Outcome in early cervical cancer following pre-operative low dose rate brachytherapy: a ten-year follow up of 257 patients treated at a single institution.
To report the outcome of preoperative low dose rate uterovaginal brachytherapy (LDR-UVBT) followed by radical surgery in the treatment of early cervical carcinoma. 257 patients treated at Institut Curie from 1985 to 2008 for cervical carcinoma less than 4cm (FIGO stages Ib1, IIA and IIB) were studied. Patients received preoperative LDR-UVBT followed by hysterectomy Piver II type, with pelvic lymph nodes dissection (PLND). Predictive factors for pathological response to brachytherapy were analyzed with logistic regression, as well as survival rates. 44% of patients had residual tumor, 4.3% of patients had parametrial invasion and 17.9% of patients had lymph node involvement. Predictive factors for an incomplete pathological response were: initial clinical tumor size 20mm (OR 2.1), pN1 (OR 2.77), glandular carcinoma (OR 2.51) and lymphovascular invasion (OR 4.35). 7.4% and 2.7% of patients had respectively grade 2 and grade 3 post-therapeutic late complications. Median follow up was 122 months [1-282]. Five-year actuarial overall survival and disease free survival were respectively 83% CI [78.3-87.5] and 80.9% CI [76.3-85.7]. In multivariate analysis, factors affecting significantly the overall survival and disease free survival rates were: lymph node involvement (RR 4.53 and 8.96 respectively), parametrial involvement (RR 5.69 and 5.62 respectively), smoking (RR 3.07 and 2.63 respectively). Preoperative LDR-UVBT results in good disease control with a low complications rate. Its accuracy could be improved by a better selection of patients. Lymph nodes and parametrial evaluation remains a challenging issue that should be achieved with imaging and minimal invasive surgery.


Lack of association of CCR gene polymorphisms and left ventricular hypertrophy in essential hypertension.
Left ventricular hypertrophy (LVH) is a major determinant of heart damage. Scientific evidence suggests the influence of genetic factors, but these have yet to be completely clarified. This study investigates a possible relationship between LVH and two chemokine receptor (CCR) gene polymorphisms: CCR5delta32 and CCR264I. Essential hypertensive out-patients (n=118, grade I-II, age 27-54) were recruited from the Catholic University Hypertension Centre. For each subject, clinical data on office blood pressure and M-mode/2D echocardiography were collected. Statistical analysis did not show a significant association between the CCR polymorphisms and LVH in the study population.


Childhood acute lymphoblastic leukaemia: outcomes of 54 consecutive patients treated in Auckland 1985-1991.
To report the survival and event-free survival of children with acute lymphoblastic leukaemia treated in Auckland between 1985-1991, using an international protocol, ANZCCSG ALL Study V. The data were collected prospectively as part of the study. The analysis was carried out using standard survival methods. At a median follow up of 7.5 years, the overall survival is 75% and event-free survival 60%. For an unselected series, these outcomes are comparable to overseas series. The survival for children diagnosed in the 1990's is likely to be similar.


Antioxidant effect of pomegranate against streptozotocin-nicotinamide generated oxidative stress induced diabetic rats.
Oxidative stress attributes a crucial role in chronic complication of diabetes. The aim of this study was to determine the most effective part of pomegranate on oxidative stress markers and antioxidant enzyme activities against streptozotocin-nicotinamide (STZ-NA)-induced diabetic rats. Male Sprague-Dawley rats were randomly divided into six groups. Experimental diabetes was induced by a single intraperitoneal injection (i.p), 15 min after the i.p administration of NA. Diabetic rats showed significant increase in plasma glucose level, and the significant decrease in plasma insulin level. The activities of antioxidant enzymes such as total antioxidant status (TAS), superoxide dismutase (SOD), and catalase (CAT) reduced while the levels of biomarkers of oxidative stress such as gamma-glutamyle transferase (GGT), and malondialdehyde (MDA) increased in diabetic control rats as compared to normal control rats. Oral treatment with pomegranate seed-juice for 21 days demonstrated significant protective effects on all the biochemical parameters studied. Besides, biochemical findings were supported by histopathological study. These results revealed that pomegranate has potential protective effect against oxidative stress induced diabetic rats.


[Electroencephalographic and computer-tomographic findings in comatose patients after cranio-cerebral injuries].
It is reported about a prospectively planned series of tests on 67 patients after cerebral trauma. During the first three days and every third day afterwards the patients were examined cliniconeurologically and by means of EEG, frequency analysis of EEG and--as far as possible--CCT. The EEG shows the cerebral function, in the CCT we see, like in a pathological-anatomic section, intracranial morphological changes. The results are discussed in detail.


Deterioration of filtering bleb morphology and function after phacoemulsification.
Trabeculectomy remains the most efficient method of lowering he IOP applied for the treatment of glaucoma refractory to pharmacological treatment. Cataract is concerned as the most frequent late complication of trabeculectomy. The aim of the study was to analyse the effect of phacoemulsification with posterior chamber lens implantation on the morphology and function of filtering bleb in patients after previous successful trabeculectomy. The retrospective study included 122 eyes treated for primary open angle glaucoma, 50 eyes (study group) in which, after a successful trabeculectomy with 5-Fluorouracil, phacoemulsification with posterior chamber lens implantation was performed, and 72 eyes (control group), in which only a successful trabeculectomy was conducted. The surgical success of the trabeculectomy was expressed as IOP < 17 mmHg. In the group of patients subjected to both trabeculectomy and phacoemulsification, mean IOP was significantly higher than in the group of patients who underwent trabeculectomy after 6 months (p = 0.003), 12 months (p = 0.01) and 18 months (p = 0.007) of observation. The filtering blebs after phacoemulsification in the study group were characterized by a greater reduction, compared to those in the control group. Cox regression survival success was 75% (SE = 5.9; 95% CI: 63.4-86.6), 75% (SE = 5.9; 95% CI: 63.4-86.6), 71% (SE = 5.4; 95% CI: 60.4-81.6) in study group and 92% (SE = 1.8; 95% CI: 91.5-98.5), 92% (SE = 1.9; 95% CI: 88.3-95.7), 91% (SE = 2.0; 95% CI: 87.1-94.9) in control group after 6, 12 and 18 months, respectively. Phacoemulsification causes a significant elevation of IOP in the eyes after previous successful trabeculectomy and deterioration of filtering bleb morphology.


Does Medical Therapy Improve SinoNasal Outcomes Test-22 Domain Scores? An Analysis of Clinically Important Differences.
Minimum clinically important differences (MCIDs) for the 22-item SinoNasal Outcomes Test (SNOT-22) in patients with chronic rhinosinusitis (CRS) electing endoscopic sinus surgery (ESS) are well described. However, similar estimations for the MCID have not been investigated for patients electing continued appropriate medical therapy (CAMT). We sought to determine MCID values for a medically treated CRS cohort and compare them to historical MCIDs associated with ESS. Prospective observational cohort study. One hundred twenty patients with refractory CRS electing CAMT were prospectively enrolled from academic referral clinics into an observational cohort study. Baseline and posttreatment SNOT-22 survey responses were collected. Four distribution-based methods for calculating MCIDs (e.g., half-standard deviation, Cohen's d, standard error of measurement, and minimum detectable change) were used to identify a range of MCID values for SNOT-22 total and domain scores. The average MCID value for SNOT-22 total scores was 8.0, whereas mean MCID values for rhinologic, extranasal rhinologic, ear/facial, psychological, and sleep symptom domain scores were 3.9, 2.5, 3.3, 3.4, and 2.9, respectively, comparable to previously reported values for patients electing ESS. Although change in SNOT-22 total scores following CAMT exceeded the MCID, none of the average SNOT-22 domain score improvements surpassed their respective MCID thresholds. MCID values for SNOT-22 total and domain scores in patients electing CAMT are similar to previously published MCID values associated with ESS, indicating that MCID values are independent of treatment modality selection. Therefore, despite evidence of statistical significance, CAMT for CRS may not be associated with clinically discernable improvements in average SNOT-22 domain scores. 2c Laryngoscope, 129:31-36, 2019.


Dyskinetic cerebral palsy. II. Pathogenetic risk factors and intra-uterine growth.
In an unselected series of 116 dyskinetic cerebral palsy cases, 35 hyperkinetic and 81 dystonic, 21% of the cases were considered to derive from the prenatal period, 67% from the perinatal, and 7% from the postnatal period, while 5% were untraceable. Isolated risk factors were found in 24% of the hyperkinetic and 24% of the dystonic cases and various combinations in 68% and 72%, respectively. Preterm appropriate-for-gestational-age cases with hyperbilirubinemia were found significantly more often among the hyperkinetics (47%) than among the dystonics (11%). Term appropriate-for-gestational-age cases with asphyxia were found significantly more often among the dystonics (30%) than among the hyperkinetics (9%). Term and preterm small-for-gestational-age cases with asphyxia and/or perinatal hypoxia were only found in the dystonic subgroup (14%). Both the hyperkinetic and the dystonic subgroups had significantly lower mean birth weights--2795 g and 2872 g, respectively--than that of the general population, 3500 g. The dystonic subgroup had birth weights significantly below the mean for gestational age. Both subgroups had birth weights significantly below the mean for the respectively birth length. This was particularly pronounced for the cases with birth asphyxia. All infants with birth weights less than or equal to -2.0 SD below the mean for birth length had had birth asphyxia, and the proportion decreased successively to 0% among those greater than +1.0 SD.


Serotonin induces temporally and mechanistically distinct phases of persistent PKA activity in Aplysia sensory neurons.
The cAMP signaling cascade has been implicated in several stages of memory formation. We have examined activation of this cascade by serotonin (5-HT) in the sensory neurons of Aplysia. We find that different patterns of 5-HT exposure induce three distinct modes of PKA activation. First, a single 5 min pulse induces transient (5 min) PKA activation that requires neither transcription nor translation. Second, 4-5 pulses induce intermediate-term persistent activation (3 hr duration) that requires translation but not transcription. Third, 5 pulses of 5-HT, as well as continuous (90 min) exposure, induce long-term persistent activation 20 hr later, which requires both transcription and translation. Thus, in the sensory neurons, different patterns of 5-HT give rise to three independent phases of PKA activation that differ in their induction requirements, their temporal profiles, and their molecular mechanisms.


