Effect of Trastuzumab Deruxtecan on QT/QTc Interval and Pharmacokinetics in HER2-Positive or HER2-Low Metastatic/Unresectable Breast Cancer.
HER2-targeted anticancer therapies may be associated with cardiovascular adverse events. This study evaluated effects of the HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd, DS-8201a) on QT/QTc interval and its pharmacokinetics. Patients with heavily pretreated, metastatic HER2-expressing breast cancer were enrolled at seven study sites in Japan. T-DXd was administered intravenously at 6.4 mg/kg on day 1 of each 21-day cycle. Primary end points were baseline-adjusted QTcF interval and pharmacokinetics parameters. Key secondary end points included safety events, serum concentration of T-DXd and DXd at the time of electrocardiographic measurements, and antitumor activity parameters. Among 51 total patients, 47 (92.2%) had HER2-low breast cancer (immunohistochemistry 1+ or 2+ and in situ hybridization-negative/equivocal/missing). Pharmacokinetic parameters after a single dose of T-DXd were consistent with previous studies. After multiple doses, T-DXd showed moderate accumulation (accumulation ratio (cycle 3/cycle 1), 1.35), but DXd showed minimal accumulation (1.09). The upper bound of the 90% confidence interval for mean ΔQTcF interval was < 10 ms at all timepoints, and at mean maximum serum concentration was also < 10 ms. Based on concentration-QT analysis, ΔQTcF increased with increasing concentrations of T-DXd and DXd. No clinically meaningful QTcF prolongation was observed. T-DXd had a manageable safety profile and showed antitumor activity in HER2-low breast cancer. In this study, a T-DXd dose of 6.4 mg/kg, higher than the 5.4-mg/kg dose currently approved for breast cancer, was not associated with clinically relevant QTcF prolongation in heavily pretreated patients with HER2-expressing metastatic breast cancer. This study adds to our understanding of T-DXd for treatment of HER2-low breast cancer.


Treatment with Tip-Edge brackets and differential tooth movement.
Differential tooth movement has been associated with the Begg technique and ribbon arch-type brackets since 1954. Its efficiency and effectiveness have been demonstrated and documented over the past 30 years. A relatively new edgewise-type bracket has been designed to permit differential tooth movement within predetermined limits. The following case reports describe the treatment of three differing malocclusions by means of Tip-Edge brackets and straight arch wires. The first was treated with the aid of mesiodistal crown size reduction, the second with the pretreatment removal of the four first premolars, and the third without the removal of any permanent teeth.


Screening and mitigating major threats of regional development to water ecosystems using ecosystem services as endpoints.
Coordinating the coercion of human activities to the ecosystem is a continuous strategic concern. A practical way to conceptualize socioeconomic development and link it to ecosystem response is urgently needed. This study proposed a two-staged method to reveal the threats concealed in socioeconomic development and show the return of water ecosystem services to regulation measures. Eight threat indexes referring to scale, structure and efficiencies of industrial, agriculture and domestic sectors were designed to assess the threats caused by unsustainable development features, while four indexes for evaluating water supply, habitat provision, regulation and quality purification service of ecosystem were set up. For each threat index, the evaluation result is a relative value derived from comparison with a reasonable level. The major threats could be screened out by ranking threat indexes, so that unreasonable development dimension could be identified and subsequent regulation scheme be prepared. On this basis, with the targeted adjustment of socioeconomic development, corresponding improvements in water ecosystem could be expected and quantified. In the case study of Beijing-Tianjin-Hebei District, the most remarkable threats include production inefficiency of the industrial sector and oversized population, of which degrees of deviation from reasonable levels exceed 70%. When all development dimensions were dragged to the suggested levels, the habitat provision and water supply service would witness the largest progress among four services, with the values rising from 0.49 to nearly 1. This method helps discover the critical defect of socioeconomic development in terms of ecosystem response and facilitate the decision maker to establish more sustainable initiatives.


Fibrinogen Osaka IV: a congenital dysfibrinogenemia found in a patient originally reported in relation to surgery, now defined to have an A alpha arginine-16 to histidine substitution.
We discovered a congenital heterozygous dysfibrinogen in a patient and reported this case in relation to surgery some time ago (Jpn J Surg (1988) 18:43-46). Further studies on the isolated abnormal population of fibrinogen derived from this patient have revealed that fibrinopeptide A was not cleaved by ancrod, a snake venom-derived thrombin-like enzyme, but by thrombin, slowly but completely. The released fibrinopeptide A components, being the A, AY, and AP peptides, were all found to be abnormal, as evidenced by slightly earlier elution positions on high-performance liquid chromatography, compared with the normal counterparts. By analyzing their amino acid sequence, we have identified an arginine to histidine substitution at position 16 of the A alpha chain, the thrombin cleavage site. Utilizing insolubilized abnormal fibrinogen, we confirmed that the polymerization site assigned to the central E domain, the "A" site, was exposed by thrombin, but not by ancrod. This dysfibrinogen, designated as fibrinogen Osaka IV, is the second abnormal molecule with an A alpha arginine-16 to histidine substitution identified among Japanese families.


Modeling of drying kiwi slices and its sensory evaluation.
In this study, monolayer drying of kiwi slices was simulated by a laboratory-scale hot-air dryer. The drying process was carried out at three different temperatures of 50, 60, and 70°C. After the end of drying process, initially, the experimental drying data were fitted to the 11 well-known drying models. The results indicated that Two-term model gave better performance compared with other models to monitor the moisture ratio (with average R2 value equal .998). Also, this study used artificial neural network (ANN) in order to feasibly predict dried kiwi slices moisture ratio (y), based on the time and temperature drying inputs (x1, x2). In order to do this research, two main activation functions called logsig and tanh, widely used in engineering calculations, were applied. The results revealed that, logsig activation function base on 13 neurons in first and second hidden layers were selected as the best configuration to predict the moisture ratio. This network was able to predict moisture ratio with R2 value .997. Furthermore, kiwi slice favorite is evaluated by sensory evaluation. In this test, sense qualities as color, aroma, flavor, appearance, and chew ability (tissue brittleness) are considered.


CT radiomics-based prediction of anaplastic lymphoma kinase and epidermal growth factor receptor mutations in lung adenocarcinoma.
To develop and validate a CT-based radiomic model to simultaneously diagnose anaplastic lymphoma kinase (ALK) rearrangements and epidermal growth factor receptor (EGFR) mutation status of lung adenocarcinoma and to assess whether peritumoural radiomic features add value in the prediction of mutation status. 503 patients with pathologically proven lung adenocarcinoma containing information on the mutation status were retrospectively included. Intratumoural and peritumoural radiomic features of the primary lesion were extracted from CT. We proposed two-level stepwise binary radiomics-based classification models to diagnose ALK (step1) and EGFR mutation status (step2). The performance of proposed models and added value of peritumoural radiomic features were evaluated by using the areas under receiver operating characteristic curves (AUC) and Obuchowski index in the development and validation sets. Regarding the prediction of ALK rearrangement, the diagnostic performance of the intratumoural radiomic model showed the AUC of 0.77 and 0.68 for the development and validation sets, respectively. As for EGFR mutation, the diagnostic performance of the intratumoural radiomic model showed the AUCs of 0.64 and 0.62 for the development and validation sets, respectively. The radiomics added value to the model based on clinical features (development set [radiomics + clinical model vs. clinical model]: Obuchowski index, 0.76 vs. 0.66, p < 0.001; validation set: 0.69 vs. 0.61, p = 0.075). Adding peritumoural features resulted in no improvement in terms of model performance. The CT radiomics-based model allowed the simultaneous prediction of the presence of ALK and EGFR mutations while adding value to the clinical features.


Urologic aspects associated with isolated hypogastric artery aneurysm.
The isolated hypogastric artery aneurysm may give rise to urologic symptoms. This occurs as a consequence of extrinsic compression exerted by the aneurysm itself to the urinary tract or the involvement of the urinary tract by the perianeurysmatic fibrosis. We report 2 cases of isolated hypogastric artery aneurysm. One of the patients had unilateral ureteral obstruction while the other revealed a mass on rectal examination. In both cases surgery was performed and the urologic manifestations were relieved completely.


Evaluating the utility of non-echo-planar diffusion-weighted imaging in the preoperative evaluation of cholesteatoma: a meta-analysis.
To describe the accuracy of non-echo-planar diffusion-weighted magnetic resonance imaging (DW MRI) in identifying middle ear cholesteatoma. A meta-analysis of the published literature. A systematic review of the literature was performed to identify studies in which patients suspected of having middle ear cholesteatoma underwent DW MRI scans prior to surgery. A meta-analysis of the included studies was performed. Ten published articles (342 patients) met inclusion criteria. Cholesteatoma was confirmed in 234 patients, of which 204 were detected by DW MRI (true positives) and 30 were not (false negatives). One hundred eight patients did not have cholesteatoma on surgical examination, and of these 100 were correctly identified by MRI (true negatives) whereas eight were not (false positives). The overall sensitivity of DW MRI in detecting cholesteatoma was 0.94 (confidence interval, 0.80-0.98) and specificity 0.94 (confidence interval, 0.85-0.98). DW MRI sequences could not reliably detect cholesteatomas under 3 mm in size. Non-echo-planar DW MRI is highly sensitive and specific in identifying middle ear cholesteatoma. DW MRI may help to stratify patients into groups of who would benefit from early second-look surgery and those who could be closely observed. 2a.


Polymerase chain reaction primer sets for the detection of genetically diverse human sapoviruses.
Sapoviruses are increasingly being recognized as pathogens associated with gastroenteritis in humans. Human sapoviruses are currently assigned to 18 genotypes (GI.1-7, GII.1-8, GIV.1, and GV.1-2) based on the sequence of the region encoding the major structural protein. In this study, we evaluated 11 polymerase chain reaction (PCR) assays using published and newly designed/modified primers and showed that four PCR assays with different primer combinations amplified all of the tested human sapovirus genotypes using either synthetic DNA or cDNA prepared from human sapovirus-positive fecal specimens. These assays can be used as improved broadly reactive screening tests or as tools for molecular characterization of human sapoviruses.


