Return-to-duty rates among US military combat-related amputees in the global war on terror: job description matters.
The purpose of this study was to identify the differences seen between military occupation services (MOS) in terms of amputation patterns, subsequent disabling conditions, and their ability to return to duty. A retrospective study of major extremity amputations sustained by US service members between October 1, 2001, and July 30, 2011, was performed. Data obtained from the amputation database, Joint Trauma Theater Database, and the Physical Evaluation Board Liaison Office included demographics, amputation location(s), Injury Severity Scores (ISSs), disabling conditions, disability ratings, and disposition status. There were 1,221 major extremity amputees identified during the specified time frame, of which 899 had data regarding disabling conditions, ratings, and disposition. All service branches were represented. Personnel from the US Army (USA) Infantry were significantly (p < 0.0001) more likely to sustain an amputation than other MOS. The USA Infantry, the US Marine Corps Infantry and the USA Armor represented the top three specialties and accounted for more than 57% of all amputees. Approximately 89% of all service members did not return to duty, and the mean combined for all amputees was 76. USA Special Forces (USA SF) operators were significantly more likely to return to duty (p = 0.0022) and be found fit for duty (p = 0.0015) than all other MOS despite having a mean ISS (20) that was no different from those of other service members. No USA SF personnel were found to have posttraumatic stress disorder as a disabling condition. All amputees, regardless of MOS, are not likely to return to active duty and especially unlikely to be found fit for duty, except for members of the USA SF. The reason(s) for the increased return to duty for USA SF personnel remains unknown but a lack of posttraumatic stress disorder may be a contributing factor.


Diazepam and local anaesthetic spray versus general anaesthesia for gastroduodenoscopy.
A randiomized, controlled trial was performed on 50 patients to compare the advantages and disadvantages of the intravenous injection of diazepam (Valium) plus local anaesthetic spray with those of general anaesthesia (methohexital (Brietal) plus succinylcholine (Scoline)) for gastroduodenoscopy. Careful records were kept of blood pressure, pulse rate nd ECG recordings before, during and after the procedure. In addition, the time taken to perform the procedure, the ease with which it was performed, and an interview with the patients before they left the hospital were recorded. Both procedures have advantages and disadvantges. While there is still a role for general anaesthesia when the endoscopist uses the large types of gastroduodenoscope, the advent of the more sophisticated paediatric endoscopes currently available makes it likely that in future general anaesthesia will rarely be necessary.


Isolated bladder exstrophy associated with a de novo 0.9 Mb microduplication on chromosome 19p13.12.
The exstrophy-epispadias complex (BEEC) is a urogenital birth defect of varying severity. The causes of the BEEC are likely to be heterogeneous, with individual environmental or genetic risk factors still being largely unknown. In this study, we aimed to identify de novo causative copy number variations (CNVs) that contribute to the BEEC. Array-based molecular karyotyping was performed to screen 110 individuals with BEEC. Promising CNVs were tested for de novo occurrence by investigating parental DNAs. Genes located in regions of rearrangements were prioritized through expression analysis in mice to be sequenced in the complete cohort, to identify high-penetrance mutations involving small sequence changes. A de novo 0.9 Mb microduplication involving chromosomal region 19p13.12 was identified in a single patient. This region harbors 20 validated RefSeq genes, and in situ hybridization data showed specific expression of the Wiz gene in regions surrounding the cloaca and the rectum between GD 9.5 and 13.5. Sanger sequencing of the complete cohort did not reveal any pathogenic alterations affecting the coding region of WIZ. The present study suggests chromosomal region 19p13.12 as possibly involved in the development of CBE, but further studies are needed to prove a causal relation. The spatiotemporal expression patterns determined for the genes encompassed suggest a role for Wiz in the development of the phenotype. Our mutation screening, however, could not confirm that WIZ mutations are a frequent cause of CBE, although rare mutations might be detectable in larger patient samples. 19p13.12, microduplication, bladder exstrophy-epispadias complex, array-based molecular karyotyping, in situ hybridization analysis, copy number variations, WIZ gene.


Expression of laminin-5 in ameloblastomas and human fetal teeth.
Extracellular matrix proteins have been shown to play important roles in the cell migration and differentiation in both normal and pathological conditions. In the present study, we used immunohistochemistry and in situ hybridization to determine the distribution of laminin-5 in ameloblastomas and developing human teeth. In ameloblastomas, the immunoreaction for the laminin-5 gamma2 chain was confined to the tumor cells of the peripheral area. The staining reaction was variable, being mostly weak and fragmented in the basement membrane structures surrounding the neoplastic islands. Some peripheral epithelial cells and some invading small ameloblastoma cell islands showed intense intracellular staining for the gamma2 chain. Tumor cells in the proliferating areas of ameloblastomas expressed gamma2 chain mRNA. The laminin-5 gamma2 chain was located beneath the dental lamina and in the outer, but not in the inner, enamel epithelium of the developing teeth. During the early hard tissue apposition stage, intense staining for the gamma2 chain was confined to ameloblasts, which also gave a strong signal for gamma2 chain mRNA. These results suggest that laminin-5 may contribute to the infiltrative and progressive growing potential of ameloblastomas. During human tooth development, however, laminin-5 may participate in the terminal differentiation of ameloblasts and in enamel matrix formation.


Phase IIB Randomized Study of Topical Difluoromethylornithine and Topical Diclofenac on Sun-Damaged Skin of the Forearm.
Prevention of nonmelanoma skin cancers remains a health priority due to high costs associated with this disease. Diclofenac and difluoromethylornithine (DFMO) have demonstrated chemopreventive efficacy for cutaneous squamous cell carcinomas. We designed a randomized study of the combination of DFMO and diclofenac in the treatment of sun-damaged skin. Individuals with visible cutaneous sun damage were eligible. Subjects were randomized to one of the three groups: topical DFMO applied twice daily, topical diclofenac applied daily, or DFMO plus diclofenac. The treatment was limited to an area on the left forearm, and the duration of use was 90 days. We hypothesized that combination therapy would have increased efficacy compared with single-agent therapy. The primary outcome was change in karyometric average nuclear abnormality (ANA) in the treated skin. Individuals assessing the biomarkers were blinded regarding the treatment for each subject. A total of 156 subjects were randomized; 144 had baseline and end-of-study biopsies, and 136 subjects completed the study. The ANA unexpectedly increased for all groups, with higher values correlating with clinical cutaneous inflammation. Nearly all of the adverse events were local cutaneous effects. One subject had cutaneous toxicity that required treatment discontinuation. Significantly more adverse events were seen in the groups taking diclofenac. Overall, the study indicated that the addition of topical DFMO to topical diclofenac did not enhance its activity. Both agents caused inflammation on a cellular and clinical level, which may have confounded the measurement of chemopreventive effects. More significant effects may be observed in subjects with greater baseline cutaneous damage.


A Novel Recombinant DNA System for High Efficiency Affinity Purification of Proteins in Saccharomyces cerevisiae.
Isolation of endogenous proteins from Saccharomyces cerevisiae has been facilitated by inserting encoding polypeptide affinity tags at the C-termini of chromosomal open reading frames (ORFs) using homologous recombination of DNA fragments. Tagged protein isolation is limited by a number of factors, including high cost of affinity resins for bulk isolation and low concentration of ligands on the resin surface, leading to low isolation efficiencies and trapping of contaminants. To address this, we have created a recombinant "CelTag" DNA construct from which PCR fragments can be created to easily tag C-termini of S. cerevisiae ORFs using selection for a nat1 marker. The tag has a C-terminal cellulose binding module to be used in the first affinity step. Microgranular cellulose is very inexpensive and has an effectively continuous ligand on its surface, allowing rapid, highly efficient purification with minimal background. Cellulose-bound proteins are released by specific cleavage of an included site for TEV protease, giving nearly pure product. The tag can be lifted from the recombinant DNA construct either with or without a 13x myc epitope tag between the target ORF and the TEV protease site. Binding of CelTag protein fusions to cellulose is stable to high salt, nonionic detergents, and 1 M urea, allowing stringent washing conditions to remove loosely associated components, as needed, before specific elution. It is anticipated that this reagent could allow isolation of protein complexes from large quantities of yeast extract, including soluble, membrane-bound, or nucleic acid-associated assemblies.


Naturally occurring Yersinia enterocolitica septicemia in patas monkeys (Erythrocebus patas).
Two cases of Yersinia enterocolitica septicemia occurred in a breeding group of 22 adult patas monkeys (Erythrocebus patas). Affected animals had acute clinical signs of depression, weakness, dehydration, hypothermia, hepatomegaly and pronounced leukopenia. Both animals died a few hours after treatment was initiated. Gross necropsy findings included jaundice, fluid in body cavities, hepatomegaly, splenomegaly, multiple white foci within the liver and spleen, generalized lymph node enlargement and numerous mucosal ulcerations in the colon. Primary histopathological lesions were multifocal hepatic necrosis, splenic necrosis, chronic ulcerative enteritis and diaphragmatic myositis with necrosis and edema. Yersinia enterocolitica was cultured from the liver, spleen, lung, jejunum and rectum. Wild rodents, particularly mice, may have been a source of infection for these animals, as the monkeys were housed in a rural, indoor-outdoor facility. A preliminary culture survey showed that some clinically normal patas monkeys harbored the organism in their intestinal tracts.


Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome.
Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics. The state of our current understanding regarding mechanisms of glomerular disease initiation and progression will be examined, as will the current state of the art regarding emergent therapeutic approaches to slow or arrest glomerular disease in Alport patients.