A look inside an alkaloid multisite plant: the Catharanthus logistics.
Environmental pressures forced plants to diversify specialized metabolisms to accumulate noxious molecules such as alkaloids constituting one of the largest classes of defense metabolites. Catharanthus roseus produces monoterpene indole alkaloids via a highly elaborated biosynthetic pathway whose characterization greatly progressed with the recent expansion of transcriptomic resources. The complex architecture of this pathway, sequentially distributed in at least four cell types and further compartmentalized into several organelles, involves partially identified inter-cellular and intra-cellular translocation events acting as potential key-regulators of metabolic fluxes. The description of this spatial organization and the inherent secretion and sequestration of metabolites not only provide new insight into alkaloid cell biology and its involvement in plant defense processes but also present new biotechnological challenges for synthetic biology.


Intraarterial nimodipine for the treatment of symptomatic vasospasm after aneurysmal subarachnoid hemorrhage: a preliminary study.
Despite dramatic advances in all medical era, cerebral vasospasm is still the major complication in patients with subarachnoid hemorrhage (SAH). The purpose of this study was to assess the influence of intraarterial (IA) nimodipine in the treatment of symptomatic vasospasm and in preventing neurological disabilities. We retrospectively reviewed 10 patients of SAH who received IA nimodipine in 15 procedures. The decision to perform angiography and endovascular treatment was based on the neurological examination, brain computed tomography (CT) and CT-angiography. The procedure reports, anesthesia records, neurological examination before and after the procedure, brain imaging and short- and long-term outcome were studied. The average dose of nimodipine was 2 mg. The median change in mean arterial pressure at 10 min was -10 mmHg. No significant change of heart rate was observed at 10 min. There was radiological improvement in 80% of the procedures. Neurological improvement was noted after eight out of 12 procedures when nimodipine was used as the sole treatment and after 10 out of 15, overall. Six patients clinically improved after the treatment and had good outcome. In one patient, an embolus caused fatal anterior and middle cerebral arteries infarction. There was no other neurological deficit or radiological abnormality due to the nimodipine treatment itself. Low-dose IA nimodipine is a valid adjunct for the endovascular treatment of cerebral vasospasm. Beneficial effects are achieved in some patients, prompting a prospective control study.


Light- and electron-microscopic demonstration of enkephalin-like immunoreactivity in paraganglia of the human urinary bladder.
The distribution of enkephalin-like immunoreactivity in paraganglia of the urinary bladder of adult humans was studied by use of immuno-electron microscopy. All paraganglionic cells were positively stained. Enkephalin-like immunoreactivity was located in chromaffin granules. Chromaffin cells in the paraganglia showed only few degenerative features, suggesting undisturbed function of the cells.


Changes in urethral resistance in the presence of detrusor activity.
This was a prospective study performed at two tertiary referral teaching hospitals. The aim of our study was to investigate changes in urethral resistance with the bladder full compared to empty in women with different urodynamic diagnoses. Consecutive women attending the urodynamic clinics were asked to undergo urethral retro-resistance pressure (URP) measurement with the bladder empty and then full. 106 women were recruited - 25 had normal urodynamic studies, 17 had detrusor overactivity, 57 had urodynamic stress incontinence and 7 had mixed incontinence. Women with urodynamic stress incontinence have lower URP values than women with normal urodynamic studies or those with detrusor overactivity with the bladder empty (p = 0.01). Women with normal urodynamic studies and urodynamic stress incontinence showed a statistically significant rise in URP with the bladder full (p = 0.013 and p = 0.003, respectively). In women with detrusor overactivity, the converse was seen - URP was significantly lower with the bladder full compared to empty (p = 0.004). Our study has shown that bladder filling alters URP measurement and bladder volume should be standardised for reporting URP.


[Exogenous tooth discoloration in children: black stains].
Black-stains are a coloring frequently met in pediatric dentistry. They can be medically diagnosed as 1-mm borders or unfinished lines formed by a dark exogenous substance which follows the gingival festoon of bet coronary (in cervical third of the crown) temporary teeth and permanent, or they can appear in like points or dark spots. They are caused by bacteria anaerobic chromogenous. The dominant responsible species are actinomyces. Blacks-stains are ferrous depots, formed following a chemical interaction on the surface of the tooth between sulphide of hydrogen (under the effect of the anaerobic bacteria which are producing hydrogen) and the iron contained in the saliva (by a healthy diet) or that released by red blood corpuscles (in case of bloody gums). Black-stains are a shape of characteristic dental plaque by its flora with trend to calcify. It contains an insoluble iron salt with a content raised in calcium and in inorganic phosphor. The coloring Black-stain is a mild pathology and has no incidence on the vitality of the tooth. Certainly these spots are unsightly. The dental surgeon in current practice can deprive them. The pediatrician plays a leading role in the diagnosis and advice to parents and patients affected by these stains.


Presentations of acute coronary syndrome related to coronary lesion morphologies as assessed by intravascular ultrasound and optical coherence tomography.
Pathologically, the lesions responsible for acute coronary syndrome (ACS) are ruptures of vulnerable plaques (and occasionally fibrous-cap erosions or calcified nodules) with a superimposed thrombosis. We aimed to clarify the clinical presentations related to the morphologies of coronary lesions of ACS using intravascular ultrasound (IVUS) and optical coherence tomography (OCT). Seventy-five culprit lesions of ACS patients were clearly assessed with IVUS and OCT. Patients were classified into two groups based on the presence or absence of a rupture of a culprit plaque as identified by OCT. Clinical characteristics and lesion morphologies were compared between the two groups. Waist circumference was significantly greater (p<0.02) and prevalence of the metabolic syndrome (MS) higher (p=0.0011) in the rupture group. The prevalence of prodromal angina was higher in patients without plaque ruptures (p<0.0001). Using multivariate analysis, the MS and prodromal angina were independent predictors of rupture of a culprit coronary plaque (odds ratio (OR): 27.30, p<0.003 and OR: 0.04, p=0.0004, respectively). Among the components of the MS, the prevalence of abdominal obesity was a significant independent predictor of rupture of a culprit plaque (OR: 4.24, p<0.02). There are two presentations related to the coronary lesion morphologies of ACS: we should understand these aspects of ACS.


Surgery is associated with ventricular enlargement as well as cognitive and functional decline.
In preclinical studies, surgery/anesthesia contribute to cognitive decline and enhance neuropathologic changes underlying Alzheimer's disease (AD). Nevertheless, the link between surgery, anesthesia, apolipoprotein E ε4 (APOE ε4), and AD remains unclear. We performed a retrospective cohort analysis of two prospective longitudinal aging studies. Mixed-effects statistical models were used to assess the relationship between surgical/anesthetic exposure, the APOE genotype, and rate of change in measures of cognition, function, and brain volumes. The surgical group (n = 182) experienced a more rapid rate of deterioration compared with the nonsurgical group (n = 345) in several cognitive, functional, and brain magnetic resonance imaging measures. Furthermore, there was a significant synergistic effect of anesthesia/surgery exposure and presence of the APOE ε4 allele in the decline of multiple cognitive and functional measures. These data provide insight into the role of surgical exposure as a risk factor for cognitive and functional decline in older adults.


Clinical Characteristics and Bone Features of Autosomal Recessive Hypophosphatemic Rickets Type 1 in Three Chinese Families: Report of Five Chinese Cases and Review of the Literature.
Autosomal recessive hypophosphatemic rickets type 1 (ARHR1) was reported to be caused by homozygous mutation of dentin matrix protein 1 (DMP1). To date, very few cases have been reported. Here, we summarized clinical, laboratory and imaging findings of ARHR1 patients in our hospital. Literature review was performed to analyze genotype-phenotype correlation. Five Chinese patients from three unrelated pedigrees presented with lower extremity deformity and short stature. Hypophosphatemia, elevated alkaline phosphatase, high intact fibroblast growth factor 23 and sclerostin were found. X-ray uncovered coexistence of osteomalacia and osteosclerosis. Although areal bone mineral density (aBMD) of axial bone measured by dual-energy X-ray absorptiometry was relatively high in all patients, volumetric BMD (vBMD) and microstructure of one adult patient's peripheral bone detected by HR-pQCT were damaged. Mutation analyses of DMP1 revealed three homozygous mutations including two novel mutations, c.54 + 1G > C and c.94C > A (p.E32X), and a reported mutation c.184-1G > A. Genotype-phenotype correlation analysis including 30 cases (25 from literature review and 5 from our study) revealed that patients harboring mutations affecting C-terminal fragment of DMP1 presented with shorter stature (Z score of height = - 3.4 ± 1.6 vs - 1.0 ± 1.6, p = 0.001) and lower serum phosphate level (0.70 ± 0.15 vs 0.84 ± 0.16, p = 0.03) than those harboring mutations only affecting N-terminal fragment. In summary, we reported five Chinese ARHR1 patients and identified two novel DMP1 mutations. High aBMD and local osteosclerosis in axial bone with low vBMD and damaged microstructure in peripheral bone were featured. Genotype-phenotype correlation analysis confirmed the important role of C-terminal fragment of DMP1.


Genotypes of autosomal dominant polycystic kidney disease in Japanese.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary disorders. The prevalence of the ADPKD genotype in the Caucasian and Latin populations has been reported. Here, we used linkage analysis to demonstrate the prevalence of the genotype and the correlation between phenotypes and genotypes among 21 Japanese ADPKD families consisting of 96 individuals and including 57 affected members. Six polymorphic markers, each linked to either the polycystic kidney disease 1 (PKD1) or polycystic kidney disease 2 (PKD2) gene, were used for polymerase chain reaction analysis. Seventeen families (81%) showed linkage to PKD1, two families (10%) showed linkage to PKD2, and two families did not show linkage to either PKD1 or PKD2. One of the PKD1-linked families was indicated to have different mutations of PKD1 gene in the same family. PKD2-linked families did not have milder symptoms than PKD1-linked families.


Ipsilateral interferences and working-side condylar movements.
There is limited knowledge of the effects of the occlusion on temporomandibular joint function. The aim was to investigate the influence of a working-side occlusal alteration (OA, i.e. interference) on trajectories of working-side condylar points during standardized lateral jaw movements (laterotrusion) tracked by a jaw-tracking system. Ten trials of right laterotrusion were repeated under: control 1 (before OA), OA (immediately after placement of a working-side interference) and control 2 (immediately after removal of OA) conditions. During right jaw movement, the paths of the working-side condylar points under OA were significantly more inferior and anterior to those under control at the same amount of mid-incisor-point displacement from the intercuspal position. The OA significantly reduced the rotation of the mandible about the antero-posterior and supero-inferior axes and significantly increased the opening angle. Controls 1 and 2 were not significantly different. A working-side interference has an immediate, significant effect on working-side condylar movement.