Learning spatiotemporal features of DSA using 3D CNN and BiConvGRU for ischemic moyamoya disease detection.
Moyamoya disease (MMD) is a serious intracranial cerebrovascular disease. Cerebral hemorrhage caused by MMD will bring life risk to patients. Therefore, MMD detection is of great significance in the prevention of cerebral hemorrhage. In order to improve the accuracy of digital subtraction angiography (DSA) in the diagnosis of ischemic MMD, in this paper, a deep network architecture combined with 3D convolutional neural network (3D CNN) and bidirectional convolutional gated recurrent unit (BiConvGRU) is proposed to learn the spatiotemporal features for ischemic MMD detection. Firstly, 2D convolutional neural network (2D CNN) is utilized to extract spatial features for each frame of DSA. Secondly, the long-term spatiotemporal features of DSA sequence are extracted by BiConvGRU. Thirdly, the short-term spatiotemporal features of DSA are further extracted by 3D convolutional neural network (3D CNN). In addition, different features are extracted when gray images and optical flow images pass through the network, and multiple features are extracted by features fusion. Finally, the fused features are utilized to classify. The proposed method was quantitatively evaluated on a data sets of 630 cases. The experimental results showed a detection accuracy of 0.9788, sensitivity and specificity were 0.9780 and 0.9796, respectively, and area under curve (AUC) was 0.9856. Compared with other methods, we can get the highest accuracy and AUC. The experimental results show that the proposed method is stable and reliable for ischemic MMD detection, which provides an option for doctors to accurately diagnose ischemic MMD.


Effect of biological and chemical oxidation on the removal of estrogenic compounds (NP and BPA) from wastewater: an integrated assessment procedure.
A major source of the wide presence of EDCs (Endocrine Disrupting Compounds) in water bodies is represented by direct/indirect discharge of sewage. Recent scientific literature reports data about their trace concentration in water, sediments and aquatic organisms, as well as removal efficiencies of different wastewater treatment schemes. Despite the availability of a huge amount of data, some doubts still persist due to the difficulty in evaluating synergistic effects of trace pollutants in complex matrices. In this paper, an integrated assessment procedure was used, based on chemical and biological analyses, in order to compare the performance of two full scale biological wastewater treatment plants (either equipped with conventional settling tanks or with an ultrafiltration membrane unit) and tertiary ozonation (pilot scale). Nonylphenol and bisphenol A were chosen as model EDCs, together with the parent compounds mono- and di-ethoxylated nonylphenol (quantified by means of GC-MS). Water estrogenic activity was evaluated by applying the human breast cancer MCF-7 based reporter gene assay. Process parameters (e.g., sludge age, temperature) and conventional pollutants (e.g., COD, suspended solids) were also measured during monitoring campaigns. Conventional activated sludge achieved satisfactory removal of both analytes and estrogenicity. A further reduction of biological activity was exerted by MBR (Membrane Biological Reactor) as well as ozonation; the latter contributed also to decrease EDC concentrations.


RISK PREDICTORS OF EARLY CHILDHOOD CARIES INCREMENT-A SYSTEMATIC REVIEW AND META-ANALYSIS.
This systematic review aimed to investigate the risk predictors of caries in primary teeth and evaluate their association with the increment of Early Childhood Caries (ECC) among preschool children. This systematic review included only cohort or case-control studies of at least 2 years duration, over 300 participants and with English full-text. Potentially eligible studies were retrieved from 4 electronic databases (Ovid Embase, Ovid MEDLINE; PubMed, Web of Science) from inception to March 1, 2021. Independent screening and data extraction by 2 reviewers to identify factors associated with ECC increment, including family and socioeconomic factors, dietary and oral health-related habits, and clinical parameters. A total of 18 studies from 163 potential reports were included, involving 1,159,226 preschool children. Lower parental education attainment was found associated with ECC increment (WMD:0.87; 95% CI 0.52, 1.21); whereas immigration status (WMD:-0.38; 95% CI -1.09, 0.34), gender (WMD:-0.02; 95% CI -0.28, 0.24), and dental service utilization (WMD:0.35; 95% CI -0.10, 0.79) were not significant factors for ECC increment. All included studies consistently suggested positive correlations between ECC increment and baseline caries experience, plaque level, cariogenic microorganisms, and prenatal and passive smoking, while mixed findings were detected between ECC increment with dietary and oral hygiene practices. Preschool children whose parents have low education level are more likely to have greater increment of ECC over 2 years. Existing caries lesions, increased dental plaque level, cariogenic microorganisms, prenatal or passive smoking were also consistently identified as risk factors for ECC in all reviewed studies. This systematic review highlights specific risk factors to target for the prevention of ECC and supports implementing more oral health promotion for preschool children with parents of lower educational attainment.


[Guideline-adherent psychiatric-psychotherapeutic hospital care: Normative definition of staff required using the example of depression].
Unipolar depression is of high relevance in German inpatient treatment. An effective psychiatric psychotherapeutic hospital treatment also requires sufficient staff for carrying out psychotherapeutic treatment. The aim of this study was to define the staff requirements for guideline-adherent psychiatric-psychotherapeutic inpatient treatment of depression on the basis of a weekly treatment schedule for a 5-week admission period. A further aim was to compare the staff required with the resources defined by the German psychiatric staffing regulations (Psych-PV). The weekly schedule was normatively defined on the basis of the current evidence for treatment efficacy and effectiveness. The staff required was calculated on the basis of the weekly schedule. The time for psychotherapy defined by the Psych-PV was calculated using the treatment classification provided by a large nationwide database. Regarding psychotherapy, 280 min per week is regarded as necessary and usually sufficient according to the current evidence. The results showed clearly higher requirements of working time of psychiatrists and psychologists than those defined by the Psych-PV. In particular, the Psych-PV allows only 72 min for psychotherapy per patient and week and only a limited amount of direct patient contact with psychiatrists. The figures provided impressively show that the Psych-PV does not allow effective guideline-adherent hospital treatment within a reasonable length of hospital stay. Despite its evidential effectiveness, psychotherapeutic treatment cannot be sufficiently provided under the current financing circumstances.


D-galactose supplementation in individuals with PMM2-CDG: results of a multicenter, open label, prospective pilot clinical trial.
PMM2-CDG is the most prevalent congenital disorder of glycosylation (CDG) with only symptomatic therapy. Some CDG have been successfully treated with D-galactose. We performed an open-label pilot trial with D-galactose in 9 PMM2-CDG patients. Overall, there was no significant improvement but some milder patients did show positive clinical changes; also there was a trend toward improved glycosylation. Larger placebo-controlled studies are required to determine whether D-galactose could be used as supportive treatment in PMM2-CDG patients.Trial registration ClinicalTrials.gov Identifier: NCT02955264. Registered 4 November 2016, https://clinicaltrials.gov/ct2/show/NCT02955264.


Mapping the Antimicrobial Supply Chain in Bangladesh: A Scoping-Review-Based Ecological Assessment Approach.
Maintaining access to antimicrobials while preventing misuse is essential to combating the threat of antimicrobial resistance (AMR). The study objectives are to propose a framework of 16 indicators that can be used at the national level to assess the capacity to ensure access and curtail inappropriate use and to profile the antimicrobial supply chain for Bangladesh. Using a framework based on a rational construct, we assessed the antimicrobial supply chain of Bangladesh, with a focus on key players and products using a scoping review to obtain and describe information on 16 indicators. With players, we mapped linkages, manufacturers' production capacity, and ownership, among others, and demand point characteristics-pharmacy and pharmacist density, pharmacy/medicine outlets dispersion, veterinary clinic/hospitals, veterinarians' density, product quality, and regulation. We assessed product characteristics including listing on the World Health Organization (WHO) Model Essential Medicines List (EML) and WHO Access, Watch, and Reserve (AWaRe) classification of the major (top 10) antibiotics for human use; the proportion of medically important antimicrobials (MIAs) in veterinary use; and pricing. Production capacity and price controls were used to assess access and listing on the WHO EML, AWaRe/MIA classification, and a calculated pharmacy-to-pharmacist ratio to assess use. Bangladesh has a high (98%) local antibiotic production capacity with pricing controls indicating the ability to ensure access. The presence of a high proportion of medicine outlets not under the control of pharmacists (4:1) and the high percentages of WHO Watch (54%) and MIAs (90%) of the major antibiotics are indicators of possible misuse. Most of the data used in the framework were publicly available. Bangladesh has the capacity to ensure access but needs to strengthen its ability to regulate the quality of antimicrobials and prevent their inappropriate use through antimicrobial stewardship at the community (medicine outlet) levels to check AMR. There may also be a need for more regulations on licensing of MIAs.


CD169+ lymph node macrophages have protective functions in mouse breast cancer metastasis.
Although the contribution of macrophages to metastasis is widely studied in primary tumors, the involvement of macrophages in tumor-draining lymph nodes (LNs) in this process is less clear. We find CD169+ macrophages as the predominant macrophage subtype in naive LNs, which undergo proliferative expansion in response to tumor stimuli. CD169+ LN macrophage depletion, using an anti-CSF-1R antibody or clodronate-loaded liposomes, leads to increased metastatic burden in two mouse breast cancer models. The expansion of CD169+ macrophages is tightly connected to B cell expansion in tumor-draining LNs, and B cell depletion abrogates the effect of CD169+ macrophage absence on metastasis, indicating that the CD169+ macrophage anti-metastatic effects require B cell presence. These results reveal a protective role of CD169+ LN macrophages in breast cancer metastasis and raise caution for the use of drugs aiming at the depletion of tumor-associated macrophages, which might simultaneously deplete macrophages in tumor-draining LNs.


Physical therapy interventions in an inpatient rehabilitation setting for functional neurological disorder: A case series.
Patients with functional neurological disorder (FND) experience a variety of symptoms that affect their functional mobility and quality of life. Physical therapy can help promote normal movement patterns and restore independence. Although consensus recommendations have been published, choosing specific interventions can be a challenge due to the heterogeneity of symptom presentation. This case series aims to detail specific interventions for three patients with FND who were admitted to an inpatient rehabilitation facility in Boston, MA, USA. Each presented with gait disturbances as his or her primary symptom and received physical therapy at least five times per week during the inpatient stay, as well as treatment from a multidisciplinary team. As emerging literature continues and the diagnosis is more widely accepted, specific symptom interventions may become more generalized and lead to better outcomes with this patient population.