Factors associated with successful dementia education for practitioners in primary care: an in-depth case study.
With increasing numbers of people in the UK living with dementia, the provision of good quality person-centred care that meets the often complex needs of this population is required. Given the majority of people with dementia live in the community, significant care and support will be provided by primary care services. This means the primary care workforce needs appropriate education to ensure they have the right knowledge, skills and attitudes to meet these care needs. However, little is understood about the most successful approaches to dementia education in this setting. An in-depth case study was undertaken in a single primary care organisation with the aim of exploring the impact of a person-centred dementia educational programme, and identify barriers and facilitators to implementation. Data was gathered from a wide range of sources and analysed using Kirkpatrick's evaluative framework. Initially, staff learners struggled to incorporate the 'whole-person' approach to dementia care, but gained knowledge and confidence through self-directed learning. They reacted positively to the training and appreciated opportunities to learn from peers in other services. They identified improvements in communication and prescribing practices, despite difficulties implementing changes during busy periods. Resultant impact for service users included more timely routine appointments, and positive satisfaction ratings from patients and families. The findings indicate the perceived value of person-centred dementia education for primary care. Further recommendations for provision in this service setting include tailored programmes designed collaboratively with clinical service providers, and bringing together an interdisciplinary mix of learners to enhance knowledge exchange.


Use of administrative claims models to assess 30-day mortality among Veterans Health Administration hospitals.
The Centers for Medicare and Medicaid Services (CMS) publicly reports hospital-specific risk-standardized, 30-day, all-cause, mortality rates (RSMRs) for all hospitalizations among fee-for-service Medicare beneficiaries for acute myocardial infarction (AMI), heart failure (HF), and pneumonia at non-Federal hospitals. To examine the performance of the statistical models used by CMS among veterans at least 65 years of age hospitalized for AMI, HF, and pneumonia in Veterans Health Administration (VHA) hospitals. Cross-sectional analysis of VHA administrative claims data between October 1, 2006 and September 30, 2009. Thirteen thousand forty-six veterans hospitalized for AMI among 123 VHA hospitals; 26,379 veterans hospitalized for HF among 124 VHA hospitals; and 31,126 veterans hospitalized for pneumonia among 124 VHA hospitals. Hospital-specific RSMR for AMI, HF, and pneumonia hospitalizations calculated using hierarchical generalized linear models. Median number of AMI hospitalizations per VHA hospital was 87. Average AMI RSMR was 14.3% [95% confidence interval (CI), 13.9%-14.6%] with modest heterogeneity among VHA hospitals (RSMR range: 8.4%-20.3%). The c-statistic for the AMI RSMR statistical model was 0.79. Median number of HF hospitalizations was 188. Average HF RSMR was 10.1% (95% CI, 9.9%-10.4%) with modest heterogeneity (RSMR range: 6.1%-14.9%). The c-statistic for the HF RSMR statistical model was 0.73. Median number of pneumonia hospitalizations was 221.5. Average pneumonia RSMR was 13.0% (95% CI, 12.7%-13.3%) with modest heterogeneity (RSMR range: 9.0%-18.4%). The c-statistic for the pneumonia RSMR statistical model was 0.72. The statistical models used by CMS to estimate RSMRs for AMI, HF, and pneumonia hospitalizations at non-Federal hospitals demonstrate similar discrimination when applied to VHA hospitals.


Quantifying soft degrees of freedom in volatile organic compounds: insight from quantum chemistry and focused single molecule experiments.
Sampling of the vast conformational landscape of organic compounds remains a challenging task in computational chemistry, especially when it comes to the characterization of soft-degrees of freedom and relatively small energy barriers between different local minima. Therefore, studying the intrinsic properties of isolated molecules using focused experiments such as high-resolution molecular spectroscopy provides a powerful approach to validate and improve available quantum chemical methods. Here, we report on the most abundant gas-phase structure of ethyl 2-methyl pentanoate under molecular jet conditions, which we used to benchmark several exchange-correlation functionals and ab initio methods at the quantum chemical level. The observed conformer of ethyl 2-methyl pentanoate in the gas-phase is of C1 symmetry and exhibits a large amplitude motion around the C-C bond in proximity to the carbonyl moiety, which, unlike in the case of its structural isomer ethyl 2-ethyl butyrate, is very sensitive to the applied quantum chemical method and basis set. Depending on the applied quantum chemical method, the dihedral angle of the lowest energy conformer is optimized to absolute values of ±20°. This is far above the usual convergence error of the theoretical methods and has a tremendous impact on the rotational constants of this conformer, which complicates the prediction of rotational spectra and the assignment of experimental data. We show that the loss of symmetry in the aliphatic chain bound to the carboxylic moiety of ethyl esters results in a shift of the dihedral angle value due to a flat potential well around the corresponding C-C bond. Our benchmark calculations further indicate the potential relevance of the wB97X-D functional for this ethyl pentanoate and other related ethyl esters.


Prevention of acute GVHD using an orthogonal IL-2/IL-2Rβ system to selectively expand regulatory T cells in vivo.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow (BM) failure syndromes. Graft-versus-host disease (GVHD) remains a leading cause of morbidity posttransplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal interleukin 2 receptor β (oIL-2Rβ) that would selectively interact with oIL-2 cytokine and not wild-type (WT) IL-2. To test whether the orthogonal system would preferentially drive donor Treg expansion, we used a murine major histocompatibility complex-disparate GVHD model of lethally irradiated BALB/c mice given T cell-depleted BM from C57BL/6 (B6) mice alone or together with B6Foxp3+GFP+ Treg or oIL-2Rβ-transduced Treg at low cell numbers that typically do not control GVHD with WT Treg. On day 2, B6 activated T cells (Tcons) were injected to induce GVHD. Recipients were treated with phosphate-buffered saline (PBS) or oIL-2 daily for 14 days, then 3 times weekly for an additional 14 days. Mice treated with oIL-2Rβ Treg and oIL-2 compared with those treated with PBS had enhanced GVHD survival, in vivo selective expansion of Tregs, and greater suppression of Tcon expansion in secondary lymphoid organs and intestines. Importantly, oIL-2Rβ Treg maintained graft-versus-tumor (GVT) responses in 2 distinct tumor models (A20 and MLL-AF9). These data demonstrate a novel approach to enhance the efficacy of Treg therapy in allo-HSCT using an oIL-2/oIL-2Rβ system that allows for selective in vivo expansion of Treg leading to GVHD protection and GVT maintenance.


Clonidine for pain in non-ventilated infants.
Critically ill newborn infants undergo a variety of painful procedures or experience a variety of painful conditions during their early life in the neonatal unit. In the critically ill paediatric and neonatal population, clonidine is prescribed as an adjunct to opioids or benzodiazepines aiming to reduce the doses of these drugs that are required for analgesia or sedation, or to facilitate weaning from mechanical ventilation. It has been shown that clonidine premedication might have a positive effect on postoperative pain in children. To assess the benefit and harms of clonidine for the prevention or treatment of procedural pain; postoperative pain; or pain associated with clinical conditions in non-ventilated neonates. We used the standard search strategy of Cochrane Neonatal to search the CENTRAL, MEDLINE via PubMed, Embase, and CINAHL to December 2018. We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials. We ran an updated search from 1 January 2018 to 11 March 2020 in CENTRAL via CRS Web, MEDLINE via Ovid, and CINAHL via EBSCOhost. Randomised controlled trials, quasi-randomised controlled trials, and cluster trials comparing clonidine to placebo or no treatment, opioids, paracetamol, dexmedetomidine, or non-pharmacological pain-reducing interventions for the management of procedural pain, postoperative pain, and pain associated with clinical conditions in preterm and term newborns. Two review authors independently planned to extract data (e.g. number of participants, birth weight, gestational age, modality of administration, and dose of clonidine) and assess the risk of bias (e.g. adequacy of randomisation, blinding, completeness of follow-up). The primary outcome considered was pain: for procedural pain, the mean values of each analgesia scale assessed during the procedure and at one to two hours after the procedure; for postoperative pain and for pain associated with clinical conditions, the mean values of each analgesia scale assessed at 30 minutes, three hours, and 12 hours after the administration of the intervention. We planned to use the GRADE approach to assess the quality of evidence. Our search strategy yielded 3383 references. Two review authors independently assessed all references for inclusion. We did not find any completed studies for inclusion. We excluded three trials where clonidine was administered for spinal anaesthesia. We did not find any studies that met our inclusion criteria and hence there is no evidence to recommend or refute the use of clonidine for the prevention or treatment of procedural or postoperative pain, or pain associated with clinical conditions in neonates.


Quality of Life and Social Isolation Among Caregivers of Adults with Schizophrenia: Policy and Outcomes.
Services have been increasingly directed at supporting carers of people living with mental illness but it is difficult to evaluate the impact of service change where benchmarks for carer functioning are sparse. Sixty Australian carers were assessed regarding their quality of life, psychological distress, social isolation and caregiving experience. Their scores were compared with two matched community samples and previous studies. Carers were ten times more likely to be socially isolated and quality of life was significantly less than matched community samples. Over 40 % of the carer sample met criteria for probable psychiatric disorder. Comparison of caregiving experiences with a study 15 years ago showed no improvement in negative caregiving experiences. Carers still face considerable challenges to their wellbeing as they support people living with mental illness, in spite of progress in the development of policy and services.


Organization of the Epstein-Barr virus DNA molecule. III. Location of the P3HR-1 deletion junction and characterization of the NotI repeat units that form part of the template for an abundant 12-O-tetradecanoylphorbol-13-acetate-induced mRNA transcript.
A 1,400-base-pair (bp) region within the BamHI H fragment of Epstein-Barr virus (EBV) (B95-8) DNA consists of a cluster of tandemly duplicated direct repetitions characterized by single sites for the NotI restriction endonuclease. Nucleotide sequencing revealed a 125-bp repeat unit of 84% guanine-plus-cytosine content which is theoretically capable of extensive secondary structure formation. The flanking sequences adjacent to the NotI repeat cluster contained an additional 38-bp portion of repeat unit DNA, thus establishing that EBV(B95-8) contains a nonintegral number of NotI repeats totalling 11.3 copies. Restriction site mapping of the homologous cloned BamHI "H" fragment from the nontransforming EBV (P3HR-1) isolate revealed that a contiguous 6,650-bp region including the entire NotI repeat cluster has been deleted from the BamHI-H, -Y, and -W regions of the P3HR-1 genome. By nucleotide sequencing across the novel junction, we have precisely identified the P3HR-1 deletion boundaries in BamHI-H and the internal repeat and suggest that a complex pattern of direct and inverted partial DNA homologies may have been involved in the original recombination event. The cloned BamHI H fragment and isolated NotI repeat unit have also been used as probes to detect homologous mRNA transcripts in the B95-8 and Raji cell lines of EBV-transformed lymphoblasts. These experiments showed that the NotI repeats form part of the template for a polyadenylated 2.5-kilobase mRNA transcript which becomes much more abundant after 12-O-tetradecanoyl-phorbol-13-acetate treatment of the cultures. The direction of transcription of this mRNA and the nucleotide sequence of most of its template and 5' flanking regions have been determined. The probable promoter for the 2.5-kilobase mRNA initiates transcription efficiently in an in vitro assay and contains several TAATGA-like elements that may be indicative of herpesvirus immediate-early class promoters. The need to repress expression of this gene during latency suggests a possible novel regulatory role for tandem repeat structures inside a eucaryotic virus transcription unit. The deletion in EBV(P3HR-1), which has been associated with the loss of lymphocyte "immortalizing" capacity in this isolate, eliminates part of the coding region as well as the NotI repeats from the 2.5-kilobase mRNA transcript, but the promoter and proximal 340-bp portions of the template remain.