Palladium acetate supported on amidoxime-functionalized magnetic cellulose: Synthesis, DFT study and application in Suzuki reaction.
A highly efficient and magnetically retrievable catalytic system involving Pd (II) acetate supported on amidoxime-functionalized cellulose nano-magnetic catalyst (nano-Fe3O4@AOFC/Pd(II)) was prepared. The structure of the organic-inorganic hybrid nanocomposite has been confirmed using various physicochemical techniques such as FT-IR, XRD, TGA, VSM, XPS, HRTEM, SAED, SEM, CHNS, EDAS and ICP-OES. In addition, to describe and go insight to the metal-ligand interactions present in the nano-Fe3O4@AOFC/Pd (II) composite, covalent and electrostatic interactions, density functional theory (DFT) model and quantum theory of atoms in molecule method were employed. The resultant nano-magnetic cellulose composite exhibits remarkable catalytic efficacy used for Suzuki cross-coupling reaction between aryl halides and aryl boronic acids to create the corresponding coupling products in good to excellent yields. Also, the catalyst is easily recovered using only an external magnet. Its recoverability and reusability for this catalyst was examined in several runs which showed no appreciable loss after five runs. The facile accessibility to the starting materials, possible performance in large scales, and conducting the reactions in the eco-friendly and cost-effective conditions are the other merits which can be mentioned for such new Pd -catalyst.


Initial viral load in cases of single human papillomavirus 16 or 52 persistent infection is associated with progression of later cytopathological findings in the uterine cervix.
The aim of this study was to investigate the relationship between viral load in single human papillomavirus (HPV) 16 or 52 persistent infection and the progression of later cytopathological findings in the uterine cervix. Cervical cytology and HPV genotyping tests were repeated within 3-6 months in 305 women with oncogenic HPV. Twenty-four cases of single HPV 52 persistent infection and 24 cases of single HPV 16 persistent infection were identified. Cases with later cytopathological findings showing progression were defined as the progression group, while those with no change or regression were the non-progression group. Relative HPV DNA loads were determined by quantitative real-time polymerase chain reaction and expressed relative to human albumin (ALB) DNA. Differences between the two groups were evaluated. The median relative HPV 52 DNA load was 2.211 in the progression group and 0.022 in the non-progression group (Mann-Whitney U-test, P = 0.003). The median relative HPV 16 DNA load was 4.206 in the progression group and 0.103 in the non-progression group (P = 0.001). HPV 52 and 16 DNA loads assessed by quantitative real-time methods may be useful short-term markers for identifying women at high risk for progression of cervical cytological pathology.


A HPLC-DAD-MS/MS Method for Simultaneous Determination of Six Active Ingredients of Salviae Miltiorrhizae and Ligustrazine Hydrochloride Injection in Rat Plasma and its Application to Pharmacokinetic Studies.
This is a pharmacokinetic study of Salviae miltiorrhizae and ligustrazine hydrochloride injection. The study aimed to evaluate the mechanism of action, safety and rational clinical use of Salviae miltiorrhizae and ligustrazine hydrochloride injection. Salviae miltiorrhizae and ligustrazine hydrochloride injection is a compound preparation consisted of Salvia miltiorrhiza extract and ligustrazine hydrochloride for the treatment of cardiovascular and cerebrovascular diseases in China. The study aimed to develop a rapid and sensitive high-performance liquid chromatography-diode array detector-tandem mass spectrometry (HPLC-DAD-MS/MS) method for simultaneous determination of six major active ingredients of Salviae miltiorrhizae and ligustrazine hydrochloride injection, namely danshensu, protocatechuic aldehyde, rosmarinic acid, lithospermic acid, salvianolic acid A, and ligustrazine hydrochloride, in rat plasma. Plasma samples were precipitated with methanol, which was spiked with ascorbic acid and the supernatant was separated on a Waters Cortecs C18 column, by using a gradient mobile phase system of acetonitrile-water containing 0.05% formic acid (v/v). For internal standards, puerarin was selected for the five salvianolic acids, while isofraxidin was used for ligustrazine hydrochloride. Besides, electrospray ionization in negative mode and multiplereaction monitoring were used to identify and quantify the five salvianolic acids, whereas ligustrazine hydrochloride was quantified at 310 nm using the diode array detector. Noticeably, all calibration curves showed good linearity (R2>0.99) over the concentration range, with a lower limit of quantification between 0.00411 and 0.0369 μg/mL for salvianolic acids, and 1.74 μg/mL for ligustrazine hydrochloride. Next, the precision of the developed method was evaluated by intra- and inter-day assays, and the percentage of relative standard deviation was within 10%. Although the extraction efficiency of some salvianolic acids was not very satisfactory, the sensitivity of the analytical method met the analysis requirements of rat plasma samples. Moreover, the validated method was successfully applied to a pharmacokinetic study of Salviae miltiorrhizae and ligustrazine hydrochloride injection in the rat model. Linear pharmacokinetic characteristics were observed for the six active ingredients after intravenous infusion administration in rats within the dose range examined here. In summary, our study proposed a HPLC-DADMS/ MS method with the simultaneous determination of multiple ingredients, and demonstrated its applicability in pharmacokinetic studies.


Symptom severity and disgust-related traits in borderline personality disorder: The role of amygdala subdivisions.
The majority of morphometric studies on borderline personality disorder (BPD) found that diagnosed patients have a reduced amygdala volume. We sought to extend this finding by focusing on amygdala subdivisions (centromedial, laterobasal, superficial) and their association with symptom severity and disgust-related traits. Additional disorder-/disgust-relevant regions (insula, somatosensory cortex) were also investigated. We compared structural imaging data from 25 female BPD patients and 25 healthy women via voxel-based morphometry. Scores on self-report measures for symptom severity, disgust proneness, and self-disgust were correlated with gray matter volume (GMV) of regions of interest. Relative to controls, BPD patients had more GMV in the laterobasal amygdala. The volume of this region was positively correlated with symptom severity. In contrast, GMV of the centromedial amygdala showed a negative correlation with symptom severity. The degree of reported self-injury and self-disgust correlated negatively with the volume of the secondary somatosensory cortex (SII). Our data point to a differential contribution of amygdala subdivisions to symptom severity in BPD. Future longitudinal studies should focus on these subregions and possible volume changes during the course of the disorder. The meaning of altered SII volume for dysfunctional auto-aggressive behavior needs further investigation.


A new lethal chondrodysplasia with spondylocostal dysostosis, multiple internal anomalies and Dandy-Walker cyst.
We describe here a female infant, exhibiting lethal short-limbed dwarfism. The condition superficially resembled achondrogenesis. However, unlike achondrogenesis there was an associated severe spondylocostal dysostosis and major non-skeletal anomalies, particularly a cerebellar Dandy-Walker cyst, cardiovascular and urogenital malformations. The chondroosseous morphology was nonspecific. The case is believed to be unique. It is therefore suggested that this constellation of anomalies constitutes a "new" lethal syndrome, different from the delineated chondrodysplasias.


Screening of epoxide hydrolase producing microorganisms for biotransformation of deoxynivalenol.
Deoxynivalenol (DON) transformation products from selected time course experiments were analyzed by thin-layer chromatography. With the strainAlternaria alternata f. sp.lycopersici AS27-3, one major metabolite of DON in ethyl acetate was observed. This unidentified metabolite was more polar than DON and has a Rf value of 0.71. Derivatization indicated that this metabolite was probably an unidentified trichothecene. Screening of 29 other microbial isolates (bacteria, yeast, filamentous fungi) for DON transformation did not result in any active organism.


Seasonally limited host supply generates microparasite population cycles.
Cycles in biological populations have been shown to arise from enemy-victim systems, delayed density dependence, and maternal effects. In an initial effort to model the year-to-year dynamics of natural populations of entomopathogenic nematodes and their insect hosts, we find that a simple, nonlinear, mechanistic model produces large amplitude, period two population cycles. The cycles are generated by seasonal dynamics within semi-isolated populations independently of inter-annual feedback in host population numbers, which differs from previously studied mechanisms. The microparasites compete for a fixed number of host insect larvae. Many nematodes at the beginning of the year quickly eliminate the pool of small hosts, and few nematodes are produced for the subsequent year. Conversely, initially small nematode populations do not over-exploit the host population, so the surviving hosts grow to be large and produce many nematodes that survive to the following year.


A longitudinal study of serum IgE in a community cohort: correlations with age, sex, smoking, and atopic status.
A number of factors, including age, sex, smoking habits, and atopic status have been reported in cross-sectional studies to influence levels of serum IgE. We have examined the effects of these variables on serum IgE in a community population cohort of 1109 subjects during a longitudinal study in which two serum samples were obtained 8 years apart from each subject. For the entire cohort, mean serum IgE level changed little during the follow-up period (28.9 versus 26.0 IU/ml). Most of the decreases were observed in children and young adults. Subjects more than the age of 35 years demonstrated no systematic change in serum IgE levels. By the end of follow-up (when there were few subjects still less than 16 years of age), significant relationships of IgE to age could no longer be demonstrated in nonatopic subjects. Also, in the nonatopic subjects of this cohort, there were no significant differences in IgE levels between the sexes. Among atopic subjects, there was a clear tendency for IgE to decrease with age, with atopic women more than 35 years of age demonstrating greater declines in IgE levels during follow-up than men of comparable age. The IgE levels in atopic male subjects were significantly higher than in atopic female subjects after the age of 35 years. Smoking was associated with an elevation in serum IgE. In this cohort, the smoking effect appeared to be limited to male subjects.(ABSTRACT TRUNCATED AT 250 WORDS)


Sliding-mode anti-disturbance speed control of permanent magnet synchronous motor based on an advanced reaching law.
In order to improve the performance of a permanent magnet synchronous motor (PMSM) speed controller, an advanced reaching law sliding mode control (ASMC) strategy is proposed in this study. The advanced sliding mode reaching law (ASMRL) introduces a power term of the system state and a checkmark function term about the sliding mode function based on the traditional constant-proportional rate reaching law(TSMRL) , and replaces the sign function with a hyperbolic tangent function. A detailed theoretical analysis of the characteristics of the ASMRL is then presented. The theoretical analysis shows that the ASMRL converges to the sliding mode surface more quickly and with less chattering than the TSMRL. In addition, a sliding mode disturbance observer (SMDO) is designed to estimate the total disturbance of the system, and the estimated disturbance is compensated to ASMC. Then the stability of the system with ASMC and the stability of the system with ASMC+SMDO is proved by Lyapunov's theorem. Finally, the proposed control strategy is validated on an experimental platform of PMSM. The experimental results show that the ASMC has a faster convergence speed, smaller chattering, better disturbance rejection performance than the traditional constant-proportional rate reaching law sliding mode control(TSMC), and better performance with the addition of SMDO.