Kasabach-Merritt syndrome treated by therapeutic embolization with polyvinyl alcohol.
The authors describe a 6 1/2-month-old boy with a large hemangioma involving the left buttock associated with a severe consumptive coagulopathy. Cosmetic improvement and resolution of the coagulation defect followed occlusion of the nutrient vessels to the hemangioma with polyvinyl alcohol. This is the first report of successful treatment of this condition with therapeutic embolization.


Incidence and trends of stroke and its subtypes in China: results from three large cities.
To examine the incidence and trends of stroke and its major subtypes during the 1990s in 3 cities in China. Stroke cases registered between 1991 to 2000 were initially identified through the stroke surveillance networks established in Beijing, Shanghai, and Changsha, and then confirmed by neurologists. The age-standardized incidence rates per 100,000 person years of overall first-ever stroke were 135.0 (95% CI, 126.5 to 144.6) in Beijing, 76.1 (70.6 to 82.6) in Shanghai, and 150.0 (141.3 to 160.0) in Changsha during the 1990s. Incidence of ischemic stroke (IS) was highest in Beijing, followed by Changsha and Shanghai; for intracerebral hemorrhage (ICH), the highest rate was found in Changsha, followed by Beijing and Shanghai. The same order as ICH was also observed for subarachnoid hemorrhage. The age-adjusted incidence of overall stroke and ICH for individuals > or =55 years of age in our populations was generally higher than that from Western populations. During the 1990s, ICH incidence decreased significantly at a rate of 12.0% per year in Beijing, 4.4% in Shanghai, and 7.7% in Changsha; in contrast, except for Changsha, IS incidence increased in Beijing (5.0% per year) and Shanghai (7.7%). There is a geographic variation in the incidence of stroke and its subtypes among these 3 cities, but the incidence of overall and hemorrhagic stroke in China is generally higher than that in the Western countries. Interestingly, the decrease in ICH and increase in IS during the past decade may reflect some underlying changes of risk factors in Chinese populations.


Preoperative systemic chemotherapy does not benefit for appendiceal pseudomyxoma peritonei.
Pseudomyxoma peritonei (PMP) is a clinically malignant tumour syndrome mainly derived from mucin-producing appendiceal tumours. This study aimed to explore the effect of preoperative systemic chemotherapy (PSC) before cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) on the safety and postoperative survival in patients with appendiceal PMP. We performed a retrospective analysis including consecutive patients with PMP undergoing primary surgery between January, 2008 and December, 2019 in Aerospace Center Hospital. The clinical data and postoperative survival were compared between PSC group and non-PSC group. Seven hundred and fifty patients were included in the study. Significant differences were found between PSC group and non-PSC group on clinicopathological data and perioperative outcomes and the independent risk factor of serious complications was blood loss >1000 mL (P = 0.026). Shorter median overall survival (OS) was found (42 months, 95% CI 31.9-52.1) in PSC group than that (67 months 95% CI 44.5-89.5) in non-PSC group. In the stratified study with PCI < 20, CC 0/1 and low-grade pathological subtype, the OS from non-PSC group was significantly better than that in PSC group (log rank P-values are <0.001, 0.006 and <0.001, respectively). Multivariate survival analysis showed that CC 0/1, HIPEC, PCI < 20 and low-grade pathological subtype were the independent prognostic factors for better OS. PSC does not increase the risk of major perioperative complications in patients with appendiceal PMP, but it also does not bring postoperative survival benefits to patients either.


Radiologic investigation of abdominal aortic aneurysm disease: comparison of three modalities in staging and the detection of inflammatory change.
The purpose of this study was to compare the ability of ultrasonography (US), contrast-enhanced computed tomography (CT), and magnetic resonance imaging (MRI) to display the anatomy of abdominal aortic aneurysms and to detect the presence of inflammatory change. We prospectively studied 79 patients with abdominal aortic aneurysms (64 noninflammatory aneurysms [NIAAs] and 15 inflammatory aneurysms [IAAs]) with US, CT, and MRI. Ultrasonography failed to diagnose the level of the aneurysm neck in three IAAs and 18 NIAAs. It failed to differentiate NIAAs from IAAs and to visualize the origins of the renal arteries in all cases. With CT the level of the aneurysm neck was incorrectly stated as lying above the level of the renal arteries in two cases of IAA and four cases of NIAA, and the renal artery origins were seen in only 10 of 77 patients. Inflammatory change was diagnosed correctly in seven of 15 patients, whereas six NIAAs were falsely diagnosed as inflammatory. MRI successfully diagnosed neck level and inflammatory change in all cases. Of two failures to visualize the renal artery origins, only one was caused by radiologic factors. In addition, characteristic radiologic features were seen in MRI images of IAAs, and these will be described both in vivo and in vitro. Our results suggest that MRI is superior to other methods in identifying the anatomy of aneurysms and the presence of inflammatory change.


Solution structure of human steroidogenic acute regulatory protein STARD1 studied by small-angle X-ray scattering.
Intracellular cholesterol transfer to mitochondria, a bottleneck of adrenal and gonadal steroidogenesis, relies on the functioning of the steroidogenic acute regulatory protein (StAR, STARD1), for which many disease-associated mutations have been described. Despite significant progress in the field, the exact mechanism of cholesterol binding and transfer by STARD1 still remains debatable and often considers significant structural rearrangements to achieve ligand binding. The crystal structure of STARD1, obtained recently at medium resolution, suggests that this protein has the same fold as other members of the START family. However, hydrodynamic properties and solution conformation of STARD1 are insufficiently characterized, partially due to poor solubility of this protein. Here, we used our recent protocol to obtain stable and soluble STARD1 and analyzed its hydrodynamic properties and solution conformation using a previously inapplicable small-angle X-ray scattering (SAXS). The SAXS data obtained exclusively from a monodisperse fraction of the monomeric protein suggest that, apart from movements of the flexible Ω1-loop, STARD1 unlikely undergoes significant spontaneous rearrangements proposed earlier as a gating mechanism for cholesterol binding. The consistency with the previously reported solution NMR structure of STARD6 suggests similarity of hydrodynamic behavior of other STARD-containing proteins.


Investigation of candidate molecular biomarkers for expression profile analysis of the Gene expression omnibus (GEO) in acute lymphocytic leukemia (ALL).
Much progress has been made in understanding the mechanism of acute lymphocytic leukemia (ALL). However, for adult ALL, there is still a lack of an effective treatment. In the present study, we first used the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between ALL cell lines and Hodgkin and non-Hodgkin cell lines. Then, the GEO database was also used to detect the DEGs in acute lymphoblastic leukemia (Reh) cells transfected with a normal control or a constitutively active variant of the IkB kinase β. Finally, we found that three key DEGs (CCL5, FSCN1, and HS3ST1) are involved in proliferation and apoptosis according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) pathway analyses. Finally, we determined that all three target genes that participate in proliferation and apoptosis are regulated via the NF-kB signaling pathway.


Treatment of relapsed acute lymphoblastic leukemia: approaches used by pediatric oncologists and bone marrow transplant physicians.
Management of relapsed B-precursor acute lymphoblastic leukemia (ALL) is challenging and varied. We hypothesized that treatment approaches differ between pediatric oncologists and bone marrow transplant (BMT) physicians. A survey addressing management of relapsed ALL was sent to pediatric oncologists (n = 883) and BMT (n = 86) physicians across North America. A number of similarities in treatment approaches were identified including: choice of chemotherapy for re-induction/consolidation, preference for unrelated donors (URDs) in very early marrow relapse and the choice to not use URD donors in late marrow relapse. However, differences between the two disciplines were noted. For patients who relapsed 18-36 months from diagnosis, the majority of oncologists (53.7%) would retreat with chemotherapy while a majority BMT physicians (70.3%) recommended URD transplant (P < 0.001). Oncologists were also less likely to use minimal residual disease (MRD) in relapse assessment compared to BMT physicians (52% vs. 67.2%; P = 0.028) and more oncologists believed MRD testing was experimental and/or not proven in relapsed ALL (27.1% vs. 12.3%; P = 0.011). This study highlights management differences in children with ALL between pediatric oncologists and BMT physicians, identifying opportunities for collaborative clinical trials.


Microgels based on 0D-3D carbon materials: Synthetic techniques, properties, applications, and challenges.
Microgels are three-dimensional (3D) colloidal hydrogel particles with outstanding features such as biocompatibility, good mechanical properties, tunable sizes from submicrometer to tens of nanometers, and large surface areas. Because of these unique qualities, microgels have been widely used in various applications. Carbon-based materials (CMs) with various dimensions (0-3D) have recently been investigated as promising candidates for the design and fabrication of microgels because of their large surface area, excellent conductivity, unique chemical stability, and low cost. Here, we provide a critical review of the specific characteristics of CMs that are being incorporated into microgels, as well as the state-of-the art applications of CM-microgels in pollutant adsorption and photodegradation, H2 evoluation, CO2 capture, soil conditioners, water retention, drug delivery, cell encapsulation, and tissue engineering. Advanced preparation techniques for CM-microgel systems are also summarized and discussed. Finally, challenges related to the low colloidal stability of CM-microgels and development strategies are examined. This review shows that CM-microgels have the potential to be widely used in various practical applications.


Identification of microbial inhibitory functional groups in corn stover hydrolysate by carbon-13 nuclear magnetic resonance spectroscopy.
Dilute-acid biomass hydrolysates contain biomass degradation products that are inhibitory to cell growth and fermentation. Overliming with Ca(OH)2 has been found to be one of the most effective methods for detoxifying the dilute-acid hydrolysate for ethanol production. However, the mechanism of overliming is not well understood. Carbon-13 nuclear magnetic resonance (13C-NMR) spectroscopy was used to elucidate the functional groups involved in the overliming reaction. The 13C-NMR spectra showed that the major functional groups removed during the overliming process were aliphatic and aromatic acids or esters, and other aromatic and aliphatic compounds. Ketone and aldehyde functionalities were not detected in the spectra. This is the first time that 13C-NMR has been used to elucidate the overliming reaction.


