[Surgery of emphysematous bullae and pulmonary cysts (author's transl)].
Following a survey of operations performed at the Ruhrland clinic, particular reference is made to the surgical treatment of emphysematous bullae and pulmonary cysts. In these cases, the frequent occurrence of a pneumothorax must here be mentioned. These large bullae are however frequently and incorrectly diagnosed as a pneumothorax. The treatment of these emphysematous bullae, which often occur on both sides of the thorax, is by means of a bilateral axillary thoracotomy. This operation can be carried out in one session, provided a distinct improvement of the pulmonal functions is expected.


A factor analysis of lumbar intradiscal electrothermal annuloplasty outcomes.
Intradiscal electrothermal annuloplasty (IDET) is a minimally invasive procedure for managing chronic discogenic low back pain (LBP). Although there have been numerous reports of IDET outcome rates, few have dissected the detailed factors affecting those outcomes. To evaluate how heating variables and the number of catheters used affect the outcomes and pain flare-up in LBP patients treated with IDET. Retrospective analysis. Data were gathered on the basis of chart records from January 6, 1999 to January 6, 2000. Twenty-five cases treated at a single level with disc protrusion < or = 2 mm, nonfocal neurological abnormalities, and positive discogram with annular tear were studied. Six patients were unavailable for follow-up at 16 months. All assessments were incorporated into our own evaluation sheet, completed before the procedure and at follow-up. Assessments included the following: 1) Visual Analog Scale (VAS) and 2) Back Pain Improvement Scales (BPI) preoperatively and at 8 and 16 months post-procedure. Post-procedure flare-up of the pain was defined as the pain aggravation after the IDET procedure from the pre-procedure baseline pain. It was evaluated by a 10-point numeric rating scale, ranging from no aggravated pain "0" to the worst aggravated pain "10". Patients were partitioned into a single-catheter group and a double-catheter group. In these two groups, statistical analyses were done to compare the outcomes and flare-up duration and intensity. In each catheter group, the correlation coefficients were analyzed between heating variables such as heating duration/temperature and two outcome scales. Then, two outcome scales relative to intensity and duration of post-IDET flare-up were analyzed with Pearson's correlation. Also the combined effect of the heating duration and temperature was evaluated as a thermal dosage, which is the total amount of heat developed during the procedure. It was calculated by multiplying the temperature and its heating duration above a starting temperature of 65 degrees C. Comparing the single- and double-catheter groups, patients placed in the single-catheter group showed significantly shorter flare-up duration (11.00+/-19.17 vs. 24.89+/-20.84 days, p < .05). In the single-catheter group, the flare-up duration manifested moderate linear correlation with heating variables (0.580 with temperature, 0.519 with thermal dosage, p < .05). Also, the improvements of pain with VAS displayed moderate reverse correlation with heating variables at 8 months (-.436 with temperature, -0.439 with thermal dosage, p < .1). In the double-catheter group, the Back Pain Improvement% had strong reverse correlations with temperature and thermal dosage at 8 months (-.735 and -.729, p < .05). The correlation between the improvement of VAS and temperature yielded a moderate reverse relationship (-.619, p < 0.1). These correlations were not, however, observed at 16 months in either the single- or double-catheter groups. Higher temperatures and larger total heating doses during IDET procedures with catheters placed in the outer annulus may increase the duration of post-procedure pain flare-ups and lead to less favorable outcomes at 8 months follow-up. The long-term outcomes at 16 months may, however, not be affected by these heating variables.


Attentional prioritization in dual-task walking: Effects of stroke, environment, and instructed focus.
The impact of high distraction, real-world environments on dual-task interference and flexibility of attentional prioritization during dual-task walking in people with stroke is unknown. How does a real-world environment affect dual-task performance and flexible task prioritization during dual-task walking in adults with and without stroke? Adults with stroke (n = 29) as well as age-, gender-, and education-matched adults without stroke (n = 23) participated. Single and dual-task walking were examined in two different environments (lab hallway, hospital lobby). Two different dual-task combinations were assessed (Stroop-gait, speech-gait). Each dual-task was performed first without explicit instruction about task prioritization (no-priority) and then with gait-priority instruction and Stroop/speech-priority instruction in randomized order. People with stroke had significantly slower dual-task gait speed (Stroop only) in the lobby than the lab, but the effect was not clinically meaningful. Stroop reaction time for all participants was also slower in the lobby than the lab. All participants slowed their walking speed while generating spontaneous speech, but this effect was not influenced by environment. The dual-task attention allocation strategy was generally inflexible to instructed prioritization in adults with and without stroke in both environments, however, the volitional attention allocation strategy differed for the two dual-task conditions such that speech was prioritized in the speech-gait dual-task and gait appeared to be prioritized in the Stroop-gait dual-task. Although dual-tasking slows walking speed and verbal responses to auditory stimuli in people with stroke, the effects are not considerably impacted by a more complex, distracting environment. Adults with and without stroke may have difficulty overriding the preferred attention allocation strategy during dual-task walking, especially for habitual dual-tasks such as walking while speaking. It may also be that the cognitive control strategy governing task prioritization is influenced by degree of cognitive engagement.


Once-Weekly Administration of Sustained-Release Growth Hormone in Korean Prepubertal Children with Idiopathic Short Stature: A Randomized, Controlled Phase II Study.
To determine the optimal dose of LB03002, a sustained-release, once-weekly formulation of recombinant human growth hormone (rhGH), and to compare its efficacy and safety with daily rhGH in children with idiopathic short stature (ISS). This multicenter, randomized, open-label, phase II study included GH-naïve, prepubertal children with ISS, randomized to receive daily rhGH 0.37 mg/kg/week (control, n = 16), LB03002 0.5 mg/kg/week (n = 14), or LB03002 0.7 mg/kg/week (n = 16). The primary endpoint was height velocity (HV) change at week 26. At week 26, the least square (LS) means for HV change (cm/year) with control, LB03002 0.5 mg/kg/week, and LB03002 0.7 mg/kg/week were 5.08, 3.65, and 4.38, and the LS means for the change in height standard deviation score were 0.65, 0.49, and 0.58, respectively. The lower bound of the 90% confidence interval for the difference between LB03002 0.7 mg/kg/week and the control in the LS mean for HV change (-1.72) satisfied the noninferiority margin (-1.75). Adverse events were generally mild and short-lived. A once-weekly regimen of LB03002 0.7 mg/kg demonstrated noninferiority to the daily regimen of rhGH 0.37 mg/kg/week in terms of HV increments. LB03002 was well tolerated and its safety profile was comparable with that of daily rhGH.


Teams in the workplace: the way to power them to productivity.
Teams! Teams! Teams! It seems you can't pick up a trade magazine or periodical without seeing something about team building. Once you get by the buzzwords and the acronyms, you have to wonder who's really doing it right. This article explains a proven process to build productive work teams. Teams that get bottom line results in the first 90 to 120 days. The author presents the five keys to assure successful work teams the very first time! In addition, you will learn five issues management must address, five skills every team member must master, five ways to help team members learn faster, and five tips to ensure a powered start to productivity.


The cytotoxic activity of Bacillus anthracis lethal factor is inhibited by leukotriene A4 hydrolase and metallopeptidase inhibitors.
The lethal factor of Bacillus anthracis is central to the pathogenesis of anthrax. Its mechanism of action is still unknown. Recently, on the basis of sequence similarities, we suggested that lethal factor might act similarly to leukotriene A4 hydrolase (LTA4), a bifunctional enzyme also endowed with a metallopeptidase activity. Here we show that some inhibitors of the LTA4 hydrolase and metallopeptidase activities of LTA4 hydrolase also affect the cytotoxicity of the anthrax lethal factor on macrophage cell lines, without interfering with the ability of the lethal factor to enter cells. These results support the proposal that anthrax lethal factor might display in the cytosol of intoxicated cells a peptidase activity similar to that of LTA4 hydrolase.


Using technology to improve adolescent healthcare.
To provide an overview of current technologies available for use in a primary healthcare setting, common indications for their use, and their effects on clinical practice. Technologies such as the internet and cell phones are an integral part of the daily lives of most adolescents. Many young people are comfortable using technology as part of their healthcare visits, especially when addressing sensitive issues. Over the past 5 years, a significant body of research has emerged introducing a variety of technologic modalities that screen for health-risk behaviors, educate patients about chronic diseases, promote preventive efforts, and provide interventions in the adolescent population. Findings suggest that integrating technology with clinical practice can improve quality of patient care. Technology can be used as an effective medium for the delivery of health information and interventions in an efficient, organized, and effective manner. Sharing knowledge of innovative tools, systems and programs will help develop further interventions and strategies to ensure optimal healthcare in young people.