Identification of a κ-opioid agonist as a potent and selective lead for drug development against human African trypanosomiasis.
A resazurin-based cell viability assay was developed for phenotypic screening of the LOPAC 1280 'library of pharmacologically active compounds' against bloodstream forms of Trypanosoma brucei in vitro identifying 33 compounds with EC(50) values <1 μM. Counter-screening vs. normal diploid human fibroblasts (MRC5 cells) was used to rank these hits for selectivity, with the most potent (<70 nM) and selective (>700-fold) compounds being suramin and pentamidine. These are well-known antitrypanosomal drugs which demonstrate the robustness of the resazurin cell viability assay. The most selective novel inhibitor was (+)-trans-(1R,2R)-U50,488 having an EC(50) value of 60 nM against T. brucei and 270-fold selectivity over human fibroblasts. Interestingly, (-)-U50,488, a known CNS-active κ-opioid receptor agonist and other structurally related compounds were >70-fold less active or inactive, as were several μ- and κ-opioid antagonists. Although (+)-U50,488 was well tolerated by the oral route and displayed good pharmaceutical properties, including high brain penetration, the compound was not curative in the mouse model of infection. Nonetheless, the divergence of antinociceptive and antitrypanosomal activity represents a promising start point for further exploratory chemistry. Bioinformatic studies did not reveal any obvious candidate opioid receptors and the target of this cytostatic compound is unknown. Among the other potent, but less selective screening hits were compound classes with activity against protein kinases, topoisomerases, tubulin, as well as DNA and energy metabolism.


Apparent diffusion coefficient: potential imaging biomarker for prediction and early detection of response to chemotherapy in hepatic metastases.
To evaluate the ability of the apparent diffusion coefficient (ADC) to help predict response to chemotherapy in patients with colorectal and gastric hepatic metastases. Institutional review board approval was obtained; all patients provided informed consent. Standard magnetic resonance (MR) imaging and diffusion-weighted (DW) MR imaging were performed before and 3, 7, and 42 days after initiating chemotherapy for 87 hepatic metastases in 23 colorectal and gastric cancer patients (16 men, seven women; mean age, 55.7 years; range, 33-71 years). Lesions were classified as either responding or nonresponding, according to changes in size at the end of therapy. Linear mixed-effects modeling was applied to analyze change in ADCs and size following treatment. The Pearson correlation test was calculated between those ADC parameters and tumor response. Thirty-eight responding and 49 nonresponding metastatic lesions were evaluated. Pretherapy mean ADCs in responding lesions were significantly lower than those of nonresponding lesions (P = .003). An early increase in ADCs (on day 3 or 7) was observed in responding lesions but not in nonresponding lesions (P = .002). Weak but significant correlations were found between final tumor size reduction and both pretreatment ADCs (P = .006) and early ADC changes (day 3, P = .004; day 7, P < .001). ADC seems to be a promising tool for helping predict and monitor the early response to chemotherapy of hepatic metastases from colorectal and gastric carcinomas.


Suppression of RAD21 gene expression decreases cell growth and enhances cytotoxicity of etoposide and bleomycin in human breast cancer cells.
A genome-wide case-control association study done in our laboratory has identified a single nucleotide polymorphism located in RAD21 as being significantly associated with breast cancer susceptibility. RAD21 is believed to function in sister chromatid alignment as part of the cohesin complex and also in double-strand break (DSB) repair. Following our initial finding, expression studies revealed a 1.25- to 2.5-fold increased expression of this gene in several human breast cancer cell lines as compared with normal breast tissue. To determine whether suppression of RAD21 expression influences cellular proliferation, RNA interference technology was used in breast cancer cell lines MCF-7 and T-47D. Proliferation of cells treated with RAD21-specific small inhibitory RNA (siRNA) was significantly reduced as compared with mock-transfected cells and cells transfected with a control siRNA (Lamin A/C). This inhibition of proliferation correlated with a significant reduction in the expression of RAD21 mRNA and with an increased level of apoptosis. Moreover, MCF-7 cell sensitivity to two DNA-damaging chemotherapeutic agents, etoposide and bleomycin, was increased after inhibition of RAD21 expression with a dose reduction factor 50 (DRF50) of 1.42 and 3.71, respectively. At the highest concentrations of etoposide and bleomycin administered, cells transfected with a single siRNA duplex targeted against RAD21 showed 57% and 60% survival as compared with control cells, respectively. Based on these findings, we conclude that RAD21 is a novel target for developing cancer therapeutics that can potentially enhance the antitumor activity of chemotherapeutic agents acting via induction of DNA damage.


Comparison of clinicopathologic characteristics and outcomes after resection in patients with hepatocellular carcinoma treated in the United States, France, and Japan.
To compare the clinicopathologic characteristics and outcomes after resection of patients with hepatocellular carcinoma (HCC) treated in the United States, France, and Japan. Some epidemiologic data suggests that HCC in different regions of the world may represent different forms of the disease. We compared the patient and tumor characteristics, underlying liver damage, and surgical outcomes of 586 patients who underwent resection of HCC from a multi-institutional database. A total of 169 patients were treated in the United States, 187 in France, and 230 in Japan. The median tumor size for patients treated in the United States was 8 cm, compared with 6 cm and 3.5 cm in France and Japan, respectively (P < 0.001); 20%, 38%, and 74% of patients in the United States, France, and Japan, respectively, had positive hepatitis C serology (P < 0.001). In addition, 65% of patients in Japan had severe fibrosis/cirrhosis in the adjacent liver compared with 52% and 23% of patients in France and the United States, respectively (P < 0.001). There was no association between site of treatment and 30-day (P = 0.4) or 1-year mortality (P = 0.3). The 5-year survival of patients treated in United States, France, and Japan was not statistically different (31% vs. 31% vs. 41%, respectively; P = 0.3). Although the etiology of HCC and clinicopathologic characteristics of patients treated at western and eastern centers vary widely, postresection 5-year survival is similar when controlling for these factors. Future studies should account for histopathologic differences using uniform criteria to allow better comparison of results.


Ba(B2OF3(OH)2)2 with well-ordered OH/F anions and a unique B2OF3(OH)2 dimer.
In minerals and artificial crystals, the OH and F groups often coexist and have a high probability of disordered structure. The OH/F position cannot be determined accurately in the crystal structure only by the direct X-ray diffraction method because of the poor contrast between O and F and the weak diffractivity of hydrogen atoms. In this work, a new fluorooxoborate Ba[B2OF3(OH)2]2, with a size of up to 12 × 4 × 3 mm3, has been synthesized successfully by a facile hydrothermal reaction. The BOF3 units with well-ordered OH/F positions are observed for the first time in alkali/alkaline earth metal fluorooxoborates. Owing to the selective fluorination of BO4, Ba(B2OF3(OH)2)2 exhibits a large birefringence and hence can be used as a DUV birefringent material. This work will guide the study of the structural chemistry of oxyfluorides.


Decline in FEV1 related to smoking status in individuals with severe alpha1-antitrypsin deficiency (PiZZ).
Severe alpha1-antitrypsin (AAT) deficiency predisposes to emphysema development. Highly variable rates of decline in lung function are reported in PiZZ individuals. The annual decline in forced expiratory volume in one second (FEV1; delta FEV1) was analysed in relation to smoking status in a cohort of 608 adult PiZZ individuals included in the Swedish national AAT deficiency register. Delta FEV1 was analysed in 211 never-smokers, in 351 exsmokers, and in 46 current smokers after performing at least two spirometries during a follow-up time of 1 yr or longer (median 5.5 yrs, range 1-31). The adjusted mean delta FEV1 in never-smokers was 47 mL x yr(-1) (95% confidence interval (CI) 41-53 mL x yr(-1)), 41 mL x yr(-1) (95% CI 36-48 mL x yr(-1)) in exsmokers, and 70 mL x yr(-1) (95% CI 58-82 mL x yr(-1)) in current smokers. A dose-response relationship was found between cigarette consumption and delta FEV1 in current smokers and exsmokers. In never-smokers, a greater delta FEV1 was found after 50 yrs of age than before. No sex differences were found in delta FEV1. In conclusion, among PiZZ individuals, the change in forced expiratory volume in one second is essentially the same in never-smokers and exsmokers. Smoking is associated with a dose-dependent increase in the change in forced expiratory volume in one second.


