Dilated cardiomyopathy secondary to hypothyroidism: case report with a review of literatures.
To date, it has been well documented that there is a relationship between alterations in thyroid hormones and cardiac dysfunction. We experienced a case of a 36-year-old man with dilated cardiomyopathy (DCM) accompanied by undiagnosed primary hypothyroidism. In the current case, there was a significant improvement in the cardiac function following heart failure management and thyroid hormone replacement. Our case highlights that clinicians should consider the possibility of hypothyroidism as a cause of DCM.


Peroxisomal alanine : glyoxylate aminotransferase (AGT1) is a photorespiratory enzyme with multiple substrates in Arabidopsis thaliana.
At least two glyoxylate aminotransferases are hypothesized to participate in the steps of photorespiration located in peroxisomes. Until recently, however, genes encoding these enzymes had not been identified. We describe the isolation and characterization of an alanine : glyoxylate aminotransferase (AGT1, formerly AGT) cDNA from Arabidopsis thaliana. Southern blot analysis confirmed that Arabidopsis AGT1 is encoded by a single gene. Homologs of this class IV aminotransferase are also known in other plants, animals, and methylotrophic bacteria, suggesting an ancient evolutionary origin of this enzyme. AGT1 transcripts were present in all tissues of Arabidopsis, but were most abundant in green, leafy tissues. Purified, recombinant Arabidopsis AGT1 expressed in Escherichia coli catalyzed three transamination reactions using the following amino donor : acceptor combinations: alanine : glyoxylate, serine : glyoxylate, and serine : pyruvate. AGT1 had the highest specific activity with the serine : glyoxylate transamination, and apparent Km measurements indicate that this is the preferred in vivo reaction. In vitro import experiments and subcellular fractionations localized AGT1 to peroxisomes. Sequence analysis of the photorespiratory sat mutants revealed a single nucleotide substitution in the AGT1 gene from these plants. This transition mutation is predicted to result in a proline-to-leucine substitution at residue 251 of AGT1. When this mutation was engineered into the recombinant AGT1 protein, enzymatic activity using all three donor : acceptor pairs was abolished. We conclude that Arabidopsis AGT1 is a peroxisomal photorespiratory enzyme that catalyzes transamination reactions with multiple substrates.


Making regulatory T cells with defined antigen specificity: role in autoimmunity and cancer.
There is increasing evidence that agonist ligand presentation either intrathymically or extrathymically plays a crucial if not essential role in the generation of regulatory T cells (Tregs). Thus, it is possible to induce Tregs of any desired specificity in vivo. The same goal can be achieved in vitro by expanding antigen-specific CD4+ T cells and retrovirally transducing them. In contrast, in vitro expansion of Tregs is limited to antigens that have resulted in Treg generation in vivo. Antigen-specific Tregs can be used in cellular therapy with the goal to prevent autoimmune disease or even to interfere with established autoimmunity. The latter requires that the Tregs can suppress effector cells that have already caused harm, which is possible because of the antigen-dependent homing properties of Tregs, i.e. these cells can accumulate in antigen-draining lymph nodes and exit into inflamed tissue. Generally, the in vivo interference is dependent on cytokines such as transforming growth factor-beta and interleukin-10 that were dispensable in in vivo analysis of immunosuppression. The precise mechanisms of suppression remain enigmatic, however, but may be further elucidated by the molecular analysis of suppressed versus non-suppressed T cells.


Pulmonary circulation and burns and trauma.
The lung is a critical organ in victims of thermal injury or multiple trauma since the blood that drains injured organs circulates through the pulmonary circulation before passing through any other organ. The lung therefore will receive the first volley of cytotoxins released postinjury. In addition to being a target of injury, the lung may also contribute to the injury of systemic organs. This injury may be the result of a reduced delivery of oxygenated blood or the direct release of cytotoxins into the systemic circulation. The injury to the lung may be to the pulmonary microvasculature or the airway. The bronchial circulation responds to injury by a marked elevation in its blood flow and microvascular permeability. These latter effects may be important in mediating the changes which occur in the lung parenchyma.


A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial of four doses of tasosartan in patients with essential hypertension. Tasosartan Investigator's Group.
Tasosartan, a new, long-acting, nonpeptide angiotensin II receptor antagonist was evaluated in a randomized, double-blind, placebo-controlled, multicenter trial at 21 sites in the United States and Canada. After a 2-week, placebo washout qualification period, 278 patients (187 men/91 women) with a mean age of 53.4+/-9.5 years (range, 30 to 70 years) and a baseline sitting diastolic blood pressure (DBP) of 95 to 114 mm Hg were randomly assigned to receive placebo (n = 56), or 10 mg (n = 57), 30 mg (n = 55), 100 mg (n = 55), or 300 mg (n = 55) tasosartan for 4 weeks. The treatment period was followed by a 2-week washout period. Ambulatory blood pressure (BP) monitoring was performed at the end of the placebo washout period and after at least 4 weeks of double-blind treatment. Clinically significant placebo-adjusted differences in baseline sitting systolic blood pressure (SBP)/DBP were observed in the 10 mg (5/3 mm Hg), 30 mg (5/4 mm Hg), 100 mg (10/7 mm Hg) and 300 mg (10/7 mm Hg) dose groups (P < .05). A dose-response relationship (P < .001) was observed within 1 to 2 weeks of treatment initiation and was maintained throughout the double-blind period. Discontinuation of tasosartan therapy was not associated with rebound hypertension. Moreover, significant (P < .05) placebo-adjusted differences in ambulatory SBP/DBP and a significant dose-response relationship (P < .001) were observed with all tasosartan dosages during the 24-h, daytime, and nighttime periods. Placebo-adjusted trough-to-peak ratios ranged from 87% to 100% for ambulatory SBP and 64% to 81% for DBP. In general, no significant differences were observed between the tasosartan treatment groups and the placebo group in the incidence of adverse events. Headache incidence was significantly lower in the 300 mg dose group than the placebo group. In conclusion, tasosartan at dosages of 10, 30, 100, or 300 mg given once daily produced a significant and dose-related reduction in both clinic and ambulatory BP that was maintained over the 24-h period. Tasosartan was generally well tolerated.


Economic evaluation of different routes of surgery for the management of endometrial cancer: a retrospective cohort study.
The benefits of minimally invasive surgery (MIS) for endometrial carcinoma (EC) are well established although the financial impact of robotic-assisted hysterectomy (RH) compared with laparoscopic hysterectomy (LH) is disputed. Retrospective cohort study. English National Health Service hospitals 2011-2017/2018. 35 304 women having a hysterectomy for EC identified from Hospital Episode Statistics. The primary outcome was the association between route of surgery on cost at intervention, 30, 90 and 365 days for women undergoing an open hysterectomy (OH) or MIS (LH/RH) for EC in England. The average marginal effect was calculated to compare RH versus OH and RH versus LH which adjusted for any differences in the characteristics of the surgical approaches. Secondary outcomes were to analyse costing data for each surgical approach by age, Charlson Comorbidity Index (CCI) and hospital MIS rate classification. A total of 35 304 procedures were performed, 20 405 (57.8%) were MIS (LH: 18 604 and RH: 1801), 14 291 (40.5%) OH. Mean cost for LH was significantly less than RH, whereas RH was significantly less than OH at intervention, 30, 90 and 365 days (p<0.001). Over time, patients who underwent RH had increasing CCI scores and by the 2015/2016 year had a higher average CCI than LH. Comparing the cost of LH and RH against CCI score identified that the costs closely reflected the patients' CCI. Increasing disparity was also seen between the MIS and OH costs with rising age. When exploring the association between provider volume, MIS rate and surgical costs, there was an association with the higher the MIS rate the lower the average cost. Further research is needed to investigate costs in matched patient cohorts to determine the optimum surgical modality in different populations.


Frequency of preoperative anxiety in Pakistani surgical patients.
To measure the frequency of preoperative anxiety in patients coming to our hospital and to correlate Visual analogue scale (VAS) with State Trait Anxiety Inventory (STAI) questionnaire. This cross sectional study included 300 ASA I and II adult surgical in-patients admitted over a period of one year. STAI questionnaire and VAS was used as study tools. STAI score of > 44 or VAS score of > or = 50 were considered as significant anxiety. Enrolled patients were visited by primary investigator the day before surgery and patients were asked to fill the STAI questionnaire and VAS score. Significant preoperative anxiety was seen in 62% patients (73% females and 42% males). Frequency of anxiety decreased with advancing age but increased with higher educational status. A total of 77% of patients with no previous exposure to surgery and 26% of patients who had previous surgery, were anxious. Also 49% of patients who had visited the clinic and 86% of patients who had not visited the clinic were anxious. VAS correlated with STAI in 90% cases. Cut off value of VAS which showed positive correlation with STAI was 45. Frequency of preoperative anxiety was 62%. Female gender, younger age and higher educational status were positively correlated while prior experience of surgery while preoperative anaesthesia clinic visit were negatively correlated with anxiety. VAS correlated well with STAI.


[Histiocytic sarcoma of the stomach].
The paper describes a case of gastric histiocytic sarcoma in a 70 year-old man, which was diagnosed from immunohistochemical examination of biopsy and surgical specimens. It gives the data available in the literature on the morphological features of this rare cancer and its diagnostic criteria.


Photocatalytic Performance Evaluation of Titanium Dioxide Nanotube-Reinforced Cement Paste.
Considering the increase in research regarding environmental pollution reduction, the utilization of cementitious material, a commonly used construction material, in photocatalysts has become a desirable research field for the widespread application of photocatalytic degradation technology. Nano-reinforcement technology for cementitious materials has been extensively researched and developed. In this work, as a new and promising reinforcing agent for cementitious materials, the photocatalytic performance of titanium dioxide nanotube (TNT) was investigated. The degradation of methylene blue was used to evaluate the photocatalytic performance of the TNT-reinforced cement paste. In addition, cement paste containing micro-TiO2 (m-TiO2) and nano-TiO2 (n-TiO2) particles were used for comparison. Moreover, the effect of these TiO2-based photocatalytic materials on the cement hydration products was monitored via X-ray diffraction (XRD) and thermogravimetric analysis (TG). The results indicated that all the TiO2 based materials promoted the formation of hydration products. After 28 days of curing, the TNT-reinforced cement paste contained the maximum amount of hydration products (Ca(OH)2). Furthermore, the cement paste containing TNT exhibited better photocatalytic effects than that containing n-TiO2, but worse than that containing m-TiO2.