Stone-scoring systems for predicting complications in percutaneous nephrolithotomy: A systematic review of the literature.
Percutaneous nephrolithotomy is a treatment of choice for larger stones of the upper urinary tract. Currently, several nephrolithometric nomograms for prediction of post-operative surgical outcomes have been proposed, although uncertainties still exist regarding their roles in the estimation of complications. We conducted a systematic review on PubMed and Web of Sciences databases including English studies with at least 100 cases and published between January 2010 and December 2021. We identified original articles evaluating correlations between the Guy's stone score, the stone size (S), tract length (T), obstruction (O), number of involved calices (N), and essence or stone density (E) (S.T.O.N.E.), Clinical Research Office of the Endourological Society (CROES), and Seoul National University Renal Stone Complexity (S-ReSC) scores and post-operative complications in adult patients. We also included newly designed nomograms for prediction of specific complications. After an initial search of 549 abstracts, we finally included a total of 18 papers. Of them, 11 investigated traditional nephrolithometric nomograms, while seven newly designed nomograms were used to predict specific complications. Overall, 7316 patients have been involved. In total, 14 out of 18 papers are derived from retrospective single-center studies. Guy's stone score obtained correlation with complications in five, S.T.O.N.E. nephrolithometry score in four, while CROES score and S-ReSC score in three and two, respectively. None of the studies investigated minimally invasive percutaneous nephrolithotomy (PCNL) and all cases have been conducted in prone position. Considering newly designed nomograms, none of them is currently externally validated; five of them predict post-operative infections; the remaining two have been designed for thromboembolic events and urinary leakage. This review presents all nomograms currently available in the PCNL field and highlights a certain number of concerns. Published data have appeared contradictory; more recent tools for prediction of post-operative complications are frequently based on small retrospective cohorts and lack external validations. Heterogeneity among studies has also been noticed. More rigorous validations are advisable in the future, involving larger prospective patients' series and with the comparison of different tools.


Studies of Epstein-Barr virus (EBV)-associated nuclear antigen: solubilization from Raji cell chromatin with 5 M-urea-2 M-nacl and fractionation on hydroxyapatite.
EBNA-containing chromatin from Raji cells was solubilized by treatment with high concentrations of urea and salt and fractionated by hydroxyapatite chromatography. Fractions eluting at different phosphate concentrations were analysed for the presence of EBNA by means of an anti-EBNA-specific 125I-labelled IgG absorption assay. The antigen was found in fractions containing non-histone chromatin proteins.


Combined effects of two arthropod herbivores and water stress on growth of Hypericum species.
The interaction between physiological stress and arthropod herbivory was studied using two perennial species of Hypericum. Seedlings of H. perforatum, a herb introduced to Australia and weedy in places, and H. gramineum, an indigenous species, were subjected to water stress and/or herbivory by a mite, Aculus hyperici and an aphid, Aphis chloris. Both arthropods have recently been released in Australia for biological control of H. perforatum. Individually, stresses reduced measures of plant growth. Combinations of the three stresses decreased plant growth by slightly more than the product of their separate effects, suggesting that there is a weak positive interaction exacerbating the damage caused by each stress. Seedlings of the target weed and the 'non-target' indigenous species were equally affected by the arthropods. The implications for weed biological control are discussed.


High-throughput screening of metal-N-heterocyclic carbene complexes against biofilm formation by pathogenic bacteria.
A set of molecules including a majority of metal-N-heterocyclic carbene (NHC) complexes (metal=Ag, Cu, and Au) and azolium salts were evaluated by high-throughput screening of their activity against biofilm formation associated with pathogenic bacteria. The anti-planktonic effects were compared in parallel. Representative biofilm-forming strains of various genera were selected (Listeria, Pseudomonas, Staphylococcus, and Escherichia). All the compounds were tested at 1 mg L(-1) by using the BioFilm Ring Test. An information score (IS, sum of the activities) and an activity score (AS, difference between anti-biofilm and anti-planktonic activity) were determined from normalized experimental values to classify the most active molecules against the panel of bacterial strains. With this method we identified lipophilic Ag(I) and Cu(I) complexes possessing aromatic groups on the NHC ligand as the most efficient at inhibiting biofilm formation.


Automatic bio-sampling chips integrated with micro-pumps and micro-valves for disease detection.
The present study reports a microfluidic system using the concept of membrane-movement to design and fabricate micro-pneumatic valves and pumps to form a bio-sensing diagnostic chip. The automatic bio-sampling system includes a micro-diagnostic chip fabricated by using MEMS (micro-electro-mechanical systems) technology and an automatic platform comprising of a control circuit, a compressed air source and several electromagnetic valve switches. The control circuit is used to regulate the electromagnetic valve switches, causing thin PDMS membranes to deflect pneumatically by the compressed air and generate valving and pumping effects. The micro-diagnostic chip allows for the quick detection of diseases. Compared to large-scale systems, the new microfluidic system uses smaller amounts of samples and reagents and performs fast diagnosis in an automated format. Instead of using traditional pneumatic micro-pumps, the current study adopts a new design called "spider-web" micro-pumps to increase the pumping rate, and more importantly, improve the uniformity of flow rates inside multiple micro-channels. Experimental data show that for disease diagnosis, the bio-sensing chips integrated with the micro-pneumatic valves and the peristaltic micro-pumps could successfully perform diagnosis tests. Small amounts of samples and reagents could be injected into the diagnosis chips using the micro-pumps and the micro-pneumatic valves could effectively control the movement of the samples and reagents. In order to demonstrate the functionality of the developed device, detection of hepatitis C virus (HCV) and syphilis has been performed using the bio-sampling chips. Experimental data show that fluorescence signals from the microfluidic system were comparable to the ones using conventional testing methods. The developed chip could be easily extended for multiple disease detection. The automatic bio-sensing chips could provide a useful tool for fast disease detection and be crucial for a micro-total-analysis system.


Immobilization of iron phthalocyanine on MOF-derived N-doped carbon for promoting oxygen reduction in zinc-air battery.
Functional carbon nanomaterials play a crucial role in the cathodic oxygen reduction reaction (ORR) for sustainable fuel cells and metal-air batteries. In this study, we propose an effective approach to immobilize iron phthalocyanines (FePc) by employing a porous N-doped carbon material, denoted as NC-1000, derived from a sheet-shaped coordination polymer. The resulting NC-1000 possesses substantial porosity and abundant pore defects. The nitrogen sites within NC-1000 not only facilitate FePc adsorption but also optimize the electron distribution at the Fe-N site. The FePc@NC-1000 composite material exhibits a significant number of active centers in the form of Fe-N4 moieties, showcasing satisfactory ORR activity. Specifically, it demonstrates an onset potential of 0.99 V, a positive half-wave potential of 0.86 V, a large limiting current of 5.96 mA cm-2, and a small Tafel slope of 44.41 mV dec-1. Additionally, theoretical calculations and experimental results confirm the favorable performance and durability of zinc-air batteries assembled using FePc@NC-1000, thereby highlighting their considerable potential for practical applications. Overall, this study provides a comprehensive exploration of the enhanced catalytic performance and increased stability of metal-organic framework-derived functional carbon nanomaterials as cost-effective, efficient, and stable catalysts for the ORR.


Gene expression changes in Epinephelus marginatus (Teleostei, Serranidae) liver reveals candidate molecular biomarker of iron ore contamination.
Wastes from iron ore mining activities are potentially damaging to adjacent aquatic ecosystems. We aimed to determine biomarkers of environmental exposure to this xenobiotic in the dusky grouper Epinephelus marginatus by differential gene expression analysis. For this, fish were exposed to iron ore (15.2 mg/L) and gene expression in liver was assessed by RNA-Seq and compared to the control group. A total of 124 differentially expressed genes were identified, from which 52 were upregulated and 72 were downregulated in response to iron ore. From these, ferritin (medium subunit), cytochrome b reductase and epoxide hydrolase genes were selected for validation by RT-qPCR that confirmed the upregulation of epoxide hydrolase in fish exposed to iron ore.


Antigenic N to H conversion of poliovirus by a monoclonal antibody at low ionic strength.
Monoclonal antibody 35-1f4 at low ionic strength converted native virions (N antigen) to noninfectious H-antigenic, empty capsids. The reaction was stoichiometric, as the amount of N antigen that could be converted to H was limited to an average of 2 virions per molecule of antibody. The antibody remained associated with virus aggregates after antigenic conversion. Using antibody immobilized onto protein A-bearing staphylococci, it could be shown that the loss of antigen-converting power was concomitant with the loss of antigen-binding ability. Only a small amount of viral protein (equivalent to 0.02 empty capsid per molecule of antibody) remained attached to the antibody. Heating to 56 degrees caused most of this material to be released and restored the antibody's antigen-binding and antigen-converting abilities. Several possible explanations for the heat-reversible inactivation of the antibody are discussed.


Epidemiology of self-medication in Ethiopia: a systematic review and meta-analysis of observational studies.
Self-medication is the use of drugs to treat self-diagnosed disorders and/or symptoms, or the intermittent or continued use of a prescribed drug for recurrent disease or symptoms. This phenomenon is alarmingly increasing over time despite the occurrence of health-related hazards. This study is, therefore, aimed to quantitatively estimate self-medication practice and possible reasons for it in Ethiopia. Data were identified from major databases and indexing services including EMBASE (Ovid), PubMed, MEDLINE (Ovid), and Google Scholar. Both published and unpublished records addressing self medication practice in Ethiopia without time limit were included for the study. Data were extracted with structured format prepared in Microsoft Excel and exported to OpenMeta[analyst] version 3.3 software for analyses. Pooled estimation of outcomes was performed with DerSimonian-Laird random-effects model at 95% confidence level. Sensitivity and subgroup analyses were also considered. Degree of heterogeneity of studies was presented with I2 statistics. Publication bias was also performed with the help of Comprehensive Meta-Analysis version-3 software and presented with funnel plots of standard error supplemented by Begg's and Egger's tests. The study protocol is registered on PROSPERO with reference number ID: CRD42018093790. A total of 27 studies with 9586 participants were included for the study. The pooled prevalence of self-medication in Ethiopia was found to be 44.0% (95% confidence interval [CI]: 35.1, 52.8). Geographical-based subgroup analysis revealed that the highest prevalence was observed at the capital of Ethiopia, Addis Ababa, 62.8% (95% CI: 42.3, 83.2). Population based analysis indicated that healthcare professionals and students were the main practitioners of self-medication. Besides, the prevalence of self-medication practice in pregnant women is approximately 22.9% (95% CI: 9.8, 36). The most common reasons to practice self-medication were previous experience of clients and/or familiarity of treatments, 31.3% (95% CI: 21.5, 41.1) and perceived mildness of the illness, 31.1% (95% CI: 26.0, 36.2). The pooled prevalence of analgesics, antimicrobial agents and gastrointestinal drugs were 46.1% (95% CI: 36.2, 56.1), 28.2% (95% CI: 19.6, 36.8), and 14.9% (95% CI: 7.8, 21.9), respectively. Self-medication practice becomes a common phenomenon in Ethiopia. The use of prescription-only medications including antimicrobial agents without medical consult has become alarmingly high. This practice will come with potential health related hazards including emergence of antimicrobial resistance. Therefore, there must be a multitude of strategies for reversing the current worrying trends of self-medication.


