Efficacy of zoledronic acid for the elimination of disseminated tumor cells in a clinically relevant, spontaneously metastatic prostate cancer xenograft model.
Bone metastases develop in >90 % of patients with castration-resistant prostate cancer (PCa) through complex interactions between the bone microenvironment and tumor cells. Previous androgen-deprivation therapy (ADT), which is known to cause bone loss, as well as anti-resorptive agents such as zoledronic acid (ZA), used to prevent skeletal complications, may influence these interactions and thereby the growth of disseminated tumor cells (DTC) in the bone marrow (BM). Here, a spontaneously metastatic xenograft tumor model of human PCa was further optimized to mimic the common clinical situation of ADT (castration) combined with primary tumor resection in vivo. The effects of these interventions, alone or in combination with ZA treatment, on tumor cell dissemination to the BM and other distant sites were analyzed. Metastatic burden was quantified by human-specific Alu-qPCR, bioluminescence imaging (BLI), and immunohistochemistry. Further, bone remodeling was assessed by static histomorphometry and serum parameters. Initial comparative analysis between NSG and SCID mice showed that spontaneous systemic dissemination of subcutaneous PC-3 xenograft tumors was considerably enhanced in NSG mice. Primary tumor resection and thereby prolonged observational periods resulted in a higher overall metastatic cell load at necropsy and tumor growth alone caused significant bone loss, which was further augmented by surgical castration. In addition, castrated mice showed a strong trend towards higher bone metastasis loads. Weekly treatment of mice with ZA completely prevented castration- and tumor-induced bone loss but had no effect on bone metastasis burden. Conversely, the total lung metastasis load as determined by BLI was significantly decreased upon ZA treatment. These findings provide a basis for future research on the role of ZA not only in preventing skeletal complications but also in reducing metastasis to other organs.


Clinical outcome of brain metastases differs significantly among breast cancer subtypes.
Brain metastases in patients with breast cancer are associated with a poor survival rate. A small number of studies have challenged this premise, suggesting that survival times following brain metastasis differ significantly between breast cancer subtypes. In the current study, overall survival (OS), brain metastases-free survival (BMFS) and survival following brain metastases (SFBM) were found to be associated with the intrinsic breast cancer subtype. A total of 1,147 patients with invasive breast cancer who were treated at the Hannover Medical School between January 2004 and December 2010 were included, from which 54 patients with brain metastases were identified. The Kaplan-Meier method or Cox regression analyses were performed for analysis of survival. OS was found to differ significantly between breast cancer subtypes: OS was significantly shorter in patients with triple-negative (TN) cancer compared with patients with human epidermal growth factor receptor (HER2)-enriched tumors (P<0.001). In addition, median BMFS times differed significantly between luminal (1,003 days), HER2-enriched (514 days) and TN breast cancer patients (460 days) (P=0.045). The median durations of SFBM were 386 days in luminal, 310 days in HER2-enriched and 147 days in TN breast cancer patients (P=0.029). The results suggested that patients with luminal breast cancer have a lower risk of brain metastases and the most favorable outcome with regard to BMFS, whereas patients with HER2-positive or TN breast cancer have a significantly higher risk of developing brain metastases. Compared with TN breast cancer, the duration of SFBM was doubled in HER2-enriched cancers. These findings may have important implications for treatment and follow-up strategies in patients with breast cancer.


Nearly Optimal Foraging in Patches Under Nutrient Constraints.
Three feeding strategies with different rules for prey selectivity were evaluated by Monte Carlo computer simulation. The predator must obtain a minimum quantity of each of three different nutrients, and it sequentially encounters one of three kinds of prey that differ in both their nutrient compositions and their relative abundances. Within patches, prey may be randomly dispersed or aggregated with Markovian transition probabilities. Overall cost is the sum of search time plus consumption cost plus emigration (between-patch traverses) risk. The predator will emigrate if it is unsuccessful in acquiring a minimum of {Gamma} units of any needed nutrient within the T most recent prey encounters. The three strategies are (1) no discrimination-with potentially high consumption costs, (2) minimal consumption-with potentially very prolonged search times, and (3) a hybrid strategy that requires a physiological monitoring of net nutrient acquisition (or the bookkeeping of highly correlated gustatory cues). Each strategy has its characteristic dynamics and optima, but collectively these simulations show that no one strategy is superior and that over a large portion of the parameter space the differences in overall cost are relatively small.


Regulation of the CRISPR-Associated Genes by Rv2837c (CnpB) via an Orn-Like Activity in Tuberculosis Complex Mycobacteria.
Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated proteins (Cas) provide bacteria and archaea with adaptive immunity to specific DNA invaders. Mycobacterium tuberculosis encodes a type III CRISPR-Cas system that has not been experimentally explored. In this study, we found that the CRISPR-Cas systems of both M. tuberculosis and Mycobacterium bovis BCG were highly upregulated by deletion of Rv2837c (cnpB), which encodes a multifunctional protein that hydrolyzes cyclic di-AMP (c-di-AMP), cyclic di-GMP (c-di-GMP), and nanoRNAs (short oligonucleotides of 5 or fewer residues). By using genetic and biochemical approaches, we demonstrated that the CnpB-controlled transcriptional regulation of the CRISPR-Cas system is mediated by an Orn-like activity rather than by hydrolyzing the cyclic dinucleotides. Additionally, our results revealed that tuberculosis (TB) complex mycobacteria are functional in processing CRISPR RNAs (crRNAs), which are also more abundant in the ΔcnpB strain than in the parent strain. The elevated crRNA levels in the ΔcnpB strain could be partially reduced by expressing Escherichia coli orn Our findings provide new insight into transcriptional regulation of bacterial CRISPR-Cas systems.IMPORTANCE Clustered regularly interspaced short palindromic repeats (CRISPR) and the CRISPR-associated proteins (Cas) provide adaptive immunity to specific DNA invaders. M. tuberculosis encodes a type III CRISPR-Cas system that has not been experimentally explored. In this study, we first demonstrated that the CRISPR-Cas systems in tuberculosis (TB) complex mycobacteria are functional in processing CRISPR RNAs (crRNAs). We also showed that Rv2837c (CnpB) controls the expression of the CRISPR-Cas systems in TB complex mycobacteria through an oligoribonuclease (Orn)-like activity, which is very likely mediated by nanoRNA. Since little is known about regulation of CRISPR-Cas systems, our findings provide new insight into transcriptional regulation of bacterial CRISPR-Cas systems.


Giant Cholangiolocellular Carcinoma With Early Recurrence That Was Difficult to Distinguish From Cholangiocellular Carcinoma: Report of a Case.
Cholangiolocellular carcinoma (CoCC) is a rare type of malignant liver tumor derived from hepatic stem cells, which exist in the canals of Hering. However, the characteristics of CoCC have not been clarified. In general, CoCC is associated with a better prognosis than cholangiocellular carcinoma (CCC). Here, we report a case of giant CoCC, which was difficult to distinguish from CCC and showed early recurrence and necrosis inside the tumor. A 59-year-old man was diagnosed with CCC based on preoperative imaging. The diameter of the tumor was approximately 14 cm, and he subsequently underwent extended right lobectomy of the liver. Histopathologic analysis revealed that tumor cells proliferated and replaced the surrounding normal liver cell cords in front of the tumor. Furthermore, the tumor cells were positive for cytokeratin 19 and epithelial membrane antigen. Epithelial membrane antigen staining pattern was positive on the membranous area of the lumen. Therefore, the tumor was diagnosed as CoCC. Although adjuvant chemotherapy was performed, intrahepatic recurrence occurred at 4 months after surgery. We present here the novel characteristics of CoCC that show early recurrence and necrosis within the tumor. These characteristics have not previously been reported in patients with CoCC.


Interleukin 17A in Patients With Stable Coronary Artery Disease: Are There Differences According to Gender?
Coronary artery disease (CAD) is a current major public health concern. Immunity and inflammation are involved in all phases of CAD and there is a dynamic balance between cells and molecules. Interleukin 17A (IL17A) concentrations are higher in male patients with acute myocardial infarction than in women. In this study, we evaluated if the IL17A concentrations in male CAD patients (MPs) differed from those in female patients (FPs) and male controls (MCs). Moreover, FPs were compared with female controls (FCs). This was a cross-sectional, prospective, and analytical study conducted between March 2012 and August 2013 that enrolled 40 patients (24 men and 16 women) with stable CAD and 20 healthy volunteers (12 men and 8 women) were selected as controls and were matched with the patients (1:2) for sex and age (± 3 years). Comparative analyses of IL17A concentrations in serum and cell culture with and without stimulation were performed between MPs and MCs, MPs and FPs, and FPs and FCs. The lower detection limit was 3.91 pg/mL. The comparison of the IL17A concentrations showed: after 48 hours of cell culture with stimulus: MP = 451.67 (99.02 - 892.58) vs. MC = 135 (3.91 - 285), P = 0.04; after 48 hours of cell culture with stimulus: MP = 451.67 (99.02 - 892.58) vs. FP = 131.21 (3.91 - 231.97), P = 0.02; after 48 hours of cell culture with stimulus: FP = 131.21 (3.91 - 231.97) vs. FC = 173.78 (3.91 - 642), P = 0.24. This study revealed higher IL17A concentrations in the stimulated cells isolated from the MPs than in those isolated from FPs and MCs. These findings support the hypothesis that when exposed to certain stimuli, cells isolated from MPs with chronic CAD may produce higher IL17A concentrations than those from FPs and MCs.


