The effect of dilazep on puromycin-induced rat renal mitochondrial dysfunction.
The effect of tetrahydro-1 H-1,4 (5H)-dipropanol bis(3,4,5-trimethoxybenzoate)hydrochloride monohydrate (dilazep, Comelian) on puromycin-induced rat renal damage was investigated. In vivo study: Rats were divided into 3 groups, the control group; untreated, the puromycin group; puromycin (150 mg/kg) was injected intraperitoneally once, the dilazep + puromycin group; puromycin (150 mg/kg) was injected 1 h after intraperitoneal dilazep injection (2 mg/kg), and dilazep (2 mg/kg) was injected every 12 h until the end of the experiment. In each group, 84 h after puromycin injection, kidneys were isolated and renal mitochondria were prepared. The endogenous phospholipase activity in kidney homogenate was determined by high performance liquid chromatography. The activities of three segments (NADH-cytochrome c reductase, succinate-cytochrome c reductase and cytochrome c oxidase) of the electron-transport chain in mitochondria were measured enzymatically. In the puromycin group, phospholipase activity was increased and activities of all of three segments of the electron-transport chain were decreased. In the dilazep + puromycin group, premedication with dilazep prevented activation of phospholipase and maintained mitochondrial electron-transport activity. In vitro study: Mitochondria prepared from intact rat kidney were incubated with phospholipase C. Activities of the mitochondrial electron-transport chain were deteriorated by phospholipase C. These results indicated that activation of endogenous phospholipase, which digests membrane phospholipids, essential components in maintaining mitochondrial electron-transport activity, is responsible for the puromycin-induced renal damage. Premedication with dilazep prevented the damage by inhibition of the activation of phospholipase.


A Phase I-II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors.
Purpose: Rucaparib is a potent, oral, small-molecule PARP inhibitor. This phase I-II study was the first to evaluate single-agent oral rucaparib at multiple doses.Experimental Design: Part 1 (phase I) sought to determine the MTD, recommended phase II dose (RP2D), and pharmacokinetics of oral rucaparib administered in 21-day continuous cycles in patients with advanced solid tumors. Part 2A (phase II) enrolled patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation who received two to four prior regimens and had a progression-free interval of 6 months or more following their most recent platinum therapy. The primary endpoint was investigator-assessed objective response rate (ORR) by RECIST version 1.1.Results: In part 1, 56 patients received oral rucaparib (40 to 500 mg once daily and 240 to 840 mg twice daily). No MTD was identified per protocol-defined criteria; 600 mg twice daily was selected as the RP2D based on manageable toxicity and clinical activity. Pharmacokinetics were approximately dose-proportional across all dose levels. In part 2A, 42 patients with germline BRCA1/2-mutated HGOC received rucaparib 600 mg twice daily. Investigator-assessed ORR was 59.5%. The most common treatment-emergent adverse events (all grades) were asthenia/fatigue (85.7%; 36/42), nausea (83.3%; 35/42), anemia (71.4%; 30/42), alanine transaminase and/or aspartate transaminase elevations (57.1%; 24/42), and vomiting (54.8%; 23/42). Among 98 patients, 5 (5.1%) discontinued because of an adverse event (excluding disease progression).Conclusions: Rucaparib was tolerable and had activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC. Clin Cancer Res; 23(15); 4095-106. ©2017 AACR.


Two novel PAX6 mutations identified in northeastern Chinese patients with aniridia.
The PAX6 gene encodes a transcriptional regulator involved in oculogenesis and other developmental processes such as aniridia, a congenital condition characterized by the underdevelopment of the eye's iris. Aniridia may be broadly divided into hereditary and sporadic forms. The function of the PAX6 gene in these two forms of aniridia is still poorly defined. Therefore, we carried out a mutation analysis of the PAX6 gene in northeastern Chinese families with aniridia to identify the role of the PAX6 gene in hereditary aniridia. Five aniridia patients from two northeastern Chinese families (Family 1 and Family 2) underwent full ophthalmologic examinations. Genomic DNA was prepared from venous leukocytes from these five patients, 10 non-carriers in these two families, as well as 100 healthy normal controls. The coding regions of PAX6 were analyzed by PCR amplification, direct sequencing and allele-specific cloning sequencing. RESULTS We identified two novel PAX6 mutations. The first is a 9 base pair (bp) deletion in exon 5 (c.483del9) that makes a PAX6 protein with de novo in-frame deletions of aspartic acid, isoleucine, and serine at the amino acid codon positions 41-43. The second is a heterozygous mutation (IVS10+1G>A) located at the boundary of exon 10 and intron 10. We identified two novel PAX6 mutations in familial aniridia from northeastern China, an ethnic group that is not well-studied. The genetic analysis confirms that these two novel mutations in PAX6 are capable of causing the classic aniridia phenotype. Therefore, by studying human familial aniridia cases, we demonstrated that PAX6 plays a role in hereditary aniridia.


[Mechanisms of bacterial resistance to beta-lactams by beta-lactamases].
The beta-lactamases are bacterial enzymes that inactivate beta-lactam antibiotics by catalyzing the hydrolysis of the amide group of the beta-lactam ring. They are the source of much bacterial resistance to those antibiotics. Structural studies on the enzymes, i.e., penicillinases and cephalosporinases, are now well-advanced and the up-to-date knowledge of this research field were explained together with the proposed mechanism of beta-lactam hydrolysis by a cephalosporinase. After the introduction of the beta-lactamase-stable beta-lactams such as oxyimino cephalosporins, R plasmid-mediated penicillinases and a chromosomal cephalosporinase have been found to be adapted to the new drugs by mutation. The characteristics of the mutant beta-lactamases and their importance in the bacterial resistance to the new beta-lactams were explained.


The Oncogenic Effects, Pathways, and Target Molecules of JC Polyoma Virus T Antigen in Cancer Cells.
JC polyoma virus (JCPyV) is a ubiquitous polyoma virus that infects the individual to cause progressive multifocal leukoencephalopathy and malignancies. Here, we found that T-antigen knockdown suppressed proliferation, glycolysis, mitochondrial respiration, migration, and invasion, and induced apoptosis and G2 arrest. The reverse was true for T-antigen overexpression, with overexpression of Akt, survivin, retinoblastoma protein, β-catenin, β-transducin repeat-containing protein (TRCP), and inhibitor of growth (ING)1, and the underexpression of mammalian target of rapamycin (mTOR), phosphorylated (p)-mTOR, p-p38, Cyclin D1, p21, vascular endothelial growth factor (VEGF), ING2, and ING4 in hepatocellular and pancreatic cancer cells and tissues. In lens tumor cells, T antigen transcriptionally targeted viral carcinogenesis, microRNAs in cancer, focal adhesion, p53, VEGF, phosphoinositide 3 kinase-Akt, and Forkhead box O signaling pathways, fructose and mannose metabolism, ribosome biosynthesis, and choline and pyrimidine metabolism. At a metabolomics level, it targeted protein digestion and absorption, aminoacryl-tRNA biosynthesis, biosynthesis of amino acids, and the AMPK signal pathway. At a proteomic level, it targeted ribosome biogenesis in eukaryotes, citrate cycle, carbon metabolism, protein digestion and absorption, aminoacryl-tRNA biosynthesis, extracellular-matrix-receptor interaction, and biosynthesis of amino acids. In lens tumor cells, T antigen might interact with various keratins, ribosomal proteins, apolipoproteins, G proteins, ubiquitin-related proteins, RPL19, β-catenin, β-TRCP, p53, and CCAAT-enhancer-binding proteins in lens tumor cells. T antigen induced a more aggressive phenotype in mouse and human cancer cells due to oncogene activation, inactivation of tumor suppressors, and disruption of metabolism, cell adhesion, and long noncoding RNA-microRNA-target axes.


INTEGRATING DATA ANALYTICS AND SIMULATION METHODS TO SUPPORT MANUFACTURING DECISION MAKING.
Modern manufacturing systems are installed with smart devices such as sensors that monitor system performance and collect data to manage uncertainties in their operations. However, multiple parameters and variables affect system performance, making it impossible for a human to make informed decisions without systematic methodologies and tools. Further, the large volume and variety of streaming data collected is beyond simulation analysis alone. Simulation models are run with well-prepared data. Novel approaches, combining different methods, are needed to use this data for making guided decisions. This paper proposes a methodology whereby parameters that most affect system performance are extracted from the data using data analytics methods. These parameters are used to develop scenarios for simulation inputs; system optimizations are performed on simulation data outputs. A case study of a machine shop demonstrates the proposed methodology. This paper also reviews candidate standards for data collection, simulation, and systems interfaces.


340B Drug Pricing Program Ceiling Price and Manufacturer Civil Monetary Penalties Regulation. Final rule; further delay of effective date.
The Health Resources and Services Administration (HRSA) administers section 340B of the Public Health Service Act (PHSA), referred to as the "340B Drug Pricing Program" or the "340B Program." HRSA published a final rule on January 5, 2017, that set forth the calculation of the ceiling price and application of civil monetary penalties. The final rule applied to all drug manufacturers that are required to make their drugs available to covered entities under the 340B Program. In accordance with a January 20, 2017, memorandum from the Assistant to the President and Chief of Staff, entitled "Regulatory Freeze Pending Review," HRSA issued an interim final rule that delayed the effective date of the final rule published in the Federal Register (82 FR 1210, (January 5, 2017)) to May 22, 2017. HHS invited commenters to provide their views on whether a longer delay of the effective date to October 1, 2017, would be more appropriate. After consideration of the comments received on the interim final rule, HHS is delaying the effective date of the January 5, 2017 final rule, to October 1, 2017.


Effectiveness of SIESTA on Objective and Subjective Metrics of Nighttime Hospital Sleep Disruptors.
We created Sleep for Inpatients: Empowering Staff to Act (SIESTA), which combines electronic "nudges" to forgo nocturnal vitals and medications with interprofessional education on improving patient sleep. In one "SIESTAenhanced unit," nurses received coaching and integrated SIESTA into daily huddles; a standard unit did not. Six months pre- and post-SIESTA, sleep-friendly orders rose in both units (foregoing vital signs: SIESTA unit, 4% to 34%; standard, 3% to 22%, P < .001 both; sleeppromoting VTE prophylaxis: SIESTA, 15% to 42%; standard, 12% to 28%, P < .001 both). In the SIESTAenhanced unit, nighttime room entries dropped by 44% (-6.3 disruptions/room, P < .001), and patients were more likely to report no disruptions for nighttime vital signs (70% vs 41%, P = .05) or medications (84% vs 57%, P = .031) than those in the standard unit. The standard unit was not changed. Although sleep-friendly orders were adopted in both units, a unit-based nursing empowerment approach was associated with fewer nighttime room entries and improved patient experience.