Liquid nitrogen: temperature control in the treatment of actinic keratosis.
Actinic keratoses (AKs) are in situ epidermal tumors that may progress to invasive squamous cell carcinomas. Liquid nitrogen is used during cryotherapy to freeze the epidermis and upper dermis and is the standard treatment for individual AKs. To evaluate the efficacy of a cryosurgery device incorporating an infrared sensor to measure the temperature at the skin surface while spraying liquid nitrogen on the surface of the skin during the treatment of AKs. Thirty-six patients with 180 thin AKs were treated with liquid nitrogen spray to a temperature of -5°C using the sensor to control the temperature at the skin surface. Patients were evaluated for cure rate, side effects, and healing time. At the 1-week follow-up, 66.7% of the lesions were cleared. By the 6-week follow-up, there was a 100% cure rate. Side effects were limited to redness, blistering, crusting, oozing, and ulceration at the 1-week follow-up and were resolved by the 6-week follow-up. No recurrence of AK, scarring, or hypopigmentation was noted. Cryotherapy with an integrated sensor for temperature control is an effective, safe, and precise treatment, allowing for a 100% short-term cure rate of AKs.


First record of acerola weevil, Anthonomus tomentosus (Faust, 1894) (Coleoptera: Curculionidae), in Brazil.
The weevil of acerola fruits, Anthonomus tomentosus (Faust, 1894) (Coleoptera: Curculionidae), is recorded for the first time in Brazil. Samples of this insect were collected in fruits of acerola, Malpighia emarginata D.C. (Malpighiaceae), in four municipalities in the north-central region of Roraima State, in the Brazilian Amazon. Information about injuries observed in fruits infested with A. tomentosus, its distribution in Roraima, and suggestions for pest management are presented.


Therapeutic alternatives in painful diabetic neuropathy: a meta-analysis of randomized controlled trials.
One of the most frequent problems caused by diabetes is the so called painful diabetic neuropathy. This condition can be treated through numerous types of therapy. The purpose of this study was to analyze, as a meta-analysis, different treatments used to alleviate painful diabetic neuropathy, with the aim of generating results that help making decisions when applying such treatments to tackle this pathology. A search was conducted in the main databases for Health Sciences, such as PUBMED, Web of Science (WOS), and IME biomedicina (Spanish Medical Reports in Biomedicine), to gather randomized controlled trials about treatments used for painful diabetic neuropathy. The analyzed studies were required to meet the inclusion criteria selected, especially those results related to pain intensity. Nine randomized controlled trials were chosen. The meta-analysis shows significant positive effects for those treatments based on tapentadol [g: -1.333, 95% CI (-1.594; -1.072), P < 0.05], duloxetine [g: -1.622, 95 % CI (-1.650; -1.594), P < 0.05], pregabalin [g: -0.607, 95% CI (-0.980; -0.325), P < 0.05], and clonidine [g: -0.242, 95 % CI (-0.543; -0.058), P < 0.05]. This meta-analysis indicates the effectiveness of the treatments based on duloxetine, gabapentin and pregabalin, as well as other drugs, such as tapentadol and topic clonidine, whose use is better prescribed in more specific situations. The results provided can help increase the knowledge about the treatment of painful diabetic neuropathy and also in the making of clinical practice guidelines for healthcare professionals.


Hepatic arterial infusion chemotherapy in the treatment of advanced hepatocellular carcinoma with portal vein thrombosis: a case-control study.
To study the treatment efficacy and survival of hepatic arterial infusion chemotherapy (HAIC) for patients with advanced hepatocellular carcinoma (HCC) and portal vein tumour thrombosis (PVTT) with compensated cirrhosis in comparison with sorafenib as the standard of care therapy versus best supportive care (BSC). This case-control study included 91 patients with advanced HCC and PVTT divided into three groups: Group 1 20 treated with HAIC, (50 mg adriamycin and 50 mg cisplatin were infused in hepatic artery); Group 2, 42 patients treated with BSC; and Group 3, 29 patients treated with sorafenib. Patients were followed up for assessment and comparison of treatment outcome by modified Response Evaluation Criteria in Solid Tumours (mRECIST) and survival. There was no significant difference among the groups studied regarding baseline demographic and tumour characteristics. The majority of patients who received sorafenib therapy (82.8%) had stable disease. The response rate (complete response + partial response) was significantly better in the HAIC group. HAIC patients had the longest survival compared with the best supportive care and sorafenib groups, which was statistically significant (29.2 ± 21.8, 4.55 ± 11.41, and 11.52 ± 8.72 months respectively, p=0.007) CONCLUSION: HAIC is a safe procedure with a better response rate and longer survival than best supportive care or sorafenib for patients with advanced HCC and PVTT.


Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma.
Matrix metalloproteinases have been implicated in invasion and metastasis of various human malignant tumors, but its role in human hepatocellular carcinoma has not been characterized in detail. The aim of the present study was to examine the secretion and activation of metalloproteinases in liver tissues from patients with hepatocellular carcinoma and evaluate its relationship with clinicopathologic characteristics. Activity of metalloproteinases was measured in 30 surgical specimen pairs of human primary hepatocellular carcinoma and adjacent nontumoral liver and in five cultured human hepatoma cell lines using zymography. A comparison of this activity with clinicopathological features was made. In the liver tissues, enhanced secretion of active forms of gelatinase A and matrilysin was associated with portal venous invasion (P < 0.05, respectively), intrahepatic metastasis (P < 0.05, respectively), and recurrence within the first postoperative year (P < 0.01 and P < 0.05, respectively). Enhanced messenger RNA expression for membrane type 1-matrix metalloproteinase was observed in 22 of 30 cases and associated with capsule invasion and the activation of progelatinase A (P < 0.05, respectively). Active gelatinase A, active matrilysin, and membrane type 1-matrix metalloproteinase may play an important role in tumor spread of human hepatocellular carcinoma.


Flexural and extensoral eruptions in dermatologic disease.
Dermatologic eruptions can be generalized or localized to specific areas of the body. Eruptions in specific body regions may suggest specific diagnosis. Recognizing such clinical patterns can facilitate the identification of the underlying pathology. In this contribution, we shall discuss those dermatologic lesions that tend to affect the flexure and extensor surfaces.


Decellularization, cross-linking and heparin immobilization of porcine carotid arteries for tissue engineering vascular grafts.
Tissue engineering vascular grafts (TEVGs) have the potential to replace small-diameter grafts in bypass surgery which is good news for patients with cardiovascular disease. Decellularized arteries can be ideal TEVGs because their natural three-dimensional structures support the migration of host cells and vascular remodeling. There are many methods for decellularization without a standard protocol. In this study, a combination of Triton X-100 and sodium dodecyl sulfate (SDS) were used to prepare decellularized arteries. However, decellularization may damage the biochemical and mechanical properties to some degree. We used the cross-linking agents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) to improve mechanical properties and immobilize heparin to inhibit thrombogenesis. Histological analysis, scanning electron microscopy, biomechanical properties test, determination of immobilized heparin, active partial thrombin time assay, and subcutaneous embedding experiment were used to evaluate the efficiency of decellularization and the efficacy of heparinized cross-linked vascular scaffold. Results showed 1% Triton X-100 combined with 0.3% SDS can decellularize successfully. EDC and NHS cross-linking can improve the mechanical properties, reduce the inflammatory reaction and slow the degradation time. Heparin immobilized on the scaffolds can inhibit thrombogenesis effectively. This study indicated the heparinized cross-linked vascular scaffolds may be ideal scaffolds for TEVGs.


Load cell analysis following silastic arthroplasty of the hallux.
The first metatarsophalangeal joint was replaced by a flexible silastic hinge prosthesis in 33 joints of 25 patients. Most patients were pleased with the operation but one third had some discomfort under the second and third metatarsal heads. We used a computer linked load cell matrix to analyse the forces under these feet during normal walking. After silastic arthroplasty there was a rise of 65% in peak load under the second and third metatarsal heads compared with that found in the opposite feet which had not undergone operation (P less than 0.001). This was associated with a fall in peak load under the hallux of 43% (P less than 0.03) compared to normal and a less significant fall averaging 23% in the peak pressure experienced under the first metatarsal head. There was a rise in peak heel loading and a reduction in the normal pronation which occurs during the stance phase of walking.


Heat transfer study of a new hybrid photovoltaic/thermal direct absorption parabolic solar collector by two-phase Buongiorno model.
Solar energy is one of the cleanest sources of renewable energy that is easily accessible in vast geographical areas. As the efficiency of the common solar collectors is very low and is limited by the absorption properties of working fluid, enhancing the thermal performance of these collectors is one of the major challenges of developing parabolic solar thermal power plants. In recent decades, researches revealed that utilizing nanofluid as a novel working fluid has a dramatic effect on the thermophysical and optical properties of the fluid. In this study, the flow and temperature fields of water/magnetite and water/aluminum nanofluids are evaluated by solving the steady form of governing equations including conservation laws of mass, volume fraction transport equation, momentum equation, energy equation, and radiation transfer equation. Moreover, the two-phase Buongiorno model is utilized and Brownian motion, thermophoresis effects, and magnetophoresis movement are taken into account in the nanofluid simulation. The numerical results demonstrate that increasing nanofluid volume fraction and flow rate can increase the thermal performance of the collector tube. It is found that the thermal efficiencies reach maximum values of 151.03% and 158.58% for water/aluminum and water/magnetite nanofluids, respectively. Furthermore, increasing the volume fraction from 0 to 0.3% leads to rise of 24.41% and 21.36% in the maximum temperature of the collector. The effects of different parameters such as nanoparticle volume fraction, flow rate, and nanoparticle kind on the collector thermal and electrical efficiencies, thermal distribution, and entropy production have been studied.


Microbial degradation of hydrophobic emerging contaminants from marine sediment slurries (Capbreton Canyon) to pure bacterial strain.
Despite emerging contaminants (ECs) are more and more monitored in environmental matrices, there is still a lack of data in marine ecosystems, especially on their fate and degradation potentials. In this work, for the first time, the degradation potential of synthetic musks (galaxolide and tonalide), UV filters (padimate O and octocrylene) and a pharmaceutical compound (carbamazepine) was studied in marine sediment samples, under laboratory conditions using sediment slurry incubations under biotic and abiotic conditions. Minimum half life times under biotic conditions were found at 21 days, 129 days and 199 days for padimate O, galaxolide and carbamazepine, respectively. Enrichments conducted under anoxic and oxic conditions demonstrated that degradations after one month of incubation either under both biotic and abiotic conditions were limited under anoxic conditions compared to oxic conditions for all the contaminants. Novel aerobic bacteria, able to degrade synthetic musks and UV filters have been isolated. These novel strains were mainly related to the Genus Bacillus. Based on these results, the isolated strains able to degrade such ECs, can have a strong implication in the natural resilience in marine environment, and could be used in remediation processes.