Demographics of Rhesus Phenotype of Blood Donors in Calabar: A Case Study of University of Calabar Teaching Hospital, Calabar, Cross River State, Nigeria.
Rhesus antigens have been documented to cause haemolytic disease of the newborn as well as acute and delayed transfusion reactions. This study was performed to evaluate the frequency of rhesus antigens (C, c, D, E, and e) in the studied population. This study was a cross-sectional study involving 130 prospective blood donors attending University of Calabar Teaching Hospital (UCTH) donor clinic. Donors were grouped for Rh antisera (anti-E, anti-e, anti-C, anti-c, and anti-D) using the standard serologic technique. The most prevalent Rh antigen was "c" (98.5%), followed by "D" (97.7%), while the least was "C" (30.7%). The most prevalent phenotype was cDe/cDe (R0R0). This work therefore concludes that the most prevalent rhesus antigen and rhesus phenotype was c and cDe/cDe among blood donors in University of Calabar Teaching Hospital.


Uveal Melanoma: GNAQ and GNA11 Mutations in a Greek Population.
Uveal melanoma is the most common primary adult intraocular malignancy. It is known to have a strong metastatic potential, fatal for the vast majority of patients. In recent years, meticulous cytogenetic and molecular profiling has led to precise prognostication, that unfortunately is not matched by advancements in adjuvant therapies. G Protein subunits alpha Q (GNAQ) and alpha 11 (GNA11) are two of the major driver genes that contribute to the development of uveal melanoma. Understanding their prognostic significance can allow tailored management and facilitate their use in the on-going quest of targeted uveal melanoma therapies. Formalin-fixed, paraffin-embedded specimens were obtained from 47 patients of Greek origin, with uveal melanoma. GNAQ and GNA11 genes were screened for mutations in exons 4 and 5, by polymerase chain reaction and Sanger sequencing. The overall mutation frequency of GNAQ/GNA11 genes was 42.4%. A novel mutation c.625_626delinsGC was identified in GNA11. No correlation was observed between the mutation status and metastasis occurrence or overall survival time of patients. Mutations in GNAQ and GNA11 genes in this Greek population present frequencies that qualify them as potential targets for customized therapy.


Health Care Utilization, Transition Readiness, and Quality of Life: A Latent Class Analysis.
To identify possible subgroups of health care utilization (HCU) patterns among adolescents and young adults (AYAs) with a chronic medical condition (CMC), and examine how these patterns relate to transition readiness and health-related quality of life (HRQoL). Undergraduates (N = 359; Mage=19.51 years, SD = 1.31) with a self-reported CMC (e.g., asthma, allergies, irritable bowel syndrome) completed measures of demographics, HCU (e.g., presence of specialty or adult providers, recent medical visits), transition readiness, and mental HRQoL (MHC) and physical HRQoL (PHC). Latent class analysis identified four distinct patterns of HCU. The BCH procedure evaluated how these patterns related to transition readiness and HRQoL outcomes. Based on seven indicators of HCU, a four-class model was found to have optimal fit. Classes were termed High Utilization (n = 95), Adult Primary Care Physician (PCP)-Moderate Utilization (n = 107), Family PCP-Moderate Utilization (n = 81), and Low Utilization (n = 76). Age, family income, and illness controllability predicted class membership. Class membership predicted transition readiness and PHC, but not MHC. The High Utilization group reported the highest transition readiness and the lowest HRQoL, while the Low Utilization group reported the lowest transition readiness and highest HRQoL. The present study characterizes the varying degrees to which AYAs with CMCs utilize health care. Our findings suggest poorer PHC may result in higher HCU, and that greater skills and health care engagement may not be sufficient for optimizing HRQoL. Future research should examine the High Utilization subgroup and their risk for poorer HRQoL.


Acute and chronic neuropathies: new aspects of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy, an overview and an update.
During the last 15 years new information about clinical, electrophysiological, immunological and histopathological features of acute and chronic inflammatory neuropathies have emerged. Thus, the Guillain-Barré syndrome (GBS) is no longer considered a simple entity. Subtypes of the disorder besides the typical predominant motor manifestation, are recognized, i.e. a cranial nerve variant with ophthalmoplegia, ataxia and areflexia, an immune-mediated primary motor axonal neuropathy (AMAN), and a motor-sensory syndrome (AMSAN). Also, the clinical pattern of GBS is related to preceding viral or bacterial infections. Two types of acute motor paralysis have been described, one with slow and incomplete recovery, another with recovery times identical with acute inflammatory demyelinating polyneuropathy (AIDP). Histologically, the first is characterized by Wallerian degeneration of motor roots and peripheral motor nerve fibres. In the latter anti-GM antibodies bind to the nodes of Ranvier producing a failure of impulse transmission. Motor-point biopsies have shown denervated neuromuscular junctions and a reduced number of intramuscular nerve fibres. Molecular mimicry has been postulated as a possible mechanism triggering GBS. Thus, in the cranial variant antibodies to ganglioside GQ1b recognizes similar epitopes on Campylobacter jejuni strains and similar observations apply to anti-GM1 antibodies. Chronic inflammatory demyelinating polyneuropathy (CIDP) also has several different clinical presentations such as a pure motor syndrome, a sensory ataxic variant, a mononeuritis multiplex pattern, relapsing GBS, and a paraparetic subtype. Each of the acute and the subtypes have different, more or less distinct, electrophysiologic and pathological findings. Instructive patient stories are presented together with there electrophysiologic and biopsy findings.


Electron-compensation: a valid strategy for chemically stabilizing boron-based clusters with hypercoordinate centres.
To eliminate the chemical instability caused by the electron-deficiency of boron, two types of usual dative π bonds are recommended for compensating boron atoms in the computational design of boron-based clusters having hypercoordinate centres, which can lead to unusually stable targets for synthesis in the condensed phase.


Insulin, cortisol and catecholamines do not regulate circadian variations in fibrinolytic activity.
To evaluate possible hormonal regulators of the diurnal rhythm in fibrinolytic activity, we measured tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor activity (PAI-1), t-PA antigen, insulin, cortisol, and catecholamines in 6 healthy males (age 34 +/- 5) every 2 hours for 24 hours. Fibrinolysis was characterized by a peak in PAI-1 activity and a trough in t-PA activity at 0600 h. PAI-1 activity increased 92% and t-PA activity decreased 56% between 2400 h and 0600 h. t-PA antigen (principally a measure of t-PA/PAI-1 complex), peaked at 0800 h. In comparison, insulin levels were lowest at night when PAI-1 activity was rising. The weak inverse correlation between insulin and PAI-1 activity (r = -0.28, p less than 0.02), was not sufficient to explain the diurnal change in fibrinolysis. While cortisol demonstrated the expected circadian change, the increase in cortisol did not occur until 0400 h, 4-6 hours after the rise in PAI-1 and decrease in t-PA activity started. Supine resting plasma epinephrine and norepinephrine showed no circadian rhythm. From this data, we hypothesize that the increased level of PAI-1 in the morning consumes t-PA, leading to decreased t-PA activity and increased t-PA/PAI-1 complex. Further, we conclude that insulin, cortisol, and catecholamines are not responsible for the circadian rhythm of fibrinolysis.


Stimulation of the amino acid transporter SLC6A19 by JAK2.
JAK2 (Janus kinase-2) is expressed in a wide variety of cells including tumor cells and contributes to the proliferation and survival of those cells. The gain of function mutation (V617F)JAK2 mutant is found in the majority of myeloproliferative diseases. Cell proliferation depends on the availability of amino acids. Concentrative cellular amino acid uptake is in part accomplished by Na(+) coupled amino acid transport through SLC6A19 (B(0)AT). The present study thus explored whether JAK2 activates SLC6A19. To this end, SLC6A19 was expressed in Xenopus oocytes with or without wild type JAK2, (V617F)JAK2 or inactive (K882E)JAK2 and electrogenic amino acid transport determined by dual electrode voltage clamp. In SLC6A19-expressing oocytes but not in oocytes injected with water or JAK2 alone, the addition of leucine (2mM) to the bath generated a current (I(le)), which was significantly increased following coexpression of JAK2 or (V617F)JAK2, but not by coexpression of (K882E)JAK2. Coexpression of JAK2 enhanced the maximal transport rate without significantly modifying the affinity of the carrier. Exposure of the oocytes to the JAK2 inhibitor AG490 (40μM) resulted in a gradual decline of I(le). According to chemiluminescence JAK2 enhanced the carrier protein abundance in the cell membrane. The decline of I(le) following inhibition of carrier insertion by brefeldin A (5μM) was similar in the absence and presence of JAK2 indicating that JAK2 stimulates carrier insertion into rather than inhibiting carrier retrival from the cell membrane. In conclusion, JAK2 up-regulates SLC6A19 activity which may foster amino acid uptake into JAK2 expressing cells.


Mapping replication forks, one replicon at a time.
Claussin et al. (2022) present an elegant approach to replication fork mapping that combines single-molecule resolution with genome-wide coverage to provide unprecedented insight into the robust nature of DNA replication.