Risk factors for perioperative complications in hand-assisted laparoscopic donor nephrectomy.
Living donor kidney transplant is the preferred treatment for end-stage renal disease; however, the shortage of kidney donors remains a big problem. One of the major reasons for the shortage of living donors is the risk of potentially serious surgical complications of a procedure in which the donor has no personal medical benefit. Therefore it is important to understand the risk factors for perioperative complications associated with donor nephrectomy. Hand-assisted laparoscopic donor nephrectomy is the preferred approach for kidney procurement in many medical centers. This review gives an overview of the risk factors in donor nephrectomy and more specifically in hand-assisted laparoscopic donor nephrectomy.


Changing sex risk behaviors, gender norms, and relationship dynamics among couples in Cape Town, South Africa: Efficacy of an intervention on the dyad.
South Africa continues to experience new HIV infections, with the highest risk among Black Africans living in poor communities. Most HIV prevention interventions target women or men separately and only a small number target couples jointly. This study examines varying strategies to engage women and men around HIV prevention and improved couple interactions. The study comprises three arms: (1) a couple-based intervention delivered to women and men jointly; (2) women and men both offered a gender-focused intervention that is delivered to them separately; and (3) an intervention offered to women only and their male partners receive standard HIV testing and counseling (comparison arm). Between June 2010 and April 2012, men were identified in and around drinking establishments in a large disadvantaged community in Cape Town and asked to participate in the study if they drink regularly, had recent unprotected sex with their partner, and have a female partner who was willing to participate in the study. A total of 299 couples completed the baseline assessment and 276 were included in the analysis of sexual risk, partner communication, conflict resolution, and gender norm outcomes at baseline and six-month follow-up. Couples that participated in the couple-level intervention and couples where both partners received the intervention separately had better couple-level gender norms than couples in the comparison arm (women only receive intervention). Further, couples in the couple-level intervention and the both partners exposed separately arms were more likely to have the man only report consistent condom use than neither partner report consistent condom use than couples in the comparison arm. Community-based HIV prevention intervention programs need to consider strategies to engage women and men and, if feasible, reach both partners jointly. Couple-level interventions are promising to improve gender norms and subsequently improve health outcomes, including reduced HIV risk among women, men, and couples.


The role of hyperthermia in the battle against cancer.
Hyperthermia, the heating of tumors to 41.5-43 degrees C, could be today considered the fourth pillar of the treatment of cancer. Employed for 20 years in Europe, the U.S.A. and Asia, hyperthermia, used in addition to radiotherapy, chemotherapy and surgery, increases both local control and overall survival, restores the chance of the surgery for inoperable tumors and allows a new low-dosage treatment of relapsed cancers previously treated with high radiotherapy dosage without increasing toxicity. Hyperthermia can be either superficial, produced by a microwave generator, or regional, produced by a radiofrequency applicator with multiple antennas, which emanate a deep focalized or interstitial heating. The results are confirmed by phase III randomized trials, with level 1 evidence. A review of the international literature on hyperthermia, the experience of the University Hospital of Verona Radiotherapy Department (Italy) and a summary of the Symposium regarding the Evolution of Clinical Hyperthermia plus Radiotherapy during the Twentieth Congress of the French Society of Radiation Oncology (SFRO) are presented. Hyperthermia is an important treatment modality in cancer treatment and its results are strongly supported by criteria of evidence-based medicine. Fifteen years of experience of the Radiation Oncology Department in Verona confirms the positive results obtained with international prospective trials, with level 1 evidence. Hyperthermia appears to be the fourth pillar beside surgery, radiotherapy and chemotherapy.


Relapse of endometrial hyperplasia after conservative treatment: a cohort study with long-term follow-up.
What is the risk of relapse for women with endometrial hyperplasia treated with levonorgestrel-releasing intrauterine system (LNG-IUS) or oral progestogens? Relapse of complex endometrial hyperplasia after initial regression occurs often and it occurs less often in women treated with LNG-IUS than with oral progestogens. The LNG-IUS and oral progestogens are used to treat women with endometrial hyperplasia and achieve regression. There is uncertainty over whether further surveillance for these women is necessary as the risk for relapse is unknown. A cohort study of 219 women with complex non-atypical or atypical endometrial hyperplasia who were treated and achieved initial regression with LNG-IUS (n = 153) or oral progestogens (n = 66) from August 1998 until December 2007 and followed up for >5 years. The mean length of follow-up was 74.7 ± SD 31.8 months for the LNG-IUS versus 87.6 ± SD 42.2 months for the oral progestogen group. We evaluated the proportion of women who relapsed or had hysterectomy after initial regression with LNG-IUS compared with oral progestogens by logistic regression and adjusting for confounding. The time from regression to relapse was explored through a survival analysis. Relapse of hyperplasia occurred in 13.7% (21/153) of women treated with LNG-IUS compared with 30.3% (20/66) of women treated with oral progestogens [adjusted odds ratio (OR) = 0.34, 95% confidence interval (CI): 0.17-0.7, P = 0.005]. Relapse rates over long-term follow-up were lower for complex non-atypical hyperplasia compared with atypical hyperplasia for both LNG-IUS (12.7%, 18/142 versus 27.3%, 3/11, respectively; P ≤ 0.001) and oral progestogens (28.3%, 17/60 versus 50%, 3/6, respectively; P ≤ 0.001). The survival analysis indicates that relapse occurred less often with LNG-IUS at 12, 24, 36, 48, 60 and >60 months of follow-up (hazard ratio 0.37, 95% CI: 0.2-0.7, P = 0.0013). There were no events of relapse after 48 months from regression with oral progestogens, but 5 women treated with LNG-IUS relapsed after 60 months when treatment was discontinued. Hysterectomy rates were lower in the LNG-IUS than oral progestogen group during follow-up (19.6%, 30/153 versus 31.8%, 21/66, respectively, OR = 0.52, 95% CI: 0.27-1, P = 0.05). Endometrial cancer was diagnosed in 2 (11.8%) women who had hysterectomy (n = 17) because of relapse. We are unable to accurately estimate the cancer risk in women who relapse during follow-up as only 17 out of 41 who relapsed underwent hysterectomy. Relapse of endometrial hyperplasia after initial regression occurs often and long-term follow-up is advised. Ioannis D. Gallos and this study were funded through a grant from Wellbeing of Women (ELS022). No competing interests.


[Coronary angioplasty through 6 French guiding catheters].
The development of new small guiding catheters with large internal lumen has allowed their use in routine coronary angioplasty. The aim of this study is to present the technical characteristics, results and complication rates obtained with the use of 6 French guiding catheters compared with those obtained with the use of 8 French. During a 23 month period, a total of 355 consecutive patients was enrolled in this study. Coronary angioplasty was performed in 177 of them using a 6F guiding catheter and 178 using an 8F. We found no differences in technical characteristics between both groups: Radiation time (15.7 +/- 14 min vs 16.2 +/- 14 min), guiding catheter to patient ratio (1.1 +/- 0.3 vs 1.06 +/- 0.2), number of balloon catheters per patient (1.2 +/- 0.7 vs 1.36 +/- 0.7). There were no differences in the results obtained (Success 93% in 6F group vs 91% in 8F), major complication rates (Death 0.5% vs 1.6%, CABG 1.1% vs 2.2% or AMI 0% vs 2.2%), or peripheral complications. In coronary angioplasty, with the use of 6F guiding catheters the same results can be achieved as with the use of larger catheters without an increase in technical difficulties or in complication rates.


Two-year outcome after lumbar microdiscectomy versus microscopic sequestrectomy: part 1: evaluation of clinical outcome.
Single-center randomized prospective study at a university hospital. The aim of the present study was to provide a 2-year outcome comparison of microdiscectomy (D) versus microscopic sequestrectomy (S) in terms of reherniation rates, clinical investigation, and self-rated parameters using a comprehensive questionnaire. Simple fragment excision in cases of herniated lumbar discs has been repeatedly reported as an alternative to standard microdiscectomy, but prospective data with sufficient follow-up is lacking to date. Preliminary results of a prospective randomized study in patients with lumbar disc herniations indicated equal reherniation rates and a trend toward superior clinical results in patients undergoing only sequestrectomy after 4 to 6 months. Eighty-four patients with lumbar disc herniations were treated with microdiscectomy or microscopic sequestrectomy in equal parts. Patients were re-evaluated thoroughly clinically after 2 years. Results of this investigation (low back pain, sciatica, motor-, sensory-, reflex-, straight leg raising test-indexes) and self-rated parameters including SF-36 were analyzed for differences between groups and between time points. Thirty-eight (D) and 40 (S) patients were attainable for follow-up. Reherniation rates did not differ significantly (10.5%, group D; 12.5%, group S; P = 1.0). Following dramatic improvement after surgery in both groups, results of the clinical investigation remained stable over time without significant differences between groups. In contrast, self-rated assessment demonstrated clinical deterioration of the surgical results within the first 2 years after microdiscectomy, while they rather improved after sequestrectomy. Because of this development, the outcome measures at 2 years pointed in favor of sequestrectomy with results being significant for important parameters such as use of analgesics, performance, and overall outcome. Reherniation rates within 2 years after sequestrectomy and microdiscectomy are comparable. However, outcome after microdiscectomy seems to worsen over time, whereas it remains stable after sequestrectomy. Thus, 2-year follow-up revealed clinical results favoring sequestrectomy. Performing sequestrectomy alone may therefore represent an advantageous alternative to standard microdiscectomy.


Cloning, mutation and distribution of a putative lipopolysaccharide biosynthesis locus in Campylobacter jejuni.
A region encoding ORFs with homology to known lipopolysaccharide (LPS) biosynthesis genes was isolated from two strains of Campylobacter jejuni. One of the strains produces LPS, but the second strain is reported to produce only lipooligosaccharide (LOS) and therefore lacks the O-chain. The two strains shared six predicted ORFs, but an additional ORF, orfE, of unknown function was identified in the LOS-producing strain. Mutation of the shared wbeE (rfbE) homologue (orfF) or deletion of five of the seven genes reduced core reactivity with specific antiserum without affecting O-chain production. Mutation of either the capD homologue (orfG) or the unique orfE had no detectable effect on LOS or LPS production. The presence or absence of orfE in 36 isolates of C. jejuni did not correlate with LOS/LPS phenotype or serotype. However, after insertion of orfE into a LPS-producing orfE-negative strain the O-chain ladder was no longer detectable on Western blots. We were not able to disrupt the wbaP (rfbP) homologue (orfC) in C jejuni.