Protein is an important but undervalued macronutrient in the nutritional care of patients with cystic fibrosis.
Achieving an optimal nutritional status in patients with cystic fibrosis (CF) is important to maintain better pulmonary function, physical performance, and to prolong survival. So far, nutrition care in CF has mainly focused on fat intake and achieving energy balance, but there is increasing information on the clinical importance of muscle maintenance and protein intake in CF. Low muscle mass is consistently associated with pulmonary decline, bone mineral loss, and poor survival in CF. High energy and fat intake contributes to an increased prevalence of overweight and obesity in CF. Obesity per se is not related to better lung function in CF and has negative metabolic and clinical consequences, particularly when muscle wasting is present. Protein digestion capacity is severely impaired in CF, but high protein intake is needed and essential amino acid mixtures appear highly anabolic even in those with severe muscle loss. Body composition assessment and achieving protein balance in the routine care in CF is important to prevent muscle loss and further improve the clinical and overall outcome of these patients. New approaches are needed to optimize the interaction between high essential amino-acid-rich protein intake and pancreatic enzyme regimen in CF. The optimal level of protein intake needs to be assessed in clinically stable CF patients as well as in those recovering from an acute exacerbation.


Associations Between Adolescents' Social Re-orientation Toward Peers Over Caregivers and Neural Response to Teenage Faces.
Adolescence is a period of intensive development in body, brain, and behavior. Potentiated by changes in hormones and neural response to social stimuli, teenagers undergo a process of social re-orientation away from their caregivers and toward expanding peer networks. The current study examines how relative relational closeness to peers (compared to parents) during adolescence is linked to neural response to the facial emotional expressions of other teenagers. Self-reported closeness with friends (same- and opposite-sex) and parents (mother and father), and neural response to facial stimuli during fMRI, were assessed in 8- to 19-year-old typically developing youth (n = 40, mean age = 13.90 years old, SD = 3.36; 25 female). Youth who reported greater relative closeness with peers than with parents showed decreased activation in the dorsolateral prefrontal cortex (dlPFC) during stimulus presentation, which may reflect lessened inhibitory control or regulatory response to peer-aged faces. Functional connectivity between the dlPFC and dorsal striatum was greatest in older youth who were closer to peers; in contrast, negative coupling between these regions was noted for both younger participants who were closer to peers and older participants who were closer to their parents. In addition, the association between relative closeness to peers and neural activation in regions of the social brain varied by emotion type and age. Results suggest that the re-orientation toward peers that occurs during adolescence is accompanied by changes in neural response to peer-aged social signals in social cognitive, prefrontal, and subcortical networks.


(+)-Catharanthine and (-)-18-methoxycoronaridine induce antidepressant-like activity in mice by differently recruiting serotonergic and norepinephrinergic neurotransmission.
The antidepressant-like activity of (+)-catharanthine and (-)-18-methoxycoronaridine [(-)-18-MC] was studied in male and female mice using forced swim (FST) and tail suspension tests (TST). The underlying molecular mechanism was assessed by electrophysiological, radioligand, and functional experiments. The FST results showed that acute administration (40 mg/kg) of (+)-catharanthine or (-)-18-MC induces similar antidepressant-like activity in male and female mice at 1 h and 24 h, whereas the TST results showed a lower effect for (-)-18-MC at 24 h. Repeated treatment at lower dose (20 mg/kg) augmented the efficacy of both congeners. The FST results showed that (-)-18-MC reduces immobility and increases swimming times without changing climbing behavior, whereas (+)-catharanthine reduces immobility time, increases swimming times more markedly, and increases climbing behavior. To investigate the contribution of the serotonin and norepinephrine transporters in the antidepressant effects of (+)-catharanthine and (-)-18-MC, we conducted in vitro radioligand and functional studies. Results obtained demonstrated that (+)-catharanthine inhibits norepinephrine transporter with higher potency/affinity than that for (-)-18-MC, whereas both congeners inhibit serotonin transporter with similar potency/affinity. Moreover, whereas no congener activated/inhibited/potentiated the function of serotonin receptor 3A or serotonin receptor 3AB, both increased serotonin receptor 3A receptor desensitization. Depletion of serotonin decreased the antidepressant-like activity of both congeners, whereas norepinephrine depletion only decreased (+)-catharanthine's activity. Our study shows that coronaridine congeners induce antidepressant-like activity in a dose- and time-dependent, and sex-independent, manner. The antidepressant-like property of both compounds involves serotonin transporter inhibition, without directly activating/inhibiting serotonin receptors 3, while (+)-catharanthine also mobilizes norepinephrinergic neurotransmission.


A genomewide association study in divergently selected lines in rabbits reveals novel genomic regions associated with litter size traits.
Uterine capacity (UC), defined as the total number of kits from unilaterally ovariectomized does at birth, has a high genetic correlation with litter size. The aim of our research was to identify genomic regions associated with litter size traits through a genomewide association study using rabbits from a divergent selection experiment for UC. A high-density SNP array (200K) was used to genotype 181 does from a control population, high and low UC lines. Traits included total number born (TNB), number born alive (NBA), number born dead, ovulation rate (OR), implanted embryos (IE) and embryo, foetal and prenatal survivals at second parity. We implemented the Bayes B method and the associations were tested by Bayes factors and the percentage of genomic variance (GV) explained by windows. Different genomic regions associated with TNB, NBA, IE and OR were found. These regions explained 7.36%, 1.27%, 15.87% and 3.95% of GV, respectively. Two consecutive windows on chromosome 17 were associated with TNB, NBA and IE. This genomic region accounted for 6.32% of GV of TNB. In this region, we found the BMP4, PTDGR, PTGER2, STYX and CDKN3 candidate genes which presented functional annotations linked to some reproductive processes. Our findings suggest that a genomic region on chromosome 17 has an important effect on litter size traits. However, further analyses are needed to validate this region in other maternal rabbit lines.


Asthma control and associated risk factors among adults with current asthma: Findings from 2019 behavioral risk factor surveillance system asthma call-back survey.
Despite the availability of effective treatments, many adults with asthma have uncontrolled asthma. Uncontrolled asthma can lead to severe exacerbations. This study aimed to determine the prevalence and predictors of uncontrolled asthma among adults (≥18 years) with current asthma in the United States. We analyzed the 2019 Behavior Risk Factor Surveillance System Asthma Call-Back Survey data from 27 states. Asthma control status was classified as "well-controlled" or "uncontrolled" according to the National Asthma Education and Prevention guidelines. The study population consisted of 7937 adults (weighted n = 13,793,220) with current asthma. We used multivariable logistic regression models to identify predictors of uncontrolled asthma. Overall, 62 % of adults with asthma reported having uncontrolled asthma, and 26 % had emergency or urgent care visits or hospitalizations in the past year. Potentially modifiable risk factors associated with uncontrolled asthma included cost barriers to asthma-related healthcare (OR = 2.94; 95%CI 1.96-4.40), complementary and alternative medicine use (OR = 1.84; 95%CI 1.45-2.32), current smoking (OR = 2.25; 95%CI 1.48-3.44), obesity (OR = 1.39; 95%CI 1.02-1.89), COPD (OR = 1.98; 95%CI 1.43-2.74), depression (OR = 1.47; 95%CI 1.16-1.88), fair/poor general health (OR = 1.54; 95%CI 1.14-2.07), household income <$15,000 (OR = 2.59; 95%CI 1.42-4.71), and less than high school education (OR = 2.59; 95%CI 1.42-4.71). Non-modifiable risk factor was Hispanic ethnicity (OR = 1.73; 95%CI 1.09-2.73). Our findings suggest that uncontrolled asthma is common among adults and can be impacted by several factors. Effective asthma control programs are needed to improve asthma management and reduce unnecessary healthcare utilization.


Institutional capacity to provide psychosocial oncology support services: A report from the Association of Oncology Social Work.
This study reports cancer-treating institutions' capacity to deliver comprehensive psychosocial support services. Oncology care providers at 60 cancer-treating institutions completed surveys assessing the capacity of their institutions to provide psychosocial care. Capacity was assessed with the Cancer Psychosocial Care Matrix (CPCM) from the National Cancer Institute (NCI). Scores represented individuals' perceptions of their cancer program's performance with respect to 10 fundamental elements of psychosocial care. Among 2134 respondents, 62% reported a mid-level capacity for ≥5 of 10 CPCM items. In comparison with other types of cancer programs (eg, NCI-designated, academic, or comprehensive centers), providers at community cancer programs reported a significantly greater capacity with respect to patient-provider communication, psychosocial needs assessment, and continuity in the delivery of psychosocial care over time. Nurses and primary medical providers reported a significantly lower capacity for linking patients and families with needed psychosocial services within their respective cancer programs. They also reported a significantly higher capacity for conducting follow-up, re-evaluations, and adjustments of psychosocial treatment plans. Cancer programs are performing moderately well in terms of communicating to patients the importance of psychosocial care, identifying patient psychosocial needs, and referring patients and families to psychosocial services. They are doing less well with respect to the provision of that care over time. Findings suggest that gaps in psychosocial service capacity are a function of patient, provider, and system characteristics. These results may be useful in formulating strategies to enhance psychosocial care delivery. Cancer 2016;122:1937-45. © 2016 American Cancer Society.


Radical cystectomy versus bladder-preserving therapy for muscle-invasive urothelial carcinoma: examining confounding and misclassification biasin cancer observational comparative effectiveness research.
Radical cystectomy (RC) is the standard treatment for muscle-invasive urothelial carcinoma of the bladder. Trimodality bladder-preserving therapy (BPT) is an alternative to RC, but randomized comparisons of RC versus BPT have proven infeasible. To compare RC versus BPT, we undertook an observational cohort study using registry and administrative claims data from the Surveillance, Epidemiology and End Results-Medicare database. We identified patients age 65 years or older diagnosed between 1995 and 2005 who received RC (n = 1426) or BPT (n = 417). We examined confounding and stage misclassification in the comparison of RC and BPT by using multivariable adjustment, propensity score-based adjustment, instrumental variable (IV) analysis, and simulations. Patients who received BPT were older and more likely to have comorbid disease. After propensity score adjustment, BPT was associated with an increased hazard of death from any cause (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.05-1.53) and from bladder cancer (HR 1.31; 95% CI 0.97-1.77). Using the local area cystectomy rate as an instrument, IV analysis demonstrated no differences in survival between BPT and RC (death from any cause HR 1.06; 95% CI 0.78-1.31; death from bladder cancer HR 0.94; 95% CI 0.55-1.18). Simulation studies for stage misclassification yielded results consistent with the IV analysis. Survival estimates in an observational cohort of patients who underwent RC versus BPT differ by analytic method. Multivariable and propensity score adjustment revealed greater mortality associated with BPT relative to RC, while IV analysis and simulation studies suggest that the two treatments are associated with similar survival outcomes.