Is there any change in the prevalence of intestinal or cardiopulmonary parasite infections in companion animals (dogs and cats) in Germany between 2004-2006 and 2015-2017? An assessment of the impact of the first ESCCAP guidelines.
Main objective of the present nationwide study was to assess the impact of the ESCCAP guideline for the control of worm infections in dogs and cats 8-10 years after its first publication in Germany. A secondary aim was to determine the prevalence of canine and feline cardiopulmonary nematodes and intestinal protozoa. Faecal samples of 53,693 dogs and 26,491 cats in 2004-2006 as well as of 129,578 dogs and 45,709 cats in 2015-2017 routinely submitted by veterinarians to a private veterinary laboratory were examined using appropriate parasitological methods. In dogs, the prevalence of Toxocara and taeniid egg shedding was significantly lower in 2015-2017 (3.8 % and 0.16 %, respectively) than in 2004-2006 (4.6 % and 0.27 %, respectively). The prevalence of hookworm and Capillaria eggs was higher in the second study period (2.3 % and 0.77 %, respectively) than in the first (1.3 % and 0.6 %, respectively). For Toxascaris leonina (0.55-0.6 %) and Trichuris (0.8-0.9 %), the difference was not significant between the study periods. Dogs shed more often Angiostrongylus vasorum larvae in the second study (3.1 %) than in the first (1.0 %), whereas the prevalence of Crenosoma vulpis did not change significantly (2.2-2.6 %). Cystoisospora canis and C. ohioensis-like infections were less detected in the second study period (1.0 % and 2.1 %, respectively) than in the first (1.8 % and 2.7 %, respectively). Neospora-like oocysts and Sarcocystis sporocysts were more prevalent in the second study period (0.19 % and 0.13 %, respectively) than in the first (0.13 % and 0.06 %, respectively). The percentage of Giardia or Cryptosporidium coproantigen-positive samples was lower in the second study period (18.9 % and 6.7 %, respectively) than in the first (22.8 % and 10.0 %, respectively). In cats, the prevalence of egg shedding of T. cati, Capillaria and taeniids was significantly lower in 2015-2017 (3.5 %, 0.25 % and 0.1 %, respectively) than in 2004-2006 (4.8 %, 0.54 % and 0.22 %, respectively). No difference was recorded for hookworms (0.12-0.13 %) and Ts. leonina (0.04-0.05 %). Aelurostrongylus-like larvae were detected more often in the second study period (6.5 %) than in the first (2.6 %). Infections with Cystoisospora felis, C. rivolta, Toxoplasma-like coccids and Sarcocystis were less prevalent in the second study period (1.9 %, 0.7 %, 0.24 % and 0.02 %, respectively) than in the first (2.7 %, 1.1 %, 0.36 % and 0.1 %, respectively). The percentage of Giardia or Cryptosporidium coproantigen-positive samples was significantly lower in the second study period (10.6 % and 4.8 %, respectively) than in the first (15.4 % and 8.3 %, respectively). Although these results indicate a decline of the occurrence of most canine and feline intestinal parasites in Germany over the years, a transmission risk of zoonotic parasites remains. Therefore, the control of helminth infections in domestic dogs and cats continues to be a challenge for veterinarians and pet owners.


Threonine modulates immune response, antioxidant status and gene expressions of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream (Megalobrama amblycephala).
A 9-week feeding trial was conducted to investigate the effects of graded dietary threonine (Thr) levels (0.58-2.58%) on the hematological parameters, immune response, antioxidant status and hepatopancreatic gene expression of antioxidant enzymes and antioxidant-immune-cytokine-related signaling molecules in juvenile blunt snout bream. For this purpose, 3 tanks were randomly arranged and assigned to each experimental diet. Fish were fed with their respective diet to apparent satiation 4 times daily. The results indicated that white blood cell, red blood cell and haemoglobin significantly responded to graded dietary Thr levels, while hematocrit didn't. Complement components (C3 and C4), total iron-binding capacity (TIBC), immunoglobulin M (IgM), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) increased with increasing dietary Thr levels up to 1.58-2.08% and thereafter tended to decrease. Dietary Thr regulated the gene expressions of Cu/Zn-SOD, Mn-SOD and CAT, GPx1, glutathione S-transferase mu (GST), nuclear factor erythroid 2-related factor 2 (Nrf2), heat shock protein-70 (Hsp70), tumor necrosis factor-alpha (TNF-α), apolipoprotein A-I (ApoA1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and fructose-bisphosphate aldolase B (ALDOB); while the gene expression of peroxiredoxin II (PrxII) was not significantly modified by graded Thr levels. These genes are involved in different functions including antioxidant, immune, and defense responses, energy metabolism and protein synthesis. Therefore, this study could provide a new molecular tool for studies in fish immunonutrition and shed light on the regulatory mechanisms that dietary Thr improved the antioxidant and immune capacities of fish.


Attitudes Toward Discussing Approved and Investigational Treatments for Cystic Fibrosis in Prenatal Genetic Counseling Practice.
This project aimed to explore the attitudes of prenatal genetic counselors toward discussion of novel approved and experimental CF treatments in the prenatal setting, and to assess how knowledge of genotype-specific, targeted treatments may influence their current practices. Targeted treatments have the potential to impact the health-related quality of life of individuals affected with CF and therefore, knowledge of the availability of such treatments may influence the decision-making process of parents who receive a fetal diagnosis of CF. Using the 2012 FDA approval and introduction of ivacaftor into CF clinical practice as a case study, a survey was designed to explore the opinions and practices of prenatal genetic counselors with regard to counseling for a prenatal diagnosis of CF, and how those practices might be impacted by the availability of a new genotype-specific treatment. Approximately 800 genetic counselors were sent questionnaires in January of 2013. Respondents were provided information about this treatment and were asked to rate its perceived benefits, along with the likelihood that they would discuss potential benefits and limitations with parents receiving a prenatal diagnosis of CF. One-hundred sixty-nine prenatal genetic counselors (21.1 %) responded to the survey. Results indicated that 80 % of respondents 'never heard of the drug', or they were 'not exactly sure' what it was. After reading the materials provided, counselors felt the new treatment would have 'some' or a 'significant' impact on an affected individual's life. Their opinions varied on what information about this treatment they would choose to discuss with their patients; even if the treatment is currently FDA approved and clinically available for affected individuals with the genotype of the fetus. However, they would 'definitely' refer these patients to a specialist to discuss targeted treatments further. Most prenatal genetic counselors indicated there are certain scenarios in the prenatal setting which warrant a discussion of targeted treatments for CF, at least on some level. Counselor's views on sharing information about new treatment options are shaped by their familiarity with the treatment and their perception of its benefits and limitations, their comfort discussing these subjects, and their interpretation of the genetic counselor's role. Most genetic counselors had never heard of ivacaftor or Kalydeco™ prior to taking the survey. Therefore, counselors need to be better educated about the availability of CFTR mutation-based treatments before they will be able to incorporate discussion of new treatment options into their counseling.


In vivo rotational three-dimensional OCTA analysis of microaneurysms in the human diabetic retina.
The aim of this study was to explore whether rotational three-dimensional (3D) visualization of optical coherence tomography angiography (OCTA) volume data may yield valuable information regarding diabetic retinal microaneurysm (MA) characteristics. In this retrospective, observational study, we collected data from 20 patients (20 eyes) with diabetic retinopathy. Subjects were imaged with the SS-OCTA system (PLEX Elite 9000, Carl Zeiss Meditec Inc., Dublin, CA, USA). The OCTA volume data were processed with a volume projection removal algorithm and then exported to imageJ in order to obtain a 3D visualization of the analyzed MAs. The rotational three-dimensional OCTA images were qualitatively and quantitatively investigated. A total of 52 MAs were included in the analysis. On rotational 3D OCTA images, the number of vessels associated with each MA varied between 1 and 4, and most MAs (59.6%) were associated with 2 vessels. Moreover, in 20 MAs (38.4%) these vessels seem to originate from the SCP, while 26 MAs (50.0%) had associated vessels originating from the DVC, and 6 MAs had associated vessels arising from both the SCP and DVC (11.6%). Most MAs (31/52) had a 'saccular' shape. The number of retinal layers occupied by each MA ranged between 1 and 3 and the inner nuclear layer was the retinal layer most frequently occupied by MAs. In conclusion, this study used an algorithm to obtain rotational three-dimensional visualization of retinal MAs. The MAs' architecture is complex and 3D visualization may clarify the true vascular origin of these lesions, which is often mistaken using en face OCTA images.


Truncated RIP3 (tRIP3) acts upstream of FADD to induce apoptosis in the human hepatocellular carcinoma cell line QGY-7703.
RIP3 (receptor-interacting protein 3) is a serine/threonine kinase that promotes apoptosis in various cell types. The C-terminal domain of RIP3 is critical for its apoptosis induction. In this study, we showed that a truncated form of RIP3 (tRIP3) containing only the unique C-terminal region (aa 224-518) induced significant apoptosis in human hepatocellular carcinoma cells QGY-7703. A FADD-dominant negative (FADD-DN) was shown to significantly block apoptosis induced by tRIP3. In contrast, the RIP3 dominant negative (RIP3-DN) was found unable to block FADD-induced apoptosis. Thus, we conclude that tRIP3 may function upstream of FADD to induce apoptosis in TNFR-1 signaling pathway. Additionally, sequence alignments of RIP3 with other death domain (DD)-containing proteins revealed that amino acids Leu 477 and Leu 488 in RIP3 are highly conserved, nonetheless, neither mutational change at Leu 477 nor at Leu 488 confers obvious effect on cell death, indicating that these two amino acids might not be critical for its pro-apoptotic activity as expected.


The management of scaphoid fractures.
Appropriate management of scaphoid fractures is important because of the risk of long-term complications such as delayed or non-union, pain and disability. Up to 25% of scaphoid fractures are not visible on the initial radiographs. Consequently, all clinically suspected scaphoid fractures are treated as fractures with cast immobilisation until cause of the symptoms is clarified. The diagnosis often utilises a number of second line investigations that are generally performed 10-14 days after the injury. Bone scintigraphy is currently the most commonly used of these as it rarely misses a fracture. However, it does not visualise anatomical structure and therefore alternative diagnoses are difficult. Magnetic resonance imaging (MRI) is at least as sensitive and more specific than bone scanning and has the advantages of being able to identify other lesions and not expose the patient to any radiation. Furthermore, the scan may be performed as early as 2.8 days following an injury rather than 10 days later in the case of a bone scan. Although the cost of MRI is higher than other imaging modalities, it may be cost-effective in the overall management of patients with occult scaphoid fractures since it may prevent unnecessary cast immobilisation in active people. The most appropriate method of cast immobilisation is presently unclear but evidence exists for improved clinical outcomes in those that have both the thumb and elbow immobilised for the first six weeks.