Data processing in Fourier transform ion cyclotron resonance mass spectrometry.
The Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer intricately couples advanced physics, instrumentation, and electronics with chemical and particularly biochemical research. However, general understanding of the data processing methodologies used lags instrumentation, and most data processing algorithms we are familiar with in FT-ICR are not well studied; thus, professional skill and training in FT-ICR operation and data analysis is still the key to achieve high performance in FT-ICR. This review article is focused on FT-ICR data processing, and explains the procedures step-by-step for users with the goal of maximizing spectral features, such as mass accuracy, resolving power, dynamic range, and detection limits.


Luminescent dual sensors reveal extracellular pH-gradients and hypoxia on chronic wounds that disrupt epidermal repair.
Wound repair is a quiescent mechanism to restore barriers in multicellular organisms upon injury. In chronic wounds, however, this program prematurely stalls. It is known that patterns of extracellular signals within the wound fluid are crucial to healing. Extracellular pH (pHe) is precisely regulated and potentially important in signaling within wounds due to its diverse cellular effects. Additionally, sufficient oxygenation is a prerequisite for cell proliferation and protein synthesis during tissue repair. It was, however, impossible to study these parameters in vivo due to the lack of imaging tools. Here, we present luminescent biocompatible sensor foils for dual imaging of pHe and oxygenation in vivo. To visualize pHe and oxygen, we used time-domain dual lifetime referencing (tdDLR) and luminescence lifetime imaging (LLI), respectively. With these dual sensors, we discovered centripetally increasing pHe-gradients on human chronic wound surfaces. In a therapeutic approach, we identify pHe-gradients as pivotal governors of cell proliferation and migration, and show that these pHe-gradients disrupt epidermal barrier repair, thus wound closure. Parallel oxygen imaging also revealed marked hypoxia, albeit with no correlating oxygen partial pressure (pO2)-gradient. This highlights the distinct role of pHe-gradients in perturbed healing. We also found that pHe-gradients on chronic wounds of humans are predominantly generated via centrifugally increasing pHe-regulatory Na+/H+-exchanger-1 (NHE1)-expression. We show that the modification of pHe on chronic wound surfaces poses a promising strategy to improve healing. The study has broad implications for cell science where spatial pHe-variations play key roles, e.g. in tumor growth. Furthermore, the novel dual sensors presented herein can be used to visualize pHe and oxygenation in various biomedical fields.


Rescue therapy using a rifabutin-based regimen is effective for cure of Helicobacter pylori infection.
To evaluate the efficacy of rescue therapy using rifabutin, amoxicillin and a proton pump inhibitor (PPI) in the eradication of Helicobacter pylori in patients who have failed at least one course of PPI-based triple therapy. The present study was a single-centre case series of 16 consecutive patients who had received at least one course of standard eradication therapy. Pretreatment evaluation included endoscopy with biopsies for histology and culture for H pylori infection. Treatment consisted of a one-week regimen containing a PPI twice daily, amoxicillin (A) 1 g twice daily and rifabutin (R) 300 mg once daily (PPI-AR). Post-treatment evaluation consisted of a repeat endoscopy with biopsy for histology and culture, or a validated urea breath test at least four weeks after treatment was completed. Pretreatment antibiotic susceptibility to metronidazole, clarithromycin and A was evaluated using a validated epsilometer test. Of the 16 patients, four had previously received one course of triple therapy, 10 had received two courses and two had received more than two courses. The overall success rate of PPI-AR was 63% (10 of 16). Resistance to A was 0% (0 of 13), metronidazole 77% (10 of 13), clarithromycin 70% (seven of 10), and both metronidazole and clarithromycin 60% (six of 10). There was no correlation between resistance patterns and cure rate. An R-containing regimen such as PPI-AR is a viable option as rescue therapy for H pylori infection.


The tRNA-associated dysregulation in immune responses and immune diseases.
Transfer RNA (tRNA), often considered as a housekeeping molecule, mainly participates in protein translation by transporting amino acids to the ribosome. Nevertheless, accumulating evidence has shown that tRNAs are closely related to various physiological and pathological processes. The proper functioning of the immune system is the key to human health. The aim of this review is to investigate the relationships between tRNAs and the immune system. We detail the biogenesis and structure of tRNAs and summarize the pathogen tRNA-mediated infection and host responses. In addition, we address recent advances in different aspects of tRNA-associated dysregulation in immune responses and immune diseases, such as tRNA molecules, tRNA modifications, tRNA derivatives and tRNA aminoacylation. Therefore, tRNAs play an important role in immune regulation. Although our knowledge of tRNAs in the context of immunity remains, for the most part, unknown, this field deserves in-depth research to provide new ideas for the treatment of immune diseases.


Obtaining the Transfer Function of optical instruments using large calibrated reference objects.
It has been suggested recently that the Transfer Function of instruments such as Coherence Scanning Interferometers could be measured via a single measurement of a large spherical artefact [Appl. Opt.53(8), 1554-1563 (2014)]. In the current paper we present analytical solutions for the Fourier transform of the 'foil' model used in this technique, which thus avoids the artefacts resulting from the numerical approach used earlier. The Fourier transform of a partial spherical shell is found to contain points of zero amplitude for spatial frequencies that lie within the Transfer Function. This implies that the Transfer Function is unmeasurable at these points when a single spherical artefact is used, in situations where the foil model is a valid representation of the physical system. We propose extensions to the method to address this issue.


Collaborative assay of a proposed international standard for tetanus toxoid (adsorbed).
An international collaborative assay was performed with the aim of establishing an international standard for tetanus toxoid (adsorbed). Six laboratories participated. A suitable preparation in the lyophilized state was made available by the Paul Ehrlich Institut, Frankfurt am Main, Federal Republic of Germany. Preliminary experiments showed that there were no significant differences between individual ampoules and that the preparation was highly thermostable.The proposed preparation (A) was compared in guinea-pigs and mice with the existing international standard for tetanus toxoid (B), which is a plain toxoid, with another arbitrarily chosen adsorbed toxoid (C), and with a number of locally prepared preparations (D). In the mouse tests preparation B was omitted. It was found in the guinea-pig tests that 1 mg of the proposed standard contained an activity equivalent to 1.5 IU if compared with the non-adsorbed international standard but since the slopes of the log dose-response lines for the adsorbed and plain types of preparation were not parallel, this is a rough approximation only. When the different adsorbed preparations were compared, there was close correlation between the guinea-pig tests and the mouse tests. In the guinea-pig test 1 ml of preparation C corresponded to 126.5 mg of preparation A and in the mouse test to 129.9 mg of preparation A. In one laboratory comparative tests were made by titrating blood antitoxins after immunization of guinea-pigs with graded doses of the toxoids. The results corresponded very well with the data from challenge tests (1 mg of preparation A contained 1.5 IU of the plain toxoid in challenge tests and|1.4 IU in the titration test).Preparation A was established by the WHO Expert Committee on Biological Standardization as the international standard for tetanus toxoid (adsorbed) and the international unit was defined as the activity contained in 0.6667 mg of the international standard.


Multi-Modal Treatment Approach to Painful Rib Syndrome: Case Series and Review of the Literature.
Mechanical chest wall pain is a common presenting complaint in the primary care office, emergency room, and specialty clinic. Diagnostic testing is often expensive due to similar presenting symptoms that may involve the heart or lungs. Since the chest wall biomechanics are poorly understood by many clinicians, few effective treatments are offered to patients with rib-related acute pain, which may lead to chronic pain. This case series and literature review illustrates biomechanics involved in the pathogenesis of rib-related chest wall pain and suggests an effective multi-modal treatment plan using interventional techniques with emphasis on manual manipulative techniques. Case series and literature review. Pain clinic in an academic medical center. This is a case series of 3 patients diagnosed with painful rib syndrome using osteopathic palpatory physical examination techniques. Ultrasound-guided intercostal nerve blocks were followed by manual manipulation of mechanically displaced ribs as a part of our multi-modal treatment plan. A review of the literature was undertaken to clarify nomenclature used in the description of rib-related pain, to describe the biomechanics involved in the pathogenesis of mechanical rib pain, and to illustrate the use of effective manual manipulation techniques. This review is introductory and not a complete review of all manual or interventional pain management techniques applicable to the treatment of mechanical rib-related pain. Manual diagnostic and therapeutic skills can be learned by physicians to treat biomechanically complex rib-related chest wall pain in combination with interventional image-guided techniques. Pain physicians should learn certain basic manual manipulation skills both for diagnostic and therapeutic purposes.


Integration of mRNA and miRNA analysis reveals the molecular mechanisms of sugar beet (Beta vulgaris L.) response to salt stress.
The continuous increase of saline-alkali areas worldwide has led to the emergence of saline-alkali conditions, which are the primary abiotic stress or hindering the growth of plants. Beet is among the main sources of sugar, and its yield and sugar content are notably affected by saline-alkali stress. Despite sugar beet being known as a salt-tolerant crop, there are few studies on the mechanisms underlying its salt tolerance, and previous studies have mainly delineated the crop's response to stress induced by NaCl. Recently, advancements in miRNA-mRNA network analysis have led to an increased understanding of how plants, including sugar beet, respond to stress. In this study, seedlings of beet variety "N98122" were grown in the laboratory using hydroponics culture and were exposed to salt stress at 40 days of growth. According to the phenotypic adaptation of the seedlings' leaves from a state of turgidity to wilting and then back to turgidity before and after exposure, 18 different time points were selected to collect samples for analysis. Subsequently, based on the data of real-time quantitative PCR (qRT-PCR) of salt-responsive genes, the samples collected at the 0, 2.5, 7.5, and 16 h time points were subjected to further analysis with experimental materials. Next, mRNA-seq data led to the identification of 8455 differentially expressed mRNAs (DEMs) under exposure to salt stress. In addition, miRNA-seq based investigation retrieved 3558 miRNAs under exposure to salt stress, encompassing 887 known miRNAs belonging to 783 families and 2,671 novel miRNAs. With the integrated analysis of miRNA-mRNA network, 57 miRNA-target gene pairs were obtained, consisting of 55 DEMIs and 57 DEMs. Afterwards, we determined the pivotal involvement of aldh2b7, thic, and δ-oat genes in the response of sugar beet to the effect of salt stress. Subsequently, we identified the miRNAs novel-m035-5p and novel-m0365-5p regulating the aldh gene and miRNA novel-m0979-3p regulating the thic gene. The findings of miRNA and mRNA expression were validated by qRT-PCR.