Reducing peak corneal haze after photorefractive keratectomy in rabbits: prednisolone acetate 1.00% versus cyclosporine A 0.05%.
To compare the effects of topical cyclosporine A 0.05% (Restasis) with those of prednisolone acetate 1.00% (Pred Forte) on corneal haze after photorefractive keratectomy (PRK). Gavin Herbert Eye Institute, University of California, Irvine-Orange, California, USA. Experimental study. After -9.00 diopter PRK, 15 rabbits were divided into 3 groups and treated for 4 weeks with prednisolone acetate 1.00% or cyclosporine A 0.05% or neither (control). Corneal haze was measured by in vivo confocal microscopy preoperatively and 2, 4, 6, 8, and 12 weeks postoperatively. At 12 weeks, the corneas were evaluated for collagen organization by ex vivo 2-photon second-harmonic generation and stromal cell density. Corneal haze was significantly less in the prednisolone acetate group than in the cyclosporine and control groups during the first 6 weeks postoperatively (P<.02). At 8 weeks, there was no significant difference between the 3 groups. There was no significant difference in haze between the cyclosporine and control groups at any time. The stroma was also significantly thinner in the prednisolone acetate group than in the other groups for the first 4 weeks postoperatively (P<.02). Second-harmonic generation scar thickness measurements at 12 weeks were not significantly different between the groups, although the prednisolone acetate group tended to have lower stromal cell density. Cyclosporine A 0.05% had no effect on wound healing after PRK, while prednisolone acetate 1.00% significantly reduced peak corneal haze but had no effect on long-term corneal haze after discontinuation of the drug.


A theoretical model for the prevention of Banana Moko (Musa AAB Simmonds).
A population simulation model with non-linear ordinary differential equations is presented, which interprets the dynamics of the banana Moko, with prevention of the disease and population of susceptible and infected plants over time. A crop with a variable population of plants and a logistic growth of replanting is assumed, taking into account the maximum capacity of plants in the delimited study area.


Diversity and functional characterization of endophytic Methylobacterium isolated from banana cultivars of South India and its impact on early growth of tissue culture banana plantlets.
This study aimed at determining the distribution, colonization and growth promoting nature of Methylobacterium spp. in tissue culture banana plantlets. Leaf samples from different field grown banana cultivars were used for Methylobacterium spp., isolation. Metabolic profile and functional characterization for plant growth-promoting traits of the isolates were assessed. The isolates were confirmed using 16S rRNA gene sequencing analysis, which resulted in six distinct species of Methylobacterium namely M. radiotolerans, M. salsuginis, M. thiocyanatum, M. rhodesianum, M. rhodinum and M. populi. Methylobacterium spp. inoculation experiment was conducted under hydroponic system in tissue culture banana plantlets (germ free) with eight selected isolates. A significant increase in growth parameters of Methylobacterium treated plantlets compared to uninoculated control was observed. Methylobacterium salsuginis TNMB03-gfp29 was developed and colonization micrograph was obtained using confocal laser scanning microscopy (CLSM) and scanning electron microscopy in different parts of banana plantlets (root, stem and leaves). Field grown banana plants found to harbour diverse endophytic Methylobacterium population. Our finding suggests that endophytic Methylobacterium species may provide significant plant growth promoting compounds/nutrients to the banana plants. The experimental results demonstrated the efficacy of Methylobacterium spp. as a potential bioinoculant and can be exploited as a phyllosphere and rhizosphere based bioinoculant for the initial establishment and growth of tissue culture banana plantlets. This study extended our knowledge on the distribution of Methylobacterium spp. in banana plants and endophytic colonization nature of this particular genus in plants. In addition, efficient isolate (M. salsuginis TNMB03) identified in this study may be promoted as bio-inoculants for banana plants after field evaluation.


Urinary deoxynivalenol as a biomarker of exposure in different age, life stage and dietary practice population groups.
The Fusarium mycotoxin deoxynivalenol (DON) and its modified forms are present in most samples of grain and grain-based products. Due to the widespread presence of DON in these highly consumed food commodities, nearly all individuals are exposed to DON. Previous estimates of the dietary DON intake in Norway indicated that children's dietary intake is close to or exceed the TDI of 1 µg/kg bw/day for the sum of DON and three modified forms. One aim of the current study was to determine whether the concentrations of DON in morning urine differ between population groups like men, women, children, vegetarians, and pregnant women. An additional aim was to compare a set of models for estimating the dietary intake of DON based on urinary DON concentrations and also compare these models with DON-intakes estimated using food consumption data. DON and metabolites were detected in the morning urine from 256 out of 257 individuals and with concentrations in similar range as reported from other countries. Children have higher urinary DON-concentration than adults and elderly. The urinary DON-concentration in pregnant women and vegetarians did not differ from other adults. The estimated intake of DON was higher for children than for other age groups on a body weight basis. The correlations between different models for estimating DON-intake based on urinary concentration as well as based on individual food consumption were good (0.79-0.99), but with some outliers. We conclude that Norwegians are exposed to DON in the same range as reported from other countries and that children have a higher exposure than adults. Furthermore, we conclude that intake estimates based on urinary DON concentration is a useful tool for evaluation of the exposure at population level, but due to outliers, the estimates for individuals are uncertain. There are also uncertainties in intake estimates both from food consumption and from urinary DON concentration, and we could not conclude on which approach provides the most accurate exposure estimate.


WFUMB Position Paper-Incidental Findings, How to Manage: Spleen.
The World Federation for Ultrasound in Medicine and Biology (WFUMB) is addressing the issue of incidental findings (IFs) with a series of publications entitled "Incidental Imaging Findings-The Role of Medical Ultrasound." IFs are less commonly encountered in the spleen than in many other abdominal organs but remain a frequent dilemma in clinical practice. A histological diagnosis is rarely necessary for patient management. Many IFs, such as secondary spleens and splenic cysts, are harmless and do not require any further investigation. The diagnosis of many other focal splenic lesions is, however, often problematic. The following overview is intended to illustrate a variety of incidentally detected spleen pathologies such as size variants, shape variants, secondary spleens, focal splenic lesions and splenic calcifications. It should aid the examiner in establishing the diagnosis. Moreover, it should help the ultrasound practitioner decide which pathologies need no further investigation, those requiring interval imaging and cases in which immediate further diagnostic procedures are required.


The effect of late preterm birth on mortality of infants with major congenital heart defects.
We evaluated the effect of late preterm delivery (34 to 36 weeks) on hospital mortality of infants with congenital heart defects (CHDs). Retrospective record review of infants with major CHD born at or after to 34 weeks, cared for in a single tertiary perinatal center between 2002 and 2009. Factors associated with death before discharge from the hospital were ascertained using univariate and multivariate analyses. Of the 753 infants with CHD, 117 were born at late preterm. Using logistic regression analysis, white race (OR; 95% CI) (0.60; 0.39 to 0.95), late preterm delivery (2.70; 1.69 to 4.33), and need for intubation in the delivery room (3.15; 1.92 to 5.17) were independently associated with hospital death. Late preterm birth of infants with major CHDs was independently associated with increased risk of hospital death compared with delivery at more mature gestational ages.


Breastmilk pumping experiences of physician mothers: quantitative and qualitative findings from a nationwide survey study.
Nearly half of graduating medical students today are women, with many having children early in their careers, necessitating thoughtful consideration of practices and policies. The short duration of maternity leave for physician mothers often means that most who choose to breastfeed must return to work while still breastfeeding their infants. To characterize the experience of physician mothers and identify facilitators and barriers related to breastmilk pumping upon return to work. Cross-sectional nationwide survey study administered to physician mothers electronically via REDCap™ to broadly characterize their personal experiences with family leave and return to work. Physician mothers in the USA (n=724). Demographic data and survey responses related to experiences during family leave and return to work, including free-text response options when participants indicated "other" experiences not captured by the survey response options and one open-ended question asking, "What do you think are the most important factors contributing to a positive maternity/family leave experience?" For this study, we searched free-text responses across the entire survey for keywords related to breastfeeding and pumping and thematically analyzed them to summarize key features of physician mothers' experiences. Lack of time, flexibility, dedicated and hygienic locations for pumping breast milk, disrespect and lack of support from others, and concerns about financial consequences of productivity changes were the most common barriers to pumping breastmilk reported by physician mothers. Flexibility in scheduling, adjusted productivity targets, and clean, private, and well-equipped pumping rooms would likely provide the greatest support to help physician mothers thrive in their careers while simultaneously allowing them to provide the nourishment needed for their developing infants.


Iatrogenic upper limb nerve injuries: a systematic review.
Peripheral nerve injuries are among the most frequent iatrogenic complications and are responsible for considerable morbidity and litigation. Most occur within surgical settings and upper limb nerves are most frequently involved. A systematic review of major iatrogenic upper limb nerve injuries was undertaken to evaluate the contemporary spectrum of such injuries. The electronic databases MEDLINE, PubMed, Cochrane Library and Google Scholar were searched for relevant articles listed between January 2000 and May 2010. Iatrogenic injuries to the brachial plexus, radial, axillary, ulnar, median, musculocutaneous and major cutaneous nerves were analysed, focusing on context, mechanisms of injury and incidence. Iatrogenic upper limb nerve injuries are relatively common and can affect patients in any surgical specialty. Even patients undergoing diagnostic procedures under general anaesthesia are at risk. Orthopaedic surgery and plastic and reconstructive surgery figure prominently in these complications. The spectrum of iatrogenic peripheral nerve injuries has changed in parallel with technological advances in surgery, anaesthesia and medicine. Some iatrogenic upper limb peripheral nerve injuries may be unavoidable, but most cases are probably preventable by an adequate knowledge of surgical anatomy and an awareness of the types of procedures in which peripheral nerves are particularly vulnerable.


Adhesion of enteropathogenic Escherichia coli to pig intestinal brush borders: the existence of two pig phenotypes.
An in-vitro test that demonstrates adhesion of K88-positive Escherichia coli to brush borders prepared from the small intestine of the pig is described. K88-positive E. coli adhered to the brush borders from some pigs ("positive" pigs) but not others ("negative" pigs). The sires of the pigs tested could be placed into two groups, namely, those that sired only "positive" piglets, and those that sired a mixture of "positive" and "negative" piglets. The incidence of the two phenotypes in litters indicated that "positive" and "negative" piglets arose as a result of simple Mendelian inheritance. It is suggested that "negative" pigs could be bred and that they might have a natural resistance to neonatal infection with K88-positive E. coli.