Peritoneal small solute transport rate is related to the malnutrition inflammation score in peritoneal dialysis patients.
A high peritoneal membrane transport status and peritoneal albumin leakage are determinants of morbidity and mortality in patients receiving continuous ambulatory peritoneal dialysis. In this study, we analyzed the relationship between the malnutrition inflammation score, peritoneal transport status, and 24-hour peritoneal albumin leakage in patients receiving peritoneal dialysis. Sixty-six patients receiving peritoneal dialysis (male-female ratio 30/36; age 46.2 +/- 14.1 years; mean duration of peritoneal dialysis 32.4 +/- 23.9 months) who had experienced no attacks of peritonitis within the prior 6 months were included. The malnutrition inflammation score was positively correlated with the serum C-reactive protein concentration, dialysate/plasma creatinine ratio, and 24-hour peritoneal albumin leakage. Triceps and biceps skinfold thicknesses and serum concentrations of prealbumin, total cholesterol, and triglyceride were negatively correlated with the malnutrition inflammation score. Multiple linear regression analysis showed that the malnutrition inflammation score was independently associated with the dialysate/plasma creatinine ratio (p = 0.039) and 24-hour peritoneal albumin amount (p = 0.005). High peritoneal transport status and peritoneal albumin leakage are significantly associated with the malnutrition inflammation score.


PIKK-ing a new partner: a new role for PKB in the DNA damage response.
The protein kinase PKB/Akt has long been associated with regulating signaling pathways that promote cell survival and cell growth, for example, in response to growth factors. In contrast, the DNA-dependent protein kinase (DNA-PK) is required for the repair of DNA damage and for cell survival after exposure to DNA-damaging agents, such as ionizing radiation. In a recent paper published in Molecular Cell, Hemmings and colleagues provide evidence that DNA-PK is required for the activation of PKB in response to exposure to ionizing radiation, suggesting that these two protein kinases may act together to promote survival after DNA damage.


Vascular endothelial and smooth muscle cells in culture selectively release adenine nucleotides.
Endothelial cells in culture can modulate platelet aggregation and vascular tone, in part by producing prostacyclin (PGI2), a powerful vasodilator and inhibitor of platelet aggregation, but also by their ecto-ADPase activity, which initiates the conversion of pro-aggregating ADP to adenosine, a potent vasodilator and platelet inhibitor. We have now demonstrated that cultured aortic endothelial cells exposed to trypsin, thrombin or other stimuli can liberate a high proportion of their adenine nucleotides without substantial loss of lactate dehydrogenase. ADP rapidly accumulates extracellularly, reaching biologically active concentrations before there is further breakdown to adenosine. Whether this selective release of nucleotides is a response to damage, or whether it represents a specific secretory mechanism remains to be resolved. Cultured aortic smooth muscle cells can secrete adenine nucleotides in a similar manner, but extracellular conversion to adenosine occurs much faster.


Predicting radiology resident errors in diagnosis of cervical spine fractures.
Our objective was to identify factors associated with resident errors of cervical spine fractures to enable targeted education. We performed a retrospective cohort study of consecutive cases of after-hours resident interpreted cervical spine fractures over 27 months at a single level 1 academic trauma center. The outcome measure was appropriate identification of all fractures by the resident. Potential predictors of resident error or discrepancy were identified from chart review and included: age, gender; fracture location/pattern (upper/lower cervical spine, occipital condyle, C1 ring, dens, C2 pars, vertebral body, posterior column, lateral mass, transverse process); consecutive and nonconsecutive additional fractures; radiologist distracting factors (number of noncervical spine injuries); number of noncervical spine studies performed. Risk ratios with confidence intervals were calculated for categorical variables using epidemiological 2 x 2 tables, and for continuous variables using difference of means. There were 59 errors among 492 cervical spine fractures in a total of 327 patients. Fifty-seven of the errors were on computed tomography and 2 errors were on radiographs. Upper cervical fractures were significantly more likely to have been errors than lower cervical fractures: risk ratio (RR) of 2.2 (confidence intervals (CI) 1.3, 3.5; P = .001). Occipital condyle fractures were more likely to have been discrepant: RR = 2.2 (CI 1.3, 3.9; P = .006). Dens fractures were also significantly more likely to have been discrepant: RR = 2.0 (CI 1.0, 3.8; P = .05). Other potential predictors were not associated with significantly increased risk. Upper cervical spine fractures, in particular occipital condyle and dens fractures were significantly associated with an increased relative risk of resident missing or misinterpreting the fracture. These findings suggest that resident education should focus in particular on upper cervical spine injuries, occipital condyle, and dens fractures. The methods used in this study could also be applied to other imaging modalities and anatomic regions in the future to target resident education to more challenging areas.


Pattern formation by cultured human epidermal cells: development of curved ridges resembling dermatoglyphs.
In cultures made from disaggregated human epidermal cells, growth to a confluent cell layer is followed by the emergence of patterns resembling those of human dermatoglyphs. These patterns reflect intrinsic properties of kertinocytes. In vivo, only the epidermis of the volar surfaces forms patterns, but in culture, patterns are formed by epidermal cells from other sites as well. Patterns develop by a process of cell movement which first produces ridges and then curves the ridges into figures of increasing complexity, ultimately whorls.


Intravesical gemcitabine in recurrent superficial bladder carcinoma: preliminary results on ablative efficacy and tolerability.
The ablative potential and toxicity of gemcitabine, administered intravesically in low stage and grade superficial transitional cell carcinoma (TCC), were evaluated. Patients with a history of recurrent Ta-T1, GI-G2 bladder TCC were considered eligible for the study. Gemcitabine was administered intravesically at 40 mg/mL concentration (2000 mg in 50 ml saline) in one weekly instillation for 4 consecutive weeks. Fifteen days after the last instillation, patients were submitted to transurethral resection (TUR). Twenty-six patients were evaluable for toxicity, and 20 were evaluable for response, 6 patients being excluded due to toxicity. A complete response was achieved by 10 out of 20 patients (50%), whereas no response was documented in the remainder. Toxicity leading to treatment interruption was grade 3 in 1 patient and grade 2 in 5 patients. Intravesical gemcitabine administered at 40 mg/mL showed the capability of ablating small volume, superficial TCC in 50% of the population under study, with acceptable tolerability.


Improving cancer therapy through the nanomaterials-assisted alleviation of hypoxia.
Hypoxia, resulting from the imbalance between oxygen supply and consumption is a critical component of the tumor microenvironment. It has a paramount impact on cancer growth, metastasis and has long been known as a major obstacle for cancer therapy. However, none of the clinically approved anticancer therapeutics currently available for human use directly tackles this problem. Previous clinical trials of targeting tumor hypoxia with bioreductive prodrugs have failed to demonstrate satisfactory results. Therefore, new ideas are needed to overcome the hypoxia barrier. The method of modulating hypoxia to improve the therapeutic activity is of great interest but remains a considerable challenge. One of the emerging concepts is to supply or generate oxygen at the tumor site to increase the partial oxygen pressure and thereby reverse the hypoxia and its effects. In this review, we present an overview of the recent progress in the development of novel nanomaterials for the alleviation of hypoxic microenvironment. Two main strategies for hypoxia augmentation, i) direct delivery of O2 into the tumor, and ii) in situ O2 generations in the tumor microenvironment through different methods such as catalytic decomposition of endogenous hydrogen peroxide (H2O2) and light-triggered water splitting are discussed in detail. At present, these emerging nanomaterials are in their early phase and expected to grow rapidly in the coming years. Despite the promising start, there are several challenges needed to overcome for successful clinical translation.


A review of 158 gunshot wounds to the chest.
One hundred and fifty-eight gunshot wounds to the chest treated at the Royal Victoria Hospital, Belfast, between August 1969 and July 1976 are reviewed. The place of open operation in the treatment is discussed.


Placebo in the investigation of psychotropic drugs, especially antidepressants.
The paper presents major ethical, legal and methodological problems related to the use of placebo in mental disorders, especially in depression. It is pointed out that although authoritative groups of experts and numerous publications in the field of psychopharmacology indicate advisability of the double blind design with placebo in clinical trials of antidepressants, in recent years there have been more and more voices questioning legitimacy of this method. Objections of an ethical nature are raised, and reliability of this approach is put into doubt from the methodological viewpoint. These issues are discussed in more detail in the paper. Available alternative solutions should be implemented in psychotropic drug studies. The author shares these objections and doubts of an ethical nature, and believes that the placebo procedure is not a necessity in clinical trials of antidepressants.


Trastuzumab does not bind rat or mouse ErbB2/neu: implications for selection of non-clinical safety models for trastuzumab-based therapeutics.
Assessment of non-clinical safety signals relies on understanding species selectivity of antibodies. This is particularly important with antibody-drug conjugates, where it is key to determine target-dependent versus target-independent toxicity. Although it appears to be widely accepted that trastuzumab does not bind mouse or rat HER2/ErbB2/neu, numerous investigators continue to use mouse models to investigate safety signals of trastuzumab and trastuzumab emtansine (T-DM1). We, therefore, conducted a broad array of both binding and biologic studies to demonstrate selectivity of trastuzumab for human HER2 versus mouse/rat neu. Binding of anti-neu and anti-HER2 antibodies was assessed by ELISA, FACS, IHC, Scatchard, and immunoblot methods in human, rat, and mouse cell lines. In human hepatocytes, T-DM1 uptake and catabolism were measured by LC-MS/MS; cell viability changes were determined using CellTiter-Glo. Our data demonstrate, using different binding methods, lack of trastuzumab binding to rat or mouse neu. Structural studies show important amino acid differences in the trastuzumab-HER2 binding interface between mouse/rat and human HER2 ECD. Substitution of these rodent amino acid residues into human HER2 abolish binding of trastuzumab. Cell viability changes, uptake, and catabolism of T-DM1 versus a DM1 non-targeted control ADC were comparable, indicating target-independent effects of the DM1-containing ADCs. Moreover, trastuzumab binding to human or mouse hepatocytes was not detected. These data, in total, demonstrate that trastuzumab, and by extension T-DM1, do not bind rat or mouse neu, underscoring the importance of species selection for safety studies investigating trastuzumab or trastuzumab-based therapeutics.


'A matter of life and death.' Public hospitals sue to stop pending CMS rule that would block extra Medicaid dollars steered to safety net providers.
With a new CMS rule looming that will strip away some funding, public hospitals went on the offensive by filing a lawsuit in Washington. The safety net providers want an injunction against the rule, which would limit payments to the bare costs of Medicaid services. Kim Wirthlin, left, says her institution in Salt Lake City stands to lose $11 million a year for its education program, and $25 million in hospital funding.