Synthesis and photophysical properties of a "face-to-face" stacked tetracene dimer.
A covalently linked tetracene dimer has been prepared and its molecular structure is characterized by (1)H NMR and MALDI-TOF mass spectroscopy, and elemental analysis. The minimized molecular structure reveals that the tetracene subunits in a dimer adopt a "face-to-face" stacked configuration. Its absorption spectrum differs significantly from that of the monomeric counterpart in solution, suggesting the presence of strong interactions between the two tetracene subunits. In solution, the fluorescence spectrum is dominated by a band at around 535 nm, due to an oxidative impurity. In the longer wavelength range, a short-lived lower energy emission can be identified as the intrinsic emission of the dimer. In a polystyrene matrix or at low temperatures, the lifetime of the lower energy emission lengthens and it becomes more prominent. We suggest that the interactions between the two tetracene subunits produce a short-lived, lower energy "excimer-like" state. The fluorescence decays show no observable dependence on an applied magnetic field, and no obvious evidence of significant singlet fission is found in this dimer. This research suggests that even though there are strong electronic interactions between the tetracene subunits in the dimer, singlet fission cannot be achieved efficiently, probably because the formation of "excimer-like" states competes effectively with singlet fission.


Node-negative non-small cell lung cancer: pathological staging and survival in 1765 consecutive cases.
This study aimed to evaluate prognostic factors in patients with node-negative non-small cell lung cancer and to assess revised International Association for the Study of Lung Cancer staging recommendations for this group. A retrospective analysis of 1765 consecutive pathologically node-negative patients treated by surgical resection between 1984 and 2007 was performed. Survival analysis was conducted using the Kaplan-Meier method. The independence of prognostic factors was analyzed using multivariate Cox proportional hazards modeling. The median age of patients was 68 years, and the average length of follow-up was 6.3 years. Perioperative mortality was 1.7%. The median survival was 6.5 years, with a 56% of the cohort surviving 5 years. Factors associated with poorer prognosis were male gender (hazard ratio [HR]: 1.30, p = <0.001), age (HR: 1.04 per year of increase, p < 0.001), limited resection (HR: 1.30, p = 0.002) tumor size (HR: 1.10 per 10 mm increase, p < 0.001), large cell histopathological cell type (HR: 1.35, p < 0.001), and positive resection margins (HR: 1.58, p = 0.002). T stage was a superior predictor of survival than tumor size (p < 0.001). There was no difference in survival by T-stage descriptor within stage T2 or T3. In surgically treated, node-negative non-small cell lung cancer, revised International Association for the Study of Lung Cancer staging criteria stratify survival well. Age, gender, and extent of resection are also important predictors of survival. Current T-stage descriptor groupings are appropriate.


[A study of otomycoses in Yaoundé].
The authors report the results of a six-month evaluation of otomycoses in the ENT Department of CHU and the Central Hospital of Yaoundé. We examined 2 592 patients of both sexes presenting with ear affections. The prevalence of Otomycoses is 6,09%. This is an adult problem with both sexes equally affected. Clinically the main symptoms were burning sensation in the ears, pruritus, sensation of fullness in the ear, hypoacousia and otorrhea. Clinical lesions are of many types including myringitis, tympanic perforation and otitis externa. The fungi responsible for these affections are mainly Aspergillus fumigatus (56,16%) for the Aaspergillus and Candida albicans (48,38%) for yeasts. The other species are Aspergillus niger, Aspergillus flavus, C. Krusei, C. pseudotropicalis, C. Tropicalis, Geotrichum candium and Torulopsis glabrata.


Gender and quality of life after cerebral stroke.
The aim of this work is to investigate the influence of gender on recovery after cerebral stroke.It is believed that functional outcome of cerebral stroke (CS) depends on gender. Female gender is mildly negative prognostic factor in after stroke results. Two hundred and two patients who had first ischemic cerebral stroke were questioned with help of, HADS and WHOQOL-Bref questionnaires, looking for differences in recovery depending on gender. Average patients' age was 72+/-13 (ME+/-IR) years. The youngest patient had 40 years, and the oldest 92 years, and medium range was 52 years. There were 112 males and 90 females. Quality of life was equally graded by both male and female after CS (p=0.208). Male patients had significantly better results in physical (p=0.035) and psychological (p=0.020) domain of life quality. After CS, male patients had better results only in memory dimension (p=0.003). Anxiety was statistically more frequent among female patients (p=0.009). Gender did not influence frequency of metabolic syndrome in patients with CS. Quality of life after CS was better in male patients, and statistically significant difference has been shown in physical, psychological domain and memory dimension. Female patients were more anxious then male after CS.


[Scientometric analysis of the main thematic fields and keywords in the subject area «Public health, environmental and occupational health»].
Research in the field of public health at the global, national, regional and organizational levels continue to be relevant, attracting attention of the researchers who find new aspects of various problems and issues for consideration and analysis in this area. The paper presents results of a scientometric analytical study of the publication landscape for 2019-2021 in the field of public health, using the analytical platform SciVal, the data source for which is the international scientific database Scopus. The study shows positive dynamics and steady growth in most scientometric indicators in the subject area under consideration during the study period. A structural-functional and semantic-linguistic analysis of the top-50 keywords was also carried out, which showed that their ranking position significantly depends on the choice of one of two indicators: either by the number of publications or by relevance. Publications on public health are characterized by a polythematic distribution, providing researchers with the opportunity to make a wide choice in conducting scientific research in the branches of medical science they are interested in, taking into account scientometric indicators characterizing the publication landscape in these areas.


Dental anxiety among adults: an epidemiological study in South India.
Dental anxiety is a major barrier for dental care utilization. Hence, identifying anxious individuals and their appropriate management becomes crucial in clinical practice. The study aims to assess dental anxiety, factors influencing dental anxiety, and anxiety towards tooth extraction procedure among patients attending a dental hospital in India. The study sample consisted of 1,148 consecutive patients aged 18-70 years. The assessment tools consisted of a consent form, history form, a questionnaire form containing the Modified Dental Anxiety Scale (MDAS) which was used to assess the level of dental anxiety, and an additional question on anxiety towards dental extraction procedure. Among the study group, 63.7% were men and 36.3% were women. Based on the MDAS score, 45.2% of the participants were identified to be less anxious, 51.8% were moderately or extremely anxious, and 3% were suffering from dental phobia. Mean MDAS total score was 10.4 (standard deviation (SD) = 3.91). Female participants and younger subjects were more anxious (P < 0.001). Subjects who were anxious had postponed their dental visit (P < 0.001). Participants who had negative dental experience were more anxious (P < 0.05). Notably, 82.6% reported anxiety towards extraction procedure. Significant association was seen between anxiety towards extraction procedure and the respondents gender (P < 0.05), age (P < 0.001), education level (P < 0.05), employment status (P < 0.001), income (P < 0.001), self-perceived oral health status (P < 0.05), and their history of visit to dentist (P < 0.05). Significant percentage of population was suffering from dental anxiety in this study population. A plethora of factors like age, gender, education level, occupation, financial stability, and previous bad dental experience influences dental anxiety to various levels. Extraction followed by drilling of tooth and receiving local anesthetic injection provoked more anxiety.


Direct Fixation of C1 Jefferson Fracture Using C1 Lateral Mass Screws: A Case Report.
Jefferson fractures are classically described as burst fractures of C1. Traditional surgical treatment of these unstable fractures is either occipito-cervical or posterior C1-C2 fusion, resulting in a significant loss of range of cervical neck movement. This case report discusses the fixation of a Jefferson fracture using C1 lateral mass screws to achieve surgical stabilization while preserving the range of movement. We aim to add to the body of evidence supporting this fixation method. A 39-year-old male presented to our emergency department with an unstable Jefferson fracture caused by trauma. The various treatment options, such as cervical collar, HALO immobilization, occipito-cervical fusion, and atlanto-axial fusion and direct fixation of C1, were evaluated and discussed with the patient. Informed consent was obtained from the patient prior to writing this case report. At 3 months postoperation, the patient demonstrated near full range of movement in his neck. He had also resumed driving. By 6 months, the patient returned to work, and at 12 months, imaging confirmed union. This case report adds to the body of evidence supporting the technique of C1 lateral mass screws for direct stable fixation of Jefferson fractures. This fixation method preserves the cervical spine range of motion with minimal functional restriction.


[Effect of obsidan on the course of experimental myocardial infarct with arrhythmias in rabbits].
Experimental myocardial infarction (EMI) was reproduced in 35 of 40 rabbits operated upon. Ampouled obsidan was slowly introduced to 12 rabbits with EMI directly after ligation of the coronary arteries and once during each subsequent two days into the marginal otic vein. The results of the antiarrhythmic action of the drug were judged about from the data of a dynamic ECG-observation in 3 standard leads. From the information thus obtained it followed that a single administration of obsidan to rabbits in the acute period of EMI (the first 3 days of the experiment) prevented the development of complex disturbances of the rhythm and reduced the lethality rate among the animals. In repeated injections of the drug it is necessary to take account of the preceding arrhythmias. Reintroduction of obsidan to rabbits with EMI complicated by sinus bradycardia and ventricular extrasystole is prognostically dangerous (ventricular extrasystole relapses and its transformation into ventricular tachycardia is possible). At later stages of EMI these animals succumbod due to complex disturbances of the rhythm and conduction.