Susceptibility of mammary tumor cells to complement-mediated cytolysis after in vitro or in vivo fatty acid manipulation.
The susceptibility of line 168 murine mammary tumor cells to complement (C)-mediated lysis was tested after in vitro treatment with several saturated or unsaturated fatty acids dissolved in different solvents or presented in the form of micelles to the cells. The lytic susceptibility of these cultured cells was compared with similar tumor cells obtained either from mice maintained on diets containing different concentrations and saturations of fatty acids or from cultures supplemented with serum from tumor-free control mice fed pair-matched diets. Although changes in dietary fat concentration and saturation resulted in alterations of the tumor cell fatty acid composition, those alterations did not influence the susceptibility of tumor cells to C-mediated lysis. However, single, or combinations of, unsaturated fatty acids dissolved in ethanol, unlike saturated fatty acids, reduced the lytic susceptibility of tumor cells in vitro. Hexane added to culture medium significantly suppressed the lytic susceptibility; however, when used as a carrier no significant differences were observed among treatments with the individual fatty acids at several concentrations. This result may be due to the effect of hexane on the cell membrane because this treatment also affected the osmotic fragility of the cells. Fatty acids as micelles did not influence the susceptibility of tumor cells to lysis. We concluded that only in vitro manipulation of fatty acids in some vehicles influenced the susceptibility of target tumor cells to C-mediated lysis; this finding did not parallel the situation that occurred in vivo. Moreover, the use of different vehicles to present fatty acids to tumor cells may further alter the susceptibility to C-mediated lysis.


Escalating Plasmodium falciparum K13 marker prevalence indicative of artemisinin resistance in southern Rwanda.
In 2023, we updated data collected since 2010 on Plasmodium falciparum K13 and MDR1 drug resistance markers in Huye district, southern Rwanda. Artemisinin resistance-associated PfK13 markers occurred in 17.5% of 212 malaria patients (561H, 9.0%; 675V, 5.7%; and 469F, 2.8%), nearly double the frequency from 2019. PfMDR1 N86, linked with lumefantrine tolerance, was close to fixation at 98%. In southern Rwanda, markers signaling resistance to artemisinin and lumefantrine are increasing, albeit at a relatively slow rate.


Profiling psychopathology of patients reporting early childhood trauma and emotional neglect: Support for a two-dimensional model?
Profiling patients who report early childhood trauma and emotional neglect may be useful for treatment planning. This study attempts to quantify a two-dimensional "trauma-neglect model" (Draijer, 2003) proposed to distinguish clinical profiles in terms of trauma-related, dissociative, and personality pathology. A sample of patients referred to a trauma program (n = 49) and a personality disorders program (n = 101) was extensively assessed. Cluster analysis was used to discriminate patients in terms of "psychiatric disease burden," based on symptom severity scores, type of disorder, and level of maladaptive personality functioning. Clusters that differed in psychiatric disease burden were mapped in the trauma-neglect space and their positions were evaluated. We found three clusters and labeled them as "mildly impaired" (26% of patients), "moderately impaired" (43% of patients), and "severely impaired" (31% of patients). The mean scores on trauma and neglect for the mild and severe groups differed significantly. These findings indicate that further investigation of the validity of the model, which may be used to plan treatment, is useful. Patients experiencing a wide range of trauma-related disorders, dissociative disorders (DD), and personality disorders (PD), combined with a high level of psychiatric symptoms and a maladaptive style of personality functioning, report a range of traumatic experiences in combination with a lack of maternal care, and can be profiled as "severely impaired." (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Sorption and desorption of 17β-estradiol to natural sediment.
The sorption and desorption of 17β-estradiol (E2) to various natural sediment were investigated. First, the quantitative solvent-water partition indices were measured. Significant differences were found between the n-octanol-water partition coefficient (K(OW)) and the n-hexane-water partition coefficient (K(HW)) of E2. The value of K(HW) (Log K(HW) = 0.07) is lower than those of two to four ring polyaromatic hydrocarbons (PAHs), while the value of K(OW) (Log K(OW) = 3.99) and that of organic matter-water partition coefficient (K(OC)) onto humic acid (Log K(OC) = 4.30) were similar to those of the PAHs. Five natural sediments of various characteristics and origins were selected for sorption and desorption experiments. Linear isotherms were obtained for sorption and desorption. The equilibrium partitioning coefficients of E2 were well-correlated with their values of weight fraction of organic carbon in sediments (f(OC)). Results suggest that E2 is sorbed mainly onto the organic portion of sediments and that its sorption coefficient can be estimated from K(OW) and f(OC), as in the case of non-polar PAHs. However, because of its polarity, the sorption mechanism of E2 onto sediments cannot be explained solely by the hydrophobic interaction.


Organelle-cytoskeleton relationships in fibroblasts: mitochondria, Golgi apparatus, and endoplasmic reticulum in phases of movement and growth.
When fibroblasts first emerge from explants of embryonic chick heart, most mitochondria are clustered tightly around the nucleus, with very few extending towards the leading lamella. Although cytoplasmic microtubules are well displayed, mitochondria do not obviously codistribute with them. As the fibroblasts cease locomotion and adapt to growth, however, the mitochondria become dispersed through the cytoplasm and clearly codistributed with the microtubules and centrioles but not with microfilament bundles or 10 nm filaments. This rearrangement occurs in concert with the other changes we have shown previously - including the development of pronounced microfilament bundles and of stable and well-defined focal adhesions - and appears to be related to changes in the motility status of the cells rather than to alterations in growth or synthetic capability. Mitochondrial mobility is strongly reduced by the actions of both colchicine and dihydrocytochalasin B showing that orientation and translocation depend on a co-ordinate interaction of microtubules and microfilamentous meshwork around the centrioles as origin. The Golgi apparatus and endoplasmic reticulum do not rearrange dramatically during the phenotypic conversion, although the locomotory cells are characterized by a zone close to the leading lamella, which is completely free from these organelles. The form and distribution of the Golgi apparatus, but not the endoplasmic reticulum, was sensitive to microtubule disruption but was also shown to have direct functional associations with the centriolar region. The relative distributions of the three types of organelle during the phases of cell movements and cell growth, are consistent with their biochemical functions in cellular activity.


Metal Complexation Properties of Schiff Bases Containing 1,3,5-Triazine Derived from 2-Hydroxy-1-Naphthaldehyde in Solution. A Simple Spectrofluorimetric Method to Determine Mercury (II).
Four new Schiff base ligands carrying naphthalene groups were prepared from the reaction of 2,4-diamino-6-methyl-1,3,5-triazine and 2,4-diamino-6-undecyl-1,3,5-triazine with 2-hydroxy-1-naphthaldehyde. The influence of a series of metal ions including Cu2+, Co2+, Hg2+, Al3+, Cr3+, Fe3+, Pb2+, Ni2+, Cd2+, Zn2+, Mn2+, Ag+, Ba2+, Ca2+ and Mg2+ on the spectroscopic properties of the ligands was investigated by means of absorption and emission spectrometry. The results of spectrophotometric and spectrofluorimetric titrations disclosed the complexation stoichiometry and complex stability constant of the ligands with metal ions. A simple spectrofluorimetric method was developed using the Schiff base derived from 2,4-diamino-6-undecyl-1,3,5-triazine to determine Hg2+ ion. No cleanup or enrichment of the tap water sample was required. A modified standard addition method was used to eliminate matrix effect. The standard addition graph was linear between 0.2 and 2.6 mg/L in determination of Hg2+. Detection and quantification limits were 0.08 and 0.23 mg/L, respectively. The simple and cost-effective method can be applied to water samples.


Excretable IR-820 for in vivo NIR-II fluorescence cerebrovascular imaging and photothermal therapy of subcutaneous tumor.
Rationale: Cerebrovascular diseases, together with malignancies, still pose a huge threat to human health nowadays. With the advantages of its high spatial resolution and large penetration depth, fluorescence bioimaging in the second near-infrared spectral region (NIR-II, 900-1700 nm) and its related imaging-guided therapy based on biocompatible fluorescence dyes have become a promising theranostics method. Methods: The biocompatibility of IR-820 we used in NIR-II fluorescence bioimaging was verified by long-term observation. The model of the mouse with a cranial window, the mouse model of middle cerebral artery occlusion (MCAO) and a subcutaneous xenograft mouse model of bladder tumor were established. NIR-II fluorescence cerebrovascular functional imaging was carried out by IR-820 assisted NIR-II fluorescence microscopy. Bladder tumor was treated by NIR-II fluorescence imaging-guided photothermal therapy. Results: We have found that IR-820 has considerable NIR-II fluorescence intensity, and shows increased brightness in serum than in water. Herein, we achieved real time and in vivo cerebrovascular functional imaging of mice with high spatial resolution and large penetration depth, based on IR-820 assisted NIR-II fluorescence microscopy. In addition, IR-820 was successfully employed for NIR-II fluorescence imaging and photothermal therapy of tumor in vivo, and the subcutaneous tumors were inhibited obviously or eradicated completely. Conclusion: Due to the considerable fluorescence intensity in NIR-II spectral region and the good photothermal effect, biocompatible and excretable IR-820 holds great potentials for functional angiography and cancer theranostics in clinical practice.


Sonographic evaluation of experimental acute renal arterial occlusion in dogs.
Eleven segmental and eight total renal artery occlusions were evaluated by sonography in transplanted kidneys of 19 adult mongrel dogs. The segmental occlusions were serially scanned daily or every other day for up to 35 days. The total occlusions were scanned daily for up to 10 days. Each occlusion was confirmed angiographically, and kidneys were examined pathologically. Acute segmental renal artery occlusion produces a sequence of sonographic changes, beginning with a focal hypoechoic mass at 24 hr, which stays unchanged for 5-7 days. At 7 days, internal echoes appear, and the infarct slowly consolidates to an echogenic, slightly depressed focus at 17 days. Total renal artery occlusion produced no appreciable change in cortical echogenicity and only slight increase in size. Acute segmental renal infarction can be detected early in its course and demonstrates a sequence of changes that may aid in dating the infarct. Total renal infarction may appear normal sonographically, and further studies are needed to confirm that diagnosis.