Photoluminescence Intermittency and Photo-Bleaching of Single Colloidal Quantum Dot.
Photoluminescence (PL) blinking of single colloidal quantum dot (QD)-PL intensity switching between different brightness states under constant excitation-and photo-bleaching are roadblocks for most applications of QDs. This progress report shall treat PL blinking and photo-bleaching both as photochemical events, namely, PL blinking as reversible and photo-bleaching being irreversible ones. Most studies on single-molecule spectroscopy of QDs in literature are related to PL blinking, which invites us to concentrate our discussions on the PL blinking, including its brief history in 20 years, analysis methods, competitive mechanisms and different strategies to battle it. In terms of suppression of the PL blinking, wavefunction confinement-confining photo-generated electron and hole within the core and inner portion of the shell of a core/shell QD-demonstrates significant advantages. This strategy yields nearly non-blinking QDs with their emission peaks covering most part of the visible window. As expected, the resulting QDs from this new strategy also show substantially improved anti-bleaching features.


[Naphthalene allyl trifluoromethyl benzocyclopentanone inhibits proliferation and induces apoptosis of lung cancer A549 cells in vitro].
To investigate the molecular mechanism by which a novel naphthalene allyl trifluoromethyl benzocyclopentanone XX0335 inhibits the proliferation and induces apoptosis of lung cancer A549 cells. Lung cancer A549 cells were treated with 0.1% DMSO (control) or different concentrations (6.25, 12.5, and 25 μg/mL) of XX0335, and the changes in cell viability, cell cycle, proliferation and apoptosis were assessed with CCK-8 assay, EdU experiment, and flow cytometry. The effects of different concentrations of XX0335 on phosphorylation levels of proliferation-related proteins Akt, mTOR, Akt/mTOR and the expressions of cleaved PARP and cyclin D1 were determined using Western blotting. We also assessed the effect of XX0335 on tumor growth in a mouse model bearing A945 cell xenograft. Treatment with XX0335 reduced the viability of A549 cells in a dose-dependent manner (P < 0.01) and significantly inhibited cell proliferation (P < 0.001). Flow cytometry showed that XX0335 treatment promoted apoptosis of the cells (P < 0.01) and caused an obvious increase of the number of G1-phase cells. Compared with DMSO, XX0335 significantly inhibited the phosphorylation of Akt and mTOR, increased the expression of cleaved PARP, and lowered the protein expression of cyclin D1. In the tumor-bearing mouse models, injection of XX0335 significantly decreased the tumor volume (P < 0.01). XX0335 inhibits the proliferation, cycle and induces apoptosis of lung cancer A549 cells possibly by inhibiting the Akt/mTOR signal pathway.


Enhanced-Performance Self-Powered Solar-Blind UV-C Photodetector Based on n-ZnO Quantum Dots Functionalized by p-CuO Micro-pyramids.
Smart solar-blind UV-C band photodetectors suffer from low responsivity in a self-powered mode. Here, we address this issue by fabricating a novel enhanced solar-blind UV-C photodetector array based on solution-processed n-ZnO quantum dots (QDs) functionalized by p-CuO micro-pyramids. Self-assembled catalyst-free p-CuO micro-pyramid arrays are fabricated on a pre-ablated Si substrate by pulsed laser deposition without a need for a catalyst layer or seeding, while the solution-processed n-ZnO QDs are synthesized by the femtosecond-laser ablation in liquid technique. The photodetector is fabricated by spray-coating ZnO QDs on a CuO micro-pyramid array. The photodetector performance is optimized via a p-n junction structure as both p-ZnO QDs and p-CuO micro-pyramid layers are characterized by wide band gap energies. Two photodetectors (with and without CuO micro-pyramids) are fabricated to show the role of p-CuO in enhancing the device performance. The n-ZnO QD/p-CuO micro-pyramid/Si photodetector is characterized by a superior photo-responsivity of ∼956 mA/W at 244 nm with a faster photoresponse (<80 ms) and 260 nm cut-off compared to ZnO QDs/Si photodetectors, confirming that the p-CuO micro-pyramids enhance the device performance. The self-powered photoresponse with a high photo-responsivity of ∼29 mA/W is demonstrated. These high-responsivity solar-bind UV-C photodetector arrays can be used for a wide range of applications.


Recording Synaptic Plasticity in Acute Hippocampal Slices Maintained in a Small-volume Recycling-, Perfusion-, and Submersion-type Chamber System.
Even though experiments on brain slices have been in use since 1951, problems remain that reduce the probability of achieving a stable and successful analysis of synaptic transmission modulation when performing field potential or intracellular recordings. This manuscript describes methodological aspects that might be helpful in improving experimental conditions for the maintenance of acute brain slices and for recording field excitatory postsynaptic potentials in a commercially available submersion chamber with an outflow-carbogenation unit. The outflow-carbogenation helps to stabilize the oxygen level in experiments that rely on the recycling of a small buffer reservoir to enhance the cost-efficiency of drug experiments. In addition, the manuscript presents representative experiments that examine the effects of different carbogenation modes and stimulation paradigms on the activity-dependent synaptic plasticity of synaptic transmission.


Life-Threatening Intracerebral Hemorrhage in Previously Undiagnosed Acute T-Cell Lymphoblastic Leukemia with Blast Crisis: A Nightmare in Neurosurgeon's Life?
Spontaneous, nontraumatic intracerebral hemorrhage is a significant cause of morbidity and mortality throughout the world. Acute lymphoblastic leukemia is the most common cancer diagnosed in children. According to the literature, only 6 cases of acute lymphoblastic leukemia presenting as intracerebral hemorrhage have been reported. Five out of the 6 patients were managed conservatively; 3 out of these 6 patients survived with correction of coagulopathy. Surgical intervention was performed in only 1 of the previously reported cases in which the patient could not be salvaged. We report a case of life-threatening intracerebral hemorrhage in previously undiagnosed acute T-cell lymphoblastic leukemia with blast crisis, in which the patient was salvaged from the catastrophic complication after surgical intervention.


Modeling the morphogenesis of brine channels in sea ice.
Brine channels are formed in sea ice under certain constraints and represent a habitat of different microorganisms. The complex system depends on a number of various quantities as salinity, density, pH value, or temperature. Each quantity governs the process of brine channel formation. There exists a strong link between bulk salinity and the presence of brine drainage channels in growing ice with respect to both the horizontal and vertical planes. We develop a suitable phenomenological model for the formation of brine channels both referring to the Ginzburg-Landau theory of phase transitions as well as to the chemical basis of morphogenesis according to Turing. It is possible to conclude from the critical wave number on the size of the structure and the critical parameters. The theoretically deduced transition rates have the same magnitude as the experimental values. The model creates channels of similar size as observed experimentally. An extension of the model toward channels with different sizes is possible. The microstructure of ice determines the albedo feedback and plays therefore an important role for large-scale global circulation models.


[Construction and in vitro antiviral activity of highly effective artificial miRNA targeting to HIV-1 pol].
RNA interference (RNAi) has exhibited huge potentials on anti-HIV-1 therapy research. The obtainment of RNAi element targeting to HIV-1 highly effectively and specifically was crucial for relevant research. Recent reports had described that microRNAs (miRNAs) posses more characteristics of inhibition and expression mechanisms than small interfering RNAs (siRNAs). In this study we explored the construction of artificial miRNA targeting to HIV-1 effectively and specifically. Sixteen siRNAs sequences were selected based on the conserved regions in the HIV-1 pol gene. ShRNA expression vectors were co-transfected with HIV-1 clone pNL4-3 to evaluate the abilities of siRNAs to inhibit HIV-1 expression. The pol1026 sequence was selected from candidates. The target sequence in the stem-loop structure of the well-characterized native miR-30a was replaced with pol1026 sequences, and the artificial miRNA expression vectors were co-transfected with the HIV-1 clone pNL4-3, results showed that HIV-1 can be effectively inhibited by miR-1026E. Target specificity of miR-1026E was confirmed by co-transfection assay with reporter plasmids containing different target sequences. The miR-1026E expression element was then inserted into Lentivirus which was used as a vector to transduce the MT-4 cells, MT-4-miR1026E expressing miR-1026E stably was cloned from transduced cells. The MT-4-miR1026E cell effectively inhibited HIV-1 replication in vitro. And the intracellular miR-181 and miR-16 expression levels and statl mRNA levels were not affected by the expression of miR-1026E in MT-4-miR1026E cells. miR-1026E is a promising candidate for future research.


Pathogenesis of inflammation. Effects of the pharmacological manipulation of arachidonic acid metabolism on the cytological response to inflammatory stimuli.
It is generally accepted that non-steroidal anti-inflammatory drugs (NSAIDs) act by the inhibition of prostaglandin biosynthesis. However, this hypothesis may not apply to all NSAIDs at all doses. It has thus been proposed that, in high doses, NSAIDs counteract inflammation by the inhibition of the activity of inflammatory cells such as the neutrophil. Neutrophils are activated by a 'twin signal' which is a part of a general stimulus response coupling mechanism involving phospholipid remodelling. This 'twin signal' consists of the mobilisation of intracellular calcium and the activation of protein kinase C. NSAIDs inhibit the aggregation of neutrophils in vivo and in vitro, and show additive effects with stable prostaglandins on the inhibition of the generation of superoxide anion, a product of inflammation. Binding studies have shown that the mechanism of this effect appears to be an interference with the ligand-receptor site modulated by the G protein. Activation of the cells of the marine sponge, which are not responsive to stable prostaglandins and do not contain a cyclo-oxygenase, can be inhibited by NSAIDs. Therefore, further investigation of this interesting hypothesis should help to clarify the precise mechanism of the anti-inflammatory effects of these drugs.