Intervertebral discolysis with collagenase.
Animal experimental studies are reported in which the enzyme collagenase was used to digest the nucleus pulposus of the intervertebral disc in both dogs and monkeys. Studies in the same animals indicated a low risk toxicity. Clinical studies were started in 1979, in which the results in 82 patients are reported. All patients were subjected to rigid standards of selection. Of 78 patients followed, 80.4% had good results, 4.9% fair results, and 14.7% had poor results. There were no instances of toxicity. A double-blind study of 30 patients indicates clearcut superiority of collagenase over placebo in relieving the symptoms of herniated disc.


Midline granuloma and Wegener's granulomatosis: clinical & therapeutic considerations.
Midline granuloma (MG), limited Wegener's granulomatosis (LWG), and generalized Wegener's granulomatosis (WG) have been viewed by some investigators as representing an interrelated disease spectrum. Others believe that MG and WG are two distinct clinicopathologic entities. A series of cases is presented suggesting that therapy of MG should be individualized. Treatment may include corticosteroids, high-dose irradiation, and/or immunosuppressive drugs. LWG may be treated initially with corticosteroids alone, but lack of response requires the addition of an immunosuppressive agent. WG should be treated with an immunosuppressive drug and, at times, corticosteroids as well. None of the cases of MG described in this report progressed to WG. This may be interpreted as supporting the contention that MG and WG are separate diseases. Alternatively, aggressive treatment of MG with irradiation or immunosuppressives may prevent its transition to more generalized disease.


Impact of socioeconomic status on survival for patients with anal cancer.
Although outcomes for patients with squamous cell carcinoma of the anus (SCCA) have improved, the gains in benefit may not be shared uniformly among patients of disparate socioeconomic status. In the current study, the authors investigated whether area-based median household income (MHI) is predictive of survival among patients with SCCA. Patients diagnosed with SCCA from 2004 through 2013 in the Surveillance, Epidemiology, and End Results registry were included. Socioeconomic status was defined by census-tract MHI level and divided into quintiles. Multivariable Cox proportional hazards models and logistic regression were used to study predictors of survival and radiotherapy receipt. A total of 9550 cases of SCCA were included. The median age of the patients was 58 years, 63% were female, 85% were white, and 38% were married. In multivariable analyses, patients living in areas with lower MHI were found to have worse overall survival and cancer-specific survival (CSS) compared with those in the highest income areas. Mortality hazard ratios for lowest to highest income were 1.32 (95% confidence interval [95% CI], 1.18-1.49), 1.31 (95% CI, 1.16-1.48), 1.19 (95% CI, 1.06-1.34), and 1.16 (95% CI, 1.03-1.30). The hazard ratios for CSS similarly ranged from 1.34 to 1.22 for lowest to highest income. Older age, black race, male sex, unmarried marital status, an earlier year of diagnosis, higher tumor grade, and later American Joint Committee on Cancer stage of disease also were associated with worse CSS. Income was not found to be associated with the odds of initiating radiotherapy in multivariable analysis (odds ratio of 0.87 for lowest to highest income level; 95% CI, 0.63-1.20). MHI appears to independently predict CSS and overall survival in patients with SCCA. Black race was found to remain a predictor of SCCA survival despite controlling for income. Further study is needed to understand the mechanisms by which socioeconomic inequalities affect cancer care and outcomes. Cancer 2018;124:1791-7. © 2018 American Cancer Society.


GuaB3, an overlooked enzyme in cyanobacteria's toolbox that sheds light on IMP dehydrogenase evolution.
IMP dehydrogenase and GMP reductase are enzymes from the same protein family with analogous structures and catalytic mechanisms that have gained attention because of their essential roles in nucleotide metabolism and as potential drug targets. This study focusses on GuaB3, a less-explored enzyme within this family. Phylogenetic analysis uncovers GuaB3's independent evolution from other members of the family and it predominantly occurs in Cyanobacteria. Within this group, GuaB3 functions as a unique IMP dehydrogenase, while its counterpart in Actinobacteria has a yet unknown function. Synechocystis sp. PCC6803 GuaB3 structures demonstrate differences in the active site compared to canonical IMP dehydrogenases, despite shared catalytic mechanisms. These findings highlight the essential role of GuaB3 in Cyanobacteria, provide insights into the diversity and evolution of the IMP dehydrogenase protein family, and reveal a distinctive characteristic in nucleotide metabolism, potentially aiding in combating harmful cyanobacterial blooms-a growing concern for humans and wildlife.


Community-based screening and triage connecting First Nations children and youth to local supports: a cross-sectional study.
First Nations children in Canada experience health inequities. We aimed to determine whether a self-report health app identified children's needs for support earlier in their illness than would typically occur. Children (aged 8 to 18 yr) were recruited from a rural First Nation community. Children completed the Aaniish Naa Gegii: the Children's Health and Well-being Measure (ACHWM) and then met with a local mental health worker who determined their risk status. ACHWM Emotional Quadrant Scores (EQS) were compared between 3 groups of children: healthy peers (HP) who were not at risk, those with newly identified needs (NIN) who were at risk and not previously identified, and a typical treatment (TT) group who were at risk and already receiving support. We included 227 children (57.1% girls), and the mean age was 12.9 (standard deviation [SD] 2.9) years. The 134 children in the HP group had a mean EQS of 80.1 (SD 11.25), the 35 children in the NIN group had a mean EQS of 67.2 (SD 13.27) and the 58 children in the TT group had a mean EQS of 66.2 (SD 16.30). The HP group had significantly better EQS than the NIN and TT groups (p < 0.001). The EQS did not differ between the NIN and TT groups (p = 0.8). The ACHWM screening process identified needs for support among 35 children, and the associated triage process connected them to local services; the similarity of EQS in the NIN and TT groups highlights the value of community screening to optimize access to services. Future research will examine the impact of this process over the subsequent year in these groups.


Accuracy of a computerized clinical decision-support system for asthma assessment and management.
To evaluate the accuracy of a computerized clinical decision-support system (CDSS) designed to support assessment and management of pediatric asthma in a subspecialty clinic. Cohort study of all asthma visits to pediatric pulmonology from January to December, 2009. CDSS and physician assessments of asthma severity, control, and treatment step. Both the clinician and the computerized CDSS generated assessments of asthma control in 767/1032 (74.3%) return patients, assessments of asthma severity in 100/167 (59.9%) new patients, and recommendations for treatment step in 66/167 (39.5%) new patients. Clinicians agreed with the CDSS in 543/767 (70.8%) of control assessments, 37/100 (37%) of severity assessments, and 19/66 (29%) of step recommendations. External review classified 72% of control disagreements (21% of all control assessments), 56% of severity disagreements (37% of all severity assessments), and 76% of step disagreements (54% of all step recommendations) as CDSS errors. The remaining disagreements resulted from pulmonologist error or ambiguous guidelines. Many CDSS flaws, such as attributing all 'cough' to asthma, were easily remediable. Pediatric pulmonologists failed to follow guidelines in 8% of return visits and 18% of new visits. The authors relied on chart notes to determine clinical reasoning. Physicians may have changed their assessments after seeing CDSS recommendations. A computerized CDSS performed relatively accurately compared to clinicians for assessment of asthma control but was inaccurate for treatment. Pediatric pulmonologists failed to follow guideline-based care in a small proportion of patients.


Use of Galleria mellonella as an Animal Model for Studying the Antimicrobial Activity of Bacteriophages with Potential Use in Phage Therapy.
Interest in phage therapy has increased in the last decade, and animal models have become essential in this field. The larval stage of the wax moth, Galleria mellonella, represents an easy-to-handle model. The larvae have an innate immune response and survive at 37 °C, which is ideal for infection and antimicrobial studies with bacteriophages. In this chapter, we describe the procedures used to study the antimicrobial activity of bacteriophages in a G. mellonella infection model.


Tutorial for the structure elucidation of small molecules by means of the LSD software.
Automatic structure elucidation of small molecules by means of the "logic for structure elucidation" (LSD) software is introduced in the context of the automatic exploitation of chemical shift correlation data and with minimal input from chemical shift values. The first step in solving a structural problem by means of LSD is the extraction of pertinent data from the 1D and 2D spectra. This operation requires the labeling of the resonances and of their correlations; its reliability highly depends on the quality of the spectra. The combination of COSY, HSQC, and HMBC spectra results in proximity relationships between nonhydrogen atoms that are associated in order to build the possible solutions of a problem. A simple molecule, camphor, serves as an example for the writing of an LSD input file and to show how solution structures are obtained. An input file for LSD must contain a nonambiguous description of each atom, or atom status, which includes the chemical element symbol, the hybridization state, the number of bound hydrogen atoms and the formal electric charge. In case of atom status ambiguity, the pyLSD program performs clarification by systematically generating the status of the atoms. PyLSD also proposes the use of the nmrshiftdb algorithm in order to rank the solutions of a problem according to the quality of the fit between the experimental carbon-13 chemical shifts, and the ones predicted from the proposed structures. To conclude, some hints toward future uses and developments of computer-assisted structure elucidation by LSD are proposed.


Effect of sub-deficient zinc status on insulin sensitivity after burn injury in rats.
Although zinc status is an important parameter in insulin sensitivity, data concerning its implication in noxious burn-induced insulin resistance are scarce. The present study was designed to evaluate the impact of zinc status before burn on the recovery of injury with focus on plasma insulin and glucose levels. The experiment was performed in male adult Wistar rats fed from weaning with a zinc normal diet (80 ppm) or a depleted zinc diet (10 ppm) for 8 weeks and burned to third degree on 20% of their total body surface area. Blood and tissue samples were collected 3, 6, and 24 h after injury in order to study biochemical parameters and the glucose/insulin response in relation with the zinc status. After burn, zinc-depleted rats presented an exacerbated decrease in plasma zinc level. In addition, the burn-induced insulin resistance, leading to protein catabolism, was emphasized, with higher plasma insulin, glucose, and leptin levels in zinc-deficient animals versus normal-fed rats. Our experimental results underlined the interest to early control the zinc status in order to limit the deleterious effects of oxidative stress and insulin resistance in burned patients.


From scientific object to commemorated victim: the children of the Spiegelgrund.
The legacy of German medical research in the era of National Socialism remains contentious, as regards identification of victims, and the appropriate handling of scientific specimens. These questions are acutely posed by the scientific slides, brain sections, and other body parts of victims, who were killed for research. These slides continued to be held by Austrian and German scientific institutes in the second half of the twentieth century. That scientists continued research on these slides between 1945 and the late 1980s suggests a disassociation of guilt and responsibility for the deaths of the victims by the German scientific community.