Direct observation of coherent interorbital spin-exchange dynamics.
We report on the first direct observation of fast spin-exchange coherent oscillations between different long-lived electronic orbitals of ultracold 173Yb fermions. We measure, in a model-independent way, the strength of the exchange interaction driving this coherent process. This observation allows us to retrieve important information on the interorbital collisional properties of 173Yb atoms and paves the way to novel quantum simulations of paradigmatic models of two-orbital quantum magnetism.


Angiography for preoperative evaluation in patients with lower gastrointestinal bleeding: are the benefits worth the risks?
To evaluate the benefits and risks of selective angiography for the evaluation of acute lower gastrointestinal (GI) bleeding to identify the site of bleeding and theoretically limit the extent of colonic resection. Retrospective chart review. Tertiary care hospital. Sixty-five patients undergoing 75 selective angiograms for evaluation of acute lower GI bleeding. Mean age was 71 years (range, 27-93 years), and 37 (57%) were women. Demographic data were collected that included any associated medical problems, potential factors contributing to an increased risk for bleeding, and the diagnostic methods used in evaluating the source of lower GI bleeding. The details of angiography procedures were recorded with special attention to the impact of the procedure on clinical management and any associated complications. Twenty-three patients (35%) had positive angiography findings, and 14 of them (61%) required operations. Forty-two patients (65%) had negative angiography findings, and 8 of them (19%) required operations. Surgery for the 22 patients included hemicolectomy in 11 patients, subtotal colectomy in 10 patients, and small-bowel tumor resection in 1 patient. In 9 patients, a hemicolectomy was performed on the basis of angiography findings. Three patients (2 with negative angiography findings) experienced rebleeding after a hemicolectomy and required a subsequent subtotal colectomy. Overall, only 8 (12%) of the 65 patients underwent a segmental colon resection that was based on angiography findings and did not bleed after their operation. Complications from angiography occurred in 7 patients (11%). Selective angiography appears to add little clinically useful information in patients with acute lower GI bleeding and carries a relatively high complication risk.


Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: A Pediatric Oncology Group Study.
To prospectively study the value of adjuvant chemotherapy in pediatric patients with surgically resected nonrhabdomyosarcomatous soft tissue sarcomas (NRSTS). From June 1986 to May 1992, after complete surgical resection (+/-radiotherapy) of their NRSTS, 81 eligible patients either received adjuvant chemotherapy comprising vincristine, dactinomycin, cyclophosphamide, and doxorubicin or were observed. Only 30 patients accepted randomization, and 15 were assigned to each regimen. Of the remaining 51 patients, 19 elected adjuvant chemotherapy and 32 elected observation. Patients were predominantly male, and 69% of all patients were white. The median age at diagnosis was 12.3 years (range, 9.2 to 20.7 years). For the 81 eligible patients, the 5-year overall survival estimate was 84.5% +/- 4.4% and event-free survival was 72.2% +/- 5.4%. Among randomized patients, the 5-year estimated overall survival rate was 93.3% +/- 7%, and the event-free survival rate was 86.7% +/- 9.5% for the observation group, compared with 69.2% +/- 13% and 40.7% +/- 14%, respectively, for those who received chemotherapy. The significantly worse outcome of patients who received adjuvant chemotherapy disappeared when survival was stratified by tumor grade. Among all patients, a grade 3 lesion conferred a significant disadvantage with respect to event-free survival (P =.0001). The administration of adjuvant chemotherapy according to the schedule and dosages used in our trial did not improve the outcome of children with resected NRSTS. In this study, tumor grade was the most important predictor of clinical outcome in patients with resected NRSTS, and this factor should be incorporated into the stratification of patients in future trials.


Characterization of gastric myoelectrical rhythms in patients with systemic sclerosis using multichannel surface electrogastrography.
The aim of this study was to characterize multichannel surface electrogastrography (EGG) recordings in patients with systemic sclerosis (scleroderma, SSc) compared to normal controls. Ten SSc patients and 13 healthy age-matched controls were enrolled in this study. Gastric myoelectrical activity was recorded using a four-channel electrogastrograph with abdominal surface electrodes. The EGG was recorded in the morning for 1 hr in the fasting state, and 1 hr after a standardized (500 kcal) test meal. It was found that: (1) The regularity of the gastric slow wave was significantly lower in the SSc patients when compared with the normal controls in both fasting and fed states. (2) There was a significantly higher incidence of bradygastria in the SSc patients. (3) The SSc patients showed a significantly lower percentage of slow wave coupling among the four-channel EGGs than the controls. (4) In comparison with the controls, the patients showed an impaired spatial distribution of gastric slow wave power in both fasting and fed states and an impaired spatial distribution of slow wave frequency in the fasting state. It was concluded that SSc patients have an abnormal gastric slow wave as shown in the multichannel EGG as a decreased percentage of normal slow waves and impaired spatial coordination of gastric slow waves. The multichannel EGG may serve as a simple, noninvasive, and cost-effective method to assess gastric motility disorders and their relevance in patients with SSc.


Role of Sirtuins in Modulating Neurodegeneration of the Enteric Nervous System and Central Nervous System.
Neurodegeneration of the central and enteric nervous systems is a common feature of aging and aging-related diseases, and is accelerated in individuals with metabolic dysfunction including obesity and diabetes. The molecular mechanisms of neurodegeneration in both the CNS and ENS are overlapping. Sirtuins are an important family of histone deacetylases that are important for genome stability, cellular response to stress, and nutrient and hormone sensing. They are activated by calorie restriction (CR) and by the coenzyme, nicotinamide adenine dinucleotide (NAD+). Sirtuins, specifically the nuclear SIRT1 and mitochondrial SIRT3, have been shown to have predominantly neuroprotective roles in the CNS while the cytoplasmic sirtuin, SIRT2 is largely associated with neurodegeneration. A systematic study of sirtuins in the ENS and their effect on enteric neuronal growth and survival has not been conducted. Recent studies, however, also link sirtuins with important hormones such as leptin, ghrelin, melatonin, and serotonin which influence many important processes including satiety, mood, circadian rhythm, and gut homeostasis. In this review, we address emerging roles of sirtuins in modulating the metabolic challenges from aging, obesity, and diabetes that lead to neurodegeneration in the ENS and CNS. We also highlight a novel role for sirtuins along the microbiota-gut-brain axis in modulating neurodegeneration.


[Toxigenicity conversion by pertussis phages in Bordetella parapertussis].
For the first time toxigenicity conversion in B. parapertussis induced by B. pertussis phages was discovered. The clones of B. parapertussis recipient strain No. 17903 used in this study were subjected to lysogenization with 4 B. pertussis phages; as a result, 95% of these clones became immune to the repeated phage infection, developed spontaneous phage production and showed toxic properties (lethal toxicity due to the action of thermolabile and thermostable toxins) characteristic of the donor strains from which B. pertussis phages had been obtained. Differences in the degree of toxicity shown by the converted strains were determined by means of the spleen index. The convertants thus obtained did not possess protective potency.


Plasma urocortin levels in the diagnosis of ovarian endometriosis.
Urocortin is a neuropeptide, member of the corticotropin-releasing hormone family, that is produced by the human endometrium. Ovarian endometrioma is a prevalent gynecologic disorder still lacking specific serum markers. In the present study we measured systemic levels of urocortin to assess the diagnostic performance of its determination in distinguishing endometriomas from other benign ovarian cysts. Plasma urocortin was measured by radioimmunoassay in women with ovarian endometrioma (n=40) and in women with benign, nonendometriotic ovarian cysts (n=40). The diagnostic accuracy of urocortin measurement was evaluated by receiver operating characteristic curve and compared with the standard marker, CA 125. To support the local origin of the peptide, we also evaluated its localization in endometriomas by immunohistochemistry and its concentrations in cyst fluid and peritoneal fluid of 12 women with endometrioma. Plasma urocortin levels were twice as high in women with endometrioma (median 49 pg/mL, interquartile range 41-63 pg/mL) than in the control group (19 [15-23] pg/mL, P<.001) and significantly higher in the cystic content of endometriomas than in the peritoneal fluid and plasma (P<.05). The peptide was immunolocalized in endometrioma glands and stromal capillary vessels. Elevated plasma urocortin levels detected 88% of the cases of endometrioma with 90% specificity, whereas CA 125 detected only 65% of the cases with the same specificity. Plasma urocortin is increased in women with endometriomas, and its measurement may be useful for the differential diagnosis of endometrioma compared with other benign ovarian cysts. II.


Variation among hospitals in coronary-angiography practices and outcomes after myocardial infarction in a large health maintenance organization.
Wide geographic variation in the use of coronary angiography after myocardial infarction has been documented internationally and within the United States. An associated variation in clinical outcomes has not been consistently demonstrated. We assessed the risk of death from heart disease and of any heart disease event (death, reinfarction, or rehospitalization) over a follow-up period of one to four years in 6851 patients hospitalized with acute myocardial infarction at 16 Kaiser Permanente hospitals from 1990 through 1992. The percentage of patients who underwent angiography within three months after infarction ranged from 30 to 77 percent. We selected a subcohort of 1109 patients from three hospitals with higher rates of angiography and four with lower rates for a record review to assess the severity of infarction, the number of coexisting conditions, treatments received, and the appropriateness and necessity of angiography, using established criteria. The rates of angiography were inversely related to the risk of death from heart disease (P= 0.03) and the risk of heart disease events (P<0.001) among the 16 hospitals after adjustment for age, sex, race, coexisting conditions, and the location of the infarction (subendocardial vs. transmural). In the subcohort, 440 patients met criteria indicating that angiography was necessary and 669 did not. Among the former, patients treated at hospitals with higher rates of angiography had a lower risk of death and of any heart disease event than those treated at hospitals with lower rates (hazard ratios, 0.67 and 0.72, respectively). Among the latter, the apparent benefits of being treated at hospitals with higher angiography rates were smaller (hazard ratios, 0.85 to 0.90 for death and any heart disease event, respectively). During the one to four years after myocardial infarction, patients treated at hospitals with higher rates of angiography had more favorable outcomes than those treated at hospitals with lower rates. This association was stronger among patients for whom published criteria indicated that angiography was necessary.