The Harnessing Online Peer Education (HOPE) Intervention for Reducing Prescription Drug Abuse: A Qualitative Study.
Social media technologies are newly emerging tools that can be used to address the growing prescription drug epidemic. In this study, we sought to determine the feasibility and acceptability of using social media to reduce complications of opioid use among patients experiencing chronic pain. Specifically, we evaluated the utility of the Harnessing Online Peer Education (HOPE) social media intervention to reduce the risk of addiction and overdose among non-cancer pain patients receiving chronic opioid therapy. University of California, Los Angeles (UCLA) patients receiving chronic opioid therapy and UCLA staff were invited to participate in interviews regarding the HOPE intervention. Questions focused on resources used to manage pain, the limitations and benefits of these approaches, and the likelihood of using an online community to reduce complications of opioid therapy. Using an open-coding process, three topics were identified for the patients: 1) online social support is important for improving outcomes, 2) offline social support is helpful for some patients but has limitations, and 3) a tailored, online peer support intervention is needed. Interviews with staff confirmed these results. The HOPE social media intervention and other online communities appear to be an acceptable technology for patients on chronic opioid therapy.


[Effect of immunization on the quantitative behavior of gamma globulins in the blood serum of cattle following whole-body x-ray irradiation].
Five experiment series were applied to 38 calves, aged between two-and-a-half and four months, using whole-body exposure to X-ray treatment based on median lethal doses (MLD) between 1.2 Gy and 1.7 Gy. Various methods of immunisation were simultaneously applied, and their effects on irradiation-caused response of gamma globulin concentrations in blood serum were studied. Gamma globulin levels were determined by Kunkel's zinc sulphate turbidity test. Immunisation applied between 14 and 21 days prior to irradiation resulted on obvious stimulation of gamma globulin production. In two experiments with parenteral antigen application, gamma globulin levels increased through about 14 days in apparently irradiated animals declined, after that period of time, but they continued to rise in really irradiated probands. A high lethal dose of 1.7 Gy, however, was followed by significant drop, three weeks after irradiation, that is in concomitance with the climax of the radiation syndrome. When 1.5 Gy were used, rise in gamma globulin concentration was recordable also following oral administration of antigen. Response of irradiated animals was even more clearly pronounced by secondary reaction of antibody formation, following booster action due to experimental infection with homologous germs. The stimulating effect of irradiation upon gamma globulin levels in blood serum, when oral or parenteral immunisation had taken place, prior to irradiation, has been attributed to reaction of the immune-globulin producing system to the release of tissue proteins or tissue antigens. Immunisation, prior to irradiation, stimulated the immunological system which underwent stronger regeneration, after irradiation, or had obviously acquired higher resistance to radiation.


Microfluidic platform enables live-cell imaging of signaling and transcription combined with multiplexed secretion measurements in the same single cells.
Innate immune cells, including macrophages and dendritic cells, protect the host from pathogenic assaults in part through secretion of a program of cytokines and chemokines (C/Cs). Cell-to-cell variability in C/C secretion appears to contribute to the regulation of the immune response, but the sources of secretion variability are largely unknown. To begin to track the biological sources that control secretion variability, we developed and validated a microfluidic device to integrate live-cell imaging of fluorescent reporter proteins with a single-cell assay of protein secretion. We used this device to image NF-κB RelA nuclear translocation dynamics and Tnf transcription dynamics in macrophages in response to stimulation with the bacterial component lipopolysaccharide (LPS), followed by quantification of secretion of TNF, CCL2, CCL3, and CCL5. We found that the timing of the initial peak of RelA signaling in part determined the relative level of TNF and CCL3 secretion, but not CCL2 and CCL5 secretion. Our results support evidence that differences in timing across cell processes partly account for cell-to-cell variability in downstream responses, but that other factors introduce variability at each biological step.


Optimization of reversed-phase solid-phase extraction for shotgun proteomics analysis.
Reversed-phase solid-phase extraction (SPE) is the method of choice for the purification of proteomics samples. Even though the efficacy of SPE methods is sample type-dependent, the manufacturers' protocols are used in most studies. Using an optimized SPE method can lead to a substantial gain in identification and recovery. In this tutorial, we give a brief introduction to the most important parameters influencing SPE performance, and we present a short workflow (16 measurements) for optimizing the SPE procedure. This is complemented by method performance assessment instructions and a short troubleshooting guide to help users further understand and investigate their SPE methods.


A Multicenter Study of the Impact of Body Mass Index (BMI) on the incidence of Pathologic Complete Response (pCR) Among Saudi Patients with locally advanced Breast cancer (LABC) post Neoadjuvant Chemotherapy (NAC).
Obesity was reported to be a poor prognostic factor for breast cancer. There is a growing evidence of increasing prevalence of obesity among Saudi women across all age groups (44%). Since the prognostic significance of obesity was not studied in Saudi patients with breast cancer, the aim of this study was to evaluate the impact of BMI on pCR in LABC patients post NAC. This is a retrospective study between May 2005 to July 2010; 246 consecutive female patients who were diagnosed of LABC (Stage II & III) and underwent surgery in three tertiary care centers, representative of the Kingdom of Saudi Arabia (King Saud Medical City, Riyadh; King Abdullah Hospital, Mecca and King Fahad Specialist Hospital, Dammam) were included in this study. All included patients have received NAC (Anthracycline/Taxane based combination chemotherapy and ± Herceptin). Patients who were diagnosed to have stage IV breast cancer due to presence of distant metastasis were excluded. Patients were categorized as normal (BMI <25 kg/m2), overweight (BMI of 25 to <30 kg/m2) and obese (BMI >30 kg/m2). pCR was defined as no invasive cancer in the breast or axillary tissue. Univariate and multivariate analysis were used to evaluate the statistical associations between pCR and BMI with respect to the other previously established prognostic factors, namely age, tumor grade, stage, ER/ PR /Her-2neu status, molecular subtypes, and lympho-vascular invasion (LVI). The median age was 50 years (range 24-68). Molecular subtypes were as follows: luminal A; 23.2%, luminal B; 45.1%, triple negative; 16.7% and Her-2 neu positive; 15%. Infiltrating ductal carcinoma represents the majority of our cohort (92.7%). Eighty-six (35%) were stage II and 160 (65%) were stage III. Intermediate and high-grade malignancies were found in 52% and 44.3% of the patients respectively. Positive lymph vascular invasion was detected in 41.5%. Obese patients constitute 55.7% of our cohort. Pathologic complete response was achieved in 62 patients (25.2%). In Univariate analysis LVI and overweight /obesity were negatively correlated with pCR (P= 0.037 and 0.000 respectively) while tumor grade was positively correlated with pCR (P= 0.008). In multivariate analysis, Overweight/ obesity was the only significant independent factor correlating with pCR (P=0.000). No impact of BMI has been demonstrated on both disease-free survival (DFS) and overall survival (OS) (P=0.93, 0.18 respectively). In this study, Overweight/Obesity (which represent more than half of the patients =81.3 %) had a negative impact on pCR in Saudi patients with LABC treated with NAC. This poorer outcome in patients with abnormal weight (Overweight/Obesity) necessitates further prospective studies of this risk factor in order to optimize the care of this group of patients.


Oxide mediated spectral shifting in aluminum resonant optical antennas.
As a key feature among metals showing good plasmonic behavior, aluminum extends the spectrum of achievable plasmon resonances of optical antennas into the deep ultraviolet. Due to degradation, a native oxide layer gives rise to a metal-core/oxide-shell nanoparticle and influences the spectral resonance peak position. In this work, we examine the role of the underlying processes by applying numerical nanoantenna models that are experimentally not feasible. Finite-difference time-domain simulations are carried out for a large variety of elongated single-arm and two-arm gap nanoantennas. In a detailed analysis, which takes into account the varying surface-to-volume ratio, we show that the overall spectral shift toward longer wavelengths is mainly driven by the higher index surrounding material rather than by the decrease of the initial aluminum volume. In addition, we demonstrate experimentally that this shifting can be minimized by an all-inert fabrication and subsequent proof-of-concept encapsulation.


Basal cell carcinoma with intravascular invasion: A case report and review of the literature.
The significance of basal cell carcinoma (BCC) invading the intravascular space is unknown. We report a case of an infiltrative BCC on the scalp that showed evidence of both intravascular and perineural invasion. The tumor locally recurred in the bone marrow space 4.5 years following the initial procedure. Since recurrence and metastasis of BCC can be delayed for many years, we recommend long term follow-up for tumors showing aggressive features.


Efficacy and Safety of Thrombectomy Combined with Intracoronary Administration of Tirofiban in ST-segment Elevation Myocardial Infarction (STEMI).
BACKGROUND No/slow reflow gives rise to serious complications in STEMI patients undergoing PCI, and can lead to worse outcomes. Several measures are used to prevent no/slow reflow, including thrombus removal processes and intensive use of anticoagulant agents. Our study was designed to evaluate the efficacy and safety of thrombectomy and intracoronary administration of GPIIb/IIIa inhibitors in STEMI patients undergoing PPCI. MATERIAL AND METHODS We randomly assigned 240 STEMI patients into 3 groups. Before PPCI, patients in group A received thrombectomy and intracoronary administration of tirofiban. Patients in group B received thrombectomy, and patients in group C neither of these 2 treatments. Their demographic data and coronary angiography results were recorded. TIMI grade flow was used to evaluate the effect. After the follow-up, major adverse cardiac events were regarded as study endpoints in evaluating the safety of the combined therapy. RESULTS We found no significant differences among the 3 groups in demographic and clinical characteristics (p>0.05). Patients in group A had better TIMI grade classifications and ST-segment elevation (p=0.005), and lower incidence of no/slow reflow (p=0.031) and MACE. During 6-month follow-up, the MACE rate was lower in group A than in groups B and C (p=0.038). CONCLUSIONS The use of thrombectomy combined with intracoronary administration of tirofiban is relatively effective and safe in STEMI patients undergoing PPCI.