MALT-1 mediates IL-17 neural signaling to regulate C. elegans behavior, immunity and longevity.
Besides pro-inflammatory roles, the ancient cytokine interleukin-17 (IL-17) modulates neural circuit function. We investigate IL-17 signaling in neurons, and the extent it can alter organismal phenotypes. We combine immunoprecipitation and mass spectrometry to biochemically characterize endogenous signaling complexes that function downstream of IL-17 receptors in C. elegans neurons. We identify the paracaspase MALT-1 as a critical output of the pathway. MALT1 mediates signaling from many immune receptors in mammals, but was not previously implicated in IL-17 signaling or nervous system function. C. elegans MALT-1 forms a complex with homologs of Act1 and IRAK and appears to function both as a scaffold and a protease. MALT-1 is expressed broadly in the C. elegans nervous system, and neuronal IL-17-MALT-1 signaling regulates multiple phenotypes, including escape behavior, associative learning, immunity and longevity. Our data suggest MALT1 has an ancient role modulating neural circuit function downstream of IL-17 to remodel physiology and behavior.


Estimating age by assessing the ossification degree of cranial sutures with the aid of Flat-Panel-CT.
Estimating age from the skeletons of adults is difficult. The accuracy decreases for old age. Ossification of the neurocranial sutures has been used as an age characteristic since Broca's time (1824-1880). Although the sutures traverse the bone, current approaches only encompass the ecto- and endocranial sutures. Evaluating the cross-section of sutures necessitates the destruction of the neurocranium. In the context of the "Digital Forensic Osteology" project that ran in cooperation with the Virtopsy-Project it emerged that the resolution of conventional MSCT-data sets was not high enough to image sutures. The eXplore Locus Ultra (eLU) Flat-Panel-CT-Scanner from GE was used for these experiments. During autopsy, the skullcap was scanned and then immediately returned to the corpse. To date, the skullcaps of 221 individuals have been scanned. The data sets were reconstructed in 3D. The cross sections of the sutures of 14 segments could be evaluated in the cross-sectional view. Seven stages of ossification were defined and each segment was assessed for these. Several regression formulae for age estimation were developed from the results. This examination method is a suitable means for non-invasively evaluating the ossification degree of cranial sutures in the entire cross-section and for the entire calvarium. An increase in the number of examined individuals in this ongoing project and a look at extreme values will further heighten the conclusiveness of the results.


Neuropeptide-S prevents 6-OHDA-induced gastric dysmotility in rats.
This study aims to explore the effect of chronic central neuropeptide-S (NPS) treatment on gastrointestinal dysmotility and the changes of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) of a Parkinson's disease (PD) rat model. The PD model was induced through a unilateral medial forebrain bundle (MFB) administration of the 6-hydroxydopamine (6-OHDA). Locomotor activity (LMA), solid gastric emptying (GE), and gastrointestinal transit (GIT) were measured 7 days after the surgery. NPS was daily administered (1 nmol, icv, 7 days). In substantia nigra (SN), dorsal motor nucleus of the vagus (DMV), and gastric whole-mount samples, changes in tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), glial fibrillary acidic protein (GFAP), NPS receptor (NPSR), and alpha-synuclein (Ser129) were examined by immunohistochemistry. Cuprolinic blue staining was used to evaluate the number of neuronal cells in myenteric ganglia. The GIT rate, the total number of myenteric neurons, and the expressions of ChAT, nNOS, TH, and GFAP in the myenteric plexus were not changed in rats that received the 6-OHDA. Chronic NPS treatment reversed 6-OHDA-induced impairment of the motor performance, and GE, while preventing the loss of dopaminergic and cholinergic neurons in SN and DMV, respectively. NPS attenuated 6-OHDA-induced α-syn (Ser129) pathology both in SN and DMV. Additionally, expression of NPSR protein was detected in gastro-projecting cells in DMV. Taken together, centrally applied NPS seems to prevent 6-OHDA-induced gastric dysmotility through a neuroprotective action on central vagal circuitry.


Nutrition for toddlers: the foundation for good health--2. Current problems and ways to overcome them.
Part 2 of a two-part review of toddler nutrition considers some current concerns, including the influence of changing lifestyles on dietary patterns; dietary imbalances; obesity; and iron deficiency anaemia. The review includes some practical steps to prevent obesity and iron deficiency anaemia.


Long-Term Effects of a Multimodal Physiotherapy Program on the Severity of Somatosensory Tinnitus and Identification of Clinical Indicators Predicting Favorable Outcomes of the Program.
Tinnitus, the perception of sound in the absence of external auditory stimuli, is commonly associated with problems of the auditory system. Head and neck disorders can also be involved in tinnitus emergence. In such cases, the term somatosensory tinnitus is used. Physiotherapy treatments have been identified as a promising avenue in the treatment of somatosensory tinnitus. The aim of the study was to explore the effect of a physiotherapy program on the intensity and severity of somatosensory tinnitus and to identify the clinical characteristics of the patients who respond well to this treatment. Quasi-experimental pre-post single-group design. Thirty-one adults with presumed somatosensory tinnitus. All participants received on average ten physiotherapy treatments over six weeks. Treatments included cervical and thoracic mobilizations, as well as muscular strengthening, stretching, postural instruction, and cervical stabilization. Outcomes were measured at baseline, at the end of the physiotherapy program, and three months later. The primary outcomes were the Tinnitus Handicap Inventory and visual analog scales for loudness and annoyance caused by tinnitus. After the last evaluation, participants were divided into two groups: improved and unimproved participants. Participants were considered improved if they (1) showed significant improvement in at least two of the three primary outcome measures and (2) indicated subjective improvement. Thereafter, the baseline characteristics that correctly identify participants susceptible to improve significantly following treatment were determined (Cohen's effect size d > 0.8). A significant improvement in tinnitus intensity was observed at the end of the program. Of the 31 participants, 14 experienced persistent improvement in the intensity of their tinnitus and were classified as improved. Baseline characteristics strongly associated with tinnitus improvement were no increase in tinnitus when exposed to noise (d = -1.57), no family history of tinnitus (d = -1.16), somatosensory modulation in response to the contraction used to resist pressure applied to the forehead (d = 1.20), and recent onset of tinnitus (d = 1.03). This exploratory study showed that a multimodal physiotherapy program is effective in decreasing the severity of tinnitus, principally in individuals presenting with somatosensory tinnitus in combination with specific clinical characteristics.


Correction: Effectiveness of a Web-Based Tailored Intervention With Virtual Assistants Promoting the Acceptability of HPV Vaccination Among Mothers of Invited Girls: Randomized Controlled Trial.
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Improved Persistence to Medication, Decreased Cardiovascular Events and Reduced All-Cause Mortality in Hypertensive Patients With Use of Single-Pill Combinations: Results From the START-Study.
Single-pill combination improves adherence and persistence to medication in hypertension. It remains unclear whether this also reduces cardiovascular outcomes and all-cause mortality. We analyzed whether single-pill combinations are superior to identical multiple pills on persistence to medication, cardiovascular outcomes, and all-cause mortality. This was a retrospective claims data (German AOK PLUS) analysis. Data from hypertensive patients ≥18 years treated with renin-angiotensin system combinations given as single pill or identical multipills covering the years 2012 to 2018 were analyzed and followed up to at least 1 year. After 1:1 propensity score matching, persistence to medication, cardiovascular events, and all-cause mortality were compared using non-parametric tests. Results were reported as incidence rate ratios and hazard ratios. After propensity score matching data from 57 998 patients were analyzed: 10 801 patients received valsartan/amlodipine, 1026 candesartan/amlodipine, 15 349 ramipril/amlodipine, and 1823 amlodipine/valsartan/hydrochlorothiazide as single pill or identical multipill. No relevant differences in patient characteristics were observed within the 4 groups. In all groups, a significant lower all-cause mortality, a significant a higher persistence to medication, a significant lower event rate in 15 out of 20 comparisons, and a tendency in the remaining 5 comparisons was observed under single pills compared with multipill combinations. Antihypertensive combination therapy reduces all-cause mortality and cardiovascular events when provided as single pill compared to identical drugs as multipills. This strongly supports the European Society of Cardiology/European Society of Hypertension and International Society of Hypertension guidelines recommending the use of a single-pill combination and thus should be more rigorously implemented into daily clinical practice.


Simultaneous transplantation of two allogeneic units of cord blood in an adult patient with acute myeloblastic leukemia: a case report.
The major obstacle to the therapeutic use of hematopoietic transplantation is the unavailability of matched, unrelated marrow donors for the large number of potential patients, although all of them have the chance to find sufficiently matched, unrelated cord blood units. However, the use of cord blood as a source of cells for transplantation is limited by its cell number, usually below 1 billion, which allows for routine transplantation only in children weighting less than 30 kg, while most potential recipients possess a higher body mass. This led to the idea of the simultaneous use of several units of cord blood which, combined, would fulfill the requirements for the necessary cell number for an adult recipient. We attempted to simultaneously transplant an adult patient with refractory acute myeloblastic leukemia utilizing two different cord blood units, one fully matched and one mismatched at one locus. The patient became reconstituted with only one unit, the mismatched, as determined using microsatellite markers, and had no signs of relapse of leukemia. Unfortunately, he died of persistent fungal (brain aspergilloma) infection on day +103. The successful engraftment may suggest that a method based on the principle of using more than one cord blood unit for transplantation is feasible in large adult patients and may reach routine application.