Association Between Vancomycin Blood Brain Barrier Penetration and Clinical Response in Postsurgical Meningitis.
This study investigated the association between vancomycin blood brain barrier penetration and clinical response in patients with postsurgical meningitis. Adult patients with postsurgical meningitis were recruited. Eligible patients received vancomycin 500 mg every 6 h for at least 5 days. On day 3 or 4, cerebrospinal fluid (CSF) and simultaneous serum samples were obtained to determine CSF minimum concentrations (Cmin), serum Cmin and CSF to serum Cmin ratio. Twenty-two patients (14 men and 8 women; mean age of 52.6± 12.1 years) were recruited. The vancomycin Cmin was 3.63 ± 1.64 mg/L in CSF and 13.38 ± 5.36 mg/L in serum, with the CSF to serum Cmin ratio of 0.291 ± 0.118. The Cmin in serum and in CSF showed a significant correlation (p=0.005, r =0.575). The vancomycin CSF Cmin had a significant correlation with the decline of white blood cell counts (WBCs) in CSF (p=0.003, r =0.609). CSF Cmin, serum Cmin and CSF to serum Cmin ratio all showed no significant correlation with clinical response (p=0.335, 0.100, 0.679, respectively). There was a positive correlation between serum Cmin and CSF Cmin. However, only CSF Cmin is positively correlated with WBCs improvement in CSF. All other parameters such as serum Cmin, CSF Cmin and CSF to serum Cmin ratio had no correlation with clinical response. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.


Anomalous swelling in phospholipid bilayers is not coupled to the formation of a ripple phase.
Aligned stacks of monomethyl and dimethyl dimyristoyl phosphatidylethanolamine (DMPE) lipid bilayers, like the much studied dimyristoyl PC (DMPC) bilayers, swell anomalously in a critical fashion as the temperature is decreased within the fluid phase towards the main transition temperature, T(M). Unlike DMPC bilayers, both monomethyl and dimethyl DMPE undergo transitions into a gel phase rather than a rippled phase below T(M). Although it is not fully understood why there is anomalous swelling, our present results should facilitate theory by showing that the formation of the phase below T(M) is not related to critical phenomena above T(M).


Baseline Circulating Tumor Cell Count as a Prognostic Marker of PSA Response and Disease Progression in Metastatic Castrate-Sensitive Prostate Cancer (SWOG S1216).
In metastatic castrate-sensitive prostate cancer (mCSPC), combined androgen axis inhibition is a standard of care. Noninvasive biomarkers that guide initial therapy decisions are needed. We hypothesized that CellSearch circulating tumor cell (CTC) count, an FDA-cleared assay in metastatic castrate-resistant prostate cancer (mCRPC), is a relevant biomarker in mCSPC. SWOG S1216 is a phase III prospective randomized trial of androgen deprivation therapy (ADT) combined with orteronel or bicalutamide for mCSPC. CellSearch CTC count was measured at registration (baseline). Prespecified CTC cut-off points of 0, 1-4, and ≥5 were correlated with baseline patient characteristics and, in a stratified subsample, were also correlated with two prespecified trial secondary endpoints: 7-month PSA ≤0.2 ng/mL versus 0.2-4.0 versus >4.0 (intermediate endpoint for overall survival); and progression-free survival (PFS) ≤ versus >2 years. A total of 523 patients submitted baseline samples, and CTCs were detected (median 3) in 33%. Adjusting for two trial stratification factors (disease burden and timing of ADT initiation), men with undetectable CTCs had nearly nine times the odds of attaining 7-month PSA ≤ 0.2 versus > 4.0 [OR 8.8, 95% confidence interval (CI), 2.7-28.6, P < 0.001, N = 264] and four times the odds of achieving > 2 years PFS (OR 4.0, 95% CI, 1.9-8.5, P < 0.001, N = 336) compared with men with baseline CTCs ≥5. Baseline CTC count in mCSPC is highly prognostic of 7-month PSA and 2-year PFS after adjusting for disease burden and discriminates men who are likely to experience poor survival outcomes.


Mapping the trajectory of the amygdalothalamic tract in the human brain.
Although the thalamus is not considered primarily as a limbic structure, abundant evidence indicates the essential role of the thalamus as a modulator of limbic functions indirectly through the amygdala. The amygdala is a central component of the limbic system and serves an essential role in modulating the core processes including the memory, decision-making, and emotional reactions. The amygdalothalamic pathway is the largest direct amygdalo-diencephalic connection in the primates including the human brain. Given the crucial role of the amygdalothalamic tract (ATT) in memory function and diencephalic amnesia in stroke patients, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. To date, few diffusion-weighted studies have focused on the amygdala, yet the fine neuronal connection of the amygdala and thalamus known as the ATT has yet to be elucidated. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the ATT in the human brain. We studied 15 healthy right-handed human subjects (12 men and 3 women with age range of 24-37 years old). Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to reconstruct and measure the trajectory of the ATT. We further revealed the close relationship of the ATT with the temporopontine tract and the fornix bilaterally in 15 healthy adult human brains.


Enzyme-linked immunoassay. Conjugation of rabbit anti-(human immunoglobulin G) antibody with beta-D-galactosidase from Escherichia coli and its use for human immunoglobulin G assay.
Rabbit immunoglobulin G (IgG) was reduced by incubating with 10 mM 2-mercaptoethylamine and then treated with excess amounts of N,N'-o-phenylenedimaleimide. As a result, maleimide residues were introduced into rabbit IgG molecules. Rabbit IgG containing maleimide residues could be coupled to beta-D-galactosidase from Escherichia coli which has sulfhydryl groups in the molecule. The resulting rabbit IgG (antibody)-enzyme complex may be useful for immunoassay of antigens. As an example, human IgG was assayed by the sandwich method using the rabbit anti-(human IgG) IgG-beta-D-galactosidase complex and amounts of human IgG as small as 3 fmoles were measurable.


Platelet transfusions reduce fibrinolysis but do not restore platelet function during trauma hemorrhage.
Platelets play a critical role in hemostasis with aberrant function implicated in trauma-induced coagulopathy. However, the impact of massive transfusion protocols on platelet function during trauma hemorrhage is unknown. The aim of this study was to characterize the effects of platelet transfusion on platelet aggregation and fibrinolytic markers during hemostatic resuscitation. Trauma patients enrolled into the prospective Activation of Coagulation and Inflammation in Trauma study between January 2008 and November 2015 who received at least four units of packed red blood cells (PRBCs) were included. Blood was drawn in the emergency department within 2 hours of injury and at intervals after every four units of PRBCs transfused. Platelet aggregation was assessed in whole blood with multiple electrode aggregometry. Plasma proteins were quantified by enzyme-linked immunosorbent assay. Of 161 patients who received four or more PRBCs as part of their initial resuscitation, 44 received 8 to 11 units and 28 received 12 units or more. At each timepoint during bleeding, platelet aggregation was similar in patients who had received a platelet transfusion compared with those who had only received other blood products (p > 0.05 for all timepoints). Platelet transfusion during the four PRBC intervals was associated with a decrease in maximum lysis on rotational thromboelastometry (start of interval, 6% [2-12] vs. end of interval, 2% [0-5]; p = 0.001), an increase in plasminogen activator inhibitor-1 (start of interval, 35.9 ± 14.9 vs. end of interval, 66.7 ± 22.0; p = 0.007) and a decrease in tissue plasminogen activator (start of interval, 26.2 ± 10.5 vs. end of interval, 19.0 +/- 5.1; p = 0.04). No statistically significant changes in these parameters occurred in intervals which did not contain platelets. Current hemostatic resuscitation strategies do not appear to restore platelet aggregation during active hemorrhage. However, stored platelets may attenuate fibrinolysis by providing an additional source of plasminogen activator inhibitor-1. Further investigation into the effects of early platelet transfusion on platelet function, hemostatic, and clinical outcomes during bleeding are warranted. Therapeutic, level III.


Seeded assembly in vitro does not replicate the structures of α-synuclein filaments from multiple system atrophy.
The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of α-synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human α-synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of the seeds. Identification of these factors will be essential for understanding the prion-like spreading of α-synuclein proteinopathies.


Who does workforce planning well? Workforce review team rapid review summary.
This paper sets out to disseminate new knowledge about workforce planning, a crucial health sector issue. The Health Select Committee criticised NHS England's failure to develop and apply effective workforce planning. The Workforce Review Team (WRT) commissioned the Institute for Employment Research, Warwick University, to undertake a "rapid review" of global literature to identify good practice. A workforce planning overview, its theoretical principles, good practice exemplars are provided before discussing their application to healthcare. The literature review, undertaken September-November 2007, determined the current workforce planning evidence within and outside health service provision and any consensus on successful workforce planning. Much of the literature was descriptive and there was a lack of comparative or evaluative research-based evidence to inform U.K. healthcare workforce planning. Workforce planning practices were similar in other countries. There was no evidence to challenge current WRT approaches to NHS England workforce planning. There are a number of indications about how this might be extended and improved, given additional resources. The evidence-base for workforce planning would be strengthened by robust and authoritative studies. Systematic workforce planning is a key healthcare quality management element. This review highlights useful information that can be turned into knowledge by informed application to the NHS. Best practice in other sectors and other countries appears to warrant exploration.