Efficacy of WBV as a modality for inducing changes in body composition, aerobic fitness, and muscular strength: a pilot study.
The purpose of this pilot study was to evaluate the effectiveness of whole body vibration (WBV) training as a modality for inducing changes in body composition, cardiovascular condition, and muscular strength in sedentary postmenopausal women. WBV training was compared with other training regimens, ie, aerobic training and circuit resistance training, commonly used to promote weight loss, cardiovascular conditioning, and muscular strength. Postmenopausal women (aged 48-60 years) were randomly assigned to WBV training, circuit resistance training, or aerobic training. Participants trained three times per week for 8 weeks. The training regimens were progressive in nature, with increases in training intensity and duration occurring throughout the 8-week period. Body composition was assessed using dual-energy X-ray absorptiometry analyses. A modified Bruce treadmill protocol was used to assess aerobic capacity (VO2peak) and time to peak exhaustion. Upper and lower body strengths were determined by one repetition maximum (1-RM) chest and leg presses, respectively. Variables were analyzed using separate 3 (exercise mode) × 2 (time) repeated-measures analysis of variance with effect sizes due to the small sample size. No significant main effects or interactions were seen for any body composition variable; however, moderate to large effect sizes (η (2)=0.243 and η (2)=0.257) were detected regarding interactions for percent body fat and lean body mass favoring aerobic training and circuit resistance training. For VO2peak, no significant main effects or interactions were detected (time, η (2)=0.150; P=0.11; time × group, η (2)=0.139; P=0.30); but a significant time effect was observed for time to peak exhaustion (η (2)=0.307; P=0.017). A significant interaction for upper body strength (η (2)=0.464; P=0.007), and main effect for time in lower body strength (η (2)=0.663; P=0.0001) was detected. Post hoc analysis indicated a significant increase in upper body strength for circuit resistance training (P=0.023) and a decrease for WBV training (P=0.015). Our results indicate that WBV may not be an effective alternative to traditional training with regard to body composition or aerobic capacity, but could have a positive impact on lower body strength.


Negative pressure wound therapy versus conventional wound dressings in treatment of open fractures: A systematic review and meta-analysis.
Though several systematic reviews concerned have been published, controversy still exists. The current systematic review was designed to clarify the detailed advantages and disadvantages of the negative pressure wound therapy (NPWT) in treatment of open fractures in comparison with the conventional wound dressings. A systematic search was performed in Pubmed, Cochrane Library, Embase, and Google Scholar for the published relevant clinical studies. Unpublished studies were searched in Clinicaltrials, ICTRP and ISRCTN. The outcome measures included presence of infection, wound healing process, length of the patient hospital stay, flap issues, frequency of amputation, and patient life quality. In the 8 randomized controlled trials (RCTs) (421 patients) and the 6 retrospective cohort studies (488 patients), NPWT resulted in a significantly lower infection rate, significantly shorter wound coverage time, wound healing time and hospital stay length, and the lower amputation rate. However, no statistically significant difference was found in the need for flap surgery, the proportion of free flaps, the flap failure rate or the fracture non-union rate. Only 1 RCT was reported to have a higher physical component score of short form 36 in the infected patients. NPWT can significantly reduce the risk of infection in treatment of open fractures and accelerate their wound healing process. Some but not much evidence suggests that NPWT may possibly help reduce the severity of the limb injury and therefore provide a chance for the limb to avoid amputation. Use of NPWT in the flap area is probably safe, but should be carried out with caution. The advantage of NPWT over the conventional wound dressings still requires to be confirmed in the other aspects.


Stability and effectiveness of chlorine disinfectants in water distribution systems.
A test system for water distribution was used to evaluate the stability and effectiveness of three residual disinfectants--free chlorine, combined chlorine, and chlorine dioxide--when challenged with a sewage contaminant. The test distribution system consisted of the street main and internal plumbing for two barracks at Fort George G. Meade, MD. To the existing pipe network, 152 m (500 ft) of 13-mm (0.5 in.) copper pipe were added for sampling, and 60 m (200 ft) of 2.54-cm (1.0 in.) plastic pipe were added for circulation. The levels of residual disinfectants tested were 0.2 mg/L and 1.0 mg/L as available chlorine. In the absence of a disinfectant residual, microorganisms in the sewage contaminant were consistently recovered at high levels. The presence of any disinfectant residual reduced the microorganism level and frequency of occurrence at the consumer's tap. Free chlorine was the most effective residual disinfectant and may serve as a marker or flag in the distribution network. Free chlorine and chlorine dioxide were the least stable in the pipe network. The loss of disinfectant in the pipe network followed first-order kinetics. The half-life determined in static tests for free chlorine, chlorine dioxide, and combined chlorine was 140, 93, and 1680 min.


The biochemical, nanomechanical and chemometric signatures of brain cancer.
Raman spectroscopy and imaging combined with AFM topography and mechanical indentation by AFM have been shown to be an effective tool for analysis and discrimination of human brain tumors from normal structures. Raman methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n=5) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma (IV grade), and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational spectra and Raman images we provide a real-time feedback that is label-free method to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, and proteins. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845cm-1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the lipid and protein contents of tumorous brain tissue compared to the non-tumor tissue. Almost all brain tumors have the Raman intensity ratios significantly higher (1.99±0.026) than that found in non-tumor brain tissue, which is 1.456±0.02, and indicates that the relative amount of lipids compared to proteins is significantly higher in the normal brain tissue. Mechanical indentation using AFM on sliced human brain tissues (medulloblastoma, grade IV) revealed that the mechanical properties of this tissue are strongly heterogeneous, between 1.8 and 75.7kPa, and the mean of 27.16kPa. The sensitivity and specificity obtained directly from PLSDA and cross validation gives a sensitivity and specificity of 98.5% and 96% and 96.3% and 92% for cross-validation, respectively. The high sensitivity and specificity demonstrates usefulness for a proper decision for a Raman diagnostic test on biochemical alterations monitored by Raman spectroscopy related to brain cancer development.


Hematological and biochemical changes in volatile substance abusing street children in İstanbul.
The aim of the study is to assess the hematological and biochemical changes of inhalant abusing adolescences in Istanbul, Turkey. The study subjects comprised 24 street children. Demographic characteristics, hematological markers, complete blood count tests and white blood cell differential and liver function tests (alanine transaminase, aspartate transaminase, alkaline phosphatase) were evaluated. The blood cell counts and studied biochemical parameters were within normal range for age and sex matched adolescences. Anemia was observed in only one girl who had hypermenorea. The duration and the amount of substance abuse were investigated for a correlation with the blood parameters, only the amount showed the possibility of a trend associated with Hb and Hct (p<0.05). There was no significant relationship between the parameters except for the age. Although volatile abuse has been supposed to be related with anemia or other hematological abnormalities, we found no significant relation between volatile abuse and hematological or studied biochemical parameters. Alkaline phosphatase was the parameter found to be most affected, though being in normal range.


The vascular architecture of the porcine small intestine.
The vascular anatomy of the porcine small intestine was studied by injection of intestinal vessels with India Ink. Examination of transverse and longitudinal serial sections of the injected intestine facilitated a three-dimensional interpretation of the vascular pattern. An artery from the mesentery penetrated the tunica muscularis, supplied muscular branches and passed on to the submucosa where it formed an arterial rete. From the submucosal arteries, arterioles arose and followed a direct axial course to the tips of villi where they ramified into a subepithelial capillary plexus. Some of the capillaries, at the midpoint of the villus, fused into paraxial venules, which emptied into a "transverse venule" at the base of the villus. Other villus capillaries were continuous with those of the crypts. The pericryptal capillary plexus received a few arterial branches from the submucosal arteries. The transverse venule and the pericryptal capillary plexus emptied into large, segmentally dilated veins in the submucosa. The submucosal veins formed an extensive anastomosing network drained by large venous trunks which passed through the muscle layers to the mesentery. The observations suggest possible relationships between the vascular pattern and intestinal fluid movement.


The biology of platelet-rich plasma and its application in oral surgery: literature review.
Platelet-rich plasma (PRP) is a new approach in tissue regeneration and a developing area for clinicians and researchers. It is used in various surgical fields, including oral and maxillofacial surgery. PRP is prepared from the patient's own blood and contains growth factors that influence wound healing. Of these growth factors, platelet-derived growth factor, transforming growth factor, insulin-like growth factor, and epidermal growth factor play a pivotal role in tissue repair mechanisms. Although the growth factors and mechanisms involved are still poorly understood, the easy application of PRP in the clinic and its possible beneficial outcome, including reduction of bleeding, rapid soft tissue healing, and bone regeneration, hold promise for new treatment approaches. However, animal studies and human trials demonstrate conflicting results regarding the application of PRP. Therefore the aim of this literature review is to evaluate the scientific evidence regarding the use of PRP in dentistry, to describe the different bioactive substances included in PRP and their participation in the healing process, to elucidate the different techniques and available technology for PRP preparation, to review animal and human studies, to clarify risks, and to provide guidance for future research.


Nomogram-Based Prediction of the Risk of Diabetic Retinopathy: A Retrospective Study.
This study is aimed at developing a risk nomogram of diabetic retinopathy (DR) in a Chinese population with type 2 diabetes mellitus (T2DM). A questionnaire survey, biochemical indicator examination, and physical examination were performed on 4170 T2DM patients, and the collected data were used to evaluate the DR risk in T2DM patients. By operating R software, firstly, the least absolute shrinkage and selection operator (LASSO) regression analysis was used to optimize variable selection by running cyclic coordinate descent with 10 times K cross-validation. Secondly, multivariable logistic regression analysis was applied to build a predicting model introducing the predictors selected from the LASSO regression analysis. The nomogram was developed based on the selected variables visually. Thirdly, calibration plot, receiver operating characteristic (ROC) curve, and decision curve analysis were used to validate the model, and further assessment was running by external validation. Seven predictors were selected by LASSO from 19 variables, including age, course of disease, postprandial blood glucose (PBG), glycosylated haemoglobin A1c (HbA1c), uric creatinine (UCR), urinary microalbumin (UMA), and systolic blood pressure (SBP). The model built by these 7 predictors displayed medium prediction ability with the area under the ROC curve of 0.700 in the training set and 0.715 in the validation set. The decision curve analysis curve showed that the nomogram could be applied clinically if the risk threshold is between 21% and 57% and 21%-51% in external validation. Introducing age, course of disease, PBG, HbA1c, UCR, UMA, and SBP, the risk nomogram is useful for prediction of DR risk in T2DM individuals.