Insulin-like growth factor binding protein secretion by breast carcinoma cell lines: correlation with estrogen receptor status.
Breast tumor cell lines have been shown to secrete several distinct polypeptide growth factors, although conflicting results exist for the insulin-like growth factors (IGFs). In contrast a limited number of breast tumor cell lines have definitely been shown to secrete the high affinity IGF binding proteins (IGFBPs) that modify IGF actions. To characterize the types of IGFBPs that are secreted by breast tumor cell lines, conditioned medium was collected from seven separate tumor cell lines, three of which were estrogen receptor (ER) negative, and four of which were ER positive. All three of the ER negative cell lines, MDA-231, MDA-330, and HS578T, secreted binding proteins of 49,000 and 43,000 Mr (IGFBP-3) as well as 29,000 (IGFBP-1) and 24,000 Mr. In contrast, all four ER positive cell lines secreted 34,000 (IGFBP-2) or 24,000 Mr forms, and none secreted the 49,000 and 43,000 or 29,000 Mr forms. BT-20, a cell line that is positive for ER messenger RNA (mRNA) but negative for ER protein, secreted predominantly a 34,000 Mr protein. The amount of total IGFBP activity released in 24 h ranged between 0.4 and 5.6 nM equivalents of IGFBP-1, and there was no significant difference between the ER positive and negative cell lines. The MCF-7 cells that produced predominantly 34,000 and 24,000 Mr forms showed a 1.8-fold increase in IGFBP secretion after estrogen stimulation. Immunoblotting and a specific RIA for IGFBP-1 showed that only the ER negative lines MDA-330, MDA-231, and HS578T secreted this form. Northern blotting analysis for the mRNA encoding this protein showed that both MDA-330 and MDA-231 contained a single 1.6 kilobase mRNA species that hybridized with an IGFBP-1 complementary DNA (cDNA) probe. Immunoblotting analysis of the other cell lines showed that only the 34,000 Mr form secreted by the ER positive cell lines reacted with IGFBP-2 antisera. Exposure of the conditioned media from the three ER negative cell lines to N-glycanase revealed that the 49,000 and 43,000 Mr forms of IGFBP were glycosylated and therefore probably represent IGFBP-3. We conclude that ER negative cell lines secrete three forms of IGFBPs, IGFBP-1, IGFBP-3, and a 24,000 Mr form. In contrast, the ER positive cell lines secrete predominantly IGFBP-2 and the 24,000 Mr form but do not secrete IGFBP-3 or 1.(ABSTRACT TRUNCATED AT 400 WORDS)


Charge Transfer Process of a Solvated Hydrogen-Bonded Organic Network.
We show the first example of an organic linker (OL) terminated by carboxylic groups that can form a hydrogen-bonded network/polymer (HBN) in solution under controlled conditions in which the photogenerated charges can hop from a monomer OL to the hydrogen-bonded backbone of OLs, as probed by transient absorption (fs-TA). While fs-TA reveals a slow twisting process in the monomer form of the OL, the formation of a hydrogen-bonded network in solution suppresses such process and favors instead a charge transfer (CT) state along the low-lying hydrogen-bonded backbone. Theoretical calculations show that such solvated HBN in a specific polar solvent is stabilized due to the huge change of the dipole moment from monomer compared to the network, leading to a charge delocalization character due to the symmetry breaking. Our findings will open new avenues for implementing solvated hydrogen-bonded molecules in applications such as sensing and photocatalysis.


Effects of γ-ray irradiation on optical absorption and laser damage performance of KDP crystals containing arsenic impurities.
The effects of γ-irradiation on potassium dihydrogen phosphate crystals containing arsenic impurities are investigated with different optical diagnostics, including UV-VIS absorption spectroscopy, photo-thermal common-path interferometer and photoluminescence spectroscopy. The optical absorption spectra indicate that a new broad absorption band near 260 nm appears after γ-irradiation. It is found that the intensity of absorption band increases with the increasing irradiation dose and arsenic impurity concentration. The simulation of radiation defects show that this absorption is assigned to the formation of AsO₄⁴⁻ centers due to arsenic ions substituting for phosphorus ions. Laser-induced damage threshold test is conducted by using 355 nm nanosecond laser pulses. The correlations between arsenic impurity concentration and laser induced damage threshold are presented. The results indicate that the damage performance of the material decreases with the increasing arsenic impurity concentration. Possible mechanisms of the irradiation-induced defects formation under γ-irradiation of KDP crystals are discussed.


Decoding circulating nucleic acids in human serum using microfluidic single molecule spectroscopy.
Circulating nucleic acid (CNA) has been the focus of recent research as a noninvasive source of biomarker candidates. Among these markers, DNA fragment size has shown promise for discerning the source of CNA molecules in cancer and prenatal diagnostics. We have developed a one-step assay for analyzing circulating DNA size and quantity directly in human serum. Microfluidic cylindrical illumination confocal spectroscopy and fluorescence burst size analysis are used to individually count and size fluorescently-labeled CNA molecules as they are driven through a microfluidic constriction. First, single molecule sizing was performed on lambda Hind III digest DNA to obtain a size calibration curve. A linear relation between DNA length and burst size was seen from 564 bp to 27.5 kbp. Subsequently, the single molecule assay parameters were optimized. Finally, DNA sizing analysis was performed on serum samples from both early and late stage lung cancer patients. This assay was performed directly in patient serum using only a single reagent, a simple DNA intercalating dye, and without the need for DNA isolation or enzymatic amplification steps. This demonstrates that microfluidic single molecule spectroscopy can be a rapid, facile, and inexpensive alternative to the established PCR-based methods that have been used near exclusively for CNA analysis.


Ten-year experience of bexarotene therapy for cutaneous T-cell lymphoma in Finland.
Bexarotene is an oral retinoid shown to be active against the cutaneous manifestations of cutaneous T-cell lym-phoma (CTCL). Literature on the efficacy, dosing and side-effects of bexarotene is sparse. We present here data on 37 Finnish patients with CTCL treated with bexarotene during the last 10 years. Bexarotene was equally effective as monotherapy or when combined with other treatment modalities, resulting in overall responses of approximately 75%. Early-stage CTCL responded better than advanced-stage CTCL (83% vs. 33%). The mean time to observable response was 3 months and the mean duration of the response was 21 months. The dose of bexarotene was generally lower than recommended due to side-effects. Abrupt elevation of liver transaminases, resulting in cessation of treatment, was observed in 4 (11%) patients. We conclude that the dose of bexarotene should be titrated individually to achieve optimal results. Maintenance therapy with low-dose bexarotene is a feasible alternative.


Antibiotic prophylaxis for fourth-degree perineal tear during vaginal birth.
One to eight per cent of women suffer third-degree perineal tears (anal sphincter injury) and fourth-degree perineal tear (rectal mucosa injury) during vaginal birth, and these tears are more common after forceps delivery (28%) and midline episiotomies. Fourth-degree tears can become contaminated with bacteria from the rectum and this significantly increases in the chance of perineal wound infection. Prophylactic antibiotics might have a role in preventing this infection. To assess the effectiveness of antibiotic prophylaxis for reducing maternal morbidity and side-effects in fourth-degree perineal tear during vaginal birth. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (30 July 2005), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2005), MEDLINE (1966 to 15 July 2005), and LILACS (1982 to 15 July 2005). Randomised controlled trials which reported data comparing outcomes of prophylactic antibiotics versus placebo or no antibiotics in fourth-degree perineal tear during vaginal birth. No trials were found that met the selection criteria. No randomised controlled trials were identified. There are insufficient data to support a policy of routine prophylactic antibiotics in fourth-degree perineal tear during vaginal birth. A well-designed randomised controlled trial is needed.


Analysis of the relationship between score components on a standardized patient clinical skills examination.
This work investigated the reliability of and relationships between individual case and composite scores on a standardized patient clinical skills examination. Four hundred ninety two fourth-year U.S. medical students received three scores [data gathering (DG), interpersonal skills (IPS), and written communication (WC)] for each of 10 standardized patient cases. mGENOVA software was used for all analyses. Estimated generalizability coefficients were 0.69, 0.80, and 0.70 for the DG, IPS, and WC scores, respectively. The universe-score correlation between DG and WC was high (.83); those for DG/IPS and IPS/WC were not as strong (0.51 and 0.37, respectively). Task difficulty appears to be modestly but positively related across the three scores. Correlations between the person-by-task effects for DG/IPS and DG/WC were positive yet modest. The estimated generalizability coefficient for a ten-case test using an equally weighted composite DG/WC score was 0.78. This work allows for interpretation of correlations between (1) proficiencies measured by multiple scores and (2) sources of error that affect those scores as well as for estimation of the reliability of composite scores. Results have important implications for test construction and test validity.


In vitro gastrointestinal digestion of highland barley protein: identification and characterization of novel bioactive peptides involved in gut cholecystokinin secretion.
The satiety hormone cholecystokinin (CCK) plays an important role in food intake inhibition. Its secretion is regulated by dietary components. The search for bioactive compounds that induce CCK secretion is currently an active area of research. The objective of this study was to evaluate the ability of highland barley protein digest (HBPD) to stimulate CCK secretion in vitro and in vivo and identify the responsible peptide sequences. HBPD was prepared by in vitro gastrointestinal digestion model. Peptides of <1000 Da in HBPD accounted for 82%. HBPD was rich in essential amino acids Leu, Phe and Val, but lack in sulfur amino acids Met and Cys. HBPD treatment at a concentration of 5 mg mL-1 significantly stimulated CCK secretion from enteroendocrine STC-1 cells (P < 0.05). Moreover, oral gavage with HBPD in mice significantly increased plasma CCK level. Chromatographic separation was performed to isolate peptide fractions involved in CCK secretion and peptide sequence was determined by ultra-performance liquid chromatography-tandem mass spectrometry. Two novel CCK-releasing peptides, PDLP and YRIVPL, were pointed out for their outstanding CCK secretagogue activity. This study demonstrated for the first time that HBPD had an ability to stimulate CCK secretion in vitro and in vivo and determined the bioactive peptides exerting CCK secretagogue activity in HBPD. © 2023 Society of Chemical Industry.


Differentiation of focal liver lesions: usefulness of parametric imaging with contrast-enhanced US.
To evaluate whether parametric imaging with contrast material-enhanced ultrasonography (US) is superior to visual assessment for the differential diagnosis of focal liver lesions (FLLs). This study had institutional review board approval, and verbal patient informed consent was obtained. Between August 2005 and October 2008, 146 FLLs in 145 patients (63 women, 82 men; mean age, 62.5 years; age range, 22-89 years) were imaged with real-time low-mechanical-index contrast-enhanced US after a bolus injection of 2.4 mL of a second-generation contrast agent. Clips showing contrast agent uptake kinetics (including arterial, portal, and late phases) were recorded and subsequently analyzed off-line with dedicated image processing software. Analysis of the dynamic vascular patterns (DVPs) of lesions with respect to adjacent parenchyma allowed mapping DVP signatures on a single parametric image. Cine loops of contrast-enhanced US and results from parametric imaging of DVP were assessed separately by three independent off-site readers who classified each lesion as benign, malignant, or indeterminate. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated for both techniques. Interobserver agreement (κ statistics) was determined. Sensitivities for visual interpretation of cine loops for the three readers were 85.0%, 77.9%, and 87.6%, which improved significantly to 96.5%, 97.3%, and 96.5% for parametric imaging, respectively (P < .05, McNemar test), while retaining high specificity (90.9% for all three readers). Accuracy scores of parametric imaging were higher than those of conventional contrast-enhanced US for all three readers (P < .001, McNemar test). Interobserver agreement increased with DVP parametric imaging compared with conventional contrast-enhanced US (change of κ from 0.54 to 0.99). Parametric imaging of DVP improves diagnostic performance of contrast-enhanced US in the differentiation between malignant and benign FLLs; it also provides excellent interobserver agreement.


