicated by the formation of bacterial biofilms, which are resistant to most current antimicrobial therapies. Due to intense research efforts, our understanding of the molecular events involved in P. aeruginosa biofilm formation, maintenance, and antimicrobial resistance has advanced significantly. Over the years, several dogmas regarding these multicellular structures have emerged. However, more recent data reveal a remarkable complexity of P. aeruginosa biofilms and force investigators to continually re-evaluate previous findings. This chapter provides examples in which paradigms regarding P. aeruginosa biofilms have been challenged, reflecting the need to critically re-assess what is emerging in this rapidly growing field. In this process, several avenues of research have been opened that will ultimately provide the foundation for the development of preventative measures and therapeutic strategies to successfully treat P. aeruginosa biofilm infections.


[Patients with metastatic prostate cancer : Recommendations for primary hormonal or chemohormonal therapy].
The standard treatment for patients with metastatic, hormone-sensitive prostate cancer (mCSPC) has so far consisted of medical or surgical castration. However, two published clinical trials using docetaxel in combination with castration (CHAARTED and STAMPEDE) recently provided evidence for a substantial improvement in overall survival. The survival benefit was 14 and 22 months, respectively, in the two trials. In addition, the CHAARTED trial showed that patients with high-volume disease may benefit most from chemohormonal treatment. According to the current available evidence, the new standard of treatment for patients therefore consists of castration in combination with docetaxel-based chemotherapy, which should be offered to all patients who are fit to receive chemotherapy. With the results of the LATITUDE and a further study-arm of the STAMPEDE trial, the combination of androgen-deprivation therapy (ADT) plus abiraterone/prednisone has recently become an alternative treatment to chemohormonal treatment. This combination leads to an identical survival benefit compared to chemohormonal treatment and is recommended by expert panels. Based on the current evidence, it is not possible to decide which patient may benefit from chemohormonal treatment and who will benefit from the combination of ADT plus abiraterone/prednisone.


Starting home nebulizer therapy: patients' expectations and subsequent outcome at 2 months.
Twenty-six patients with severe COPD or asthma completed standard questionnaires before, and 2 months after, starting home nebulized bronchodilator therapy. Patients' perceived illness severity and their expectations of treatment with regard to symptoms were examined in the first questionnaire, and outcome was assessed in the second. Before treatment started patients expected a definite improvement in all symptoms studied. After treatment the group showed only a marginal subjective improvement in all symptoms. The improvement attained with regard to breathlessness, ability to get out and about, and general quality of life was significantly lower than had been expected. While home nebulized bronchodilator therapy is well tolerated and confers some subjective benefit in selected individuals, patients appear to have unrealistically high expectations of treatment.


Novelties in the pharmacological approaches for chronic heart failure: new drugs and cardiovascular targets.
Despite recent advances in chronic heart failure (HF) management, the prognosis of HF patients is poor. This highlights the need for researching new drugs targeting, beyond neurohumoral and hemodynamic modulation approach, such as cardiomyocyte metabolism, myocardial interstitium, intracellular regulation and NO-sGC pathway. In this review we report main novelties on new possible pharmacological targets for HF therapy, mainly on new drugs acting on cardiac metabolism, GCs-cGMP pathway, mitochondrial function and intracellular calcium dysregulation.


Mechanism for the paradoxical aciduria following alkali administration to prolonged-fasted patients.
Rapidly induced systemic alkalinization due to either sodium-lactate or sodium-bicarbonate infusion in prolonged-fasted subjects with steady-state ketoacidosis was associated with a decrease in urine pH. This decrease in urine pH from 5.50 to 5.20 was the result of a significant decrease in urinary ammonium excretion from 8.40 to 6.35 mEg/hr and was not accompanied by an increase in net acid excretion (11.3 vs. 10.6 mEg/hr). The decreased ammonium excretion is attributed to the raised pH of the proximal tubular fluid resulting in a less favorable pH gradient for gaseous ammonia entry. This would decrease gaseous ammonia generated in the loop of Henle for collecting duct buffering of secreted hydrogen ions.