Global longitudinal strain improves risk assessment after ST-segment elevation myocardial infarction: a comparative prognostic evaluation of left ventricular functional parameters.
We aimed to investigate the comparative prognostic value of left ventricular ejection fraction (LVEF), mitral annular plane systolic excursion (MAPSE), fast manual long-axis strain (LAS) and global longitudinal strain (GLS) determined by cardiac magnetic resonance (CMR) in patients after ST-segment elevation myocardial infarction (STEMI). This observational cohort study included 445 acute STEMI patients treated with primary percutaneous coronary intervention (pPCI). Comprehensive CMR examinations were performed 3 [interquartile range (IQR): 2-4] days after pPCI for the determination of left ventricular (LV) functional parameters and infarct characteristics. Primary endpoint was the occurrence of major adverse cardiac events (MACE) defined as composite of death, re-infarction and congestive heart failure. During a follow-up of 16 [IQR: 12-49] months, 48 (11%) patients experienced a MACE. LVEF (p = 0.023), MAPSE (p < 0.001), LAS (p < 0.001) and GLS (p < 0.001) were significantly related to MACE. According to receiver operating characteristic analyses, only the area under the curve (AUC) of GLS was significantly higher compared to LVEF (0.69, 95% confidence interval (CI) 0.64-0.73; p < 0.001 vs. 0.60, 95% CI 0.55-0.65; p = 0.031. AUC difference: 0.09, p = 0.020). After multivariable analysis, GLS emerged as independent predictor of MACE even after adjustment for LV function, infarct size and microvascular obstruction (hazard ratio (HR): 1.13, 95% CI 1.01-1.27; p = 0.030), as well as angiographical (HR: 1.13, 95% CI 1.01-1.28; p = 0.037) and clinical parameters (HR: 1.16, 95% CI 1.05-1.29; p = 0.003). GLS emerged as independent predictor of MACE after adjustment for parameters of LV function and myocardial damage as well as angiographical and clinical characteristics with superior prognostic validity compared to LVEF.


Investing in children: The best way to prevent separation from parents and families.
The reliable and disaggregated data on children deprived of family care, living in different forms of public care is essential information to implement the UN Guidelines on Alternative Care of Children and its principle on necessity and suitability. At the same time all needed information and data would also be needed on all forms of support, universal, targeted and specialized services provided or not provided to children and their families locally to prevent separation of children, on different forms of informal care. While there have been many efforts made to prevent institutionalization of children worldwide especially in the most developed countries, placement of children out of their families for different reasons, many of them closely related to poverty is still too often accepted. Some current programs in Europe described in the article can contribute to better implementation of the current policies and recommendations globally, however there is a parallel movement towards emphasizing the need and value of institutional care and the lack of alternatives in many cases, that should also be taken into consideration. More research, evidence and data is needed to defend the arguments for deinstitutionalization.


Effects of intermittent sprint and plyometric training on endurance running performance.
The purpose of this study was to compare the effects of intermittent sprint training and plyometric training on endurance running performance. Fourteen moderately trained male endurance runners were allocated into either the intermittent sprint training group (n = 7) or the plyometric training group (n = 7). The preliminary tests required subjects to perform a treadmill graded exercise test, a countermovement jump test for peak power measurement, and a 10-km time trial. Training included 12 sessions of either intermittent sprint or plyometric training carried out twice per week. On completion of the intervention, post-tests were conducted. Both groups showed significant reduction in weekly training mileage from pre-intervention during the intervention period. There were significant improvements in the 10-km time trial performance and peak power. There was also significant improvement in relative peak power for both groups. The 10-km time trial performance and relative peak power showed a moderate inverse correlation. These findings showed that both intermittent sprint and plyometric training resulted in improved 10-km running performance despite reduction in training mileage. The improvement in running performance was accompanied by an improvement in peak power and showed an inverse relationship with relative peak power.


Mammographic Surveillance in Older Women With Breast Cancer in Canada and the United States: Are We Choosing Wisely?
Guidelines on mammographic surveillance after breast cancer treatment have been disseminated internationally and incorporated into Choosing Wisely recommendations to reduce low-value care. However, adherence within different countries before their publication is unknown. Low-value mammography, defined as "short-interval" (within 6 months of radiation) or "high-frequency" (>1 within 12 months of radiation), was compared in Medicare fee-for-service in the United States and Ontario, Canada. Women ≥65 years diagnosed with breast cancer who underwent breast-conserving therapy with a minimum of 24 months of follow-up were included (n = 19,715 United States; 6479 Ontario). Secondary outcomes were patient and physician characteristics associated with discordance. Short-interval mammography was higher in the United States than in Ontario (55.9% vs 38.0%, P < .001), as was high-frequency (39.6% vs 7.9%, P < .001). In Ontario, younger age (42% ≥85 vs 58% <74 years, P < .001) and chemotherapy (69% vs 51%, P < .001) were associated with short-interval mammography; in the United States, age, earlier diagnosis year, stage, chemotherapy, rurality, and academic center treatment were associated with greater use. Chemotherapy was associated with high-frequency mammography in both countries (13% vs 7% in Ontario, P < .001; 69% vs 51% in United States, P = .02); younger age, earlier diagnosis year, stage, and nonacademic center treatment were associated in the United States. In both countries, radiation oncologists had the highest proportion of providers ordering low-value mammograms. Despite significant evidence guiding surveillance mammography recommendations, there are high rates of short-interval mammography in both the United States and Ontario, and high rates of high-frequency mammography in the United States. Further international efforts, such as Choosing Wisely, are needed to reduce low-value mammography.


Distinguishing primary from secondary mucinous ovarian tumors: an algorithm using the novel marker DPEP1.
Distinguishing primary mucinous ovarian cancers from ovarian metastases of digestive organ cancers is often challenging. Dipeptidase 1 was selected as the candidate novel marker of colorectal cancer based on an analysis of a gene expression microarray. Immunohistochemical analysis indicated that 13/16 ovarian metastases of colorectal cancers, but only 1/58 primary mucinous ovarian cancers, were dipeptidase 1-positive (threshold; ≧25% expression, P<0.0001). Next, five immunohistochemical markers (dipeptidase 1, estrogen receptor-α, cytokeratin 7, cytokeratin 20, and caudal type homeobox 2) were analyzed in combination. In a hierarchical clustering analysis, the mutually exclusive expression of cytokeratin 7 and dipeptidase 1 specifically identified the ovarian metastases of colorectal cancers (P<0.0001). In a decision tree analysis, cytokeratin 7, caudal type homeobox 2, and dipeptidase 1 classified primary mucinous ovarian cancers and ovarian metastases of digestive organ cancers with 90% accuracy. Finally, the five immunohistochemical markers were combined with six preoperative factors (patient's age, tumor size, laterality, serum CEA, CA19-9, and CA125) and combinations were analyzed. Of the 11 factors, 4 (dipeptidase 1, cytokeratin 7, caudal type homeobox 2, and tumor size) were used to generate a decision tree to classify primary mucinous ovarian cancers and metastases of digestive organ cancers with 93% accuracy. In conclusion, we identified a novel immunohistochemical marker, dipeptidase 1, to distinguish primary mucinous ovarian cancers from ovarian metastasis of colorectal cancers. The algorithm using immunohistochemical and clinical factors to distinguish metastases of digestive organ cancers from primary mucinous ovarian cancers will be useful to establish a protocol for the diagnosis of ovarian metastasis.


Engineering the precursor pool to modulate the production of pamamycins in the heterologous host S. albus J1074.
Pamamycins, a group of polyketides originally discovered in Streptomyces alboniger, induce sporulation in Streptomyces and inhibit the growth of Gram-positive bacteria, Mycobacterium tuberculosis and fungi. The pamamycin biosynthetic gene cluster encodes 6 ketosynthases that utilize a variety of three-carbon to five-carbon CoA thioesters as starter and extender units. This promiscuity in production results in an up to 18 different derivatives during fermentation. For more-selective production and simplified purification, we aimed to modify the precursor supply to narrow the spectrum of the produced derivatives. Eight genes potentially responsible for the supply of two major precursors, 2-S-methylmalonyl-CoA and 2-S-ethylmalonyl-CoA, were identified using the NCBI Basic Local Alignment Search Tool (BLAST) against the genome of the heterologous host S. albus J1074. Knockout mutants of the identified genes were constructed and their impact on intracellular CoA ester concentrations and on the production of pamamycins was determined. The created mutants enabled us to conclusively identify the ethylmalonyl-CoA supplying routes and their impact on the production of pamamycin. Furthermore, we gained significant information on the origin of the methylmalonyl-CoA supply in Streptomyces albus.


Anatomy of pudendal nerve at urogenital diaphragm--new critical site for nerve entrapment.
To investigate the relations of the pudendal nerve in this complex anatomic region and determine possible entrapment sites that are accessible for surgical decompression. Entrapment neuropathies of the pudendal nerve are an uncommon and, therefore, often overlooked or misdiagnosed clinical entity. The detailed relations of this nerve as it exits the pelvis through the urogenital diaphragm and enters the mobile part of the penis have not yet been studied. Detailed anatomic dissections were performed in 10 formalin preserved hemipelves under 3.5x loupe magnification. The pudendal nerve was dissected from the entrance into the Alcock canal to the dorsum of the penis. The branching pattern of the nerve and its topographic relationship were recorded and photographs taken. The anatomic dissections revealed that the pudendal nerve passes through a tight osteofibrotic canal just distal to the urogenital diaphragm at the entrance to the base of the penis. This canal is, in part, formed by the inferior ramus of the pubic bone, the suspensory ligament of the penis, and the ischiocavernous body. In two specimens, a fusiform pseudoneuromatous thickening was found. The pudendal nerve is susceptible to compression at the passage from the Alcock canal to the dorsum of the penis. Individuals exposed to repetitive mechanical irritation in this region are especially endangered. Diabetic patients with peripheral neuropathy can have additional compression neuropathy with decreased penile sensibility and will benefit from decompression of the pudendal nerve.


Unmasking of an essential thiol during function of the membrane bound enzyme II of the phosphoenolpyruvate glucose phosphotransferase system of Escherichia coli.
The addition of N-ethylmaleimide (MalNEt), or of fluoro dinitrobenzene to a suspension of Escherichia coli during the phosphorylating uptake of methyl-alpha-D-glucopyranoside (Me-Glc), a glucose analog, stops uptake and phosphorylation and causes the loss of previously accumulated sugar and of its phosphate ester. After removal of the reagents, the phosphotransferase system remains irreversibly inactive. Pretreatment of the bacteria with the same reagents under the same conditions of concentration, pH, temperature and for the same length of time causes very little inactivation. Mercuric chloride, a reversible inactivator, prevents the phosphotransferase system from reacting simultaneously with MaINEt or with fluorodinitrobenzene. This protection strongly suggests that all three reagents react with the same site, presumably an -SH group. The change which makes this site available to the reagents depends on the phosphorylative uptake of Me-Glc. Preload of the cells and efflux of Me-Glc do not achieve the same change. The rate of inactivation is directly proportional to the rate of phosphorylative uptake. When the Km of phosphorylative uptake is modified by an uncoupling agent, the substrate concentration allowing half maximal rate of inactivation by MaINEt changes accordingly. The reactive sites of the phosphotransferase system can also be made accessible to the -SH group reagents by fluoride inhibition of phosphoenolpyruvate synthesis. This suggests that the inactivator resistent form is an "energized form" of the enzyme. The unmasking of the reactive site is not due to a change in transmembrane penetration of the reagents since incubation of toluene treated cells with MaINEt in the presence of phosphoenolpyruvate fails to inactivate the phosphotransferase activity, while incubation with MaINEt plus Me-Glc causes fast inactivation.