Intimate partner violence and its implication for pregnancy.
Intimate partner violence (IPV) is a common occurrence in pregnancy and results in an increased risk of adverse outcomes. Homicide may be the most common cause of maternal death. Women who are pregnant and the victims of IPV have high rates of stress, are more likely to smoke or use other drugs, deliver a preterm or low birth weight infant, have an increase in infectious complications, and are less likely to obtain prenatal care. The IPV continues in the postpartum period. Adolescents may be at even higher risk than their adult counterparts. Children raised in violent homes have both immediate and life long adverse health outcomes as a result of their exposure to IPV. IPV adds substantially to healthcare costs both for direct services to treat the injuries and higher utilization of a wide range of healthcare services. Healthcare providers, particularly those who care for pregnant women, are in a unique position to identify these women and direct them and their families to the help they need to end the violence in their lives.


Sentinel node procedures in gynecologic cancers: an overview.
The aim of this study was to assess the value of sentinel lymph node procedures in gynecologic cancers. A systematic literature overview, using the PubMed database, was performed. In early stage vulvar, endometrial and cervical cancer, lymph node status is the most important prognostic factor. Lymphadenectomy, performed for adequate staging, is associated with high morbidity rates. Sentinel node procedures hold the promise of adequate staging with less treatment-related morbidity. Sentinel lymph node procedures in patients with early-stage vulvar cancer are associated with low recurrence rates, excellent survival, lower morbidity and shorter hospital stay compared to classical inguinal dissection. Therefore, these procedures should be the standard of care in early-stage unilateral vulvar cancer. Reports on sentinel lymph node procedures in endometrial and cervical cancer are ambiguous. The procedures in these cancers are reported in small studies only. Detection rates vary depending on the used injection sites and the used tracers. Bilateral detection rates are low and are not mentioned by default. Large controlled multi-institutional studies are necessary to evaluate the validity and the prognostic significance of the sentinel lymph node procedures in endometrial and cervical cancer.


A mixture modeling framework for differential analysis of high-throughput data.
The inventions of microarray and next generation sequencing technologies have revolutionized research in genomics; platforms have led to massive amount of data in gene expression, methylation, and protein-DNA interactions. A common theme among a number of biological problems using high-throughput technologies is differential analysis. Despite the common theme, different data types have their own unique features, creating a "moving target" scenario. As such, methods specifically designed for one data type may not lead to satisfactory results when applied to another data type. To meet this challenge so that not only currently existing data types but also data from future problems, platforms, or experiments can be analyzed, we propose a mixture modeling framework that is flexible enough to automatically adapt to any moving target. More specifically, the approach considers several classes of mixture models and essentially provides a model-based procedure whose model is adaptive to the particular data being analyzed. We demonstrate the utility of the methodology by applying it to three types of real data: gene expression, methylation, and ChIP-seq. We also carried out simulations to gauge the performance and showed that the approach can be more efficient than any individual model without inflating type I error.


Comparative Evaluation of Artifacts Originated by Four Different Post Materials Using Different CBCT Settings.
The aim of this study was to evaluate whether cone beam computed tomography (CBCT) images in the presence of four different post materials, obtained from different kVps with varying resolutions and varying metal artifact reduction (MAR) algorithms, differed in artifact estimation, and to compare tooth regions in terms of artifact value. Forty premolar teeth were used in this study. Root canals were treated, and teeth were randomly distributed into four subgroups (n = 10) for the preparation of post materials: titanium, gold (Nordin), quartz fiber (Bisco DT Light), and glass fiber (Rely X). The CBCT images were taken with two different kVps, three different metal artifact reduction (MAR) algorithm options, and two different resolutions. For each protocol, the effective dose was calculated according to the dose area production (DAP) value. The standard analysis of variance technique and the Tukey multiple comparison adjustment method were used to assess interactions among material types, kVp, MAR, and voxel settings. More artifacts were found in the middle third than in the cervical third (p < 0.05). The mean value of artifacts was highest for gold (Nordin), 90 kVp, no MAR, and 100 voxel size. Glass or quartz fiber posts at low resolution, with high MAR and 96 kVp, originated fewer artifacts. Moreover, the use of 90 and 96 kVp with 200 voxel size and high MAR provided the least amount of radiation. The best setting for radiographic follow-up of post materials on the Planmeca ProMax is 96 kVp with low resolution and high MAR; this setting produced one of the lowest effective doses. This study estimated the best scanning protocol by lowering the effective dose to a minimum level according to the "as low as reasonably achievable" principle, as well as assessing the tooth region and the post material generating the fewest artifacts, in order to prevent image interpretation challenges such as false-positive and false-negative results stemming from the deterioration of the visibility of the root canal due to perforation, fractures, and voids in the root canal region.


[Regulatory mechanisms of oxygen transport function of hemoglobin in irradiated animals].
The oxygen affinity of hemoglobin of both common and 2,3-diphosphoglycerate concentration-purified erythrocyte hemolysates, hemoglobin stability, 2,3-diphosphoglycerate concentration in erythrocytes, morphological blood content were studied in rabbits irradiated with X-rays in a dose of 0.155 C/kg. An increase in the oxygen affinity of common hemolysate hemoglobin at a higher 2,3-diphosphoglycerate concentration on the 1st, 4th day after irradiation and a decrease in the oxygen affinity of both common and purified hemolysate hemoglobin on the 18th-30th day after irradiation were observed. A conclusion is made that disturbance of the hemoglobin function control by 2,3-diphosphoglycerate in irradiated animals is determined by alteration of protein physicochemical properties.


Blimp-1 induced by IL-4 plays a critical role in suppressing IL-2 production in activated CD4 T cells.
Although an inhibitory function of IL-4 in CD4 T cell IL-2 production has long been recognized, a mechanism mediating the inhibition remains unclear. In this study we demonstrate that IL-4 displays a potent suppressive function in IL-2 production of activated CD4 T cells through STAT6. IL-4-induced IL-2 suppression required IL-2 because IL-2 neutralization restored the production of IL-2 even in the presence of IL-4. In vivo, enhanced IL-2 production was found in nematode-infected IL-4- or STAT6-deficient animals, whereas immunization in the presence of IL-4 substantially diminished IL-2 production by Ag-specific CD4 T cells. IL-2 mRNA expression was reduced when T cells were stimulated in the presence of IL-4, whereas IL-2 mRNA decay was unaltered, suggesting that IL-4 mediates the suppression at a transcriptional level. Blimp-1 induced by IL-4 stimulation in activated CD4 T cells was found to be necessary to mediate the IL-2 inhibition as IL-4-mediated IL-2 suppression was less pronounced in activated CD4 T cells deficient in Blimp-1. Taken together, our results demonstrate a potential link with IL-4, Blimp-1, and IL-2 production, suggesting that Blimp-1 may play an important role in controlling IL-2 production in activated T cells and in adaptive T cell immunity.


Proton MR spectroscopy of delayed cerebral radiation in monkeys and humans after brachytherapy.
To determine whether radiation necrosis can be differentiated from residual/recurrent tumor by proton MR spectroscopy. We studied the effects of interstitial brachytherapy on the brains of healthy monkeys and in humans with glioblastoma multiforme. The effects of radiation therapy on normal brain tissue in monkeys were assessed with sequential proton MR spectroscopic studies 1 week to 6 months after brachytherapy. Proton MR spectroscopy was also performed in five patients with residual/recurrent glioblastoma multiforme (three of whom had radiation necrosis after brachytherapy), seven patients with newly diagnosed untreated glioblastoma multiforme, and 16 healthy volunteers, who served as a control group. In monkeys, the ratio of N-acetylaspartate (NAA) to creatine-phosphocreatine (Cr) and the ratio of choline-containing compounds (Cho) to Cr of the reference point were significantly lower 1 week after brachytherapy than before treatment. The ratio of NAA to Cho of the irradiated area tended to be higher 1 week after brachytherapy than before irradiation. These peak metabolic ratios showed characteristic changes 6 months after treatment. In two of three monkeys, lipid signal was elevated 6 months after irradiation. In the clinical study, the ratio of NAA to Cho in the area of radiation necrosis was significantly different from that in glioblastoma multiforme when compared with the contralateral hemisphere after irradiation. In addition, lipid signal was detected in all patients with radiation necrosis. It might be possible to use proton MR spectroscopy to differentiate radiation necrosis from residual/recurrent glioblastoma multiforme on the basis of comparisons with the contralateral hemisphere after radiation therapy.


Lin28b regulates age-dependent differences in murine platelet function.
Platelets are essential for hemostasis; however, several studies have identified age-dependent differences in platelet function. To better understand the origins of fetal platelet function, we have evaluated the contribution of the fetal-specific RNA binding protein Lin28b in the megakaryocyte/platelet lineage. Because activated fetal platelets have very low levels of P-selectin, we hypothesized that the expression of platelet P-selectin is part of a fetal-specific hematopoietic program conferred by Lin28b. Using the mouse as a model, we find that activated fetal platelets have low levels of P-selectin and do not readily associate with granulocytes in vitro and in vivo, relative to adult controls. Transcriptional analysis revealed high levels of Lin28b and Hmga2 in fetal, but not adult, megakaryocytes. Overexpression of LIN28B in adult mice significantly reduces the expression of P-selectin in platelets, and therefore identifies Lin28b as a negative regulator of P-selectin expression. Transplantation of fetal hematopoietic progenitors resulted in the production of platelets with low levels of P-selectin, suggesting that the developmental regulation of P-selectin is intrinsic and independent of differences between fetal and adult microenvironments. Last, we observe that the upregulation of P-selectin expression occurs postnatally, and the temporal kinetics of this upregulation are recapitulated by transplantation of fetal hematopoietic stem and progenitor cells into adult recipients. Taken together, these studies identify Lin28b as a new intrinsic regulator of fetal platelet function.