Management and Outcomes of Isolated Axillary Artery Injury: A Five-Year National Trauma Data Bank Analysis.
The aim of this study is to evaluate recent national trends in the clinical characteristics, management, and outcomes of patients with isolated axillary artery injuries. The National Trauma Data Bank was queried to identify records submitted from 2011 to 2015 that contained an ICD-9-CM diagnosis code for an injury to axillary artery (903.01) and an external cause of injury code indicating blunt or penetrating trauma. Records that contained a diagnosis code for an injury to an additional blood vessel (900.00-903.00, 903.2-904.9), an injury to a nonupper extremity or unclassifiable body region, or whose operative management could not be discerned were excluded. The final study sample included 221 patients with isolated axillary artery injury. The patient's clinical management was the primary outcome of interest. The study sample was stratified by trauma type, and descriptive statistics were performed on all variables. Seventy-one percent of patients received operative management. Patients with penetrating injury were 24% more likely to be managed operatively than bluntly injured patients (76.9% vs. 62.1%, P = 0.0178). In operatively managed patients, the open repair rate was 82.8% and endovascular repair rate was 10.2%. Graft repair was performed most often (28.0%), followed by placement of a temporary intravenous shunt (17.8%) and surgical occlusion (10.2%). Surgical vessel occlusion was significantly more likely to be performed on patients with penetrating injury than with blunt injury (14.6% vs. 1.9%, P = 0.0124). Patients with penetrating injury had significantly shorter median emergency department length of stay (87.0 min vs. 152.0 min, P < 0.0001), intensive care unit length of stay (2.0 days vs. 3.0 days, P < 0.0388), hospital length of stay (4.0 days vs. 5.0 days, P = 0.0026), and time-to-operative management (1.6 hr vs. 3.9 hr, P < 0.001) compared to bluntly injured patients. Patients with blunt injury had a higher reportable in-hospital complication rate (13.8% vs. 6.0%, P = 0.0477). The overall mortality rate was 3.1% for isolated axillary artery injuries and did not significantly differ by trauma type. Axillary artery injury is more often caused by penetrating trauma. Despite introduction of novel endovascular techniques, the majority of patients with isolated axillary artery injury are managed using open repair. Penetrating axillary artery injury is significantly more likely to be managed using open repair and by surgical occlusion. Patients with blunt injury have higher complication rates and longer hospital length of stays. The mortality rate is lower than previously published.


Insights into spatiotemporal variations of the water quality in Taihu Lake Basin, China.
Taihu Lake Basin is highly developed but suffers from perennial water shortages due to pollution. Most studies have been limited to examining the water quality in specific areas, but few have investigated the entire basin. This study was based on official water quality data obtained from 565 sites in the monitoring network, thereby covering the entire basin. The water quality spatiotemporal variations were explored by statistical analysis, and the precise spatial distribution of the main pollutants was analyzed by heat maps. Only 29.09% of the water quality assessment results showed "drinkable," whereas 28.63% showed "moderate" and "severe" pollution. The "severe" proportion had a significant declining trend (R2 = 0.933) and was affected by the variations of nitrogen that was related to rainfall and anthropogenic activities. The water quality spatial variation was most likely related to anthropogenic influence and land use. The water quality in the developed and densely populated urban areas was poor, especially in downtown Shanghai. NH3-N, TN, TP, BOD5, COD, CODMn, and DO were the main pollutants that affected the water quality. NH3-N and TN were major reduction targets. NH3-N was the main pollutant that deteriorated the water quality in most densely populated urban areas. Many lakes and reservoirs were highly polluted with TN. Controlling domestic sewage may be effective to improve the water quality. This study makes up for the limited research on the water quality spatiotemporal variations in the entire Taihu Lake Basin and provides beneficial information and suggestions for decision-making regarding the water management.


Tamsulosin reduces the incidence of acute urinary retention following early removal of the urinary catheter after radical retropubic prostatectomy.
To determine the efficacy of tamsulosin in preventing acute urinary retention following early catheter removal after radical retropubic prostatectomy. Between February 2000 and October 2000, cystography was performed on postoperative day 7 after radical retropubic prostatectomy by a single surgeon (group 1). Between September 2001 and August 2002, cystography was performed on postoperative day 8 after radical retropubic prostatectomy by the same surgeon (group 2). The protocol for performing cystography and assessment of extravasation was similar for both groups. Tamsulosin 0.4 mg was administered 3 days before and 4 days after cystography for all men in group 2. Of 179 cystograms in group 1, 135 (75%) revealed no extravasation, and the catheters were removed in 130 of these cases. Of 246 cystograms in group 2, 230 (93.5%) revealed no extravasation, and the catheters were removed in 229 of these cases. A significantly greater proportion of men in group 2 had no extravasation (P = 0.0007). The incidence of acute urinary retention in groups 1 and 2 was 10% and 2.6%, respectively (P = 0.0018). The incidence of anastomotic stricture was not significantly different between the two groups. Our data strongly suggest that tamsulosin significantly reduces the risk of acute urinary retention after attempts at early catheter removal following radical retropubic prostatectomy. Therefore, we recommend administering a 7-day course of tamsulosin therapy when attempting to remove the urinary catheter before postoperative day 8.


Antibody-Based Cancer Therapy: Successful Agents and Novel Approaches.
Since their discovery, antibodies have been viewed as ideal candidates or "magic bullets" for use in targeted therapy in the fields of cancer, autoimmunity, and chronic inflammatory disorders. A wave of antibody-dedicated research followed, which resulted in the clinical approval of a first generation of monoclonal antibodies for cancer therapy such as rituximab (1997) and cetuximab (2004), and infliximab (2002) for the treatment of autoimmune diseases. More recently, the development of antibodies that prevent checkpoint-mediated inhibition of T cell responses invigorated the field of cancer immunotherapy. Such antibodies induced unprecedented long-term remissions in patients with advanced stage malignancies, most notably melanoma and lung cancer, that do not respond to conventional therapies. In this review, we will recapitulate the development of antibody-based therapy, and detail recent advances and new functions, particularly in the field of cancer immunotherapy. With the advent of recombinant DNA engineering, a number of rationally designed molecular formats of antibodies and antibody-derived agents have become available, and we will discuss various molecular formats including antibodies with improved effector functions, bispecific antibodies, antibody-drug conjugates, antibody-cytokine fusion proteins, and T cells genetically modified with chimeric antigen receptors. With these exciting advances, new antibody-based treatment options will likely enter clinical practice and pave the way toward more successful control of malignant diseases.


Group sequential designs for three-arm 'gold standard' non-inferiority trials with fixed margin.
In the recent years there have been numerous publications on the design and the analysis of three-arm 'gold standard' noninferiority trials. Whenever feasible, regulatory authorities recommend the use of such three-arm designs including a test treatment, an active control, and a placebo. Nevertheless, it is desirable in many respects, for example, ethical reasons, to keep the placebo group size as small as possible. We first give a short overview on the fixed sample size design of a three-arm noninferiority trial with normally distributed outcomes and a fixed noninferiority margin. An optimal single stage design is derived that should serve as a benchmark for the group sequential designs proposed in the main part of this work. It turns out, that the number of patients allocated to placebo is substantially low for the optimal design. Subsequently, approaches for group sequential designs aiming to further reduce the expected sample sizes are presented. By means of choosing different rejection boundaries for the respective null hypotheses, we obtain designs with quite different operating characteristics. We illustrate the approaches via numerical calculations and a comparison with the optimal single stage design. Furthermore, we derive approximately optimal boundaries for different goals, for example, to reduce the overall average sample size. The results show that the implementation of a group sequential design further improves the optimal single stage design. Besides cost and time savings, the possible early termination of the placebo arm is a key advantage that could help to overcome ethical concerns.


Using Lean Six Sigma to Improve Controlled Drug Processes and Release Nursing Time.
Hospital controlled drug processes are established to adhere to legislation, with little consideration of efficiency of processes. A controlled drug process existed, where nurses requested a porter to collect a hand-written order; however, only 19% of drug orders were processed this way. Instead, an unscheduled, ad hoc process led to an average of 17 nurse journeys to pharmacy daily. We aimed to reduce nurse journeys to the pharmacy by 25% to release nursing time. A pre-/postintervention design was used with Lean Six Sigma methods. A multifaceted intervention involved process redesign, increasing the frequency of a porter-led delivery service, amending delivery times to reflect times of greatest need, and streamlining checking requirements. Following implementation, there was a statistically significant 44% decrease in nurse journeys to pharmacy for drug collections, which was maintained after 18 months. Interprofessional collaboration improving hospital-wide processes can have significant benefits for the release of nursing time.


AT1A-deficient mice show less severe progression of liver fibrosis induced by CCl(4).
The renin-angiotensin system has been shown to contribute to fibrogenesis in varieties of organs, including the liver. Here, we investigated whether the angiotensin II type 1A receptor (AT1A) is implicated in the development of liver fibrosis, using AT1A-deficient and wild-type (WT) mice. After single dose of carbon tetrachloride (CCl(4)), there were no significant differences between two groups with regard to hepatic inflammation and necrosis. After 4 weeks of treatment with CCl(4), histological examination revealed that AT1A-deficient mice showed less infiltration of inflammatory cells and less severe progression of liver fibrosis compared with WT mice. These findings were accompanied by the hepatic content of hydoxyproline and the expression of alpha-smooth muscle actin (alpha SMA). The level of transforming growth factor-beta 1 (TGF-beta 1) messenger RNA was markedly higher in WT mice when compared with AT1A-deficient mice. These results confirm that signaling via AT1A plays a pivotal role in hepatic fibrogenesis.


Rapid identification of penicillin and macrolide resistance genes and simultaneous quantification of Streptococcus pneumoniae in purulent sputum samples by use of a novel real-time multiplex PCR assay.
We evaluated a real-time quantitative PCR combined with a multiplex PCR assay for the quantification of Streptococcus pneumoniae and the simultaneous detection of drug-resistant genes by gel-based PCR, using purulent sputum samples. This assay correctly quantified S. pneumoniae and identified their penicillin and erythromycin susceptibilities directly from samples within 3 h.


Development of a cost model for the production of carbon fibres.
Carbon fibre composites offer considerable potential for mass reduction in automotive applications. However, raw material cost is one of the major factors that constraints its extensive use in this mass market. Here we report a systematic study that presents the cost contributors by considering the entire process chain of the carbon fibre manufacturing. The sensitivity analysis revealed that the final cost of Polyacrylonitrile (PAN) precursor and carbon fibres were strongly influenced by tow size. It was observed that a prompt decrease in the precursor and carbon fibre cost per kg for tow sizes from 3k to 12k, later this decrement was gradual and almost became stable above 50k. Moreover, with an increase in tow size from 3k to 50k, the contribution of the precursor on the final carbon fibre cost decreased from 76.6% to 49.6%. On the other hand, the contribution of the other factors increased with increase in the tow size, for instance, labour (9.86%-17.78%), Energy (2.49%-6.48%) and Depreciation (6.11%-11.01%). Nevertheless, precursor holds the major share in determining the final price of the carbon fibres.