Different MRI findings for normal elderly and very mild Alzheimer's disease in a community: implications for clinical practice the Tajiri Project.
To investigate magnetic resonance imaging (MRI) findings of very mild dementia, 485 participants were randomly selected in a community. Three hundred and forty participants were of Clinical Dementia Rating (CDR) 0 (healthy), 113 were of CDR 0.5 (questionable dementia), and 32 were of CDR 1 and 2 (including 20 Alzheimer's disease, AD). Cortical atrophy, white matter lesion, etc., were visually assessed. We found that each part of the brain showed atrophy in older adults for CDR 0. For CDR 0.5, the relationships between MRI findings and age were weaker, and for AD, there were no such relationship. Atrophy related with dementia severity was found to be limited to the lateral and medial temporal lobes. For CDR 0.5, amygdala atrophy was the only finding indicating CDR effect but no age effect. The amygdala or anterior entorhinal atrophy is important for discriminating very mild dementia from normal elderly.


Value of pharmacy services: perceptions of consumers, physicians, and third party prescription plan administrators.
A study of patients, physicians, and third party prescription plan administrators was conducted to identify those pharmacy services they believe are important and valuable and to determine whether third party plan administrators would reimburse pharmacists for such services. Patient and physician focus groups indicated that both wanted personalized services related to medications. Physicians believe that pharmacists are talking to patients about their medications, whereas patients want more drug information but report that pharmacists are not always providing such information. A mail survey of 41 third party prescription plan administrators indicated they believe that pharmacy services are important to consumers and that pharmacists are already providing most of the services identified. One-third of the third party administrators said their companies would consider implementing a structured pharmacist incentive plan to improve enrollee satisfaction. Those whose companies would not most often gave "increased cost" as the reason. No clear relationship was shown between number or type of services and the incentive value offered. Providing administrators with evidence that enhanced pharmacy services will increase overall program cost savings may lead to implementation of pharmacy incentives.


Cardiovascular mechanosensitive ion channels-Translating physical forces into physiological responses.
Cells and tissues are constantly exposed to mechanical stress. In order to respond to alterations in mechanical stimuli, specific cellular machinery must be in place to rapidly convert physical force into chemical signaling to achieve the desired physiological responses. Mechanosensitive ion channels respond to such physical stimuli in the order of microseconds and are therefore essential components to mechanotransduction. Our understanding of how these ion channels contribute to cellular and physiological responses to mechanical force has vastly expanded in the last few decades due to engineering ingenuities accompanying patch clamp electrophysiology, as well as sophisticated molecular and genetic approaches. Such investigations have unveiled major implications for mechanosensitive ion channels in cardiovascular health and disease. Therefore, in this chapter I focus on our present understanding of how biophysical activation of various mechanosensitive ion channels promotes distinct cell signaling events with tissue-specific physiological responses in the cardiovascular system. Specifically, I discuss the roles of mechanosensitive ion channels in mediating (i) endothelial and smooth muscle cell control of vascular tone, (ii) mechano-electric feedback and cell signaling pathways in cardiomyocytes and cardiac fibroblasts, and (iii) the baroreflex.


Cisplatin-induced neurotoxicity involves the disruption of serotonergic neurotransmission.
Neurotoxicity is a frequent side effect of cisplatin (CisPt)-based anticancer therapy whose pathophysiology is largely vague. Here, we exploited C. elegans as a 3R-compliant in vivo model to elucidate molecular mechanisms contributing to CisPt-induced neuronal dysfunction. To this end, we monitored the impact of CisPt on various sensory functions as well as pharyngeal neurotransmission by recording electropharyngeograms (EPGs). CisPt neither affected food and odor sensation nor mechano-sensation, which involve dopaminergic and glutaminergic neurotransmission. However, CisPt reduced serotonin-regulated pharyngeal pumping activity independent of changes in the morphology of related neurons. CisPt-mediated alterations in EPGs were fully rescued by addition of serotonin (5-HT) (≤ 2 mM). Moreover, the CisPt-induced pharyngeal injury was prevented by co-incubation with the clinically approved serotonin re-uptake inhibitory drug duloxetine. A protective effect of 5-HT was also observed with respect to CisPt-mediated impairment of another 5-HT-dependent process, the egg laying activity. Importantly, CisPt-induced apoptosis in the gonad and learning disability were not influenced by 5-HT. Using different C. elegans mutants we found that CisPt-mediated (neuro)toxicity is independent of serotonin biosynthesis and re-uptake and likely involves serotonin-receptor subtype 7 (SER-7)-related functions. In conclusion, by measuring EPGs as a surrogate parameter of neuronal dysfunction, we provide first evidence that CisPt-induced neurotoxicity in C. elegans involves 5-HT-dependent neurotransmission and SER-7-mediated signaling mechanisms and can be prevented by the clinically approved antidepressant duloxetine. The data highlight the particular suitability of C. elegans as a 3R-conform in vivo model in molecular (neuro)toxicology and, moreover, for the pre-clinical identification of neuroprotective candidate drugs.


Comparison of diameter and length of subclavian arteries to external jugular veins in variably sized dogs: A cadaveric study.
To evaluate the length and diameter of a left external jugular vein graft as a substitute for the left subclavian artery in the modified Blalock-Thomas-Taussig shunt (mBTTS) in differently sized dogs. Cadaveric study. Dog cadavers of three weight categories (10/group): <9.5 kg, 9.5 to 27 kg, and > 27 kg. The length and infused external diameters of harvested vessels were measured with vernier calipers and recorded. A matched-pairs t test was used to test the difference in vessel lengths. The agreement in vessel diameters was assessed by using Lin's concordance correlation coefficient (CCC). Pearson's correlation coefficients (CC) were determined for vessel diameter to weight category and vessel length to weight category. The external jugular vein measured longer than the subclavian artery in all dogs (52.0 ± 20.8 mm and 23.0 ± 8.9 mm, respectively), with a mean difference of 28 ± 14.3 mm (P < .001). The mean external infused subclavian and external jugular diameters measured 7.8 ± 2.2 mm and 8.0 ± 2.5 mm, respectively (P = .32). Lin's CCC was 0.87. Pearson's CC were 0.74 in both vessel diameters (P < .001); they were 0.36 and 0.43, respectively, for subclavian artery and external juglar vein length (P < .001). Autologous external jugular vein grafts had an external diameter similar to subclavian artery and a significantly longer length in variably sized dogs. External jugular vein grafts may be an acceptable graft choice for mBTTS.


Inpatient hospital complications and lengths of stay: a short report.
Increasingly, efforts are being made to link health care outcomes with more efficient use of resources. The current difficult economic times and health care reform efforts provide incentives for specific efforts in this area. This study defined relationships between inpatient complications for urinary tract infection and pneumonia and hospital lengths of stay in three general hospitals in the metropolitan area of Syracuse, New York. It employed the Potentially Preventable Complications (PPC) software developed by 3M™ Health Information Services to identify lengths of stay for patients with and without urinary tract infection and pneumonia. The patient populations included individuals assigned to the same All Patients Refined Diagnosis Related Groups and severity of illness. The comparisons involved two nine month periods in 2008 and 2009.The study demonstrated that patients who experienced the complications had substantially longer inpatient hospital stays than those who did not. Patients with a PPC of urinary tract infection stayed a mean of 8.9 - 11.9 days or 161 - 216 percent longer than those who did not for the two time periods. This increased stay produced 2,020 - 2,427 additional patient days.The study demonstrated that patients who experienced the complications had substantially longer inpatient hospital stays than those who did not. Patients with a PPC of pneumonia stayed a mean of 13.0 - 16.3 days or 232 - 281 percent longer than those who did not for the two time periods. This increased stay produced 2,626 - 3,456 additional patient days. Similar differences were generated for median lengths of stay. The differences in hospital stays for patients in the same APR DRGs and severity of illness with and without urinary tract infection and pneumonia in the Syracuse hospitals were substantial. The additional utilization for these complications was valued at between $2,000,000 - $3,000,000 for a three month period. These differences in the use of hospital resources have important implications for reduction of health care costs among providers and payors of care.


The appearance of hypodense eosinophils during interleukin-2 treatment.
Based on membrane receptors, metabolic activity, and cell density, human eosinophils (EOSs) are a heterogeneous population of leukocytes. EOS heterogeneity translates into biologic significance, since low density cells can be metabolically more active and thus more capable of causing tissue injury. Efforts to identify mechanisms that lead to the development of hypodense EOSs have found that an in vitro exposure to cytokines reduces cell density and is associated with increased cell activity. Consequently, we evaluated the effect of an in vivo administration of interleukin-2 (IL-2) on the cell counts and density of circulating EOSs in six patients who received IL-2 as cancer biologic-modifier therapy. To determine the pattern of EOS density in relationship to IL-2 treatment, granulocyte suspensions were isolated from peripheral blood and then centrifuged over multiple discontinuous density Percoll gradients. During IL-2 treatment, the percentage of circulating hypodense EOSs increased significantly (p less than 0.01) until nearly all (97.6 +/- 1.6%) EOSs were hypodense (density less than 1.095 gm/ml). Similarly, the absolute blood EOS counts significantly increased throughout treatment. On completion of IL-2 therapy, the EOS counts and density distribution returned to pretreatment values. In contrast, no increase in blood EOS counts was observed in similar patients receiving interferon (gamma or beta) therapy. Our observations support a hypothesis that IL-2, either directly or, more likely, through the generation of other factors, participates in a change in EOS density that may, in turn, establish a subpopulation of cells with altered metabolic activity.