[Expenditures on medicines at provincial hospitals in the Cape. A comparative analysis from 1982-1989].
Total expenditure on medicines at various hospitals within the Cape Provincial Administration (CPA) branch of hospital and health services has increased minimally in relation to the consumer price index of 1982 (CPI-1982). However, the calculated cost of medication per patient unit differed greatly between the hospitals studied. Calculations based on CPI-1982 showed the increase at Tygerberg Hospital (TBH) to be 24.3% lower than the increase in CPI. Based on the CPI-1985, the increase at TBH was 4.01% higher than the CPI increase. At another academic hospital the increase based on CPI-1982 was 35.78%, at two large non-academic hospitals it was 45.31% and 17.71% respectively, and for the CPA as a whole it was 18.83%. Direct comparisons of cost per patient unit between hospitals are inappropriate, because of the varying patient profiles and consequent differences in required treatments. However, a cost awareness programme seems to have been at least partially responsible for the variance in cost increase at TBH. A more intensive and sustained programme to encourage cost awareness in the prescribing of medicines is called for.


A role for DRAK2 in the germinal center reaction and the antibody response.
DAP-related apoptotic kinase-2 (DRAK2), a death-associated protein kinase family member, is highly expressed in B and T lymphocytes in the human and the mouse. To determine whether DRAK2 plays a role in B-cell activation and differentiation, we analyzed germinal centers (GCs) and the specific antibody response to NP in drak2-/- mice immunized with the thymus-dependent (TD) conjugated hapten NP16-CGG. In drak2-/- mice, spleen GCs were normal in size and morphology, but their number was reduced by as much as 5-fold, as compared to their wild-type littermates. This was not due to a defect in B-cell proliferation, as the BrdU uptake was comparable in DRAK2-deficient and wild-type B cells. Rather, the proportion of apoptotic GC B and T cells in drak2-/- mice was significantly higher than that in wild-type control mice, as shown by 7-AAD and terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL) staining. In drak2-/- mice, the generation high affinity IgG antibodies was impaired in spite of the seemingly normal somatic hypermutation and class switch DNA recombination machineries in drak2-/- B cells. In NP16-CGG-immunized drak2-/- mice, T-cell-intrinsic Bcl-xL transgene expression increased the number of GCs and rescued the high affinity IgG response to NP. These findings suggest a novel role for DRAK2 in regulating the GC reaction and the response to TD antigens, perhaps through increased survival of T cells and enhanced B-cell positive selection. They also suggest that DRAK2-deficiency is not involved in regulating intrinsic B-cell apoptosis.


A monoclonal antibody specifically modulates dihydropyridine-sensitive calcium current in BC3H1 myocytes.
The nonfusing muscle cell line BC3H1 expresses functional Na and Ca channels similar to those found in skeletal muscle (1). We have utilized a monoclonal antibody that cross-reacts with a 45-50-kDa glycoprotein in differentiated BC3H1 myocytes but not in cardiac or neuronal cells. This antibody, MAb1223, specifically modulates 45Ca influx and slowly activating, dihydropyridine-sensitive Ca currents when added to BC3H1 myocytes. Low-threshold, dihydropyridine-insensitive Ca currents and Na and K currents are unaffected. MAb1223 action is voltage dependent. At very negative holding potentials, similar to those of the resting cell, MAb1223 increases slow Ca current without significant changes in the voltage dependence of activation. At more positive potentials, at which channel opening probability is reduced by inactivation, exposure to MAb1223 reduces current. Agonist and antagonist dihydropyridines modulate the action of MAb1223 on the slow Ca channel in a manner that suggests that their respective binding sites may interact directly with the channel.


Chemoprevention of head and neck cancer with celecoxib and erlotinib: results of a phase ib and pharmacokinetic study.
Epidermal growth factor receptor (EGFR) and COX-2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. Thirty-six subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100 mg orally daily and celecoxib was fixed at 400 mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6, and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400 mg BID was 50 mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response, 43%; partial response, 14%; stable disease, 29%; and disease progression, 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (approximately 308 L) and CL/F (8.3 L/h) compared with previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6 hours. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.


Induction of the hyaluronic acid-binding protein, tumor necrosis factor-stimulated gene-6, in cervical smooth muscle cells by tumor necrosis factor-alpha and prostaglandin E(2).
Immediately before parturition the cervix undergoes striking changes in structure (ripening) that facilitate dilatation and effacement. Cervical ripening shares many features in common with inflammation-associated tissue remodeling, making it a valuable process to explore with respect to the biochemical events in extracellular matrix restructuring. Cervical ripening can be pharmacologically induced with prostaglandin E(2) (PGE(2)). Among the biochemical changes in the cervix at parturition is a marked increase in the hyaluronic acid (HA) content. HA and HA-binding proteins have been implicated in tissue hydration, release of collagenase, and leukocyte migration, but their roles in cervical ripening have not been explored. In the present study we examined the ability of PGE(2) to induce expression of the HA-binding protein, tumor necrosis factor-stimulated gene (TSG)-6, in human cervical smooth muscle cells (hCSMCs) and compared the PGE(2) response to that of tumor necrosis factor-alpha (TNF-alpha), an established inducer of TSG-6. TNF-alpha stimulated TSG-6 mRNA accumulation in a dose- and time-dependent manner, with the maximal response observed at 10 ng/ml after 6 hours of incubation. PGE(2) stimulated TSG-6 mRNA expression, but the magnitude of response was substantially less than that produced by TNF-alpha, and it was maximal only after 24 hours of incubation. Quantitative real-time polymerase chain reaction was performed to assess the induction of TSG-6 mRNA and nascent transcripts at 24 hours of treatment. Induction of TSG-6 mRNA and nascent transcripts in response to 10 micromol/L of PGE(2) was 5.7-fold and 6.3-fold greater than control values, respectively, whereas TNF-alpha (10 ng/ml) induced TSG-6 mRNA and nascent transcripts by 80-fold and 134-fold, respectively. TNF-alpha and PGE(2) stimulated secretion of TSG-6 into the culture medium as detected by Western blotting. The effects of PGE(2) on secretion of TSG-6 were delayed compared to TNF-alpha. A 1.3-kb fragment of the human TSG-6 proximal promoter drove luciferase expression in transfected hCSMCs. PGE(2) increased TSG-6 promoter activity 1.75-fold. Paradoxically, TNF-alpha reduced TSG-6 promoter activity by 50%. We conclude that hCSMCs express the hyaladherin TSG-6; that TSG-6 expression in these cells is regulated by PGE(2) as well as proinflammatory cytokines; responses of hCSMCs to TNF-alpha and PGE(2) are distinct in terms of magnitude and the time course; and PGE(2) and TNF-alpha exert different effects on the TSG-6 proximal promoter.


A Meta-analysis of Stent Placement vs. Angioplasty for Dialysis Vascular Access Stenosis.
Dysfunction of arteriovenous fistulas (AVF) and arteriovenous grafts (AVG) contribute significantly to morbidity and hospitalization in the dialysis population. Despite advances in endovascular techniques, the incidence of vascular access stenosis remains problematic. Currently, the role of endovascular stent placement in the treatment of vascular access stenosis is poorly defined. This meta-analysis compares the primary patency rates of stenotic vascular access treated with stent placement vs. angioplasty. We searched Medline for English language publications from 1980 through December 2013, along with national conference proceedings and reference lists of all included publications. Inclusion criteria were a measure of primary patency, secondary patency, or access dysfunction. Studies were excluded if they were not in English or if they included pediatric patients. Ten studies with a total of 860 subjects met the inclusion criteria, including six experimental studies and four observational studies. There was significantly higher overall primary patency in those receiving stent placement than in those treated with angioplasty (pooled relative risk [RR] = 0.79; 95% confidence interval [CI]: 0.65-0.96). The estimate did not differ by study design. The effect of treatment differed significantly (p = 0.001) by the type of stents used, however. In studies including nitinol stents (six studies, 678 patients), 6-month patency was significantly better for stent placement than angioplasty (pooled RR = 0.67; 95% CI: 0.54-0.84), whereas there was no significant differences between stent placement and angioplasty in those studies using bare metal stents exclusively (four studies, 182 patients; pooled RR = 1.09; 95% CI: 0.91-1.32). There was significant heterogeneity between studies (I(2) = 70.6%; p < 0.0001). Our results suggest that stent placement may confer an advantage over balloon angioplasty in primary patency of dialysis access stenoses.


Phosphorylation of estrogen receptor beta at serine 105 is associated with good prognosis in breast cancer.
Estrogen receptor (ER) action is modulated by posttranslational modifications. Although ERalpha phosphorylation correlates with patient outcome, ERbeta is similarly phosphorylated but its significance in breast cancer has not been addressed. We investigated whether ERbeta that is phosphorylated at serine 105 (S105-ERbeta) is expressed in breast cancer and assessed potential clinical implications of this phosphorylation. Following antibody validation, S105-ERbeta expression was studied in tissue microarrays comprising 108 tamoxifen-resistant and 351 tamoxifen-sensitive cases and analyzed against clinical data. S105-ERbeta regulation in vitro was assessed by Western blot, flow cytometry, and immunofluorescence. Nuclear S105-ERbeta was observed in breast carcinoma and was associated with better survival (Allred score > or =3), even in tamoxifen-resistant cases, and additionally correlated with ERbeta1 and ERbeta2 expression. Distinct S105-ERbeta nuclear speckles were seen in some higher grade tumors. S105-ERbeta levels increased in MCF-7 cells in response to 17beta-estradiol, the ERbeta-specific agonist diarylpropionitrile, and the partial ERbeta-agonist genistein. S105-ERbeta nuclear speckles were also seen in MCF-7 cells and markedly increased in size and number at 24 hours following 17beta-estradiol and, in particular diarylpropionitrile, treatment. These speckles were coexpressed with ERbeta1 and ERbeta2. Presence of S105-ERbeta in breast cancer and association with improved survival, even in endocrine resistant breast tumors suggest S105-ERbeta might be a useful additional prognostic marker in this disease.