Video-assisted thoracoscopic surgery versus open lobectomy for primary non-small-cell lung cancer: a propensity-matched analysis of outcome from the European Society of Thoracic Surgeon database.
Video-assisted thoracoscopic anatomical resections are increasingly used in Europe to manage primary lung cancer. The purpose of this study was to compare the outcome following thoracoscopic versus open lobectomy in case-matched groups of patients from the European Society of Thoracic Surgeon (ESTS) database. All patients having lobectomy as the primary procedure via thoracoscopy [video-assisted thoracoscopic surgery (VATS)-L)] or thoracotomy (TH-L) were identified in the ESTS database (January 2007 to December 2013). A propensity score was constructed using several patients' baseline characteristics. The matching using the propensity score was responsible for the minimization of selection bias. A propensity score-matched analysis was performed to compare the incidence of postoperative major complications (according to the ESTS database definitions) and mortality at hospital discharge between the matched groups. After exclusions, 28 771 patients were identified: 26 050 having thoracotomy and 2721 having thoracoscopy. Propensity score yielded two well-matched groups of 2721 patients. Numeric variables were compared by Student's t-tests and categorical variables were compared by McNemar's tests. Compared with TH-L, VATS-L was associated with a lower incidence of total complications [n = 792 (29.1%) vs 863 (31.7%), P = 0.0357], major cardiopulmonary complications [n = 316 (15.9%) vs 435 (19.6%), P = 0.0094], atelectasis requiring bronchoscopy [n = 65 (2.4%) vs 150 (5.5%), P < 0.0001], initial ventilation >48 h [n = 18 (0.7%) vs 38 (1.4%), P = 0.0075] and wound infection [n = 6 (0.2%) vs 17 (0.6%), P = 0.0218]. There was no difference in the incidence of postoperative atrial fibrillation between the two groups (P = 0.14). Postoperative hospital stay was 2 days shorter in the VATS-L patients (mean: 7.8 vs 9.8 days; P = 0.0003). In terms of outcome at hospital discharge, there were 27 deaths in the VATS-L group (1%) versus 50 in the TH-L group (1.9%, P = 0.0201). Data from the ESTS database confirmed that lobectomy performed through VATS is associated with a lower incidence of complications compared with thoracotomy.


Abnormal Cone and Rod Photoreceptor Morphogenesis in gdf6a Mutant Zebrafish.
Analysis of photoreceptor morphology and gene expression in mispatterned eyes of zebrafish growth differentiation factor 6a (gdf6a) mutants. Rod and cone photoreceptors were compared between gdf6a mutant and control zebrafish from larval to late adult stages using transgenic labels, immunofluorescence, and confocal microscopy, as well as by transmission electron microscopy. To compare transcriptomes between larval gdf6a mutant and control zebrafish, RNA-Seq was performed on isolated eyes. Although rod and cone photoreceptors differentiate in gdf6a mutant zebrafish, the cells display aberrant growth and morphology. The cone outer segments, the light-detecting sensory endings, are reduced in size in the mutant larvae and fail to recover to control size at subsequent stages. In contrast, rods form temporarily expanded outer segments. The inner segments, which generate the required energy and proteins for the outer segments, are shortened in both rods and cones at all stages. RNA-Seq analysis provides a set of misregulated genes associated with the observed abnormal photoreceptor morphogenesis. GDF6 mutations were previously identified in patients with Leber congenital amaurosis. Here, we reveal a unique photoreceptor phenotype in the gdf6a mutant zebrafish whereby rods and cones undergo abnormal maturation distinct for each cell type. Further, subsequent development shows partial recovery of cell morphology and maintenance of the photoreceptor layer. By conducting a transcriptomic analysis of the gdf6a larval eyes, we identified a collection of genes that are candidate regulators of photoreceptor size and morphology.


Norepinephrine regulation of cerebral glycogen utilization during seizures and ischemia.
Norepinephrine (NE) depletion of the cerebral cortex after lesion of the ipsilateral locus ceruleus (LC) causes abnormalities of cerebral oxidative metabolism when the cortex is stimulated to increased energy demand (Harik, S. I., J. C. LaManna, A. I. Light, and M. Rosenthal (1979) Science 206: 69-71; LaManna, J. C., S. I. Harik, A. I. Light, and M. Rosenthal (1981) Brain Res. 204: 87-101). These abnormalities were exhibited as decreased mitochondrial reducing equivalent flow. One possible cause of this would be the decreased availability of oxidative metabolic substrates in the NE-depleted cortex. We therefore investigated the effect of unilateral LC lesion and the resultant depletion of ipsilateral endogenous NE on glycogen and other energy metabolites in the cerebral cortex of rats under three conditions: (1) at "rest," (2) when energy demand is inncreased markedly by seizures, and (3) during total cerebral ischemia. We report no differences in cerebral metabolites between NE-depleted and control hemispheres at "rest." In seizures and ischemia, however, the increase in the level of adenosine 3':5'-monophosphate (cyclic AMP) and the breakdown of glycogen were impaired considerably in the NE-depleted cortex. The data suggest that depletion of central NE impairs cerebral glycogenolysis in response to increased energy demands and ischemia. Such impairment may be mediated via a cyclic AMP-related mechanism.


Objective Quantification of Spontaneous Retinal Venous Pulsations Using a Novel Tablet-Based Ophthalmoscope.
Dynamic assessment of retinal vascular characteristics can aid in identifying glaucoma-specific biomarkers. More specifically, a loss of spontaneous retinal venous pulsations (SVPs) has been reported in glaucoma, but a lack of readily available tools has limited the ability to explore the full potential of SVP analysis in glaucoma assessment. Advancements in smart technology have paved the way for the development of portable, noninvasive, and inexpensive imaging modalities. By combining off-the-shelf optical elements and smart devices, the current study aims to determine whether SVPs can be detected and quantified using a novel tablet-based ophthalmoscope in glaucoma and glaucoma suspects. Thirty patients, including 21 with confirmed glaucoma (9 men; average age 75 ± 8 years) and 9 glaucoma suspects (5 men; average age 64 ± 9 years), were studied. All patients had intraocular pressure measurements, Humphrey visual field assessment, optical coherence tomography, and a 10-second videoscopy of the retinal circulation. The retinal vasculature recordings (46° field of view at 30 frames per second) were analyzed to extract SVP amplitudes. SVPs were detected and quantified in 100% of patients with glaucoma and those with suspected glaucoma using the novel device. The average SVP amplitudes in glaucoma and glaucoma suspects were 42.6% ± 10.7% and 34% ± 6.7%, respectively. Our results suggest that a novel tablet-based ophthalmoscope can aid in documenting and objectively quantifying SVPs in all patients. Outcomes of this study provide an innovative, portable, noninvasive, and inexpensive solution for objective assessment of SVPs, which may have clinical relevance in glaucoma screening.


A pathologist-in-the-loop IHC antibody test selection using the entropy-based probabilistic method.
Immunohistochemistry (IHC) is an important tool to identify and quantify expression of certain proteins (antigens) to gain insights into the molecular processes in a diseased tissue. However, it is a challenge for pathologists to remember the discriminative characteristics of the growing number of such antigens across multiple diseases. The complexity of their expression patterns, fueled by continuous discoveries in molecular pathology, gives rise to a combinatorial explosion that places an unprecedented burden on a practicing pathologist and therefore increases cost and variability of IHC studies. To tackle these issues, we have developed antibody test optimized selection method, a novel informatics tool to help pathologists in improving the IHC antibody selection process. The method uses extensions of Shannon's information entropies and Bayesian probabilities to dynamically build an efficient diagnostic tree. A comparative analysis of our method with the expert and World Health Organization classification guidelines showed that the proposed method brings threefold reduction in number of antibody tests required to reach a diagnostic conclusion. The developed method can significantly streamline the antibody test selection process, decrease associated costs and reduce inter- and intrapathologist variability in IHC decision-making.


Cytomegalovirus vaccine. Specific humoral and cellular immune responses in human volunteers.
Four seronegative adult male volunteers were immunized with Towne strain cytomegalovirus (CMV) vaccine. The only reaction was transient pain and swelling at the inoculation site. Viral cultures were performed during the first 12 weeks after immunization, and CMV was not recovered from throat, urine, or peripheral blood mononuclear cells. Both CMV-specific humoral and cellular immunity developed within three weeks of vaccination. Whereas humoral antibody titers declined steadily with time, the cellular immune responses seemed biphasic. An early peak in lymphocyte proliferation to CMV antigen occurred three to six weeks after immunization. Responses then diminished but increased again six to ten months after immunization. This study in a small group of normal male volunteers indicated that CMV vaccine was safe and immunogenic. That CMV vaccine elicited CMV-specific humoral and cell-mediated immunity is important, because there is evidence that both are necessary for protection from CMV infections.


A DNA/Ki67-Based Flow Cytometry Assay for Cell Cycle Analysis of Antigen-Specific CD8 T Cells in Vaccinated Mice.
The cell cycle of antigen-specific T cells in vivo has been examined by using a few methods, all of which possess some limitations. Bromodeoxyuridine (BrdU) marks cells that are in or recently completed S-phase, and carboxyfluorescein succinimidyl ester (CFSE) detects daughter cells after division. However, these dyes do not allow identification of the cell cycle phase at the time of analysis. An alternative approach is to exploit Ki67, a marker that is highly expressed by cells in all phases of the cell cycle except the quiescent phase G0. Unfortunately, Ki67 does not allow further differentiation as it does not separate cells in S-phase that are committed to mitosis from those in G1 that can remain in this phase, proceed into cycling, or move into G0. Here, we describe a flow cytometric method for capturing a "snapshot" of T cells in different cell cycle phases in mouse secondary lymphoid organs. The method combines Ki67 and DNA staining with major histocompatibility complex (MHC)-peptide-multimer staining and an innovative gating strategy, allowing us to successfully differentiate between antigen-specific CD8 T cells in G0, in G1 and in S-G2/M phases of the cell cycle in the spleen and draining lymph nodes of mice after vaccination with viral vectors carrying the model antigen gag of human immunodeficiency virus (HIV)-1. Critical steps of the method were the choice of the DNA dye and the gating strategy to increase the assay sensitivity and to include highly activated/proliferating antigen-specific T cells that would have been missed by current criteria of analysis. The DNA dye, Hoechst 33342, enabled us to obtain a high-quality discrimination of the G0/G1 and G2/M DNA peaks, while preserving membrane and intracellular staining. The method has great potential to increase knowledge about T cell response in vivo and to improve immuno-monitoring analysis.