Co(II) Coordination in Prokaryotic Zinc Finger Domains as Revealed by UV-Vis Spectroscopy.
Co(II) electronic configuration allows its use as a spectroscopic probe in UV-Vis experiments to characterize the metal coordination sphere that is an essential component of the functional structure of zinc-binding proteins and to evaluate the metal ion affinities of these proteins. Here, exploiting the capability of the prokaryotic zinc finger to use different combinations of residues to properly coordinate the structural metal ion, we provide the UV-Vis characterization of Co(II) addition to Ros87 and its mutant Ros87_C27D which bears an unusual CysAspHis2 coordination sphere. Zinc finger sites containing only one cysteine have been infrequently characterized. We show for the CysAspHis2 coordination an intense d-d transition band, blue-shifted with respect to the Cys2His2 sphere. These data complemented by NMR and CD data demonstrate that the tetrahedral geometry of the metal site is retained also in the case of a single-cysteine coordination sphere.


Nanoparticles in Gastrooncology.
Gastrointestinal malignancies have the greatest incidence and cancer-associated death rates worldwide. Routine therapeutic modalities include surgery, chemotherapy and radiation but they often fail to reach the goal of cancer-free survival. In the light of this urgent medical need for the treatment of GI tumors, nanotech-nology-based approaches, i.e. nanomedicine, promise new therapeutic options. Using nanoparticles instead of classically designed drugs, targeting anticancer agents directly to the tumor site may revolutionize both diagnostic and therapeutic tools thereby facilitating the identification and elimination of malignant cells. Importantly, diagnostic insight and therapeutic effects can be achieved simultaneously through the same nanoparticle. Additionally, a nanoparticle may be loaded with more than one agent, thereby further increasing the value and power of the nanotechnology approach in oncologic therapeutic concepts. Although most insight into mechanisms of nanomedicine has been gained from in vitro and preclinical in vivo models, few clinical trials have been conducted, and nanomedicine-based concepts are already part of standard treatment algorithms. However, despite substantial progress it remains a challenge to design nanoparticles that feature all desirable characteristics at the same time. This review seeks to provide substantial insight into the current status of nanomedicine-based approaches employed for diagnostic and/or therapeutic purposes in the field of gastrointestinal cancers by highlighting achievements and pointing out unresolved issues that need to be further addressed by future research attempts.


Perceptions of injury and prevention practices among pregnant and parenting teenagers.
Injury is a leading cause of death for young children, and the children of teenaged parents may be at increased risk. This qualitative study explored pregnant and parenting teenagers' child safety beliefs and practices related to 4 topics: preventing accidental suffocation via safe sleeping practices, motor vehicle collision safety, prevention of inflicted head trauma, and drowning prevention. Twenty-four focus groups were held with 93 pregnant and/or parenting teenagers. Participants reported variation in their sleeping arrangements, transportation methods, caregivers, and childcare settings. Confusion over safety information was common. Child safety practices were influenced by boyfriends/husbands, parents, grandparents, and teachers.


Intelligibility of speech transduced via classroom-installed FM and conventional audio induction loop amplification systems.
This study was designed to investigate the intelligibility of speech transduced through a classroom-installed FM system and a conventional induction loop amplification (ILA) system and to examine the applicability of an FM adapter when used with commercially available hearing aids. Findings indicate that speech reproduced via the FM system is significantly better than that of the conventional audio induction loop used in this study. It seems likely that the irregular high-frequency response of the ILA system was responsible for this difference. When an FM adapter was used in conjunction with body-type hearing aids, the frequency response of the telecoil along with the positioning of the adapter determine the total performance of the aid.


From small molecules to polymeric catalysts in the oscillatory carbonylation reaction: multiple effects of adding HI.
The oscillatory palladium-catalysed carbonylation reaction opens new horizons for applications in smart materials due to the versatility of its conditions and substrates, as well as the adjustability of amplitude and period of pH oscillations. A variety of viable substrates have been demonstrated, including polymeric alkyne-terminated substrates. However, so far, there have not been any reports of polymer-based palladium catalysts in oscillatory mode. In this paper, we demonstrate pH oscillations in various systems, using commercially available palladium acetate, a triphenylphosphine palladium acetate complex and a polymer-bound palladium catalyst. While palladium acetate was able to generate oscillations under the conditions already established in our previous research on PdI2-catalysed oscillators, the other two catalysts needed the addition of HI to induce oscillations. HI forced an initial pH drop, bringing pH into the range where oscillations generally occur. Addition of HI had a significant effect on all catalysts, modifying the amplitude and period of oscillations, oscillation mode, as well as starting material conversion and product distribution.


Comparison of particle image velocimetry and phase contrast MRI in a patient-specific extracardiac total cavopulmonary connection.
Particle image velocimetry (PIV) and phase contrast magnetic resonance imaging (PC-MRI) have not been compared in complex biofluid environments. Such analysis is particularly useful to investigate flow structures in the correction of single ventricle congenital heart defects, where fluid dynamic efficiency is essential. A stereolithographic replica of an extracardiac total cavopulmonary connection (TCPC) is studied using PIV and PC-MRI in a steady flow loop. Volumetric two-component PIV is compared to volumetric three-component PC-MRI at various flow conditions. Similar flow structures are observed in both PIV and PC-MRI, where smooth flow dominates the extracardiac TCPC, and superior vena cava flow is preferential to the right pulmonary artery, while inferior vena cava flow is preferential to the left pulmonary artery. Where three-component velocity is available in PC-MRI studies, some helical flow in the extracardiac TCPC is observed. Vessel cross sections provide an effective means of validation for both experiments, and velocity magnitudes are of the same order. The results highlight similarities to validate flow in a complex patient-specific extracardiac TCPC. Additional information obtained by velocity in three components further describes the complexity of the flow in anatomic structures.


Pharmacist Counseling and the Use of Nonsteroidal Anti-Inflammatory Drugs by Older Adults.
To determine the impact a medication review has on the detection and use of nonsteroidal anti-inflammatory drugs (NSAIDs) by older adults compared with non-NSAID users in regard to interacting drug classes, interacting comorbidities, and prior counseling by providers. Prospective, quasi-experiment without control. Ambulatory. Patients 60 years of age and older who contacted the pharmacy outreach program. In total, 83 patients consented. Twenty-eight patients were eligible for three-month follow-up. Pharmacists and pharmacy students provided NSAID counseling. Patient-reported changes of NSAID use, change from inappropriate to appropriate use, impression of risk awareness, and further discussion with health care providers. NSAID use was reported by 39 (47.6%) of 83 patients. Inappropriate use was detected in 28 (71.8%) of NSAID users; of these, 18 (64.3%) were reached for post-counseling follow-up. The number of appropriate users increased to 20 (51.3%), with a concomitant reduction of inappropriate users to 19 (48.7%). Nine (50%) reported change in the use of NSAIDs, 13 (72.2%) had a better understanding of the risks associated with NSAID use, and 10 (55.6%) had a more meaningful conversation with providers. Older adults who use NSAIDs may be unaware of potential risks. Counseling older adults may reduce potentially inappropriate use and increase patient risk awareness. Pharmacists can improve their role in recognizing and counseling patients on NSAIDs.


Cinnamon-Derived Hierarchically Porous Carbon as an Effective Lithium Polysulfide Reservoir in Lithium-Sulfur Batteries.
Lithium-sulfur batteries are attractive candidates for next generation high energy applications, but more research works are needed to overcome their current challenges, namely: (a) the poor electronic conductivity of sulfur, and (b) the dissolution and migration of long-chain polysulfides. Inspired by eco-friendly and bio-derived materials, we synthesized highly porous carbon from cinnamon sticks. The bio-carbon had an ultra-high surface area and large pore volume, which serves the dual functions of making sulfur particles highly conductive and acting as a polysulfide reservoir. Sulfur was predominantly impregnated into pores of the carbon, and the inter-connected hierarchical pore structure facilitated a faster ionic transport. The strong carbon framework maintained structural integrity upon volume expansion, and the unoccupied pores served as polysulfide trapping sites, thereby retaining the polysulfide within the cathode and preventing sulfur loss. These mechanisms contributed to the superior performance of the lithium-sulfur cell, which delivered a discharge capacity of 1020 mAh g-1 at a 0.2C rate. Furthermore, the cell exhibited improved kinetics, with an excellent cycling stability for 150 cycles with a very low capacity decay of 0.10% per cycle. This strategy of combining all types of pores (micro, meso and macro) with a high pore volume and ultra-high surface area had a synergistic effect on improving the performance of the sulfur cathode.


[The clinical significance of the risk factor hyperlipoproteinemia. Study on 2700 patients].
In a clinical study on 2,700 inpatients of the medical clinic of Rostock University systematic examinations of the lipids and lipoproteins were carried out. 2.5% of the examined patients showed a primary hyperlipoproteinemia, 14,8% disturbances of the lipid metabolism of different degree of severity, taking into consideration borderline regions of 300 mg/100 ml for cholesterol and of 250 mg/100 ml for triglycerides. In coronary sclerosis and myocardial infarction the frequency of hyperlipoproteinemia was, as we expected, very high, it was about 63 and 77%, respectively. In part groups in primary hyperlipoproteinemia as additional examinations the triglyceride content in the material of liver punction, various coagulation parameters, such as function and kinetics of the platelets were determined and examinations of the secretion of the exocrine pancreas were carried out. In patients of the programme of chronic dialysis, apart from this in temporary dependence on the treatment determinations of the heparin-induced lipoprotein lipase were performed. The consequences resulting from the mutual relations of the factor of risk hyperlipoproteinemia to the diseases of various organic systems are shown.


The sensitivity of direct identification from positive BacT/ALERT™ (bioMérieux) blood culture bottles by matrix-assisted laser desorption ionization time-of-flight mass spectrometry is low.
Recently, matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been presented as a novel method for the direct identification of bacteria from positive blood culture bottles. The rate of the MALDI TOF MS-based identification in the present study from positive BacT/ALERT (bioMérieux, Marcy l'Etoile, France) blood culture bottles was 30%, which is far below the previously reported sensitivities using the BACTEC (Becton Dickinson, Franklin Lakes, NJ, USA) system. We also found evidence that the Biotyper algorithm did not identify a second pathogen in cases of positive BacT/ALERT blood culture bottles containing two different species.