Derived relational responding as generalized operant behavior.
The major aim of the present study was to demonstrate that derived relational responding may be viewed as a form of generalized operant behavior. In Experiment 1, 4 subjects were divided into two conditions (2 in each condition). Using a two-comparison matching-to-sample procedure, all subjects were trained and tested for the formation of two combinatorially entailed relations. Subjects were trained and tested across multiple stimulus sets. Each set was composed of novel stimuli. Both Conditions 1 and 2 involved explicit performance-contingent feedback presented at the end of each block of test trials (i.e., delayed feedback). In Condition 1, feedback was accurate (consistent with the experimenter-designated relations) following exposure to the initial stimulus sets. When subjects' responding reached a predefined mastery criterion, the feedback then switched to inaccurate (not consistent with the experimenter-designated relations) until responding once again reached a predefined criterion. Condition 2 was similar to Condition 1, except that exposure to the initial stimulus sets was followed by inaccurate feedback and once the criterion was reached feedback switched to accurate. Once relational responding emerged and stabilized, response patterns on novel stimulus sets were controlled by the feedback delivered for previous stimulus sets. Experiment 2 replicated Experiment 1, except that during Conditions 3 and 4 four comparison stimuli were employed during training and testing. Experiment 3 was similar to Condition 1 of Experiment 1, except that after the mastery criterion was reached for class-consistent responding, feedback alternated from accurate to inaccurate across each successive stimulus set. Experiment 4 involved two types of feedback, one type following tests for mutual entailment and the other type following tests for combinatorial entailment. Results from this experiment demonstrated that mutual and combinatorial entailment may be controlled independently by accurate and inaccurate feedback. Overall, the data support the suggestion, made by relational frame theory, that derived relational responding is a form of generalized operant behavior.


The impact of diabetes mellitus on the anti-tuberculosis treatment outcome: a series of cases from the Republic of Moldova.
The Republic of Moldova ranks among the European Region countries with the highest global incidence of tuberculosis. Almost 5% of the cases with pulmonary TB had been diagnosed with DM in 2017. The aim of this study was to assess the impact of diabetes mellitus on the anti-tuberculosis treatment effectiveness for the improvement of the disease outcome. A retrospective, longitudinal and case-control study, which included a total number of 252 patients diagnosed with pulmonary tuberculosis and distributed into a study group of 93 patients diagnosed with diabetes mellitus and a control group of 159 patients without glycemic disorders was performed. The statistical analysis was performed using EpiInfo software. The statistical analysis of the differences between normally distributed continuous variables was tested with the Student T-test. Based on the collected data we established that the majority of the patients with glycemic disorders were diagnosed with the type 2 diabetes, associated with hyperglycemia and in half of them complications of diabetes were revealed. The age older 55 years and the low economical state were common characteristics of the diabetic patients. Tuberculosis was detected in every second diabetic patient through the radiological screening compared with the passive detection of most of the non-diabetic patients. The anti-tuberculosis treatment outcome was endangered by a higher rate of the adverse drug events in patients with diabetes, which contributed to death in 15%, lost to follow-up 7%, and therapeutic failure in 6%. The anti-tuberculous treatment outcome in patients diagnosed with tuberculosis and diabetes mellitus was significantly diminished by glycemic disorders, history of the previous anti-tuberculous treatment and adverse drug reactions. Individualized therapeutic approach to tuberculosis could improve the treatment effectiveness.


Heart rate variability is encoded in the spontaneous discharge of thalamic somatosensory neurones in cat.
1. We studied the spontaneous discharge variability of thalamocortical somatosensory neurones in the awake cat in order to disclose its possible information content. The presence of slow (0.09-1.39 Hz) regular fluctuations in the discharge rate of these cells during the waking state has been previously reported. Oscillations in a similar frequency range are known to characterize the activity of central and peripheral neurones pertaining to the autonomic nervous system and the variability of heart period (RR interval variability). 2. A surrogate data test, performed on our database, confirmed the presence of slow (0.05-1 Hz) non-random fluctuations in firing rate. 3. Linear regression detected the presence of an inverse relationship between the values of RR interval and the concurrent levels of neural discharge. 4. Frequency domain analysis indicated that a significant coupling between the two variability signals preferentially occurred in two frequency bands: in the frequency of the respiratory sinus arrhythmia and in correspondence with a slower rhythm (0.07-0.3 Hz), the two signals being in phase opposition in most of the cases. 5. Coherent fluctuations could also be observed when epochs of evoked activity were analysed, while coupling between the two variability signals appeared to be disrupted after sleep onset. 6. We conclude that RR interval variability, an internally generated dynamic related to basic visceral regulation, is encoded in the discharge of single somatosensory thalamocortical neurones during wakefulness. A possible interaction with the transmission of somatosensory information has to be evaluated.


Effect of menstrual cycle phase on the concentration of individual carotenoids in lipoproteins of premenopausal women: a controlled dietary study.
Because premenopausal women experience cyclic fluctuations of plasma carotenoids and their lipoprotein carriers, it is hypothesized that carotenoid concentrations in lipoprotein fractions fluctuate by phase of the menstrual cycle. Nine women ate a standard set of carotenoid-rich foods daily for two cycles under isoenergetic conditions. In the second cycle, hormones and carotenoids in lipoprotein fractions were measured in the early and late follicular and luteal phases. alpha-Carotene concentrations in the LDL fraction were lower in the early than in the late follicular phase (P = 0.03) on the basis of regression analysis. beta-carotene concentrations in the LDL fraction and the HDL2 subfraction were higher in the late follicular than in the luteal phase (P = 0.02 and P = 0.04, respectively). Lutein/zeaxanthin concentrations in the LDL and HDL fractions were higher in the late follicular than in the luteal phase (P = 0.03 and P = 0.02, respectively). In each phase, 80% of alpha-carotene, 82% of beta-carotene, 85% of lycopene, and 64% of lutein/zeaxanthin were distributed in the LDL fraction. Among the hydrocarbon cartenoids, 18% of alpha-carotene and of beta-carotene and 13% of lycopene were distributed in the HDL fraction, with slightly more in the HDL2 than in the HDL3 subfraction. In contrast 34% of lutein/zeaxanthin was distributed in the HDL fraction with more concentrated in the HDL3 than in the HDL2 subfraction. Less than 4% of any carotenoid was found in the VLDL + IDL (intermediate-density-lipoprotein) fractions. Thus, the hydrocarbon carotenoids were highly concentrated in the LDL fraction and xanthophyll was more evenly distributed in the LDL and HDL fractions. The cyclic fluctuations of these carotenoids in lipoprotein fractions add another dimension to the understanding of their transport and physiologic function.


Detecting intramolecular dynamics and multiple Förster resonance energy transfer states by fluorescence correlation spectroscopy.
Fluorescence correlation spectroscopy (FCS) is a robust method for the detection of intramolecular dynamics in proteins but is also susceptible to interference from other dynamic processes such as triplet kinetics and photobleaching. We describe an approach for the detection of intramolecular dynamics in proteins labeled with a FRET dye pair based on global fitting to the two autocorrelation functions (green-green and red-red) and the two cross-correlation functions (green-red and red-green). We applied the method to detect intramolecular dynamics in the Ca(2+) signaling protein calmodulin. Dynamics were detected on the 100 mus time scale in Ca(2+)-activated calmodulin, whereas in apocalmodulin dynamics were not detected on this time scale. Control measurements on a polyproline FRET construct (Gly-Pro(15)-Cys) demonstrate the reliability of the method for isolating intramolecular dynamics from other dynamic processes on the microsecond time scale and confirm the absence of intramolecular dynamics of polyproline. We further show the sensitivity of the initial amplitudes of the FCS auto- and cross-correlation functions to the presence of multiple FRET states, static or dynamic. The FCS measurements also show that the diffusion of Ca(2+)-calmodulin is slower than that of apocalmodulin, indicating either a larger average hydrodynamic radius or shape effects resulting in a slower translational diffusion.