Knowledge among important actors in the field of adaptive equipment for young people with disabilities.
Purpose: Access to adaptive equipment is a crucial factor that can determine if a child or youth with disabilities is going to participate in physical activities, sports and play in different local settings. A prerequisite for success is awareness of and specific knowledge concerning the equipment and its use among relevant actors. The aim of this paper is to explore how important groups of actors working with young people with disabilities perceive their level of knowledge concerning adaptive equipment and discuss these actors' role in children and youths' opportunities to obtain relevant equipment to participate in activities.Methods: An online, population-based national survey was distributed to: (1) occupational therapists and physiotherapists, (2) teachers, and (3) leaders and coaches in sports clubs in Norway.Results: The findings generally indicate that overall knowledge concerning adaptive equipment among the three groups is limited. However, significant statistical difference is found, indicating that occupational therapists and physiotherapists have higher levels of general knowledge, about the accessibility of equipment, regulations and legislation and that they are more familiar with adaptive equipment than teachers, leaders and coaches.Conclusions: A practical implication of the results is that the actors' varying knowledge and experiences need to be brought together to form a coherent picture of how the equipment will be used and by whom. This can contribute to an increased understanding concerning adaptive equipment and its importance among different actors, which could help more young people with disabilities to participate.Implications for RehabilitationImportant actors must utilize the knowledge and experience possessed by young people with disabilities concerning adaptive equipment.Improved access to knowledge concerning adaptive equipment among important actors is required.Increased collaboration between different actors relating to adaptive equipment and participation is needed.


[Improvements in Lifestyle from a Lifestyle Consecutive Self-Review at a Pharmacy].
In 2015, Japan's Ministry of Health, Labour and Welfare released a report on the need for pharmacies to support public health, although the details of such a service was left to each pharmacy. Consequently, pharmacists had to determine the nature of such services. We considered the services that pharmacists could offer to improve people's lifestyles. This study tests such a service at a pharmacy. We prepared a lifestyle self-review test. From September 2015 to February 2016, pharmacists interviewed members of the community using the test, and pharmacists at 50 pharmacies in Aichi prefecture, Japan, set goals for lifestyle improvement. We analyzed 289 tests. The number of people who had a dietary goal concerning snacking was reduced from 19 people who snacked every day to 11. The number of people who had a goal to reduce their drinking was reduced from 7 people who drank every day to 4. The number of people who had an exercise goal was reduced from 17 people who did not exercise every day to 7. The people who had a sleep goal increased the number of days in which they got adequate rest. Those who had specific, tangible goals for walking achieved their goal at a higher rate than did those who had a goal but no tangible elements, such as time spent or number of steps achieved. Overall, the lifestyle self-review at the pharmacy was effective for lifestyle improvement. Pharmacists should help people set goals with tangible elements to improve their lifestyle more effectively.


Rapid simultaneous determination of 7 fat-soluble vitamins in human serum by ultra high performance liquid chromatography tandem mass spectrometry.
Accurate detection of vitamins is critically important for clinical diagnosis, metabolomics and epidemiological studies. However, the amounts of different vitamins vary dramatically in human serum. It is a challenge to achieve simultaneous detection of multiple vitamins rapidly. Herein, we developed and validated a sensitive and specific method using ultra high-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for simultaneous quantification of 7 fat-soluble vitamins (FSVs) across their physiological concentrations in serum for the first time, which was subjected to protein precipitation, liquid-liquid extraction to an organic phase, evaporation to dryness and reconstitution with acetonitrile. In the present procedure, retinol (vitamin A), ergocalciferol (25-OH-D2), cholecalciferol (25-OH-D3), α-tocopherol (vitamin E), phylloquinone (vitamin K1), menatetrenone-4 (MK-4), and menaquinone-7 (MK-7) were detected in one analytical procedure for the first time within 5.0 min by triple quadrupole tandem mass spectrometry. The limit of quantification (LOQ) for vitamin A was 10.0 ng mL-1, LOQs for 25-OH-D2 and 25-OH-D3 were 1.0 ng mL-1, LOQ for vitamin E was 100.0 ng mL-1, and LOQs for vitamin K1, MK-4 and MK-7 were 0.10 ng mL-1, respectively, with a correlation (R2) of 0.995-0.999. Recoveries ranged from 80.5% to 118.5% and the intra-day and inter-day coefficients of variance (CVs) were 0.72-8.89% and 3.2-9.0% respectively. The method was validated according to the European Medicines Agency (EMA) and U.S. Food and Drug guidelines and C62-A on bioanalytical methods, and was used for clinical routine determination.


Mitochondrial genome diversity of Native Americans supports a single early entry of founder populations into America.
There is general agreement that the Native American founder populations migrated from Asia into America through Beringia sometime during the Pleistocene, but the hypotheses concerning the ages and the number of these migrations and the size of the ancestral populations are surrounded by controversy. DNA sequence variations of several regions of the genome of Native Americans, especially in the mitochondrial DNA (mtDNA) control region, have been studied as a tool to help answer these questions. However, the small number of nucleotides studied and the nonclocklike rate of mtDNA control-region evolution impose several limitations to these results. Here we provide the sequence analysis of a continuous region of 8.8 kb of the mtDNA outside the D-loop for 40 individuals, 30 of whom are Native Americans whose mtDNA belongs to the four founder haplogroups. Haplogroups A, B, and C form monophyletic clades, but the five haplogroup D sequences have unstable positions and usually do not group together. The high degree of similarity in the nucleotide diversity and time of differentiation (i.e., approximately 21,000 years before present) of these four haplogroups support a common origin for these sequences and suggest that the populations who harbor them may also have a common history. Additional evidence supports the idea that this age of differentiation coincides with the process of colonization of the New World and supports the hypothesis of a single and early entry of the ancestral Asian population into the Americas.


Lymphoedema post-mastectomy: is elevation alone an effective treatment?
In an attempt to obtain information about the efficacy of arm elevation on the reduction of lymphoedema following mastectomy, a study on 33 patients was carried out in which both the control, contralateral and lymphoedematous arms were elevated for periods of 1 and 5 h. There were statistically significant (p < 0.05) reductions in the volumes of the control and lymphoedematous arms after 1 and 5 h of elevation. After 1 h of elevation, significantly more fluid was removed from the control arm (2.7%) than the lymphoedematous one (1.3%). At 5 h there was no significant difference in the volume of fluid removed from the control arm (3.3%) compared with the lymphoedematous one (3.1%).


Lamin A/C Ablation Restricted to Vascular Smooth Muscle Cells, Cardiomyocytes, and Cardiac Fibroblasts Causes Cardiac and Vascular Dysfunction.
Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through which LMNA mutations provoke cardiac alterations, with a particular focus on cardiomyocytes. To investigate if LMNA mutations also cause vascular alterations that might contribute to the etiopathogenesis of LMNA-DCM, we generated and characterized Lmnaflox/floxSM22αCre mice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation, Lmnaflox/floxSM22αCre mice recapitulated the main hallmarks of human LMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with elevated expression of total and phosphorylated (active) Smad3 and cleaved (active) caspase 3 in the heart. Lmnaflox/floxSM22αCre mice also exhibited perivascular fibrosis in the coronary arteries and a switch of aortic VSMCs from the 'contractile' to the 'synthetic' phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents in Lmnaflox/floxSM22αCre mice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms of LMNA-DCM. Future work addressing the mechanisms underlying vascular defects in LMNA-DCM may open new therapeutic avenues for these diseases.


[Treatment of advanced pancreatic cancer with 5-fluorouracil, 4-epidoxorubicin and mitomycin C (FEM II). From the Chemotherapy of Gastrointestinal Tumors Group].
In a multicentre phase II trial, 20 patients with advanced pancreatic carcinoma were treated with 5-fluorouracil, 4-epidoxorubicin and mitomycin C, in which 4-epidoxorubicin was administered by escalated dose and split course (FEM II). From among 12 patients evaluable for response, 2 partial and 1 minimal remission were observed, suggesting a response rate of 25%. Four patients (30%) showed a no change and 5 progression. The median survival of all patients was 3.4 months, of the responders 8.4 months, of those with no change 5.2, and of those showing progression 3.4 months. Considerable nausea/vomiting and leukopenia was observed. The preliminary data suggest that the FEM II regimen does not offer any progress in terms of efficacy, survival and toxicity for advanced pancreatic carcinoma.


Costs and outcomes in rheumatoid arthritis and osteoarthritis.
A prospective descriptive study was done on the direct and indirect costs to ambulatory patients with rheumatoid arthritis and osteoarthritis, stratified at study entry by level of function. Measures of health status over a 1-year period were taken. On a yearly basis, in 1979 dollars, patients spent an average of $147 for arthritis medications, aids, and devices, and $207 for outpatient visits. A small number were hospitalized and incurred an average charge of $245, and an additional $84 for physician fees. In addition to direct monetary costs, patients averaged 6.8 days of restricted activity costs, patients averaged 6.8 days of restricted activity per month, in some cases so severe as to confine patients to bed for an average of 1.3 days per month. Among students and working patients, 2.5 work-days per month were lost due to arthritis, and 30% reported that they were unemployed or retired because of impaired health. Functional capacity and specific diagnosis on entry to the study were the most important determinants of arthritis-related expenditures. Both direct and indirect costs varied considerably from the observed average. Twenty percent of patients incurred no costs for arthritis-related purchases, 42+ had no costs for outpatient visits, and 93% had no inpatient costs. Yet for some patients, the financial burden was very high.