The role of FDG-PET in distinguishing between septic and aseptic loosening in hip prosthesis: a review of literature.
Infection in prosthesis surgery is very dangerous because it changes the patient's prognosis. Differential diagnosis between septic and aseptic loosening is fundamental in order to apply the correct treatment. The correct diagnostic approach is still debated in literature. The aim of this study was to perform a review of literature evaluating positron emission tomography (PET) capacity to distinguish between septic and aseptic loosening in hip prosthesis. Research was done principally among medical archives. Five studies were selected which satisfied the required characteristics, and a weighted average of sensitivity and specificity of the different studies was determined. The fluorodeoxyglucose positron emission tomography (FDG-PET) sensitivity in individuating hip prosthesis infections was 82.8% and specificity was 87.3%. Positron emission tomography based on 2-fluoro-2-deoxy-D-glucose could be a valid option if research is able to find an uptake pattern specific for septic and aseptic loosening.


Correlation between relaxation and automaticity in embryonic heart cell aggregates.
Diastolic depolarization in cardiac muscle is due to a decline in potassium permeability that has been ascribed to removal of intracellular free calcium. A continued decline in tension during the pacemaker potential might therefore occur. In this study, contractile responses of chicken embryonic heart cell aggregates are recorded with a photodiode. Photodiode output is well correlated with the position of the aggregate's edge. Movements of different edges are synchronous, and their amplitude and duration vary appropriately during experimental maneuvers that alter the magnitude and duration of contractile force. Edge movement during relaxation has two phases, a rapid phase lasting about 100 msec and a slow phase that may last over 10 sec. The slow phase is not due to viscoelasticity because its time course does not depend on the magnitude or duration of the initial deformation. The rate of relaxation is correlated with the rate of depolarization during the pacemaker potential. Reduction in automaticity during cooling, spontaneous variation, and overdrive pacing are associated with impairment of the slow component of relaxation. Electrophysiological evidence suggests that the diastolic potassium permeability of the aggregates is controlled by intracellular calcium. A possible explanation for the correlation between the slope of the pacemaker potential and the slow component of relaxation is that both phenomena reflect a common physiological process-i.e., the removal of free calcium from the cytoplasm.


Characterizations of low-temperature electroluminescence from ZnO nanowire light-emitting arrays on the p-GaN layer.
Low-temperature electroluminescence from ZnO nanowire light-emitting arrays is reported. By inserting a thin MgO current blocking layer in between ZnO nanowire and p-GaN, high-purity UV light emission at wavelength 398 nm was obtained. As the temperature is decreased, contrary to the typical GaN-based light emitting diodes, our device shows a decrease of optical output intensity. The results are associated with various carrier tunneling processes and frozen MgO defects.


Comprehensive lifestyle modification and blood pressure control: a review of the PREMIER trial.
The PREMIER trial assessed the aggregate effect on blood pressure (BP) of nationally recommended lifestyle modifications in free-living adults with high-normal (stage 1) hypertension. Participants (N=810) were randomized to the advice-only group; the established group (consisting of weight loss, increased physical activity, and reduced sodium and alcohol intake); or the established plus Dietary Approaches to Stop Hypertension (DASH) diet group (consisting of the established interventions in addition to the DASH dietary pattern). The primary outcome was change in systolic BP at 6 months. Net of advice only, mean systolic BP declined by 3.7 mm Hg for members of the established group (p<0.001) and 4.3 mm Hg for the established plus DASH group (p<0.001). The prevalence of hypertension decreased from a baseline of 38% to 17% in the established group (p=0.01) and to 12% in the established plus DASH group (p<0.001) compared with a decrease to 26% in the advice-only group. The PREMIER trial demonstrated that persons with above-optimal BP and stage 1 hypertension can make multiple lifestyle changes leading to better control of BP.


IgG4 disease.
Immunoglobulin (Ig) G4-related disease (IgG4-RD) is a chronic inflammatory disorder characterized by elevated serum level of IgG4 and abundant infiltration of IgG4-bearing plasmacytes and fibrosis in various organs, typically including the lacrimal glands, salivary glands, pancreas, thyroid gland, lungs, and kidneys. Lacrimal and orbital involvements are called IgG4-related ophthalmic disease, often presenting as orbital myositis, perineuritis of the optic and trigeminal nerves, and orbital inflammation. In particular, a characteristic finding is infraorbital nerve enlargement on magnetic resonance imaging. Systemic screening is necessary to establish the diagnosis of IgG4-RD, and it must be distinguished from neoplastic disease. Corticosteroid treatment is effective in inducing remission but some patients may relapse during tapering of pharmacotherapy. This review encompasses the history, clinical profile, diagnostic criteria, treatment, and prognosis of IgG4-RD.


Gene diagnosis and pedigree analysis of two Han ethnicity families with propionic acidemia in Fujian.
Propionic acidemia is associated with pathogenic variants in PCCA or PCCB gene. We investigated the potential pathogenic variants in PCCA or PCCB genes in Fujian Han population.Two probands and their families of Han ethnicity containing two generations were subject to newborn screening using tandem mass spectrometry, followed by diagnosis using urine gas chromatography mass spectrometry. Sanger sequencing was used to identify potential mutations in PCCA and PCCB genes.Compound heterozygous variants were identified in PCCB gene in two siblings of the first family, the youngest girl showed a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 and a heterozygous missense variant c.1301C>T (p.Ala434Val) in exon 13, which were inherited respectively from their parents. The oldest boy is a carrier with a novel missense variant c.1381G>C (p.Ala461Pro) in exon 13 which were inherited from his father. In the second family, c.1535G>A homozygous mutations were identified in the baby girl, which were inherited respectively from their parents. In silico analysis, several different types of bioinformatic software were utilized, which predicted that the novel variant c.1381G>C in PCCB gene was damaged. According to ACMG principle, the missense variant c.1381G>C (p.Ala461Pro) in exon 13 was a Variant of Undetermined Significance (VUS).One novel missense variant and two missense variants in PCCB gene were identified in the study. The novel variant of PCCB gene identified VUS was identified for the first time in the Chinese population, which enriched the mutational spectrum of PCCB gene.


A numerical investigation of intrathecal isobaric drug dispersion within the cervical subarachnoid space.
Intrathecal drug and gene vector delivery is a procedure to release a solute within the cerebrospinal fluid. This procedure is currently used in clinical practice and shows promise for treatment of several central nervous system pathologies. However, intrathecal delivery protocols and systems are not yet optimized. The aim of this study was to investigate the effects of injection parameters on solute distribution within the cervical subarachnoid space using a numerical platform. We developed a numerical model based on a patient-specific three dimensional geometry of the cervical subarachnoid space with idealized dorsal and ventral nerve roots and denticulate ligament anatomy. We considered the drug as massless particles within the flow field and with similar properties as the CSF, and we analyzed the effects of anatomy, catheter position, angle and injection flow rate on solute distribution within the cerebrospinal fluid by performing a series of numerical simulations. Results were compared quantitatively in terms of drug peak concentration, spread, accumulation rate and appearance instant over 15 seconds following the injection. Results indicated that solute distribution within the cervical spine was altered by all parameters investigated within the time range analyzed following the injection. The presence of spinal cord nerve roots and denticulate ligaments increased drug spread by 60% compared to simulations without these anatomical features. Catheter position and angle were both found to alter spread rate up to 86%, and catheter flow rate altered drug peak concentration up to 78%. The presented numerical platform fills a first gap towards the realization of a tool to parametrically assess and optimize intrathecal drug and gene vector delivery protocols and systems. Further investigation is needed to analyze drug spread over a longer clinically relevant time frame.


Renal cell carcinoma metastatic to the pituitary gland: clinical manifestations and successful treatment with transsphenoidal resection.
To describe two cases of metastatic involvement of the pituitary gland by renal cell carcinoma (RCCA) and review the medical literature regarding this entity. We present two case reports and discuss the published literature to illustrate the clinical findings, radiographic features, and recommended management of RCCA metastatic to the pituitary gland. During a 12-month period, we encountered two patients, one with visual deficits and both with anterior pituitary dysfunction, who had large sellar lesions that were histologically proved to be RCCA. Both patients were successfully treated with transsphenoidal surgical resection of the lesion, one of whom is alive and well more than 2 years later. A pituitary metastatic tumor is an uncommon complication of RCCA; it may be difficult to diagnose and potentially fatal. Anterior pituitary dysfunction and visual disturbances are more common initial features than is diabetes insipidus, in contrast to pituitary metastatic involvement from other tumors. Transsphenoidal resection is a safe and effective method of treatment of RCCA metastatic to the pituitary gland.


Parental insightfulness is associated with mother-father-child interactions among families of preschoolers with an Autism Spectrum Disorder diagnosis.
Parental insightfulness underlies parental sensitive behavior and is associated with secure attachment among Typically Developing (TD) children and also among children with Autism Spectrum Disorder (ASD). Moving beyond the parent-child dyad, a study of TD children and their parents linked mothers' and fathers' combined insightfulness to triadic interactions. The goal of the current study was to examine this association in families with children with ASD. The hypothesis was that the interactions in families in which both parents are insightful will be more cooperative than in families in which only one or neither parent was insightful. Eighty preschooler boys with ASD and both of their parents participated in the study. Parental insightfulness was assessed employing the Insightfulness Assessment (IA) and mother-father-child interactions were observed and coded employing the Lausanne Triadic Play (LTP) procedure. As expected, families in which both parents were insightful displayed higher parental coordinated support in the LTP than families in which one or neither parent was insightful, controlling for children's IQ and severity of symptoms. Children's engagement with their parents was associated with their IQ and severity of symptoms but not with parental insightfulness. The importance of considering paternal, in addition to maternal insightfulness as a foundation for parental coordinated support in family interactions, is discussed, as well as the contribution of the LTP in assessing family interactions with children diagnosed with ASD.