Association of thyroid disease and risk of fatty liver disease: an exposure-wide Mendelian randomization study.
Previous studies have often observed a possible association between thyroid and fatty liver diseases. The pathogenesis of both diseases is complex, with many confounding factors and controversies. We used a two-sample Mendelian randomization (MR) analysis to test the causality between thyroid disease and the risk of developing fatty liver disease. All data were obtained from the genome-wide association studies (GWAS) Catalog database. Thyroid disorders include hypothyroidism, hyperthyroidism, autoimmune thyroiditis, and Hashimoto's thyroiditis. Fatty liver diseases include alcoholic fatty liver disease and non-alcoholic fatty liver disease (NAFLD). The inverse variance weighting (IVW) method was used for MR analysis, and sensitivity analysis was further performed to test its robustness. We discovered no causal relationship between thyroid disease and alcoholic fatty liver disease after excluding weak instrumental variables (IVs). Hyperthyroidism and hypothyroidism had a significant causal relationship with NAFLD. Hypothyroidism increased the risk of NAFLD using the IVW method (OR=7.62, 95% CI: 2.61-22.25, p<0.001). MR-Egger regression did not suggest potential evidence of directional pleiotropy (intercept, p=0.698). Hyperthyroidism also significantly increased the risk of NAFLD (OR=11.83, 95% CI: 2.9-22.54, p=0.026). MR-Egger regression did not suggest any potential directional pleiotropy (intercept, p=0.295). Hypothyroidism can significantly increase NAFLD incidence, and hyperthyroidism may be a risk factor for NAFLD.


Pharmacology of human trace amine-associated receptors: Therapeutic opportunities and challenges.
The discovery in 2001 of a G protein-coupled receptor family, subsequently termed trace amine-associated receptors (TAAR), triggered a resurgence of interest in so-called trace amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopaminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.


Depression in multiple sclerosis patients.
Multiple sclerosis (MS) manifests also with the symptoms of affective disorders. Depression is the most common mental disorder among patients with MS and it has negative impact on their working ability, social relations and quality of life. The aim of this study is to investigate gender, age, marital status, education level and employment related to patients with depressive symptoms in population of MS, treated at the Department of Neurology, Clinical Center University of Sarajevo. In the study it was analyzed 50 randomly selected patients with various types of multiple sclerosis. Severity of depression was evaluated using the Beck Depression Inventory (BDI). The study included 33 female and 17 male patients aged 21 to 60 years. In the sample of MS patients there were 56% with depressive disorder. There is no statistically significant difference between patients gender. Depression is more frequent among younger and middle age patients, while all the patients older than 51 years are in a normal mood (total 31.9%). Significantly higher percentage of non-depressive patients (72.2%) are married, while depression is present among all divorced patients (10.7%), majority of single (35.8%) and widowers (21.4%). Taking into consideration level of education, there is a statistically significant difference as follows: depression is more frequent among patients who graduated university (46.4%) and secondary school (50%) compared to ones who finished only primary school (3.6%). There is significantly higher number of unemployed and retired patients with depressive symptoms (75%) in comparison to the employed ones. Depression occurs more frequently among MS patients who are younger, unemployed, highly educated and without spouse. There is no statistically significant difference between male and female patients.


ADAM-10 message is expressed in human articular cartilage.
The depletion of the pericellular and territorial matrices in articular cartilage is considered to be one of the earliest events in pathobiology of osteoarthritis (OA). A newly discovered family of proteins with a disintegrin-like and metalloproteinase-like domain (ADAM) may be involved in matrix degradation as well as in cell-cell and cell-matrix interactions. The purpose of this study was to determine by in situ hybridization whether human articular chondrocytes from newborn, normal adult, and OA cartilages express messenger RNA for ADAM-10, one of the members of this family, and by semiquantitative RT-PCR to compare the levels of this expression. The results confirmed the expression of ADAM-10 by human articular chondrocytes and revealed the highest levels of expression in the continuously remodeling cartilage of newborns and the most fibrillated areas of OA cartilage, especially the regions of cell clusters. Importantly, ADAM-10 mRNA expression was evident in tissues with the greatest loss of Safranin O staining from the territorial and interterritorial matrix of the chondrocytes. Messenger RNA was upregulated in OA tissue compared to the age-matched normal cartilage, as detected by RT-PCR. Upregulated levels of ADAM-10 mRNA expression appear to be related to the degree of cartilage damage and/or degradation, which suggests a potential role for at least one member of this new family in the cartilage matrix destruction accompanying OA.


Pulsed radiofrequency of the sural nerve for the treatment of chronic ankle pain.
The application of radiofrequency (RF) has been successfully used in the treatment of chronic pain conditions, including facet arthropathy, sacroiliac joint pain, groin pain, radicular pain, cervicogenic headaches, and phantom limb pain. Due to the neurodestructive effect of continuous RF ablation and possible deafferentation sequelae, only pulsed radiofrequency (PRF) has been applied to peripheral sensory nerves. There are no previous reports of successful PRF application to the sural nerve. To report on the successful use of PRF to the sural nerve for the treatment of ankle pain. To discuss current theories on the mechanism by which PRF produces pain relief. The report presented here describes the case of a 39-year old patient who sustained injury to her ankle. The patient was complaining of pain in the distribution of the sural nerve, which was confirmed by electrodiagnostic studies. The pain did not respond to oral and topical analgesics. The patient had short-term relief with a sural block with bupivacaine and triamcinolone. The patient then underwent PRF application to the right sural nerve for 240 seconds at 45 volts. The patient reported complete relief. There was no pain recurrence 5 months after the procedure. This report describes a single case report. It is conceivable that PRF may provide long-term pain relief in cases of sural nerve injury. The exact mechanism of the antinociceptive effect is still unknown. Possible mechanisms include changes in molecular structure by the electric field, early gene expression, stimulation of descending inhibitory pathways, and transient inhibition of excitatory transmission.


DNA interactions during bacteriophage lambda site-specific recombination.
Extensive research on site-specific recombination has provided many details, particularly with respect to the protein-DNA interactions. However, very little is known about the molecular mechanism of recombination during synapsis and strand exchange. Presumably, these steps of recombination involve various forms of DNA-DNA, DNA-protein, and protein-protein interactions. One stage at which DNA-DNA interactions may be occurring is at the level of synapsis where the recombining DNAs are juxtaposed. In this paper we have presented evidence that homology-dependent DNA interactions do occur within the overlap region before strand exchange. This interaction is presumably at the synaptic stage of recombination. Furthermore, we have demonstrated that the homology-dependent interactions require that only one strand of attB have homology to attP. Another stage in recombination at which DNA-DNA interactions could occur is during strand exchange where complementary strands from the recombining parents are paired and resealed. We have also presented evidence that homology-dependent DNA interactions occur during strand exchange prior to the resealing of the strands and that disruption of this interaction results in nonreciprocal recombination. Taken together, these results suggest that DNA-DNA interactions during reciprocal site-specific recombination occur during at least two stages in the reaction.


Congenital dyserythropoietic anemia type II: exclusion of seven candidate genes.
Congenital dyserythropoietic anemias (CDA) are genetic disorders characterized by anemia and ineffective erythropoiesis. Three main types of CDA have been distinguished: CDA I, CDAII and CDA III, whose loci have been already mapped. After the identification of the locus for CDA II, also known as HEMPAS (hereditary erythroblast multinuclearity with positive acidified serum test), on the long arm of chromosome 20 (20q11.2) we have analyzed by a mutational search seven candidate genes in a large series of CDA II patients. In particular, the following genes have been investigated: integrin beta 4 binding protein, ribophorin II, ubiquitin protein ligase ITCH, mannosil-oligosaccharide alpha-1,2-mannosidase like protein, erythrocyte protein band 4.1 like protein, zinc finger protein PLAGL2, and finally novel zinc finger protein. None of them resulted as the causative gene but several protein variants and DNA polymorphisms have been identified. These data exclude the role of the above mentioned genes in causing CDA II and add further information in the process of cloning the CDA II gene.


Triage of Patients in the Child and Adolescent Psychiatry Outpatient Clinic.
The aim of this study was to evaluate and describe the three-stage triage method used in a child and adolescent psychiatry outpatient clinic. The study investigated the new allocation process of 1482 children and adolescents who were assessed using this triage system for the duration of one year, in the year 2005. Data of 1423 children and adolescents who presented in 2003 regarding the waiting time for the first appointment and the rate of nonattendance at the first appointment were used for the comparison. In triage system, new patients presenting to the outpatient clinic in the morning four days a week were assessed by a three-stage procedure: An initial Strengths and Difficulties Questionnaire screening and a structured interview administered by an intern was then followed by a clinical interview. Of the 1482 children and adolescents who presented to the outpatient clinic during the study period, 1291 were given further appointments. Among patients who presented in 2005, the 207 non-attendant patients were significantly more likely to have longer waiting times than the 1084 attendant patients. When compared to year 2003, it was found that there was a significant decrease in the median waiting time for the first appointment and the rate of nonattendance at the first appointment among patients who presented in 2005. The triage procedure used in this study may constitute a model for developing countries with limited health care resources.


Massive hepatic necrosis after chemotherapy withdrawal in a hepatitis B virus carrier.
A chronic hepatitis B virus (HBV) carrier with diffuse nodular transformation of the liver and malignant lymphoma in the lymph nodes and spleen developed massive hepatic necrosis and died three weeks after the third cycle of chemotherapy. Immunosuppressive drug treatment may favor replication of HBV, resulting in massive hepatocyte destruction when the immune response recovers following withdrawal of chemotherapy. This outcome must be considered in patients with chronic hepatitis B who are treated with a course of prednisone followed by antiviral therapy as well as in HBV carriers following chemotherapy for malignant disease.