[Thomsen myotonia congenita and strabismus: recording saccades in myotonic diseases].
Thomsen myotonia is an autosomal dominant, but not dystrophic myotonia. We report a family case associating congenital Thomsen's myotonia, strabismus, and ocular myopathy. We successively studied seven isolated patients presenting a myotonic disease and two controls and recorded the ocular saccades of these patients (amplitude, velocity) as a comparison for our family case. Four women from the same family presented Thomsen myotonia associated with strabismus. In addition to the clinical manifestations, the electro-oculographic analysis showed saccade alterations. The saccades of the seven other isolated patients, recruited in a neurology department, were evaluated by electro-oculographic recordings according to four different paradigms. The patients within our family case all presented esotropia, with or without a vertical oculomotor disorder. Clinical examination reported alterations in ocular motility--impairment and slowness of ocular movements--suggesting a myopathic disorder. The electro-oculographic recordings reported a slowing of saccades with increasing duration. For the isolated cases, the slowing of saccades observed was only reported for the patients with myotonic dystrophy (Steinert disease); nevertheless, we failed to show any myotonic phenomena. No cases associating Thomsen myotonia, strabismus, and electro-oculographic disorders have been reported in the literature to date. The electro-oculographic slowing of saccades is not rare in myotonic dystrophy (Steinert disease), but in Thomsen myotonia this has never been reported. This is the first report concerning Thomsen myotonia associated with strabismus and alterations of saccades. The mechanism of this disorder has yet to be discovered, as for Steinert disease.


Disability pattern in chronic migraine with medication overuse: a comparison with migraine without aura.
To assess headache-related disability in chronic migraine with medication overuse (CMO), as defined by Silberstein and Lipton (1996, 2001) in comparison to that caused by migraine without aura, investigating similarities and differences in disability patterns in these two conditions. It is well known that migraine has a marked impact on daily activities. Less information is available on the functional consequences of chronic migraine. This was a prospective study on 247 patients with CMO and 264 with migraine without aura. All completed the validated Italian version of the Migraine Disability Assessment questionnaire (MIDAS). The MIDAS total score and scores of each question (investigating total or partial inability to perform different daily activities) were evaluated, and compared in the two groups using the Mann-Whitney rank sum test. We also evaluated the number of missed days (question 1) and days with significantly reduced effectiveness at work (question 2) and in nonwork activities (questions 3, 4, and 5), using descriptive statistics. MIDAS total score in the CMO group was rather high (mean 84.1, median 70) and significantly higher than in the migraine group (mean 23.4, median 19). CMO patients also reported higher scores than migraine patients in MIDAS questions investigating disability in different domains, the differences being highly significant for questions 3, 4, and 5. In both CMO and migraine the number of days with total or significant disability in nonwork activities was higher than the number of days with total or significant disability in work activities, and days spent at work with significantly reduced effectiveness were more than work days missed. Our findings show that CMO has a profound effect on patients' daily functioning. They suggest that differences between CMO and migraine are mainly quantitative, while the two groups are similar in terms of disability pattern. These results are consistent with the fact that CMO may be an evolution of episodic migraine, characterized by increase in headache frequency and more evident disability in performing different daily duties.


What schools teach our patients about sex: content, quality, and influences on sex education.
To identify predictors of comprehensive sex education in public schools. Using a three-stage design, 335 sex education teachers from a probability sample of 201 schools in 112 Illinois school districts were surveyed regarding the 2003-2004 school year. Coverage of at least all of the following topics constituted "comprehensiveness": abstinence, human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), other sexually transmitted diseases (STDs), and contraception. A logistic regression model identified predictors of comprehensiveness. Representing 91.3% of sampled schools, the teacher survey response rate was 62.4%. The most frequently taught topics included HIV/AIDS (97%), STDs (96%), and abstinence-until-marriage (89%). The least frequently taught topics were emergency contraception (31%), sexual orientation (33%), condom (34%) and other contraceptive (37%) use, and abortion (39%). Abstinence-only curricula were used by 74% of teachers, but 33% of these teachers supplemented with "other" curricula. Overall, two thirds met comprehensiveness criteria based on topics taught. Curricular material availability was most commonly cited as having a "great deal" of influence on topics taught. Thirty percent had no training in sex education; training was the only significant predictor of providing comprehensive sex education in multivariable analysis. Illinois public school-based sex education emphasizes abstinence and STDs and is heavily influenced by the available curricular materials. Nearly one in three sex education teachers were not trained. Obstetrician-gynecologists caring for adolescents may need to fill gaps in adolescent knowledge and skills due to deficits in content, quality, and teacher training in sex education. III.


Causes of pain in patients with axial spondyloarthritis.
Back pain, most frequently of the inflammatory type, is the leading symptom in patients with axial spondyloarthritis (axSpA). Back pain in these patients is usually either due to axial inflammation or structural changes based on new bone formation. However, there are other possible causes of pain in these patients. There is, for example, a strongly increased risk of vertebral fractures, and, especially in patients with longstanding disease, degenerative spinal changes may play an additional role as a cause of pain. Rarely, but rather specifically, patients with ankylosing spondylitis may develop subarachnoidal cysts that often cause neurologic symptoms, in extreme cases a cauda equina syndrome. It is therefore mandatory to always carefully evaluate the origin of back pain in these patients and to consider all possible differential diagnoses. The correct diagnosis is of major importance because treatments may differ considerably. In the monitoring of patients with axSpA it is especially important to consider that pain may have a different origin and it is crucial to notice changes in the nature of the reported back pain. Accordingly, the recently updated Assessment of Spondyloarthritis international Society (ASAS)/European League Against Rheumatism (EULAR) and the treat-to-target recommendations both define improvement of symptoms, a reduction of pain and abrogation of inflammation as important targets in axSpA that can be achieved by pharmacological and nonpharmacological treatments, in rare cases including surgical methods.


Risks of multimodal signaling: bat predators attend to dynamic motion in frog sexual displays.
Many sexual displays contain multiple components that are received through a variety of sensory modalities. Primary and secondary signal components can interact to induce novel receiver responses and become targets of sexual selection as complex signals. However, predators can also use these complex signals for prey assessment, which may limit the evolution of elaborate sexual signals. We tested whether a multimodal sexual display of the male túngara frog (Physalaemus pustulosus) increases predation risk from the fringe-lipped bat (Trachops cirrhosus) when compared with a unimodal display. We gave bats a choice to attack one of two frog models: a model with a vocal sac moving in synchrony with a mating call (multisensory cue), or a control model with the call but no vocal sac movement (unimodal cue). Bats preferred to attack the model associated with the multimodal display. Furthermore, we determined that bats perceive the vocal sac using echolocation rather than visual cues. Our data illustrate the costs associated with multimodal signaling and that sexual and natural selection pressures on the same trait are not always mediated through the same sensory modalities. These data are important when considering the role of environmental fluctuations on signal evolution as different sensory modalities will be differentially affected.


Photoacoustic imaging for in vivo quantification of alcohol-induced structural and functional changes in cerebral vasculature in high alcohol-preferring mice (HAP).
Alcohol-induced structural and functional changes were studied in vivo by photoacoustic tomography (PAT) of the cerebrovascular system in selectively bred alcohol-preferring mice. High (HAP) and low (LAP) alcohol-preferring mice are replicate lines of mice selectively bred to prefer 10% (v/v) ethanol to water and water to ethanol, respectively, in a free-access two-bottle choice scenario. A cohort of 15 singly-housed alcohol-preferring mice (five HAP mice for the experimental group, five LAP mice for the control group, and five other LAP mice set aside) were given free-access two-bottle choice 10% ethanol (v/v) and water in 50-mL graduated drinking bottles mounted on each of their cages for 4 weeks prior to PAT brain scanning. A daily log of the volume of ethanol consumed over a 24-h period was kept. At the end of the fourth week, blood samples were collected from the HAP mice and blood ethanol concentrations (BECs) were measured to ascertain their levels of ethanol intoxication. The mice were then grouped into five weight-matched pairs of HAP and LAP for comparison purposes, and noninvasive in vivo PAT imaging was performed on each weight-matched pair. To mimic a binge drinking paradigm, mice were rearranged into four weight-matched groups of three animals each: an HAP mouse and two LAP mice. For each group, one HAP mouse and one LAP mouse received a 20% ethanol solution via intraperitoneal (i.p.) injection after 24 h of ethanol abstinence, in weight-based doses of 3 g/kg prior to imaging, while the last LAP mouse received a sham i.p. injection. PAT images of the brain were collected for 30 min thereafter. Cerebral vascular diameters for selected vessels of interest were extracted from the PAT images and compared between HAP mice and LAP mice. For the binge scenario, changes in vessel diameter and hemoglobin oxygen saturation were extracted from PAT images and studied over a 30-min duration. Vascular diameter was significantly smaller in HAP mice compared to LAP mice in weight-matched pairs. Hemoglobin-oxygen saturation and vessel diameter dropped more quickly in LAP mice than in HAP mice following a 20% ethanol i.p. injection (3 g/kg), with a 32% reduction in cerebrovascular diameter in a 30-min period. This study demonstrates the effectiveness of PAT in alcohol addiction imaging and diagnosis, and its feasibility in studying alcohol-induced changes in vascular structure and perfusion. It also adds to other bodies of evidence to suggest that the effects of binge drinking are more adverse in occasional drinkers than habitual drinkers.


Engineering metallic nanostructures for plasmonics and nanophotonics.
Metallic nanostructures now play an important role in many applications. In particular, for the emerging fields of plasmonics and nanophotonics, the ability to engineer metals on nanometric scales allows the development of new devices and the study of exciting physics. This review focuses on top-down nanofabrication techniques for engineering metallic nanostructures, along with computational and experimental characterization techniques. A variety of current and emerging applications are also covered.