LSD1 demethylates HIF1α to inhibit hydroxylation and ubiquitin-mediated degradation in tumor angiogenesis.
Lysine-specific demethylase 1 (LSD1), which has been considered as a potential therapeutic target in human cancer, has been known to regulate many biological functions through its non-histone substrates. Although LSD1-induced hypoxia-inducible factor alpha (HIF1α) demethylation has recently been proposed, the effect of LSD1 on the relationship between HIF1α post-translational modifications (PTMs) and HIF1α-induced tumor angiogenesis remains to be elucidated. Here, we identify a new methylation site of the HIF1α protein antagonized by LSD1 and the interplay between HIF1α protein methylation and other PTMs in regulating tumor angiogenesis. LSD1 demethylates HIF1α at lysine (K) 391, which protects HIF1α against ubiquitin-mediated protein degradation. LSD1 also directly suppresses PHD2-induced HIF1α hydroxylation, which has a mutually dependent interplay with Set9-mediated HIF1α methylation. Moreover, the HIF1α acetylation that occurs in a HIF1α methylation-dependent manner is inhibited by the LSD1/NuRD complex. HIF1α stabilized by LSD1 cooperates with CBP and MTA1 to enhance vascular endothelial growth factor (VEGF)-induced tumor angiogenesis. Thus, LSD1 is a key regulator of HIF1α/VEGF-mediated tumor angiogenesis by antagonizing the crosstalk between PTMs involving HIF1α protein degradation.


Hepatic oncocytes. Incidence, staining characteristics, and ultrastructural features.
Hepatocytes with orcein-positive ground-glass cytoplasm have been shown to contain abundant hepatitis B surface antigen in the cisternae of excess smooth endoplasmic reticulum. Hepatocytes with similar cytoplasmic changes that did not react with orcein were observed in 26.5% of 49 cases of cirrhosis. These cells exhibited granular, deeply eosinophilic cytoplasm that stained with phosphotungstic acid-hematoxylin and contained numerous densely packed mitochondria as demonstrated by electron microscopy. Therefore, these cells were designated hepatic oncocytes. They were detected predominantly in cases of established cirrhosis, unrelated to etiology. Hepatic oncocytes may form nodular aggregates, but they did not show evidence of regeneration. The nature and pathogenesis of these cells remain unclear. Because of similar appearance, histochemical stains may be necessary to distinguish ground-glass hepatocytes from hepatic oncocytes.


Reconstitution and poly(ADP-ribosyl)ation of proteolytically fragmented poly(ADP-ribose) synthetase.
Calf thymus poly(ADP-ribose) synthetase (Mr = 120,000) is cleaved with papain into two fragments of M(r) = 74,000 and 46,000 and also split with chymotrypsin into two fragments of M(r) = 66,000 and 54,000. Each fragment purified to homogeneity is enzymatically inactive, but combined incubation of the 74,000 and 46,000 fragments in the presence of DNA restored 20% of the enzyme activity. In contrast, combined incubation of the 66,000 and 54,000 fragments does not restore any enzyme activity. In the former incubation, autopoly(ADP-ribosyl)ation reaction occurs exclusively on the 74,000 fragment. When each fragment is incubated with [adenine-U-14C]NAD in the presence of DNA and a catalytic amount of the native enzyme, poly(ADP-ribosyl)action occurs in the overlapped portion (22,000) of the 66,000 fragment and the 74,000 fragment. Nevertheless, the purified 22,000 fragment is a poor acceptor for poly(ADP-ribosyl)ation. The degree of poly(ADP-ribosyl)ation of the proteolytic fragments is significantly reduced by increasing NaCl concentration, probably due to the lack of the interaction between the enzyme fragments and DNA. These results, taken together, indicate that DNA is indispensable for the reconstitution of the catalytic activity as well as the poly(ADP-ribosyl)ation of the fragmented enzyme.


Inflammatory Profiles of Tracheal Biopsies From SARS-CoV-2 Patients.
An increasing number of laryngotracheal complications in mechanically ventilated COVID-19 patients has been reported in the last few months. Many etiopathogenetic hypotheses were proposed but no clear explanation of these complications was identified. In this paper we evaluated the possibility that the tracheal mucosa could be a high viral replication site that could weaken the epithelium itself. Subjects for the COVID-19 group and the control group were selected retrospectively according to specific criteria. Patients' basic and clinical data were recorded and analyzed. Tracheal samples of both groups were collected during surgical tracheostomies and then analyzed from a histological and genetic-transcriptional point of view. Four COVID-19 patients were enrolled in this study and compared with four non-COVID-19 patients. No laryngotracheal complications were identified in both groups. The SARS-CoV-2 was detected in one out of four COVID-19 samples. A subepithelial inflammatory lymphomonocyte infiltrate was observed in all patients but two cases of the COVID-19 group showed vasculitis of small subepithelial vessels associated with foci of coagulative necrosis. Two gene sets (HALLMARK_INFLAMMATORY_RESPONSE and HALLMARK_ESTROGEN_RESPONSE_LATE) were significantly deregulated in COVID-19 patients compared to the control group. The altered inflammatory response of the COVID-19 patients could be another possible explanation of the increasing number of laryngotracheal complications.


Palladium-catalyzed synthesis of 5-amino-1,2,4-oxadiazoles via isocyanide insertion.
A convenient and efficient palladium-catalyzed approach has been developed for the synthesis of 5-amino-1,2,4-oxadiazoles from amidoximes and isocyanides. Various 5-amino-1,2,4-oxadiazoles were obtained in moderate to high yields under mild conditions. The key to the success of this strategy involves new C-N bond and C-O bond formation via palladium-catalyzed isocyanide insertion.


Intracellular electrolytes and hormonal parameters during weight reduction.
The mechanisms of the blood pressure lowering effect of weight reduction have not yet been fully elucidated. In this study the intracellular electrolyte composition and hormonal parameters were monitored in 12 obese subjects during a 10-day diet with 800 kcal/day. A decrease in intracellular free Na+ (p less than 0.05) and Mg2+ (p less than 0.01) and in total intracellular K+ (p less than 0.05) was observed. Furthermore, plasma aldosterone and renin activity (p less than 0.05) increased, probably due to a moderate simultaneous salt restriction. There was also an increase in plasma PGI2 concentration (p less than 0.05). The observed decrease in intracellular free Na+ may be caused by salt restriction. The decrease in intracellular K+ and free Mg2+ may be induced by hormonal factors, e.g. an altered insulin secretion. Possible causes for the known hemodynamic effects of weight reduction are the diminution of intracellular Na+ and the increase in plasma PGI2.


[Recent findings on the importance of vitamin A and its metabolism in man and laboratory animals].
A survey is given concerning recent realizations of importance and metabolism of vitamin A in man and experimental animals. The transport of vitamin A from the small intestine takes place in form of esters by inclusion in chylomicrons and lipoproteins. A higher content in the blood plasma over a longer period evokes toxic effects. In the liver one part of the vitamin A in form of an ester with binding to lipoproteins is accumulated, one part is - according to the need - associated with a vitamin-A-binding protein, which forms complexes with prealbumin molecules and transports the vitamin to the various places of effect. With the help of the receptor proteins the vitamin A is included in the cells, in which it is effective and is transported into the vitamin-A-aldehyde and the vitamin-A-acid. The vitamin A and the vitamin-A-acid are transported into the cell nuclei with the help of receptor-proteins and play a role in the differentiation of the tissues and in the regulation of the synthesis of RNA. When a deficit or an abundance of vitamin A is present in the early phase of pregnancy malformations in the fetuses appear. The vitamin A and structure-similar connections have an inhibiting effect on the development of tumours.


Red Blood Cell Membrane-Camouflaged Gold Nanoparticles for Treatment of Melanoma.
Patients with melanoma have poor response and low long-term survival to conventional cisplatin (CP). Recently, biomimetic nanoparticles have played a significant role in tumor therapy. The purpose of this study was to mechanistically evaluate the effect of red blood cell membrane camouflaged gold nanoparticles loaded with CP (RBCm@AuNPs-CP) on enhancing chemotherapy in melanoma. Treated B16-F10 cells with RBCm@AuNPs-CP, the antimelanoma effect in vitro was explored by detecting cell viability, apoptosis rate, level of reactive oxygen species (ROS), and singlet oxygen. RBCm@AuNPs-CP was injected into the melanoma-bearing mice via tail vein, and the target-ability, therapeutic effect, and toxicity were detected in melanoma tumor-bearing mice. RBCm@AuNPs-CP had an antiproliferation and apoptosis-inducing effect on B16-F10 cells, which might be mediated by oxidative stress of ROS, and its effect was significantly enhanced compared with the CP treatment group. In vivo experiments suggested the same outcome, with better target-ability of RBCm@AuNPs-CP. The erythrocyte camouflage nanosystem RBCm@AuNPs-CP exhibited well passive tumor target-ability and promoted apoptosis of melanocytes by inducing ROS. RBCm@AuNPs-CP as a novel safe and effective targeted drug delivery system may provide a promising choice for the treatment of melanoma.


Phase II and III clinical trials of toremifene for metastatic breast cancer.
Toremifene (Fareston) received FDA approval in 1997 for the first-line treatment of postmenopausal women with estrogen receptor (ER)-positive or -unknown metastatic breast cancer. Phase II and III trials have demonstrated that first-line therapy with toremifene, 60 mg/d, is as effective and as well tolerated as tamoxifen (Nolvadex), 20 or 40 mg/d, in such patients. To date, phase III trials have failed to show a statistically significant advantage of higher toremifene doses over standard doses of tamoxifen in these women. Studies appeared to indicate minimal efficacy of high toremifene doses in women with ER-negative tumors, but the number of patients studied was small. Although results of some trials of high-dose (240 mg/d) toremifene in tamoxifen-"refractory" patients were negative, other trials that included prolonged (> or = 6 months) stable disease as an indication of clinical benefit yielded positive results.


Unfolded protein response in balancing plant growth and stress tolerance.
The ER (endoplasmic reticulum) is the largest membrane-bound multifunctional organelle in eukaryotic cells, serving particularly important in protein synthesis, modification, folding and transport. UPR (unfolded protein response) is one of the systematized strategies that eukaryotic cells employ for responding to ER stress, a condition represents the processing capability of ER is overwhelmed and stressed. UPR is usually triggered when the protein folding capacity of ER is overloaded, and indeed, mounting studies were focused on the stress responding side of UPR. In plants, beyond stress response, accumulating evidence suggests that UPR is essential for growth and development, and more importantly, the necessity of UPR in this regard requires its endogenous basal activation even without stress. Then plants must have to fine tune the activation level of UPR pathway for balancing growth and stress response. In this review, we summarized the recent progresses in plant UPR, centering on its role in controlling plant reproduction and root growth, and lay out some outstanding questions to be addressed in the future.