Shared genetic effects on chromatin and gene expression indicate a role for enhancer priming in immune response.
Regulatory variants are often context specific, modulating gene expression in a subset of possible cellular states. Although these genetic effects can play important roles in disease, the molecular mechanisms underlying context specificity are poorly understood. Here, we identified shared quantitative trait loci (QTLs) for chromatin accessibility and gene expression in human macrophages exposed to IFNγ, Salmonella and IFNγ plus Salmonella. We observed that ~60% of stimulus-specific expression QTLs with a detectable effect on chromatin altered the chromatin accessibility in naive cells, thus suggesting that they perturb enhancer priming. Such variants probably influence binding of cell-type-specific transcription factors, such as PU.1, which can then indirectly alter the binding of stimulus-specific transcription factors, such as NF-κB or STAT2. Thus, although chromatin accessibility assays are powerful for fine-mapping causal regulatory variants, detecting their downstream effects on gene expression will be challenging, requiring profiling of large numbers of stimulated cellular states and time points.


[Stercoral rectosigmoid colonic perforation with fecal peritonitis].
Chronic constipation can lead to fecal impaction and catastrophic complication such as colonic obstruction, perforation and fecal peritonitis. A case is reported of stercoral perforation of the rectosigmoid with pneumoperitoneum and fecal peritonitis. The patient was admitted for the signs of acute abdomen with pneumoperitoneum diagnosed on native radiological imaging.


Glenohumeral instability: evaluation with MR arthrography.
Magnetic resonance arthrography is superior to other imaging techniques in evaluation of the glenohumeral joint. Normal variants that can be diagnostic pitfalls include the anterosuperior sublabral foramen, the Buford complex, and hyaline cartilage under the labrum. Anteroinferior dislocation is the most frequent cause of anterior glenohumeral instability and produces a constellation of lesions (anteroinferior labral tear, classic and osseous Bankart lesions, Hill-Sachs lesion). Variants of anteroinferior labral tears include anterior labroligamentous periosteal sleeve avulsion and glenoid labral articular disruption. Anterior glenohumeral instability can also involve tears of the anterior or anterosuperior labrum or the glenohumeral ligaments. Posterior glenohumeral instability can involve a posterior labral tear, posterior capsular stripping or laxity; fracture, erosion, or sclerosis and ectopic ossification of the posterior glenoid fossa; reverse Hill-Sachs lesion; McLaughlin fracture; or posterosuperior glenoid impingement. Superior labral anterior and posterior lesions involve the superior labrum with varying degrees of biceps tendon involvement.


Situs Inversus Totalis in the Critical Care Unit: A Case Report and Literature Review.
Situs inversus is a rare congenital disorder where the reversal of some of the major thoracic or abdominal organs is present. In this disorder, alterations in the fetus's organ lateralization lead to a complete reversal in the arrangement of the internal organs. Most of the time, they are found incidentally when having a procedure or imaging modality. Little has been written regarding the challenges encountered while providing critical care to these patients. Here we present the case of a 68-year-old male patient admitted to the intensive care unit (ICU) with hypoxemic respiratory failure secondary to pneumonia who underwent diagnostic bronchoscopy for organism identification and was confirmed to have situs inversus totalis. Situs inversus totalis represents a challenge at different levels of care to these patients, including in the ICU. Limitations in critical care can be seen upon imaging identification, and during routine procedures performed at the ICU. Confusion might appear while performing bedside point of care ultrasound, obtaining vascular access, performing electrocardiogram, and sample identification, among others. The case brings the relevance of being able to recognize this rare disorder, which can be diagnosed even in advanced age since it might present the clinician with challenges at the time of providing care to patients.


Association between diabetes mellitus and depressive symptoms in the Brazilian population.
To determine the prevalence of current depressive symptoms in people with diabetes mellitus and their association with the disease. Data were collected from the Brazilian National Health Survey (Pesquisa Nacional de Saúde - PNS), a cross-sectional, population-based study conducted in 2013. Study participants were selected by simple random cluster sampling in three stages: census tracts, households, and residents aged ≥ 18 years. The presence of diabetes was self-reported, whereas the presence of current depressive symptoms was determined by the Patient Health Questionnaire-9 (PHQ-9) and mean scores of this questionnaire were calculated for the variables assessed. Tobit regression was used to evaluate variation in these individuals. Of the 60,202 interviewees, 6.03% (n = 3,636) reported diabetes mellitus. The disease was more frequent in female, older, widowed, obese and with incomplete elementary education. Depression symptoms were mild-to-moderately severe in 22% of the diabetics. The severity of current depressive symptoms was higher in individuals that were female (PHQ-9 mean = 3.35), older adults (PHQ-9 mean = 3.01), indigenous (PHQ-9 mean = 3.46), separated/divorced (PHQ-9 mean = 3.13), widowed (PHQ-9 mean = 3.39), obese (PHQ-9 mean = 3.13) and with incomplete primary education (PHQ-9 mean = 3.21). Higher severity of depressive symptoms was associated with the use of insulin and with coma (PHQ-9 mean = 8.32), limb amputation (PHQ-9 mean = 7.55), circulatory problems (PHQ-9 mean = 6.94), infarction (PHQ-9 mean = 6.83), diabetic foot (PHQ-9 mean = 6.62), and kidney problems (PHQ-9 mean = 6.68). The severity of current depressive symptoms was associated with diabetes severity and degree of limitation in activities of daily living (PHQ-9 mean = 10.62). Interventions to improve depressive symptoms should be prioritized in people with diabetes are female, older adults, indigenous, widowed, separated/divorced, obese and with incomplete elementary education.


Effects of a Particular Heptapeptide on the IFN-α-Sensitive CML Cells.
Using the phage display biopanning technique, we have previously identified a heptapeptide KLWVIPQ which specifically binds to the surface of the IFN-α-sensitive but not the IFN-α-resistant CML cells. The effects of this heptapeptide on the IFN-α-sensitive CML cells were investigated in the present study. IFN-α-sensitive KT-1/A3 and IFN-α-resistant KT-1/A3R CML cells were transfected by pEGFP-KLWVIPQ expression vector and/or induced by IFN-α. WST-1 cell proliferation assay, flow cytometry, and western blotting were performed to determine the effects of this heptapeptide and/or IFN-α on CML cells. The viability of the KT-1/A3 cells was inhibited and apoptosis was induced by either expression of the heptapeptide KLWVIPQ or IFN-α treatment with concurrent upregulation of P53 and downregulation of P210(bcr/abl). However, these effects were not observed in the IFN-α-resistant KT-1/A3R cells. These results suggest that the heptapeptide KLWVIPQ shares a similar mechanism with IFN-α in the regulation of CML cell growth and apoptosis, implying that the heptapeptide KLWVIPQ could be a novel target to go further into mechanisms of IFN-α sensitivity and/or resistance in CML.


[Evaluation of the substantia nigra by means of transcranial ultrasound imaging].
AIM. To describe the prevalence of hyperechogenicity of the substantia nigra in two samples of patients: one group who had been diagnosed with Parkinson's disease (PD) in accordance with United Kingdom Parkinson's Disease Society criteria and a control population, so as to be able to establish the reference values for our neurosonology laboratory. SUBJECTS AND METHODS. Two samples of patients consisting of healthy controls with no neurodegenerative disease and patients with PD were selected. Planimetric measurements of the area of echogenicity in the substantia nigra were performed in both groups. The greatest area of echogenicity measured on each side of each patient was considered. Descriptive statistics of the sample were carried out. The ROC curve was constructed in order to show the overall precision, sensitivity and specificity of transcranial Doppler ultrasonography in comparison to the clinical diagnosis of PD. RESULTS. Altogether 45 patients with PD and 91 controls were analysed. Using our own cut-off point (percentile 90 of the controls = 0.22 cm2), hyperechogenicity of the substantia nigra was observed in 73.33% of patients with PD and 8.79% of the controls (p = 0). An area below the curve of 93% was seen, which represents good overall precision for transcranial Doppler ultrasonography in the diagnosis of PD. CONCLUSIONS. The evaluation of the substantia nigra conducted in our laboratory using ultrasound imaging reveals significant differences between subjects with PD and normal subjects. The values obtained in our laboratory are slightly below those established as an international reference and offer excellent values for specificity and an acceptable level of sensitivity in our locale.


Correlates and consequences of workplace violence.
A random telephone survey was used to interview 598 employees about instances, if any, when they had been physically attacked or threatened in the workplace. Demographic and workplace characteristics are analyzed as correlates of these forms of violence. The only characteristic consistently associated with higher risk is a work schedule that included nighttime hours. However, although few strong or consistent correlates of workplace violence were found, there were clear negative consequences associated with being victimized at work: lower job satisfaction, greater job stress, increased considerations of job change, and an increased likelihood of bringing mace, a gun, or another weapon to work.


[Effects of phosphate fertilizer on active ingredients and antioxidant activities of Chrysanthemum morifolium].
In order to provide a scientific fertilizer application for the standardized cultivation, the effects of phosphate (P) fertilizer on the active ingredients and antioxidant activities of Chrysanthemum morifolium were studied. Pot experiment was adopted to study the effects of P supply on the yield and the content of flavonoids, chlorogenic acid, soluble sugar, soluble amino acids and crude protein of C. morifolium flower. And effects of P supply on the hydroxyl radical scavenging activity, superoxide anion radical scavenging activity, and 2, 2-diphenyl-1-picrylhydrazyl hydrate (DPPH) free radical scavenging activity of flower were researched too. The yield of C. morifolium dry flower increased 129. 94% when P fertilizer was applied. Appropriate application of P fertilizer could also significantly improve the content and accumulation of total flavonoids, chlorogenic acid and soluble sugar in C. morifolium. Thus, the inhibition rates of hydroxyl radical, superoxide anion radical and DPPH free radical of C. morifolium was increased. When the level of P supply exceeded 0.20 g P2O5 per plant, P had also negative influence on the yield and the content of active ingredients and the scavenging activity of hydroxyl radical, superoxide anion radical and DPPH free radical of C. morifolium. Furthermore, there were significant positive correlations between the content of total flavonoids and chlorogenic acid and the inhibition rate of hydroxyl radical, superoxide anion radical and DPPH free radical, respectively. Appropriate application of P fertilizer could be beneficial to the increase the active components and antioxidant activity of C. morifolium. And recommended level of P fertilizer is 0.26-0.28 g x kg(-1).