Expanding the genetic and phenotypic spectrum of branched-chain amino acid transferase 2 deficiency.
The first step in branched-chain amino acid (BCAA) catabolism is catalyzed by the two BCAA transferase isoenzymes, cytoplasmic branched-chain amino acid transferase (BCAT) 1, and mitochondrial BCAT2. Defects in the second step of BCAA catabolism cause maple syrup urine disease (MSUD), a condition which has been far more extensively investigated. Here, we studied the consequences of BCAT2 deficiency, an ultra-rare condition in humans. We present genetic, clinical, and functional data in five individuals from four different families with homozygous or compound heterozygous BCAT2 mutations which were all detected following abnormal biochemical profile results or familial mutation segregation studies. We demonstrate that BCAT2 deficiency has a recognizable biochemical profile with raised plasma BCAAs and, in contrast with MSUD, low-normal branched-chain keto acids (BCKAs) with undetectable l-allo-isoleucine. Interestingly, unlike in MSUD, none of the individuals with BCAT2 deficiency developed acute encephalopathy even with exceptionally high BCAA levels. We observed wide-ranging clinical phenotypes in individuals with BCAT2 deficiency. While one adult was apparently asymptomatic, three individuals had presented with developmental delay and autistic features. We show that the biochemical characteristics of BCAT2 deficiency may be amenable to protein-restricted diet and that early treatment may improve outcome in affected individuals. BCAT2 deficiency is an inborn error of BCAA catabolism. At present, it is unclear whether developmental delay and autism are parts of the variable phenotypic spectrum of this condition or coincidental. Further studies will be required to explore this.


Alveolar macrophage stimulation of T-cell proliferation in autologous mixed lymphocyte reactions. Role of HLA-DR antigens.
Alveolar macrophages act as accessory cells in lymphocyte response to mitogens or alloantigens. Because the autologous mixed lymphocyte reaction (MLR), in which HLA-DR-positive non-T cells stimulate the proliferation of autologous T lymphocytes, represents a good model to study macrophage-T cell interaction, we examined and compared the ability of human alveolar macrophages and peripheral blood-derived monocytes to induce T-cell proliferation in autologous MLR. Maximal T lymphocyte proliferation was observed in both alveolar-macrophage- and blood-monocyte-stimulated autologous MLR at a T cell to alveolar macrophage or blood monocyte ratio of 4:1, but the ability to stimulate T-cell proliferation was lower for alveolar macrophages than for blood monocytes (p less than 0.01). Because HLA-DR antigens modulate monocyte-T cell interaction, we quantified the proportions of HLA-DR-positive cells in alveolar macrophage and blood monocyte suspensions and determined the inhibitory effects on T-cell proliferation of masking HLA-DR antigens on stimulator cells with monoclonal antibodies. The proportions of HLA-DR-positive cells were higher in alveolar macrophage than in blood suspensions (p less than 0.01); interestingly, however, the preincubation of the stimulator cells with anti-HLA-DR monoclonal antibodies inhibited to a similar extent both alveolar-macrophage- and blood-monocyte-stimulated autologous MLR (p greater than 0.2). These studies indicate that alveolar macrophages are less effective than blood monocytes are as stimulator cells in autologous MLR and that, although the masking of HLA-DR molecules results in inhibition of autologous MLR, T-cell proliferation is not dependent on the numbers of stimulator cells bearing HLA-DR antigens. The autologous MLR may represent a good model to study the functions of alveolar macrophages during their interaction with autologous T cells in health and disease.


Anoctamin-1/TMEM16A is the major apical iodide channel of the thyrocyte.
Iodide is captured by thyrocytes through the Na(+)/I(-) symporter (NIS) before being released into the follicular lumen, where it is oxidized and incorporated into thyroglobulin for the production of thyroid hormones. Several reports point to pendrin as a candidate protein for iodide export from thyroid cells into the follicular lumen. Here, we show that a recently discovered Ca(2+)-activated anion channel, TMEM16A or anoctamin-1 (ANO1), also exports iodide from rat thyroid cell lines and from HEK 293T cells expressing human NIS and ANO1. The Ano1 mRNA is expressed in PCCl3 and FRTL-5 rat thyroid cell lines, and this expression is stimulated by thyrotropin (TSH) in rat in vivo, leading to the accumulation of the ANO1 protein at the apical membrane of thyroid follicles. Moreover, ANO1 properties, i.e., activation by intracellular calcium (i.e., by ionomycin or by ATP), low but positive affinity for pertechnetate, and nonrequirement for chloride, better fit with the iodide release characteristics of PCCl3 and FRTL-5 rat thyroid cell lines than the dissimilar properties of pendrin. Most importantly, iodide release by PCCl3 and FRTL-5 cells is efficiently blocked by T16Ainh-A01, an ANO1-specific inhibitor, and upon ANO1 knockdown by RNA interference. Finally, we show that the T16Ainh-A01 inhibitor efficiently blocks ATP-induced iodide efflux from in vitro-cultured human thyrocytes. In conclusion, our data strongly suggest that ANO1 is responsible for most of the iodide efflux across the apical membrane of thyroid cells.


A study of noise phenomena in microwave components using an advanced noise measurement system.
A novel 9 GHz measurement system with thermal noise limited sensitivity has been developed for studying the fluctuations in passive microwave components. The noise floor of the measurement system is flat at offset frequencies above 1 kHz and equal to -193 dBc/Hz. The developed system is capable of measuring the noise in the quietest microwave components in real time. We discuss the results of phase and amplitude noise measurements in precision voltage controlled phase shifters and attenuators. The first reliable experimental evidences regarding the intrinsic flicker phase noise in microwave isolators are also presented.


The Molecular Basis and Pathophysiology of Trigeminal Neuralgia.
Trigeminal neuralgia (TN) is a complex orofacial pain syndrome characterized by the paroxysmal onset of pain attacks in the trigeminal distribution. The underlying mechanism for this debilitating condition is still not clearly understood. Decades of basic and clinical evidence support the demyelination hypothesis, where demyelination along the trigeminal afferent pathway is a major driver for TN pathogenesis and pathophysiology. Such pathological demyelination can be triggered by physical compression of the trigeminal ganglion or another primary demyelinating disease, such as multiple sclerosis. Further examination of TN patients and animal models has revealed significant molecular changes, channelopathies, and electrophysiological abnormalities in the affected trigeminal nerve. Interestingly, recent electrophysiological recordings and advanced functional neuroimaging data have shed new light on the global structural changes and the altered connectivity in the central pain-related circuits in TN patients. The current article aims to review the latest findings on the pathophysiology of TN and cross-examining them with the current surgical and pharmacologic management for TN patients. Understanding the underlying biology of TN could help scientists and clinicians to identify novel targets and improve treatments for this complex, debilitating disease.


Is learning in problem-based learning cumulative?
Problem-based learning (PBL) is generally organized in three phases, involving collaborative and self-directed learning processes. The hypothesis tested here is whether learning in the different phases of PBL is cumulative, with learning in each phase depending on that of the previous phase. The scientific concepts recalled by 218 students at the end of each PBL phase were used to estimate the extent of students' learning. The data were then analyzed using structural equation modeling. Results show that our hypothesized model fits the data well. Alternative hypotheses according to which achievement is predicted either by collaborative learning alone or by self-directed learning alone did not fit the data. We conclude that the learning in each PBL phase is cumulative, and strongly influenced by the earlier phase, thus providing support for the PBL cycle of problem analysis, self-directed learning, and a subsequent reporting phase. We also demonstrate an efficient method to capture and quantify students' learning during the PBL process.


Behavior of the mass transfer zone in a biosorption column.
Modeling of the mass transfer zone behavior under variable conditions in a flow-through fixed-bed sorption column enabled the prediction of breakthrough curves for Cu2+ and Ca-preloaded Sargassum fluitans biomass. The mass transfer resistance, particle diffusion, and the axial dispersion were incorporated in the model. The dynamics of the mass transfer zone was described under variable sorption column operating conditions including different column lengths and fluid flow rates. Accurate estimation of the behavior of the mass transfer zone as it progressed through the column, reflected eventually in the breakthrough curve, assisted in its relevant interpretations. Furthermore, the proposed mathematical model of the biosorption process was capable of demonstrating the expanding and broadening of the mass transfer zone linked to the equilibrium sorption isotherm. The fundamental understanding of the mass transfer zone dynamics is particularly important for process scale-up where maintaining the process efficiency is critical.