ISLpl1 is a functional IS30-related insertion element in Lactobacillus plantarum that is also found in other lactic acid bacteria.
We describe the first functional insertion sequence (IS) element in Lactobacillus plantarum. ISLpl1, an IS30-related element, was found on the pLp3 plasmid in strain FB335. By selection of spontaneous mutants able to grow in the presence of uracil, it was demonstrated that the IS had transposed into the uracil phosphoribosyltransferase-encoding gene upp on the FB335 chromosome. The plasmid-carried IS element was also sequenced, and a second potential IS element was found: ISLpl2, an IS150-related element adjacent to ISLpl1. When Southern hybridization was used, the copy number and genome (plasmid versus chromosome) distribution data revealed different numbers and patterns of ISLpl1-related sequences in different L. plantarum strains as well as in Pediococcus strains. The ISLpl1 pattern changed over many generations of the strain L. plantarum NCIMB 1406. This finding strongly supports our hypothesis that ISLpl1 is a mobile element in L. plantarum. Database analysis revealed five quasi-identical ISLpl1 elements in Lactobacillus, Pediococcus, and Oenococcus strains. Three of these elements may be cryptic IS, since point mutations or 1-nucleotide deletions were found in their transposase-encoding genes. In some cases, ISLpl1 was linked to genes involved in cold shock adaptation, bacteriocin production, sugar utilization, or antibiotic resistance. ISLpl1 is transferred among lactic acid bacteria (LAB) and may play a role in LAB genome plasticity and adaptation to their environment.


Propolis inhibits TGF-β1-induced epithelial-mesenchymal transition in human alveolar epithelial cells via PPARγ activation.
Emerging evidence suggests that the transforming growth factor (TGF)-β1-induced epithelial-mesenchymal transition (EMT) of alveolar epithelial cells (AEC) may contribute to airway remodeling in severe asthma and fibrotic lung diseases. Studies have shown that extracts from propolis protect chemical-induced cardiac and liver fibrosis in animals. This study assesses the inhibitory effect of propolis on TGF-β1-induced EMT in serum-deprived A549 cells (human AECs). Experimental results show progressive cell morphological changes, decreased E-cadherin, increased N-cadherin production, intracellular F-actin rearrangement, increased reactive oxygen species (ROS) production, and increased cell motility with increasing TGF-β1 concentration. A549 cells pretreated with propolis and then treated with TGF-β1 for 24 h regained epithelial cell morphology, decreased the production of N-cadherin and ROS, and had reduced motility. Propolis prevents the effects of TGF-β1-induced Smad2 and AKT activation pathways and Snail expression. Moreover, propolis pretreatment may prevent the TGF-β1-induced down-regulation of nuclear hormone receptors and peroxisome proliferator-activated receptor gamma (PPARγ) protein in A549 cells, whose effect was blocked by adding PPARγ antagonist, GW9662. Two active components of propolis, caffeic acid phenethyl ester (CAPE) and pinocembrin (PIN), only had partial effects on TGF-β1-induced EMT in A549 cells. The results of this study suggest that natural propolis extracts may prevent TGF-β1-induced EMT in immortalized type II AECs via multiple inhibitory pathways, which may be clinically applied in the prevention and/or treatment of EMT-related fibrotic diseases as well as airway remodeling in chronic asthma.


"I wish he hadn't told me that": methodological and ethical issues in social trauma and conflict research.
Undertaking research on individuals who have experienced social traumas, such as being a victim or perpetrator of genocides and wars, presents difficult decisions for qualitative researchers. Deciding how to deal with these issues becomes more problematic when the researcher is a member of the society in conflict. To do this work, and to work collaboratively with researchers from the other side, sensitive ways to collect data have to be chosen. Interpretations of the materials can be no less difficult: Analyses often lead to information and understandings that may be difficult for the researcher to deal with from ethical, moral, and personal standpoints, especially when he or she is a member of the society and culture under study. In this keynote address, the author explores methodological and ethical issues connected to these topics. She brings examples from her work on the Palestinian-Israeli conflict and focuses on use of the life story methodology.


Simultaneous multiresidue analysis of beta-lactam antibiotics in bovine milk by liquid chromatography with ultraviolet detection and confirmation by electrospray mass spectrometry.
A multiresidue analytical method was developed for the simultaneous determination of amoxicillin, cephapirin, procaine penicillin G, ampicillin, cloxacillin, and ceftiofur in bovine milk. The method involved ultrafiltration of milk diluted with an equal volume of 50% acetonitrile through a 10,000 dalton molecular mass cutoff filter. Separation of these beta-lactam antibiotics from other milk components was performed by ion-paired (octane- and dodecanesulfonate) liquid chromatography using a phenyl column eluted with acetonitrile-water solution. Ultraviolet absorbance of the column effluent was monitored in the 200-350 nm range of a photodiode-array detector. For quantitation, the chromatograms were acquired at lambda 210 nm for penicillin G, ampicillin, and cloxacillin; lambda 230 nm for amoxicillin; and lambda 290 for cephapirin, procaine, and ceftiofur. The limit of detection for the simultaneous determination of these antibiotics was estimated to be 100 ppb. Liquid chromatography/electrospray mass spectrometry could be used to confirm these antibiotics for quantities down to 100 pg entering the mass spectrometer.


Measuring the effectiveness of patient-chosen reminder methods in a private orthodontic practice.
To evaluate the effectiveness of patient-chosen appointment reminder methods (phone call, e-mail, or SMS text) in reducing no-show rates. This was a retrospective case study that determined the correlation between patient-chosen appointment reminder methods and no-show rates in a private orthodontic practice. This study was conducted in a single office location of a multioffice private orthodontic practice using data gathered in 2015. The subjects were patients who self-selected the appointment reminder method (phone call, e-mail, or SMS text). Patient appointment data were collected over a 6-month period. Patient attendance was analyzed with descriptive statistics to determine any significant differences among patient-chosen reminder methods. There was a total of 1193 appointments with an average no-show rate of 2.43% across the three reminder methods. No statistically significant differences ( P = .569) were observed in the no-show rates between the three methods: phone call (3.49%), e-mail (2.68%), and SMS text (1.90%). The electronic appointment reminder methods (SMS text and e-mail) had lower no-show rates compared with the phone call method, with SMS text having the lowest no-show rate of 1.90%. However, since no significant differences were observed between the three patient-chosen reminder methods, providers may want to allow patients to choose their reminder method to decrease no-shows.


A nanosensor for transmembrane capture and identification of single nucleic Acid molecules.
We have engineered a nanosensor for sequence-specific detection of single nucleic acid molecules across a lipid bilayer. The sensor is composed of a protein channel nanopore (alpha-hemolysin) housing a DNA probe with an avidin anchor at the 5' end and a nucleotide sequence designed to noncovalently bind a specific single-stranded oligonucleotide at the 3' end. The 3' end of the DNA probe is driven to the opposite side of the pore by an applied electric potential, where it can specifically bind to oligonucleotides. Reversal of the applied potential withdraws the probe from the pore, dissociating it from a bound oligonucleotide. The time required for dissociation of the probe-oligonucleotide duplex under this force yields identifying characteristics of the oligonucleotide. We demonstrate transmembrane detection of individual oligonucleotides, discriminate between molecules differing by a single nucleotide, and investigate the relationship between dissociation time and hybridization energy of the probe and analyte molecules. The detection method presented in this article is a candidate for in vivo single-molecule detection and, through parallelization in a synthetic device, for genotyping and global transcription profiling from small samples.


Nitrosopumilus as main source of isoprenoid glycerol dialkyl glycerol tetraether lipids in the central Baltic Sea.
Nitrososphaeria in the phylum Crenarchaeota, is a widespread archaeal class in the oceanic realm, playing an important role in the marine carbon and nitrogen cycle. Nitrososphaeria-derived membrane lipids, i.e., isoprenoid glycerol dialkyl glycerol tetraethers (GDGTs), are commonly employed to reconstruct past water temperatures using the TetraEther indeX of 86 carbon atoms (TEX86). This index is of particular importance for the brackish Baltic Sea as to date it appears to be the only applicable organic temperature proxy. In this study, we investigated the distribution of intact and core GDGTs and their potential source organisms in the water column of three deep basins located in the central Baltic Sea to evaluate the application of TEX86. A lipidomic approach on suspended particulate matter was combined with the molecular techniques 16S rRNA gene amplicon sequencing and CARD-FISH. The archaeal community was dominated by Nitrosopumilus (~83-100% of the total archaeal sequences). As other detected taxa known to produce GDGTs each represented less than 2% of the total archaeal sequences, Nitrosopumilus is likely the most dominant GDGT producer in the central Baltic Sea. However, the occurrence of phosphohexose (PH), instead of hexose-phosphohexose (HPH) headgroups, suggested that Nitrosopumilus in the Baltic Sea may differ physiologically from representatives of marine settings and other marginal seas, such as the Black Sea. In the Baltic Sea, Nitrosopumilus is most abundant in the suboxic zone, where intact cells peak according to both CARD-FISH data and intact polar lipid concentrations. The presented data therefore suggest that TEX86 reflects subsurface rather than surface temperature in the central Baltic Sea.


Life's Essential 8 is associated with atherosclerotic cardiovascular disease but not venous thromboembolism in men: a prospective cohort study.
Background: Atherosclerotic cardiovascular disease (ASCVD) shares several risk factors with venous thromboembolism (VTE). The American Heart Association's Life's Simple 7 (LS7), which included seven health and behavioural factors for CVD prevention, has recently been upgraded to Life's Essential 8 (LE8) score. We aimed to examine the prospective association between LE8 and the risks of ASCVD and VTE in Finland.Methods: We utilized data based on 1899 men aged 42-61 years in the Kuopio Ischaemic Heart Disease (KIHD) prospective study. The LE8 score was generated from baselines measures of four health behaviours (physical activity, diet, nicotine exposure and sleep health) and four health factors (BMI, blood lipids, blood glucose and blood pressure). Each factor was scored from 0 to 100 and summed into a composite score. Participants were classified into quartiles (Q) based on the total LE8 score - Q1, ≤ 420; Q2, >420 to 485; Q3, >485 to 550; Q4, >550. Multivariable Cox regression models were utilized to determine the hazard ratios (HRs) along with the 95% confidence intervals (CI) for ASCVD and VTE.Results: After median follow-up durations of 24 and 25 years, 889 ASCVD and 127 VTE events were recorded, respectively. The risk of ASCVD was found to be 58% lower in men belonging to the highest LE8 quartile compared to those in the lowest quartile (HR:0.42; 95%CI: 0.34-0.51). There was no significant evidence of an association between LE8 and VTE risk (Q4 vs Q1, HR:1.02; 95%CI: 0.60-1.74).Conclusion: The risk of ASCVD was significantly lower in middle-aged and older Finnish men who had a high LE8 score, but there was no significant association with VTE. Further large-scale prospective studies conducted in women and other population groups are necessary to confirm these findings.