[Evaluation of a supervision program of health centers at the district level in Madagascar].
Poor supervision and follow-up have long been recognized as major weaknesses in the development of primary health care in many countries. A program has therefore been specifically developed to strengthen the supervision activities of 18 rural health centers in Madagascar. District health officers were appropriately trained and then conducted two-monthly supervision visits. The emphasis of the training program was on problem solving, program integration and on-site training. The effects of the supervision program was assessed quantitatively and objectively. Various activities of each health center were scored before intervention, and one year after implementation of the supervision program. The improvement in most health centers was substantial, both in quantitative coverage and qualitative practice. Nevertheless, some centers appear to have been resistant to change.


Perception of risk and the attribution of responsibility for accidents.
Accidents, one often hears, "happen"; we accept, and even expect, that they will be part of daily life. But in situations in which injury or death result, judgments of responsibility become critical. How might our perceptions of risk influence the ways in which we allocate responsibility for an accident? Drawing from attribution and risk perception theory, this study investigates how perceived controllability and desirability of risk, in addition to perceived danger and recreational risk-taking, relate to attributions of responsibility for the cause of unintentional injury in a unique setting: U.S. national parks. Three parks, Mount Rainier, Olympic, and Delaware Water Gap, provide the setting for this survey-based study, which considers how park visitors (N = 447) attribute responsibility for the cause of a hypothetical visitor accident. Results suggest that respondents tended to make more internal (i.e., related to characteristics of the victim), rather than external (i.e., related to characteristics of the park, or park management) attributions. As respondents viewed park-related risk as controllable, they were more likely to attribute the cause of the accident to the victim. Moreover, among other significant variables, having experienced a similar accident predicted lower internal causal attribution. Opportunities for future research linking risk perception and attribution variables, as well as practical implications for the management of public outdoor settings, are presented.


Discovery and characterization of cross-reactive intrahepatic antibodies in severe alcoholic hepatitis.
The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and Escherichia coli K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and E. coli antigens. Further, both Ig- and E. coli-captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and E. coli-captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.


Vision with different presbyopia corrections simulated with a portable binocular visual simulator.
Presbyopes can choose today among different corrections to provide them with functional vision at far and near, and the outcomes and patient satisfaction depend on the selection. In this study, we present a binocular and portable vision simulator, based on temporal multiplexing of two synchronized tunable lenses allowing see-through and programmable visual simulations of presbyopic corrections. Seventeen binocular corrections were tested: 3 Monofocal (Far, Intermediate, Near), 4 Simultaneous Vision (bifocal, trifocal), 2 Monovision (far and near in either eye) and 8 Modified Monovision corrections (Simultaneous vision in one eye, Monofocal in the other eye). Perceived visual quality was assessed through the simulated corrections in 8 cyclopleged subjects who viewed a composite realistic visual scene with high contrast letters and a landscape at far (4 m) and a high contrast text at intermediate (66 cm) and near (33 cm) distances. Perceptual scores were obtained on a scale of 0 to 5 (low to high perceived quality). Perceptual preference was assessed by judging 36 random image pairs (6 repetitions) viewed through 9 binocular presbyopic corrections using two-interval forced choice procedures. The average score, across far and near distances, was the highest for Monovision (4.4±0.3), followed by Modified Monovision (3.4±0.1), Simultaneous Vision (3.0±0.1) and Monofocal corrections (2.9±0.2). However, the mean difference between far and near was lower for Simultaneous Vision and Monovision (0.4±0.1 PS) than Modified Monovision (1.8±0.7) or monofocal corrections (3.3±1.5). A strong significant correlation was found between the perceptual scores and the percentages of energy in focus, for each correction and distance (R = 0.64, p<0.0001). Multivariate ANOVA revealed significant influence of observation distances (p<10-9) and patients (p = 0.01) on Perceptual Score. In conclusion, we have developed a binocular portable vision simulator that can simulate rapidly and non-invasively different combinations of presbyopic corrections. This tool has applications in systematic clinical evaluation of presbyopia corrections.


Pronator Teres Myotendinous Tear.
Pronator teres muscle strain is a rare sporting injury reported thus far only in cricket and golf players. The injury appears to occur when the sporting club or racket strikes the ground during a forceful swing and causes the elbow to experience an eccentric force during resisted elbow flexion and pronation. On initial presentation, this injury can be mistaken for injury to the medial ulnar collateral ligament, or exacerbation of medial epicondylitis. On examination, bruising and tenderness distal to the elbow over the course of the pronator teres are often present. Advanced imaging confirms the diagnosis and can help in grading injury severity. In this article, we report the case of a patient who was conservatively treated, and returned to function and sport by 6 weeks after a period of rest and restricted activities. The prognosis is excellent for even high-grade strains. Complete return to sporting function without residual weakness is expected.


Osteoblastoma of the clavicle.
A 14-year-old female with a 1-year history of a painful clavicle mass underwent resection and reconstruction with an intercalated autograft and rigid plate fixation. The histopathology was diagnostic for osteoblastoma. Although a clavicle mass is a common entity following clavicle trauma, less common disorders such as bone tumors need to be considered in the differential diagnosis. Osteoblastoma is an uncommon, benign bone tumor representing 1% of all primary bone tumors. An extensive review of the literature reveals only one reported case of clavicular osteoblastoma.


Measurement of endogenous and exogenous alpha-granular platelet proteins in patients with immune and nonimmune thrombocytopenia.
Idiopathic thrombocytopenic purpura (ITP) is caused by antiplatelet antibodies and is characterized by increased platelet destruction and elevated levels of IgG (platelet-associated IgG, PAIgG). Nonimmune thrombocytopenic patients also have elevated levels of PAIgG. In this study we investigated two possible biological explanations for the increased levels of PAIgG in these patients. The first hypothesis suggests that a thrombocytopenic stress causes increased thrombocytopoiesis with increased numbers and content of the platelet alpha granules. The second hypothesis is that for uncertain reasons (immunological or cytokine) there is increased absorption of plasma proteins by either megakaryocytes or by the platelets themselves. To address this issue, we compared the level of megakaryocyte synthesized alpha granular proteins [platelet factor 4 (PF4) and beta-thromboglobulin (beta-TG)] to plasma-absorbed alpha granular proteins (albumin, IgG and fibrinogen) in patients with immune (n = 39) and nonimmune (n = 60) thrombocytopenias. Plasma-absorbed alpha-granular proteins were elevated in both immune and nonimmune thrombocytopenia with no increase in megakaryocyte synthesized alpha-granular proteins. These plasma-derived protein elevations were not attributable to elevated mean platelet volumes or elevated plasma concentrations of the respective protein. We hypothesize that the increased IgG in these platelets is not the result of production of larger platelets, but reflects a selective increase in the endocytosis of plasma-absorbed alpha-granular proteins at the megakaryocyte and/or platelet level.


Dental anxiety in 6-7-year-old children treated in accordance with conventional restorative treatment, ART and ultra-conservative treatment protocols.
To test the hypothesis that dental anxiety levels of children treated in accordance with the conventional restorative treatment (CRT) are higher than in children treated with the atraumatic restorative treatment (ART) or ultra-conservative treatment (UCT) protocols. In total, 302 children aged 6-7-years old, with at least two dentine carious lesions, constituted the sample. A parallel group study design was used with ART and UCT as test groups and CRT as the control. The treatment was divided into two sessions. In the first session, one carious tooth (class II in a primary molar) was randomly selected and treated according to one of the treatments. All other treatments were performed in the second session. Before the first (FIS Tx-1) and before the second session (FIS Tx-2) the level of dental anxiety was assessed using the Facial Image Scale (FIS). The GLM test and Spearman's Rank Correlation Coefficient were used to analyse the data. No treatment group effect was observed on the FIS Tx-2 score (p = 0.64). A FIS Tx-1 score (p < 0.0001) effect on the FIS Tx-2 score was observed. The correlation coefficient between FIS Tx-1 and FIS Tx-2 scores was r = 0.30 (p < 0.0001). At the beginning of the second session there was no difference in dental anxiety levels of the children treated in the first session according to the three treatment protocols. A high dental anxiety score before the first session was a predictor of a high dental anxiety score at the second treatment session.


Vocational adjustment after total laryngectomy.
In-depth interviews were conducted with 60 laryngectomy patients. Data were collected on postsurgical rehabilitation in terms of employment, speech, and social functioning. Analysis of the data indicated that only one-third of the respondents were working fulltime or parttime. Twenty-six (43%) of the respondents were retired or not working, due to their health. Employment after surgery was not statistically related to the other measures of rehabilitation success that indicated levels of social functioning in general. In addition, most of the respondents did not cite employer discrimination as their reason for not working. Failure to work after surgery appeared in most cases to be initiated by the respondent, and did not indicate a failure to achieve a high level of rehabilitation in other areas of functioning.