Preliminary efficacy investigations of oral fipronil against Anopheles arabiensis when administered to Zebu cattle (Bos indicus) under field conditions.
Globally, malaria remains one of the most important vector-borne diseases despite the extensive use of vector control, including indoor residual spraying (IRS) and insecticide-treated nets (ITNs). These control methods target endophagic vectors, whereas some malaria vectors, such as Anopheles arabiensis, preferentially feed outdoors on cattle, making it a complicated vector to control using conventional strategies. Our study evaluated whether treating cattle with a capsule containing the active ingredient (AI) fipronil could reduce vector density and sporozoite rates, and alter blood feeding behavior, when applied in a small-scale field study. A pilot field study was carried out in the Samia District, Western Kenya, from May to July 2015. Four plots, each comprised of 50 huts used for sleeping, were randomly designated to serve as control or treatment. A week before cattle treatment, baseline mosquito collections were performed inside the houses using mechanical aspirators. Animals in the treatment (and buffer) were administered a single oral application of fipronil at ∼0.5mg/kg of body weight. Indoor mosquito collections were performed once a week for four weeks following treatment. Female mosquitoes were first identified morphologically to species complex, followed by PCR-based methods to obtain species identity, sporozoite presence, and the host source of the blood meal. All three species of anophelines found in the study area (An. gambiae s.s., An. arabiensis, An. funestus s.s.) were actively transmitting Plasmodium falciparum during the study period. The indoor resting density of An. arabiensis was significantly reduced in treatment plot one at three weeks post-treatment (T1) (efficacy=89%; T1 density=0.08, 95% credibility intervals [0.05, 0.10]; control plot density=0.78 [0.22, 0.29]) and at four weeks post-treatment (efficacy=64%; T1 density=0.16 [0.08, 0.14]; control plot density=0.48 [0.17, 0.22]). The reduction of An. arabiensis mosquitoes captured in the treatment plot two was higher: zero females were collected after treatment. The indoor resting density of An. gambiae s.s. was not significantly different between the treatment (T1, T2) and their corresponding control plots (C1, C2). An. funestus s.s. showed an increase in density over time. The results of this preliminary study suggest that treating cattle orally with fipronil, to target exophagic and zoophagic malaria vectors, could be a valuable control strategy to supplement existing vector control interventions which target endophilic anthropophilic species.


Efficacy of artemisinin-based combination therapies and prevalence of molecular markers associated with artemisinin, piperaquine and sulfadoxine-pyrimethamine resistance in Sierra Leone.
Currently, the national malaria control programme (NMCP) of Sierra Leone recommends artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) as first- and second-line treatment for uncomplicated malaria, respectively, and artesunate + sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment during pregnancy and for infants. In 2016, the NMCP conducted a study to assess the clinical and parasitological responses of children under five years to ASAQ, AL and dihydroartemisinin-piperaquine (DHA/PPQ) according to the WHO protocol. Day-0 samples were tested for mutations in the Kelch 13 gene (pfk13) and dihydrofolate reductase/dihydropteroate synthase (pfdhfr/pfdhps) genes associated with artemisinin and SP resistance, respectively, and amplification in the pfplasmepsin2 gene for piperaquine resistance. A total of 295 (ASAQ = 128, AL = 64 and DHA/PPQ = 103) eligible children were enrolled at three sites. PCR-corrected 100% adequate clinical and parasitological response and no parasitaemia on day-3 were observed for all patients in each treatment group. Of the 278 samples with interpretable molecular data, only 2.2% carried non-synonymous pfk13 mutants (A578S, I646T), which are not associated with artemisinin resistance. None of the 103 day-0 samples from the DAH/PPQ group had pfplasmepsin2 gene amplification, confirming the absence of piperaquine resistance. The prevalence of the triple pfdhfr mutant (N51I/C59R/S108N) was close to or reached fixation (97.4-100%). For combined pfdhfr/pfdhps mutation, 55-71% carried the quadruple (N51I/C59R/S108N+A437G) mutant and about 10% the quintuple mutant N51I/C59R/S108N+A437G/K540E. Our findings confirm that ASAQ, AL and DHA/PPQ were highly effective for the treatment of uncomplicated malaria in the study areas, and neither pfk13 validated mutations nor pfplasmepsin2 multiple copies were found. The very low prevalence of the quintuple mutant in this study supports the NMCP's decision to introduce intermittent preventive treatment for infants with SP in the districts with high malaria transmission.


Studies on preweaning piglet diarrhoea.
The aim of this study was to determine the cause and risk factors involved in preweaning piglet diarrhoea. Faecal samples from 2380 diarrhoeic piglets, 5 to 30 days of age, were examined for enteropathogens. Isospora suis oocysts were detected in 53.8% of samples, Escherichia coli in 18.2% and rotavirus in 16.9%. I suis had the widest distribution, being present on 70.9% of 151 piggeries. The onset of diarrhoea occurred mainly between 7 and 14 days (77.5%), peaking at 10 days. Records of 4086 litters from two intensive piggeries were analysed and showed no seasonal variation or effect of sow parity on the incidence of piglet diarrhoea. I suis was the most common enteropathogen associated with diarrhoea in piglets from 5 days of age until weaning.


Periprocedural Stroke and Myocardial Infarction as Risks for Long-Term Mortality in CREST.
The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) previously reported increased mortality in patients who sustained a periprocedural stroke or cardiac event (myocardial infarction [MI] or biomarker only) in follow-up to 4 years. We now extend these observations to 10 years. CREST is a randomized controlled trial designed to compare the outcomes of carotid stenting versus carotid endarterectomy. Proportional hazards models were used to assess the association between mortality and periprocedural stroke, MI, or biomarker-only events. For 10-year follow-up, patients with periprocedural stroke were at 1.74× the risk of death compared with those without stroke (adjusted hazard ratio [HR]=1.74; 95% CI, 1.21-2.50; P<0.003). This increased risk was driven by increased early (between 0 and 90 days) mortality (adjusted HR=14.41; 95% CI, 5.33-38.94; P<0.0001), with no significant increase in late (between 91 days and 10 years) mortality (adjusted HR=1.40; 95% CI, 0.93-2.10; P=0.11). Patients with a protocol MI were at 3.61× increased risk of death compared with those without MI (adjusted HR=3.61; 95% CI, 2.28-5.73; P<0.0001), with an increased hazard both early (adjusted HR=8.20; 95% CI, 1.86-36.2; P=0.006) and late (adjusted HR=3.40; 95% CI, 2.09-5.53; P<0.0001). Patients with a biomarker-only event were at 2.04× increased risk overall (adjusted HR=2.04; 95% CI, 1.09-3.84; P=0.03) than those without MI, with an increased early hazard (adjusted HR=8.44; 95% CI, 1.09-65.5; P=0.04) and a suggestive but nonsignificant association toward higher 91-day to 10-year risk (1.88; 95% CI, 0.97-3.64; P=0.062) contributing to the increased risk. In the CREST trial, patients with periprocedural events demonstrate a substantial increase in future mortality to 10 years. For stroke, this risk is largely confined to an early time frame while periprocedural MI or biomarker-only events confer a continuous increased mortality for 10 years. Strategies to reduce periprocedural events and to optimize the evaluation and management of patients with cardiac events should be considered in efforts to reduce not only early but also long-term mortality. URL: https://www.clinicaltrials.gov . Unique identifier: NCT00004732.


An Integrated, Clinician-focused Telehealth Monitoring System to Reduce Hospitalization Rates for Home Health Care Patients with Diabetes.
Diabetes is one of the leading causes of death and disability in the United States, and hospitalization rates related to this health condition are high and costly to the United States health care system. The purpose of this study was to examine the effect of an integrated, clinician-focused telehealth monitoring system on the probability of hospitalization for home health care patients with diabetes. The study included 2009 data from 699 Medicare beneficiaries receiving home health services in Texas and Louisiana. Propensity score matching, logistic regression, and post-estimation parameter simulation were used to assess how telehealth affects the probability of hospitalization during the first 30 days of home health care. The 30-day hospitalization probability for telehealth and non-telehealth patients was 7% and 19%, respectively. Patients in the telehealth group had a 12 (95% confidence interval = 4.2-20.3) percentage point-lower probability of hospitalization within the first 30 days of home health care than non-telehealth matched patients. The results suggest that telehealth monitoring systems that integrate skilled clinicians with critical care experience can lead to substantially lower hospitalization rates during the first 30 days of home health care, large cost savings, and more effective home health management of patients with diabetes.


Uropathogenic Escherichia coli-induced fibrosis, leading to lower urinary tract symptoms, is associated with type 2 cytokine signaling.
Chronic inflammation and prostate fibrosis have been identified as contributors to lower urinary tract symptoms (LUTS) pathophysiology in humans. It has been shown that transurethral infection of an Escherichia coli strain named CP1, which was isolated from a patient with chronic prostatitis, can lead to the develop of differential chronic inflammation and pain in certain mouse strains. Therefore, we hypothesized that differential inflammation would influence fibrotic response in the prostate. This study showed that while prostatic infection by CP1 causes the development of chronic tactile allodynia in NOD/ShiltJ (NOD) but not C57BL/6 (B6) mice, both mice developed evidence of prostate inflammation, prostate fibrosis, and urinary dysfunction. Fibrosis was confirmed by the upregulation of fibrosis-associated messenger RNAs (mRNAs), α-smooth muscle actin immunohistochemistry, and collagen staining with picrosirius red. These findings were mainly focused on the dorsolateral lobes of the prostate. Both mouse strains also developed smaller, more frequent voiding patterns postinfection, examined via cystometry. B6 mice responded to CP1 infection with type 2 cytokines (IL-4 and IL-13), while NOD mice did not, which may explain the differing tactile allodynia responses and level of collagen deposition. When mice lacking signal transducer and activator of transcription 6 (STAT6), a transcription factor known to be important for the production and signaling of IL-4 and IL-13, were infected with CP1, fibrosis was attenuated. This study provides a potential model for studying the development of infection-induced prostatic fibrosis and LUTS. This study also demonstrates that CP1-induced prostate fibrosis has a STAT6-dependent mechanism in B6 mice.