Methimazole discontinuation before radioiodine therapy in patients with Graves' disease.
Although radioiodine therapy (RIT) has been used for the treatment of hyperthyroidism for many decades, there is no consensus on the optimal time of methimazole (MMI) discontinuation before RIT. The aim of this clinical trial is to study the effect of three different time points of MMI discontinuation on response to RIT. Overall, 151 patients (18-65 years old), with Graves' disease who were taking MMI and referred to I-131 therapy, were consecutively assigned to one of three groups, and MMI was discontinued for 24-48, 48.1-72, and 72.1-168 h in group, 1, 2, and 3, respectively. Radioiodine uptake was measured in all patients and the radioiodine dose was calculated according to the Quimby formula to deliver 7.4 MBq of I-131 per gram of thyroid weight. Response to RIT was assessed at 1, 3, 6, and 12 months after RIT. A total of 102 women and 49 men were included in the study. The mean administered dose of I-131 was 362.9±188.7 MBq (9.8±5.1 mCi) and the mean time to response for radioiodine was 4.1±3.6 months. There was no significant difference between the three groups in age, thyroid weight, anti-TPO level, radioactive iodine uptake level, and radioiodine dose (P>0.1). Response to RIT at 1, 3, 6, and 12 months after administration was also not different between the three groups (P>0.57). No difference was found in the response to treatment between patients with MMI discontinuation for 24-48, 48.1-72, and 72.1-96 h before RIT. Shorter discontinuation of MMI before RIT may be preferable in most patients. Video Abstract: http://links.lww.com/NMC/A39.


Mechanistic Studies on the Peroxyoxalate Chemiluminescence Using Sodium Salicylate as Base Catalyst.
Mechanistic studies on the peroxyoxalate chemiluminescence are often conducted with imidazole as base and nucleophilic catalyst. However, it is also known that this compound, at high concentrations, leads to a drastic reduction in the chemiluminescence quantum yields, apparently due to the destruction of the high-energy intermediate. Consequently, the search for new catalysts for this transformation is of importance for mechanistic studies as well as analytical application. Therefore, we report here a study on the mechanism of the peroxyoxalate reaction with sodium salicylate as base catalyst, which has already been utilized in this reaction; however, no detailed mechanistic investigation is known. In this work, a kinetic study on the sodium salicylate-catalyzed reaction of bis(2,4,6-trichlorophenyl) oxalate with hydrogen peroxide using 9,10-diphenylanthracene as activator is reported, where observed rate constants, singlet quantum yields and activation parameters are determined in different reaction conditions, leading to the formulation of a general mechanistic reaction scheme.


Time-domain mid-infrared frequency-comb spectrometer.
A novel type of Fourier-transform infrared spectrometer (FTIR) is demonstrated. It is based on two Ti:sapphire lasers emitting femtosecond pulse trains with slightly different repetition frequencies. Two mid-infrared beams-derived from those lasers by rectification in GaSe-are superimposed upon a detector to produce purely time-domain interferograms that encode the infrared spectrum. The advantages of this spectrometer compared with the common FTIR include ease of operation (no moving parts), speed of acquisition (100 micros demonstrated), and not-yet-shown collimated long-distance propagation, diffraction-limited microscopic probing, and electronically controllable chemometric factoring. Extending time-domain frequency-comb spectroscopy to lower (terahertz) or higher (visible, ultraviolet) frequencies should be feasible.


Electrochemical Promotion of CO2 Hydrogenation Using a Pt/YSZ Fuel Cell Type Reactor.
The hydrogenation of CO2 is a reaction of key technological and environmental importance, as it contributes to the sustainable production of fuels while assisting in the reduction of a major greenhouse gas. The reaction has received substantial attention over the years within the catalysis and electrocatalysis communities. In this respect, the electrochemical promotion of catalysis (EPOC) has been applied successfully to the CO2 hydrogenation reaction to improve the catalytic activity and selectivity of conductive films supported on solid electrolytes. However, designing an effective electrocatalytic reactor remains a challenge due to the connections required between the electrodes and the external potentiostat/galvanostat. This drawback could be alleviated if the catalytic reaction occurs in a reactor that simultaneously operates as a power generator. In this work, the Electrochemical Promotion of the CO2 hydrogenation reaction in a low-temperature solid oxide electrolyte fuel cell (SOFC) reactor is studied using yttria-stabilized zirconia (YSZ) and a platinum (Pt) electrode catalyst. The system has been studied in two distinct operation modes: (i) when the necessary energy for the electrochemical promotion is produced through the parallel reaction of H2 oxidation (galvanic operation) and (ii) when a galvanostat/potentiostat is used to impose the necessary potential (electrolytic operation). The performance of the fuel cell declines less than 15% in the presence of the reactant mixture (CO2 and H2) while producing enough current to conduct EPOC experiments. During the electrolytic operation of the electrochemical cell, the CO production rate is significantly increased by up to 50%.


Cinnamoyl inhibitors of tissue transglutaminase.
Transglutaminases (TGases) catalyze the intermolecular cross-linking of certain proteins and tissue TGases (TG2) are involved in diverse biological processes. Unregulated, high TGase activities have been implicated in several physiological disorders, but few reversible inhibitors of TG2 have been reported. Herein, we report the synthesis of a series of novel trans-cinammoyl derivatives, discovered to be potent inhibitors of guinea pig liver transglutaminase. The most effective inhibitors evaluated can be sorted into two subclasses: substituted cinnamoyl benzotriazolyl amides and the 3-(substituted cinnamoyl)pyridines, referred to more commonly as azachalcones. Kinetic evaluation of both of these subclasses revealed that they display reversible inhibition and are competitive with acyl donor TGase substrates at IC50 values as low as 18 microM. An analysis of structure-activity relationships within these series of inhibitors permitted the identification of potentially important binding interactions. Further testing of some of the most potent inhibitors demonstrated their selectivity for TG2 and their potential for further development.


Effects of long-term, once-daily administration of atenolol on ambulatory blood pressure of hypertensive patients.
We measured intraarterial, ambulatory blood pressure over a 24-h period in 12 subjects 24--63 years (mean 47.6) of age with newly diagnosed untreated hypertension. Measurements were performed both before and after 2--9 months of once-daily treatment with atenolol, a cardioselective beta-adrenoceptor antagonist. Significant reductions in arterial pressure (p less than 0.005) during treatment with atenolol (dose range 50--200 mg) were observed over the full 24-h period.


Spatial genome organization: contrasting views from chromosome conformation capture and fluorescence in situ hybridization.
Although important for gene regulation, most studies of genome organization use either fluorescence in situ hybridization (FISH) or chromosome conformation capture (3C) methods. FISH directly visualizes the spatial relationship of sequences but is usually applied to a few loci at a time. The frequency at which sequences are ligated together by formaldehyde cross-linking can be measured genome-wide by 3C methods, with higher frequencies thought to reflect shorter distances. FISH and 3C should therefore give the same views of genome organization, but this has not been tested extensively. We investigated the murine HoxD locus with 3C carbon copy (5C) and FISH in different developmental and activity states and in the presence or absence of epigenetic regulators. We identified situations in which the two data sets are concordant but found other conditions under which chromatin topographies extrapolated from 5C or FISH data are not compatible. We suggest that products captured by 3C do not always reflect spatial proximity, with ligation occurring between sequences located hundreds of nanometers apart, influenced by nuclear environment and chromatin composition. We conclude that results obtained at high resolution with either 3C methods or FISH alone must be interpreted with caution and that views about genome organization should be validated by independent methods.


Colobronchial fistula: a rare cause of chronic cough.
We report a colobronchial fistula in a middle-aged woman. She had been having cough with expectoration of sputum with a faeculent odour since the age of 7 years. Imaging revealed a fistulous connection between the hepatic flexure and the right bronchial tree, which was successfully repaired surgically.


Perception of Policy and Environmental Action to Promote Healthy Behaviors in African American Communities.
The present study aimed to examine the perceptions of African American communities regarding the involvement of political leaders in facilitating policy and environmental change promoting healthy eating and physical activity. We selected the Metro Jackson Area comprised of Hinds, Madison and Rankin Counties because it is a combination of urban and rural communities. The sample consisted of 70 participants from seven sites. A total of seven focus groups were asked to respond to one question to assess political leaders' involvement in healthy living: "When you think about your political leaders that you have in the Jackson, Mississippi area, do any of them promote healthy eating and physical activity?" Focus groups consisted of six to 12 participants and were asked to comment on their participation in physical activity. The focus group interviews were digitally recorded. The recorded interviews were transcribed by a professional transcriptionist. Community members could not recollect much participation from political leaders in the health prevention/intervention efforts. In each of the counties, there was evidence that there was some involvement by local politicians in health promotion issues, but not on a large scale. In conclusion, making healthy foods and products available in neighborhood stores has long been associated with healthy behaviors and positive health outcomes. This can make a difference in the Mississippi communities where supermarkets are not accessible and health disparities abound.