Risk factors for unsafe behaviors toward grenades among rural populations affected by explosive devices in Colombia.
Following decades of armed conflict, Colombia remains highly affected by explosive device (ED) contamination, especially in rural areas. Many victims are injured by EDs despite knowing their dangers. Determining risk factors for unsafe behaviors toward EDs, including grenades, is critical for preventing injuries. In 2012, CDC assisted Colombian partners in conducting a multi-stage knowledge, attitudes, and practices survey in rural ED-affected areas. Within each of 40 clusters, 28 households were selected, and participants aged 10 years or older were asked about behaviors toward EDs. Participants reported actual behaviors toward past EDs encountered and theoretical behaviors toward EDs not encountered. Behaviors were a priori classified as unsafe or safe. This analysis focuses on behaviors toward the most commonly encountered device, grenades. Of 928 adult and 562 child participants, 488 (52.5%) adults and 249 (43.9%) children encountered ED, while 121 (13.7%) adults and 148 (26.9%) children received mine risk education (MRE). Among the 430 (46.7%) adults who encountered grenades, 113 (25.7%) reported unsafe behaviors; multivariable analysis showed that unsafe behavior was associated with working outdoors (adjusted odds ratio [aOR]: 1.7, 95% confidence interval [CI]: 1.1-2.7). Among the 429 (46.5%) adults who did not encounter ED, 61 (14.6%) described unsafe theoretical behaviors toward grenades; multivariable analysis showed that unsafe behavior was associated with older age (aOR: 1.02, 95% confidence limit [CL]: 1.00-1.05) and black or Afro-Colombian identity (aOR: 2.5, 95% CI 1.3-5.1). Among the 181 (32.0%) children who encountered grenades, 41 (23.8%) reported unsafe behaviors, while among the 311 (55.9%) children who did not encounter ED, 30 (10.2%) reported unsafe behavior. In both groups of children, multivariable analysis showed that unsafe behavior was associated with lower mean score on knowledge of ED, with aOR: 0.7, 95% CL: 0.6-0.9, and aOR: 0.8, 95% CL: 0.6-0.98, respectively. Participants reported frequent ED exposure but low receipt of MRE. Our findings should guide MRE improvement in ED-affected areas by strengthening the connection between ED knowledge and avoiding unsafe behavior, with a particular focus on people working outdoors. MRE should promote knowledge of ED risks but should also recognize socioeconomic factors that lead to engaging in unsafe behaviors.


Economic downturns and suicide mortality in the USA, 1980-2010: observational study.
Several studies have suggested strong associations between economic downturns and suicide mortality, but are at risk of bias due to unmeasured confounding. The rationale for our study was to provide more robust evidence by using a quasi-experimental design. We analysed 955,561 suicides occurring in the USA from 1980 to 2010 and used a broad index of economic activity in each US state to measure economic conditions. We used a quasi-experimental, fixed-effects design and we also assessed whether the effects were heterogeneous by demographic group and during periods of official recession. After accounting for secular trends, seasonality and unmeasured fixed characteristics of states, we found that an economic downturn similar in magnitude to the 2007 Great Recession increased suicide mortality by 0.14 deaths per 100,000 population [95% confidence interval (CI) 0.00, 0.28] or around 350 deaths. Effects were stronger for men (0.28, 95% CI 0.07, 0.49) than women and for those with less than 12 years of education (1.22 95% CI 0.83, 1.60) compared with more than 12 years of education. The overall effect did not differ for recessionary (0.11, 95% CI -0.02, 0.25) vs non-recessionary periods (0.15, 95% CI 0.01, 0.29). The main study limitation is the potential for misclassified death certificates and we cannot definitively rule out unmeasured confounding. We found limited evidence of a strong, population-wide detrimental effect of economic downturns on suicide mortality. The overall effect hides considerable heterogeneity by gender, socioeconomic position and time period.


Visualizing energy landscapes with metric disconnectivity graphs.
The visualization of multidimensional energy landscapes is important, providing insight into the kinetics and thermodynamics of a system, as well the range of structures a system can adopt. It is, however, highly nontrivial, with the number of dimensions required for a faithful reproduction of the landscape far higher than can be represented in two or three dimensions. Metric disconnectivity graphs provide a possible solution, incorporating the landscape connectivity information present in disconnectivity graphs with structural information in the form of a metric. In this study, we present a new software package, PyConnect, which is capable of producing both disconnectivity graphs and metric disconnectivity graphs in two or three dimensions. We present as a test case the analysis of the 69-bead BLN coarse-grained model protein and show that, by choosing appropriate order parameters, metric disconnectivity graphs can resolve correlations between structural features on the energy landscape with the landscapes energetic and kinetic properties.


A comparison of high and low dosage regimes of maprotiline (Ludiomil).
A double-blind, randomized, multicentre trial is described which was designed to compare the clinical effect of 30 mg and 75 mg daily of maprotiline (Ludiomil) administered as either once or thrice daily therapy. Physicians' assessment of patients' progress was made following 7, 14 and 28 days of treatment. Patients also assessed themselves using a visual analogue scale at the same time intervals. Of the 231 patients admitted to the study, 40 dropped out for various reasons, leaving 191 patients completing. Of the 40 drop-outs, drug-induced side-effects were considered to be responsible in the case of 17 patients. No differences between the four treatment groups were demonstrated on the physicians' assessment; however, the patients' self-assessments using the 10 cm visual analogue scale indicated that the 25 mg three times daily regime appeared to be the most satisfactory, but not statistically significantly so, when compared with the 10 mg thrice daily and 75 mg nocte regimes. The 30 mg nocte dose proved to be distinctly inferior.


Mode and site of action of therapies targeting CGRP signaling.
Targeting CGRP has proved to be efficacious, tolerable, and safe to treat migraine; however, many patients with migraine do not benefit from drugs that antagonize the CGRPergic system. Therefore, this review focuses on summarizing the general pharmacology of the different types of treatments currently available, which target directly or indirectly the CGRP receptor or its ligand. Moreover, the latest evidence regarding the selectivity and site of action of CGRP small molecule antagonists (gepants) and monoclonal antibodies is critically discussed. Finally, the reasons behind non-responders to anti-CGRP drugs and rationale for combining and/or switching between these therapies are addressed.


Low-temperature synthesis of superconducting iron selenide using a triphenylphosphine flux.
Many functional materials have relatively low decomposition temperatures (T≤ 400 °C), which makes their synthesis challenging using conventional high-temperature solid-state chemistry. Therefore, non-conventional techniques such as metathesis, hydrothermal, and solution chemistry are often employed to access low-temperature phases; the discovery of new chemistries is needed to expand access to these phases. This contribution discusses the use of triphenylphosphine (PPh3) as a molten flux to synthesize superconducting iron selenide (Fe1+δSe) at low temperature (T = 325 °C). Powder X-ray diffraction and magnetism measurements confirm the successful formation of superconducting iron selenide while nuclear magnetic resonance spectroscopy and in situ X-ray diffraction show that the formation of superconducting FeSe at low temperatures is enabled by an adduct between the triphenylphosphine and selenium. Exploration of the Fe-Se-PPh3 phase space indicates that the PPh3-Se adduct effectively reduces the chemical potential of the selenium at high concentrations of triphenylphosphine. This contribution demonstrates that the use of a poorly-solvating yet reactive flux has the potential to enable the synthesis of new low-temperature phases of solid materials.


Pathogenesis of chronic wasting disease in cervidized transgenic mice.
Chronic wasting disease (CWD) is a fatal, endemic prion disease of wild and captive cervids, including deer, elk, and moose. Typical of prion diseases, CWD is characterized by the conversion of the native, protease-sensitive protein PrP(C) to a protease-resistant isoform, denoted as PrP(RES). Here we have studied the expression of cervid PrP(C) and the pathogenesis of CWD infection in transgenic mice expressing the normal cervid prion protein (Tg[CerPrP] mice). Using tissue-based in situ immunohistochemistry protocols, we first identified cervid PrP(C) expression in the lymphoid, nervous, hemopoietic, endocrine, and certain epithelial tissues of Tg[CerPrP] mice. Tg[CerPrP] mice were then inoculated with CWD via one of four routes (intracerebral, intravenous, intraperitoneal, or oral); all groups developed spongiform encephalopathy, although the oral route required a larger infecting dose. Incubation periods were 184 +/- 13, 218 +/- 15, 200 +/- 7, and 350 +/- 27 days after inoculation, respectively. In longitudinal studies, we tracked the appearance of PrP(RES) in the brain, spleen, Peyer's patches, lymph nodes, pancreatic islets of Langerhans, bone marrow, and salivary glands of preclinical and terminal mice. In addition, we documented horizontal transmission of CWD from inoculated mice and to un-inoculated cohabitant cage-mates. This work documents the multiroute susceptibility, pathogenesis, and lateral transmission of CWD infection in Tg[CerPrP] mice, affirming this model as a robust system to study this cervid transmissible spongiform encephalopathy.


A SMART approach to optimizing delivery of an mHealth intervention among cancer survivors with posttraumatic stress symptoms.
Many cancer survivors who received intensive treatment such as hematopoietic stem cell transplantation (HCT) experience posttraumatic stress disorder (PTSD) symptoms. PTSD is associated with lower quality of life and other symptoms that require clinical treatment. The iterative treatment decisions that happen in clinical practice are not adequately represented in traditional randomized controlled trials (RCT) of PTSD treatments. The proposed stepped-care SMART design allows for evaluation of initial response to the Cancer Distress Coach mobile app; adaptive stepped-care interventions; and precision treatment strategies that tailor treatment selection to patient characteristics. HCT survivors (N = 400) reporting PTSD symptoms are being recruited at two cancer centers and randomly assigned to: 1) Cancer Distress Coach app or 2) Usual Care. The app includes educational and cognitive behavioral therapy (CBT)-based activities. Four weeks post-randomization, participants re-rate their PTSD symptoms and, based on intervention response, non-responders are re-randomized to receive video-conferenced sessions with a therapist: 3) coaching sessions in using the mobile app; or 4) CBT specific to HCT survivors. Participants complete outcome measures of PTSD, depression, and anxiety after Months 1, 3, and 6. Participant characteristics moderating intervention responses will be examined. This novel adaptive trial design will afford evidence that furthers knowledge about optimizing PTSD interventions for HCT survivors. To our knowledge, this study is the first SMART design evaluating PTSD symptom management in cancer survivors. If successful, it could be used to optimize treatment among a range of cancer and other trauma survivors.


[Psychometric evaluation of the Hare Psychopathy Questionnaire in a Belgian prison population].
The PCL-R (Hare, 1991) presents high reliability and validity characteristics. The instrument is the measure of choice for the assessment of psychopathic personality. The PCL-R has never been submitted to psychometric analysis in french speaking european samples. The study examines the psychometric characteristics of the PCL-R on an Belgian prison sample. The study assessed the inter-raters reliability parameters, the Alpha Cronbach coefficient and the PCL-R mean scores. The two correlated factors extracted were compared with those of others European and Nord American samples. The study also described the concomitant validity of the instrument by computing the correlations between the PCL-R scores and the type of offence.