Preparation of urine samples for trace metal determination: a study with aluminium analysis by inductively coupled plasma optical emission spectrometry.
Urinary analysis of trace metals forms a significant role in clinical chemistry, but the optimal preparation and analysis of urine samples has not been investigated. Human urine is generally supersaturated with dissolved solids. Therefore, samples often precipitate following collection. X-ray microanalysis showed that this precipitate was predominantly rich in calcium and phosphorus but could include some trace metals from urine, potentially lowering their concentrations in solution. Hence, the precipitate must be fully redissolved for accurate analysis of trace metals in urine. Methods are emphasized for the best collection and preparation of urine samples for subsequent trace metal analysis; in this work inductively coupled plasma optical emission spectrometry (ICPOES) was used for the analysis of aluminium. For optimal accuracy, peak profiles were collected over 396.147 nm-396.157 nm. Urinary aluminium levels were investigated from 10 healthy volunteers and concentrations were obtained using either aqueous, pooled or individual urine-based standard curves. Since urine has a highly variable matrix, individual sample-based standards, which are unique to that particular sample, gave the most accurate results. However, where sample size is small or sample numbers are unfeasibly large, pooled sample-based standards give good approximations to within 15% and, with appropriate validation, other elements as internal standards could also be used for approximations. Aqueous standards should be avoided. Spike-recovery experiments confirmed these data since individual sample based standards showed optimal recovery [99.3 (4.4)%], while pooled sample-based standards were a close proxy [101.6 (9.2)%] but aqueous standards were inappropriate [137.4 (12.8)%]. Postprandial urinary aluminium levels of the 10 volunteers were [7.2 (3.7)micrograms/L] after analysis using individual sample-based standard curves.


Identification of fenestrated capillary segments in microvascular corrosion casts of the rat exocrine pancreas.
The capillary bed of the rat exocrine pancreas was studied by scanning and transmission electron microscopy of corrosion casts and tissue sections. Two types of capillaries were distinguished in corrosion casts. First, there were straight capillaries of relatively constant width (mean diameter 4.79 +/- 0.87 microns), which were characterized by numerous circular constrictions on their surface. About 37% of the capillaries belonged to this type. Second, there were undulating capillaries which showed smooth surfaced eccentric dilatations defined by similar surface constrictions. The bulging areas measured 8.43 +/- 1.33 microns, the constrictions next to the bulges figured for 6.45 +/- 1.53 microns. About 63% of the capillaries belonged to the second type. Two types of capillaries were also identified in tissue sections. First, there were capillaries with continuous endothelial lining (26% of capillary profiles; mean diameter 5.48 +/- 1.67 microns); 27% of their endothelial lining was provided with underlying pericytes. Second, there were capillaries with fenestrated endothelium (64% of capillary profiles; mean diameter 6.16 +/- 1.75 microns); 12% of their endothelial lining was accompanied by pericytes. According to frequency and dimension of these two types of capillaries, we conclude that bulged and undulating capillary casts correspond to fenestrated capillaries and straight capillary casts of constant width correspond to nonfenestrated capillaries. The frequency of crests on the surface of capillary casts correlates with the different frequency of pericyte processes on fenestrated and nonfenestrated capillaries. It is concluded that pericyte processes beneath the endothelium hold resistance against luminal pressure. Bulging areas of capillary casts correlate with fenestrated areas of endothelial lining, that is, areas which are not reinforced by pericyte processes.


Empirical Bayes estimation of demographic schedules for small areas.
In this article, we analyze empirical Bayes (EB) methods for estimating small-area rate schedules. We develop EB methods that treat schedules as vectors and use adaptive neighborhoods to keep estimates appropriately local. This method estimates demographic rates for local subpopulations by borrowing strength not only from similar individuals elsewhere but also from other groups in the same area and from regularities in schedules across locations. EB is substantially better than standard methods when rates have strong spatial and age patterns. We illustrate this method with estimates of age-specific fertility schedules for over 3,800 Brazilian municipalities.


Microbial behavior in a heterogeneous world.
Most microorganisms are motile during at least part of their life cycle, because they need to find optimal conditions in a patchy world. The sheer volume of microorganisms in the biosphere means that their motile sensory behavior also contributes to the global transformation and cycling of matter. How microorganisms move and how they orient themselves using environmental cues are integral to understanding the complex structure and function of microbial communities, but although motility in response to external stimuli was first described more than 120 years ago, understanding of the cellular and molecular mechanisms involved has only been achieved more recently.


A role for G(z) in pancreatic islet beta-cell biology.
Glucose-stimulated insulin secretion and beta-cell growth are important facets of pancreatic islet beta-cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein G(z) and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic beta-cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which G alpha(z) impacts are intact in beta-cells, and G alpha(z) activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) beta-cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E (PGE1) is pertussis-toxin insensitive, indicating that other G alpha(i) family members are not involved in this process in this beta-cell line. Indeed, overexpression of a selective deactivator of G alpha(z), the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucose-stimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by small interfering RNA-mediated knockdown of G alpha(z) expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13) beta-cell line couples to G(z) predominantly and perhaps even exclusively. These data provide the first evidence for G(z) signaling in pancreatic beta-cells, and identify an endogenous receptor-mediated signaling process in beta-cells that is dependent on G alpha(z) function.


Anisotropies of tactile distance perception on the face.
The distances between pairs of tactile stimuli oriented across the width of the hand dorsum are perceived as about 40% larger than equivalent distances oriented along the hand length. Clear anisotropies of varying magnitudes have been found on different sites on the limbs and less consistently on other parts of the body, with anisotropies on the center of the forehead, but not on the belly. Reported anisotropies on the center of the forehead, however, might reflect an artefact of categorical perception from the face midline, which might be comparable to the expansion of tactile distance perception observed for stimuli presented across joint boundaries. To test whether tactile anisotropy is indeed a general characteristic of the tactile representation of the face, we assessed the perceived distance between pairs of touches on the cheeks and three locations on the forehead: left, right, and center. Consistent with previous results, a clear anisotropy was apparent on the center of the forehead. Importantly, similar anisotropies were also evident on the left and right sides of the forehead and both cheeks. These results provide evidence that anisotropy of perceived tactile distance is not a specific feature of tactile organization at the limbs but it also exists for the face, and further suggest that the spatial distortions found for tactile distances that extend across multiple body parts are not present for stimuli that extend across the body midline.


The cellular mechanisms by which adenosine evokes release of nitric oxide from rat aortic endothelium.
Adenosine and nitric oxide (NO) are important local mediators of vasodilatation. The aim of this study was to elucidate the mechanisms underlying adenosine receptor-mediated NO release from the endothelium. In studies on freshly excised rat aorta, second-messenger systems were pharmacologically modulated by appropriate antagonists while a NO-sensitive electrode was used to measure adenosine-evoked NO release from the endothelium. We showed that A1-mediated NO release requires extracellular Ca2+, phospholipase A2 (PLA2) and ATP-sensitive K+ (KATP) channel activation whereas A2A-mediated NO release requires extracellular Ca2+ and Ca2+-activated K+ (KCa) channels. Since our previous study showed that A1- and A2A-receptor-mediated NO release requires activation of adenylate cyclase (AC), we propose the following novel pathways. The K+ efflux resulting from A1-receptor-coupled KATP-channel activation facilitates Ca2+ influx which may cause some stimulation of endothelial NO synthase (eNOS). However, the increase in [Ca2+]i also stimulates PLA2 to liberate arachidonic acid and stimulate cyclooxygenase to generate prostacyclin (PGI2). PGI2 acts on its endothelial receptors to increase cAMP, so activating protein kinase A (PKA) to phosphorylate and activate eNOS resulting in NO release. By contrast, the K+ efflux resulting from A2A-coupled KCa channels facilitates Ca2+ influx, thereby activating eNOS and NO release. This process may be facilitated by phosphorylation of eNOS by PKA via the action of A2A-receptor-mediated stimulation of AC increasing cAMP. These pathways may be important in mediating vasodilatation during exercise and systemic hypoxia when adenosine acting in an endothelium- and NO-dependent manner has been shown to be important.


The potential of combi-molecules with DNA-damaging function as anticancer agents.
DNA-damaging agents, such as methylating agents, chloroethylating agents and platinum-based agents, have been extensively used as anticancer drugs. However, the side effects, high toxicity, lack of selectivity and resistance severely limit their clinical applications. In recent years, a strategy combining a DNA-damaging agent with a bioactive molecule (e.g., enzyme inhibitors) or carrier (e.g., steroid hormone and DNA intercalators) to produce a new 'combi-molecule' with improved efficacy or selectivity has been attempted to overcome these drawbacks. The combi-molecule simultaneously acts on two targets and is expected to possess better potency than the parent compounds. Many studies have shown DNA-damaging combi-molecules exhibiting excellent anticancer activity in vitro and in vivo. This review focuses on the development of combi-molecules, which possess increased DNA-damaging potency, anticancer efficacy and tumor selectivity and reduced side reactions than the parent compounds. The future opportunities and challenges in the discovery of combi-molecules were also discussed.


Lessons learned from radiology mentors.
As in any field, radiologists may face a number of challenges as they navigate their early careers. Because with experience comes wisdom, early-career radiologists may find helpful the advice and perspectives of mid- and late-career radiologists. The Society of Abdominal Radiology recognizes the value of this pool of knowledge and experience, prompting the establishment of the Early Career Committee. This group is designed to support early-career radiologists by sharing the experiences and insights of leaders in the field. In this series, the authors interview trailblazers Matthew S. Davenport, MD; Jonathan B. Kruskal, MD, PhD; Katherine E. Maturen, MD, MS; David B. Larson, MD, MBA; and Desiree E. Morgan, MD. This perspective explores a wide range of subjects, including personal values in medicine, the role of teleradiology, diversity of backgrounds in radiology, how to navigate workplace conflict, and lifelong learning in medicine. Beyond conveying these pearls of wisdom, the aim of this perspective is to highlight for early-career radiologists the value that mid- and late-career mentors can provide in navigating careers in medicine.


Physiochemical properties of copper doped calcium sulfate in vitro and angiogenesis in vivo.
Bone cements were prepared by mixing calcium sulfate and copper sulfate in various proportions. We examined physical and physicochemical properties of the copper doped calcium sulfates and the effects of the cements on angiogenesis in vivo. Rod shaped calcium sulfate crystals were visible by scanning electron microscopy in the cement that contained no copper sulfate, whereas plate-like crystals covered the surface of the cement with high copper content. After immersion of the cements in simulated body fluid (SBF) for 1 day, X-ray diffractometric analysis showed that gypsum precipitates had formed in the copper doped calcium sulfate. The compressive strength of the cements increased from 3.3 MPa for pure calcium sulfate to 6.4 MPa for samples with copper sulfate added. Calcium ion release was greatest from pure calcium sulfate, and the rate of copper ion release was higher for cements containing the most copper. We found that 6 weeks after implantation, more blood vessels had formed around the high copper cement than for the copper-free cement. Copper doped calcium sulfate appears to be useful for application to regenerative medicine including wound healing and bone tissue engineering.