Integrated pharmacokinetic-pharmacodynamic modeling to evaluate empiric carbapenem therapy in bloodstream infections.
Treatment for nosocomial bloodstream infections (BSI) caused by multidrug-resistant (MDR) Gram-negative bacteria (GNB) is challenging. Rising antimicrobial resistance, especially in extended spectrum beta-lactamase production, inadvertently increases empiric carbapenem consumption. Three antipseudomonal carbapenems (imipenem, meropenem [MER], and doripenem [DOR]) are available commercially against MDR GNB in Singapore. The study aims to determine the most optimal empiric carbapenem dosing regimens (CDR) and evaluate their cost-effectiveness for GNB-BSI in the face of increasing MDR GNB. Carbapenem minimum inhibitory concentrations (MICs) were generated for non-repeat GNB-BSI obtained in 2013-2014 from two hospitals. Monte Carlo simulations were used to assess the cumulative fraction of response (CFR) of various CDRs using the percentage of time above MIC for 40% (%T > MIC of 40%) as the pharmacokinetic (PK)-pharmacodynamic (PD) parameter for efficacy. Carbapenem costs were based on patient antibiotic costs. Antibiotic cost-effectiveness was calculated as total daily drug cost/CFR. A total of 1,140 bloodstream isolates were collected. They comprised 116 Acinetobacter baumannii, 237 Pseudomonas aeruginosa, and 787 Enterobacteriaceae. All CDRs achieved ~40, ~80, and ≥90% CFRs against A. baumannii, P. aeruginosa, and Enterobacteriaceae, respectively. Against P. aeruginosa, MER 2 g every 8 h infused over 3 h and DOR 1 g every 8 h infused over 4 h achieved CFRs 84 and 81%, respectively. Against Enterobacteriaceae, the cost of MER 2 g every 8 h infused over 3 h was the lowest among the three carbapenems at $0.40/percentage of CFR. This study demonstrates the utility of PK-PD modeling to formulate the optimal selection of a cost-effective empiric CDR in antibiotics guidelines and formulary inclusion. The findings support the selection of high MER doses of prolonged infusions as empiric coverage for GNB-BSI in our institutions.


Release of acetylcholinesterase (AChE) from beta-amyloid plaques assemblies improves the spatial memory impairments in APP-transgenic mice.
The major protein constituent of amyloid deposits in Alzheimer's disease (AD) is the amyloid-beta-peptide (Abeta). Amyloid deposits contain "chaperone molecules" which play critical roles in amyloid formation and toxicity. In the present work, we test an analog of hyperforin (IDN 5706) which releases the AChE from both the Abeta fibrils and the AChE-Abeta burdens in transgenic mice. Hyperforin is an acylphloroglucinol compound isolated from Hypericum perforatum (St. John's Wort), which is able to prevent the Abeta-induced spatial memory impairments and Abeta neurotoxicity. Altogether this gathered evidence indicates the important role of AChE in the neurotoxicity of Abeta plaques and finding new compounds which decrease the AChE-Abeta interaction may be a putative therapeutic agent to fight the disease.


89Zr-Lumretuzumab PET Imaging before and during HER3 Antibody Lumretuzumab Treatment in Patients with Solid Tumors.
Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received 89Zr-lumretuzumab and underwent positron emission tomography (PET). In part A, 89Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5), and 24.6% (±20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab.Conclusions: PET imaging showed biodistribution and tumor-specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. Clin Cancer Res; 23(20); 6128-37. ©2017 AACR.


Heat conduction in a three dimensional anharmonic crystal.
We perform nonequilibrium simulations of heat conduction in a three dimensional anharmonic lattice. By studying slabs of length N and width W, we examine the crossover from one dimensional to three dimensional behavior of the thermal conductivity kappa. We find that for large N, the crossover takes place at a small value of the aspect ratio W/N. From our numerical data we conclude that the three dimensional system has a finite nondiverging kappa and thus provides the first verification of Fourier's law in a system without pinning.


Changes within the stabilizing layer of ZnO nanoparticles upon washing.
ZnO nanoparticles (NPs) are highly relevant for various industrial applications, however, after synthesis of the NPs residual chemicals need to be removed from the colloidal raw product by washing, as they may influence the performance of the final device. In the present study we focus on the effect of washing by antisolvent flocculation with subsequent redispersion of the NPs on the stabilizing acetate shell. Purification of the ZnO nanoparticles is reported to be optimal with respect to zeta potential that has a maximum after one washing cycle. In this work, we will shed light on this observation using small angle X-ray and neutron scattering (SAXS, SANS) by demonstrating that after the first washing cycle the content of acetate in the ligand shell around the ZnO NPs increases. In detail, it was observed that the diffuse acetate shell shrinks to the size of a monolayer upon washing but the acetate content of this monolayer is higher than within the diffuse shell of the particles of the native dispersion. A second washing cycle reduces the acetate concentration within the stabilizing shell and the stability of the dispersion drops accordingly. After another (third) washing cycle strong agglomeration was observed for all investigated samples.


Two-year-old girl with impacted ureteral stone successfully treated with a single session of combined percutaneous nephrostomy and ureteroscopy.
Impacted stones frequently cause changes in the ureter, including edema of the ureteral wall, stone embedding in the ureteral mucosa or ureteral bending, which often preclude spontaneous passing of the stone and increase the risk of complications during surgery. When stone impaction is suspected preoperatively, management should be adapted accordingly. However, surgical treatment strategies remain controversial in pediatric patients because of the scarcity of cases reported. We describe the case of a 2-year-old girl with a right impacted ureteral stone who presented with gross hematuria and pyuria, but no metabolic risk factors or hematological abnormalities. Ureteroscopy was carried out in the presence of a percutaneous nephrostomy catheter. At the 7-month follow up, hydronephrosis had improved from grade 3 to grade 1, and the ureter was free from residual or recurrent stones. No complications were noted. We believe that percutaneous nephrostomy before the lithotripsy facilitates treatment for impacted stones in pediatric patients.


Finding Middle Ground in Constructing a Clinically Useful Expanded Carrier Screening Panel.
Expanded carrier screening for autosomal-recessive conditions effectively identifies more carrier couples than traditional guideline-based carrier screening. However, clinically available expanded carrier screening panels include numerous conditions, some of which have questionable clinical utility as a result of very low carrier frequency, low or unknown testing sensitivity, and mild or incompletely penetrant phenotypes. Using the 2013 American College of Medical Genetics and Genomics Position Statement on Prenatal and Preconception Expanded Carrier Screening and the 2017 American College of Obstetricians and Gynecologists' Committee Opinion on Carrier Screening in the Age of Genomic Medicine as guidance, we propose specific criteria for the development of expanded carrier screening panels that will maximize clinical utility and minimize patient stress, unnecessary cost of follow-up testing, and clinician time spent facilitating and performing follow-up counseling and testing. We identified 96 conditions that meet our proposed criteria, far more than current guidelines recommend. On the other hand, a considerable percentage (73%) of conditions on current expanded carrier screen panels does not meet our proposed criteria. The purpose of this commentary is to acknowledge the benefits of expanded panels, but to also recognize that in their current state, we are putting patients at risk for undue stress and spending excessive time and money on follow-up testing for remarkably rare or mild conditions and conditions with low screening performance. We encourage laboratories and clinicians to work together to create the most clinically useful screening panels for patients desiring reproductive risk information.


The Influence of Social Communication Impairments on Gaze in Adolescents with Social Anxiety Disorder.
Adolescents with social anxiety disorder (SAD) often present distorted beliefs related to expected social rejection, coupled with avoidance of social stimuli including interpersonal interactions and others' gaze. Social communication (SC) deficits, often seen in SAD, may play a role in avoidance of social stimuli. The present study evaluated whether SC impairment uniquely contributes to diminished or heightened attention to social stimuli. Gaze patterns to social stimuli were examined in a sample of 41 adolescents with SAD (12-16 years of age; 68% female). Unexpectedly, no significant relationship was observed between SC impairment and fixation duration to angry or neutral faces. However, SC impairment did predict greater fixation duration to happy faces, after controlling for social anxiety severity [adjusted R 2 = 0.201, F(2, 38) = 4.536, p = 0.018]. Clinical implications are discussed, focusing on the potential utility of targeting SC impairments directly in light of the role of SC difficulties in youth with SAD.


Elderberry extract improves molecular markers of endothelial dysfunction linked to atherosclerosis.
Endothelial dysfunction (ED), secondary to diminished nitric oxide (NO) production and oxidative stress, is an early subclinical marker of atherosclerosis. Reduced NO bioavailability enhances the adhesion of monocytes to endothelial cells and promotes atherosclerosis. Elderberry extract (EB) is known to contain high levels of anthocyanins which could exert vascular protective effects. Specifically, we investigated the functional capacity of EB on various markers of ED. Human umbilical vein endothelial cells (HUVEC) were pretreated with EB 50 μg/mL and stimulated with TNF-α 10 ng/mL. Cell viability, apoptosis, oxidative stress; eNOS, Akt, Nrf2, NOX-4, and NF-κB at the protein level were measured. A co-culture model was used to determine whether EB could prevent the adhesion of monocytes (THP-1) to HUVECs. Moreover, the expression of adhesion molecules and pro-inflammatory cytokines were also measured. It was demonstrated that EB prevented TNF-α induced apoptosis and reactive oxygen species production in HUVECs. Additionally, EB upregulated Akt and eNOS activity, and Nrf2 expression in response to TNF-α, whereas it decreased NOX-4 expression and NF-κB activity. EB prevented the adhesion of monocytes to HUVECs, as well as reduced IL-6 and MCP-1 levels, which was associated with inhibition of VCAM-1 expression. Our results demonstrate that EB upregulates key cellular markers of endothelial function and ameliorates markers of ED. EB could be used as a potential nutritional aid for preventing atherosclerosis progression.


The endometrial and breast safety of menopausal hormone therapy containing micronised progesterone: A short review.
For a significant minority of women, menopausal symptoms can be very unpleasant; however, many are worried about taking menopausal hormone therapy (MHT) for fear of causing breast cancer. Micronised progesterone (mP4) has been available in Europe since the 1990s and clinical trials have shown that 100 mg oral daily, 200 mg oral sequentially or 100 mg vaginal every second day effectively protect the endometrium from the stimulatory effects of oestrogen. MHT containing mP4 has a significantly lower breast cancer risk than those containing progestins. Micronised progesterone does not appear to attenuate the cardiovascular benefits of oestrogen. Pharmaceutical grade, body identical MHT is now available in Australia.