Demographics and Health Profiles of Depressive Symptoms in Korean Older Adults.
This study examined the demographics and health characteristics of depressive symptoms of Korean older adults. Data were from the 2014 survey of the Korean Longitudinal Study of Aging (KLoSA). Hierarchical logistic regression was conducted to identify risk factors of depressive symptoms. Model 2 including socio-demographics and health characteristics explained 19.2% of depressive symptoms. Significant risk factors of depressive symptoms were men, age of 53-60 years, mid-sized city and rural area residents, less than high-school education, adults without spouse, 1st (lowest) quintile of annual household income, body shape as underweight, ex-smokers, non-drinkers, no regular exercise, perceived health status as poor, limited activities of daily living, and the number of comorbidities. Interventions to reduce depressive symptoms in these populations should include strategies to change some of these modifiable risk factors.


Galectin-8 predicts postoperative recurrence of patients with localized T1 clear cell renal cell carcinoma.
Galectin-8 (Gal-8), belonging to a family of the "tandem repeat"-type galectins that contain 2 carbohydrate recognition domains, serves to retain cell surface residency and signaling of glycoproteins including cytokine and growth factor receptors, and thereby promoting development and progression of various malignancies. This study aims to evaluate the effect of Gal-8 expression on postoperative recurrence of patients with localized pathologic T1 (pT1) clear cell renal cell carcinoma (ccRCC). In this retrospective study, we enrolled 244 patients (122 in group A and 122 in group B) with localized pT1 ccRCC undergoing nephrectomy at a single institution. Specimens from patients were collected from January 2003 to December 2008. Median follow-up was 71 months (range: 12-120 mo) in group A and 70 months (range: 12-119 mo) in group B. Overall, 14 patients experienced recurrence in group A (n = 122) and 22 patients had recurrence in group B (n = 122). Gal-8 expression was assessed by immunohistochemistry in clinical specimens. Kaplan-Meier method with log-rank test was performed to compare survival curves. Cox regression models were used to evaluate the prognostic values of variables on recurrence-free survival. Concordance index was calculated to assess prognostic accuracy. In both groups, patients with high expression of Gal-8 were significantly inclined to have high rates of necrosis. High Gal-8 expression indicated early recurrence of patients with localized pT1 ccRCC. Gal-8 expression was determined to be an independent adverse prognostic indicator for recurrence. The accuracy of The Mayo Clinic Stage, Size, Grade, and Necrosis score and University of Los Angeles Integrated Staging System prognostic models was improved when Gal-8 expression was added. Gal-8 expression is a potential independent unfavorable prognostic indicator for postoperative recurrence of patients with localized pT1 ccRCC.


Biosocial Correlates of Nutrition and Chronic Energy Deficiency among Adult Females of two Ecological Zones in Madhya Pradesh and Uttarakhand, India.
The paper aims to draw out biosocial correlates of nutrition through body mass index (BMI) and chronic energy deficiency (CED). The findings are based on cross-sectional data of 446 women aged 18-60 years from six different endogamous groups of two ecological zones. The mean age of studied women varied from 31 to 36 years. The mean age at menarche was found to be 14.50±1.32 years. Similarly mean age at menopause was found to be 46.22±4.00 years. The mean of reproductive life span varied from 27 to 35 years. Average number of pregnancies per women was 4.44±2.52, average foetal loss was 0.11, children surviving per women was 3.61, whereas average child loss per women was found to be 0.62 and average family size was 9.51. Variations in mean BMI kg/m2 between populations ranged between 18.56 and 20.71. Prevalence of CED was highest among the Brahmin women of Uttarakhand (58.3%) followed by Ahirwar of Madhya Pradesh (47.1%). Incidence of CED was found lowest among Brahmin women of Madhya Pradesh (24.0%). Linear regression coefficient (b ± standard error) of BMI on Cormic Index for these women was 33.1 ± 8.1 (t=4.0, p=0.001), and correlation coefficient (R) was 0.189. Out of 6 anthropometric variables considered for regression analysis, 5, namely weight, hip circumference, waist circumference, mid arm circumference and sitting height showed significant correlations with BMI. Significant differences in sitting height and Cormic Index of women from the hills and plains indicate the role of ecology in shaping its habitants. Out of 9 demographic variables, only age of respondent and family size were found to have a significant impact on low BMI status. The present study postulates that the nutritional status of women has improved over the last decades.


A rare case of cavitary lung cancer complicated with mycotic pneumonia and bullous emphysema: A case report and review of the literature.
The accurate diagnosis and staging of cavitary lung cancer is challenging but essential for the choice of therapy; therefore, the differential diagnosis of cystic pulmonary lesions needs to be elucidated. A patient was admitted with multifocal thin-walled cystic lesions in chest computed tomography. The patient had been diagnosed as heterogeneous bullous emphysema pathologically about 3 years ago. His diagnosis turned out to be metastatic cavitary lung cancer complicated with fungal pneumonia this time. The patient underwent lung volume reduction surgery during his first hospitalization. Concurrent systemic chemotherapy and whole brain radiotherapy were administered after the diagnosis of cystic lung cancer. The patient was lost to follow-up after the chemoradiotherapy. Cavitary lung cancer should always be kept in mind during differential diagnosis of pulmonary cystic lesions. Pathological diagnosis by biopsy and surgery could be considered to avoid delayed treatment of malignancy.


Effects of immunoneutralization of substance P on hypothalamic neurotransmitters in normal mice and in transgenic mice expressing bovine growth hormone.
It is well known that transgenic mice expressing bovine growth hormone have altered neuroendocrine functions. Substance P was shown to influence the secretion of gonadotropins. In this investigation, the effect of a single injection of an antiserum to substance P was investigated in intact and castrated transgenic (MT-bGH) mice and in their normal litter mates. In the median eminence, the administration of antisubstance P serum resulted in a decreased dihydroxyphenyl acetic acid/dopamine index in intact and castrated normal mice but was without effect in transgenics. The homovanillic/dopamine index was decreased in normal mice (intact or castrated) but unchanged in transgenics. Norepinephrine and epinephrine were increased in normal mice (intact and castrated) treated with the anti-SP serum, but in transgenic mice, the anti-SP serum induced significant changes of norepinephrine only in intact animals, with no modifications in epinephrine levels. In the whole hypothalamus (minus the median eminence), the injection of antisubstance P serum resulted in an increased dihydroxyphenyl acetic acid/dopamine index in castrated, but not in intact, normal mice. In transgenic mice, this index was increased in intact but decreased in castrated animals. The homovanillic/dopamine index was decreased in normal intact mice treated with the antiserum but increased in intact transgenic mice. Norepinephrine and epinephrine were decreased by the antiserum treatment in normal intact mice but were unchanged in transgenics, except for norepinephrine in castrated transgenics, in which it was found increased. The administration of the antiserum did not affect plasma LH, FSH, or prolactin in normal mice but it reduced LH levels in intact transgenic mice. These results indicate that the response to the treatment with the antiserum to substance P shows considerable alterations in transgenic mice as compared with their litter-mate, normal controls, producing divergent effects on hypothalamic catecholamine metabolism. The present findings confirm that transgenic mice overexpressing the bGH gene have marked neuroendocrine alterations as compared with their normal litter mates.


Resistance mutations and CTL epitopes in archived HIV-1 DNA of patients on antiviral treatment: toward a new concept of vaccine.
Eleven patients responding successfully to first-line antiretroviral therapy (ART) were investigated for proviral drug resistance mutations (DRMs) in RT by ultra-deep pyrosequencing (UDPS). After molecular typing of the class I alleles A and B, the CTL epitopes in the Gag, Nef and Pol regions of the provirus were sequenced and compared to the reference HXB2 HIV-1 epitopes. They were then matched with the HLA alleles with determination of theoretical affinity (TA). For 3 patients, the results could be compared with an RNA sample of the circulating virus at initiation of therapy. Five out of 11 patients exhibited DRMs by UDPS. The issue is whether a therapeutic switch is relevant in these patients by taking into account the identity of the archived resistance mutations. When the archived CTL epitopes were determined on the basis of the HLA alleles, different patterns were observed. Some epitopes were identical to those reported for the reference with the same TA, while others were mutated with a decrease in TA. In 2 cases, an epitope was observed as a combination of subpopulations at entry and was retrieved as a single population with lower TA at success. With regard to immunological stimulation and given the variability of the archived CTL epitopes, we propose a new concept of curative vaccine based on identification of HIV-1 CTL epitopes after prior sequencing of proviral DNA and matching with HLA class I alleles.


The selective effects of central masking on brain stem potentials.
The effect of contralateral white noise stimulation on ipsilaterally presented click evoked brain stem potentials was examined. Continuous contralateral white noise does not influence the brain stem response components but pulsed white noise simultaneously presented with the clicks produced a central masking effect which was observed as an amplitude reduction confined to Wave V. Our findings confirm those of Zwislocki (1971) that pulsed noise is a more effective central masker than continuous noise. A computer addition of the responses to pulsed white noise and clicks recorded independently revealed no reduction in Wave V amplitude but the response to the two stimuli presented simultaneously showed a specific reduction in Wave V amplitude. No change in the latency of Wave V was observed to suggest any 'cross-over' masking of the click stimulus. Patients with total unilateral deafness did not exhibit this phenomenon. The effect of a time delay of the masker to one ear in relation to the click presented to the other ear reduced the amplitude of Wave V less than when the two stimuli were presented simultaneously. The reduction in the amplitude, being specific to Wave V, suggests that the effect is central and that the particular locus for this aspect of central masking is at the level of the inferior colliculus.


Inhibiting Effect of Browned Processed Foods on Trypsin.
Inhibition of proteases was examined in browned foods including soy pastes, soy sauces, fish sauce, sauces, teas, coffees, and others in association with melanoidin, a Maillard product, which had been found to be a potent inhibitor of trypsin. Most of the foods were effective in restraining trypsin activity based on hydrolysis of N-α-benzoyl-DL-arginine-p-nitroanilide, while being ineffective on chymotrypsin except for black tea and cola. Especially, teas were noted for their strong inhibitory effect on trypsin. The color intensity of the foods in terms of optical density at 400 nm appeared not to correlate with the extent of inhibition except for soy sauces.