Cellular Prion Protein Mediates α-Synuclein Uptake, Localization, and Toxicity In Vitro and In Vivo.
The cellular prion protein (PrPC ) is a membrane-bound, multifunctional protein mainly expressed in neuronal tissues. Recent studies indicate that the native trafficking of PrPC can be misused to internalize misfolded amyloid beta and α-synuclein (aSyn) oligomers. We define PrPC 's role in internalizing misfolded aSyn in α-synucleinopathies and identify further involved proteins. We performed comprehensive behavioral studies on four transgenic mouse models (ThySyn and ThySynPrP00, TgM83 and TgMPrP00) at different ages. We developed PrPC -(over)-expressing cell models (cell line and primary cortical neurons), used confocal laser microscopy to perform colocalization studies, applied mass spectrometry to identify interactomes, and determined disassociation constants using surface plasmon resonance (SPR) spectroscopy. Behavioral deficits (memory, anxiety, locomotion, etc.), reduced lifespans, and higher oligomeric aSyn levels were observed in PrPC -expressing mice (ThySyn and TgM83), but not in homologous Prnp ablated mice (ThySynPrP00 and TgMPrP00). PrPC colocalized with and facilitated aSyn (oligomeric and monomeric) internalization in our cell-based models. Glimepiride treatment of PrPC -overexpressing cells reduced aSyn internalization in a dose-dependent manner. SPR analysis showed that the binding affinity of PrPC to monomeric aSyn was lower than to oligomeric aSyn. Mass spectrometry-based proteomic studies identified clathrin in the immunoprecipitates of PrPC and aSyn. SPR was used to show that clathrin binds to recombinant PrP, but not aSyn. Experimental disruption of clathrin-coated vesicles significantly decreased aSyn internalization. PrPC 's native trafficking can be misused to internalize misfolded aSyn through a clathrin-based mechanism, which may facilitate the spreading of pathological aSyn. Disruption of aSyn-PrPC binding is, therefore, an appealing therapeutic target in α-synucleinopathies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease.
Genetic prion diseases are late onset fatal neurodegenerative disorders linked to pathogenic mutations in the prion protein-encoding gene, PRNP. The most prevalent of these is the substitution of Glutamate for Lysine at codon 200 (E200K), causing genetic Creutzfeldt-Jakob disease (gCJD) in several clusters, including Jews of Libyan origin. Investigating the pathogenesis of genetic CJD, as well as developing prophylactic treatments for young asymptomatic carriers of this and other PrP mutations, may well depend upon the availability of appropriate animal models in which long term treatments can be evaluated for efficacy and toxicity. Here we present the first effective mouse model for E200KCJD, which expresses chimeric mouse/human (TgMHu2M) E199KPrP on both a null and a wt PrP background, as is the case for heterozygous patients and carriers. Mice from both lines suffered from distinct neurological symptoms as early as 5-6 month of age and deteriorated to death several months thereafter. Histopathological examination of the brain and spinal cord revealed early gliosis and age-related intraneuronal deposition of disease-associated PrP similarly to human E200K gCJD. Concomitantly we detected aggregated, proteinase K resistant, truncated and oxidized PrP forms on immunoblots. Inoculation of brain extracts from TgMHu2ME199K mice readily induced, the first time for any mutant prion transgenic model, a distinct fatal prion disease in wt mice. We believe that these mice may serve as an ideal platform for the investigation of the pathogenesis of genetic prion disease and thus for the monitoring of anti-prion treatments.


Synthesis and photoluminescence properties of rhenium(I) complexes based on 2,2':6',2''-terpyridine derivatives with hole-transporting units.
Based on 2,2′:6′,2′′-terpyridine ligands (L1), five terpyridine derivatives, namely 4′-carbazol-9-yl-2,2′:6′,2′′-terpyridine (L2), 4′-diphenylamino-2,2′:6′,2′′-terpyridine (L3), 4′-bis(4-tert-butylphenyl)amino-2,2′:6′,2′′-terpyridine (L4), 4′-[naphthalen-1-yl-(phenyl)amino]-2,2′:6′,2′′-terpyridine (L5), 4′-[naphthalen-2-yl(phenyl)amino]-2,2′:6′,2′′-terpyridine (L6) and their corresponding Re(I) complexes ReL(n)(CO)3Cl (n = 1–6) have been synthesized and characterized by elemental analysis and 1H NMR spectroscopy. The X-ray crystal structure of ReL3(CO)3Cl has also been obtained. The luminescence spectra of ReL2(CO)3Cl–ReL5(CO)3Cl, obtained in CH2Cl2 solution at room temperature, show strong dπ (Re) → π* (diimine) MLCT character (λ(max) 600 nm) and a small red shift relative to ReL1(CO)3Cl. This, confirmed by the study of the triplet energy levels of the L1–L6 ligands at low temperature (77 K rigid matrix), indicates that the introduction of electron-donating moieties on the terpyridine unit decreases the triplet levels of the ligands, leading to a reduction of the energy gap between d and π* orbitals. In the solid state, upon MLCT excitation, all the complexes show an even stronger emission and a blue spectral shift (λ(max) ∼ 550 nm) compared to those obtained in solution.


Proteomics on an Orbitrap benchtop mass spectrometer using all-ion fragmentation.
The orbitrap mass analyzer combines high sensitivity, high resolution, and high mass accuracy in a compact format. In proteomics applications, it is used in a hybrid configuration with a linear ion trap (LTQ-Orbitrap) where the linear trap quadrupole (LTQ) accumulates, isolates, and fragments peptide ions. Alternatively, isolated ions can be fragmented by higher energy collisional dissociation. A recently introduced stand-alone orbitrap analyzer (Exactive) also features a higher energy collisional dissociation cell but cannot isolate ions. Here we report that this instrument can efficiently characterize protein mixtures by alternating MS and "all-ion fragmentation" (AIF) MS/MS scans in a manner similar to that previously described for quadrupole time-of-flight instruments. We applied the peak recognition algorithms of the MaxQuant software at both the precursor and product ion levels. Assignment of fragment ions to co-eluting precursor ions was facilitated by high resolution (100,000 at m/z 200) and high mass accuracy. For efficient fragmentation of different mass precursors, we implemented a stepped collision energy procedure with cumulative MS readout. AIF on the Exactive identified 45 of 48 proteins in an equimolar protein standard mixture and all of them when using a small database. The technique also identified proteins with more than 100-fold abundance differences in a high dynamic range standard. When applied to protein identification in gel slices, AIF unambiguously characterized an immunoprecipitated protein that was barely visible by Coomassie staining and quantified it relative to contaminating proteins. AIF on a benchtop orbitrap instrument is therefore an attractive technology for a wide range of proteomics analyses.


Severe hypovitaminosis D is widespread and more common in non-diabetics than diabetics in Saudi adults.
To compare the incidence of hypovitaminosis D in subjects, with and without type 2 diabetes mellitus (T2DM), and determine its association to various risk factors. Three hundred and forty-one (177 non-diabetic, and 164 T2DM) Saudi adults were included in this cross-sectional study conducted at the Biomarkers Research Program (BRP) of King Saud University, Riyadh, Kingdom of Saudi Arabia from March to August 2009. Anthropometrics and fasting blood samples were obtained. Fasting glucose (FG) and lipid profiles were determined. Serum 25-hydroxy vitamin D (25[OH]D) and parathyroid hormone (PTH) were quantified using enzyme-linked immunosorbent assay. Severe hypovitaminosis D was defined as serum 25(OH)D with levels <12.5 nmol/l. Age was the most significant predictor of 25(OH)D in both groups, explaining 25% (p=0.0005) and 16% of variances (p=0.0005). Waist-hip ratio, systolic blood pressure and body mass index were significant predictors of 25(OH)D among non-diabetics after age adjustment, explaining 21% of variance perceived (p=0.039). Serum PTH levels were higher in non-diabetic men and women. Severe hypovitaminosis D is prevalent in both non-diabetic and diabetic Saudis, but was more common in the young and middle-aged non-diabetics. The study further underscores the need for vitamin D fortification of the Saudi diet, and the promotion of vitamin D supplementation in both groups.


Problems of child health in a Peruvian shanty town.
The basic child-health problems in the shanty towns of Lima are protein-calorie malnutrition and infectious disease. The background of social, economic and cultural conditionsa are related to these main health problems. The basic problems are poverty, lack of sewage disposal and running water, and the maldistribution of public expenditure between city and countryside on one hand and curative and preventive medicine on the other. Despite official statistics, which show a steadily decreasing infant mortality rate in Peru, and all other Latin American countries, it seems that the Infant Mortality Rate is almost twice the official states rate. Health education, particularly in nutritional matters, is not adapted to indigenous foods and customs, but attempts to promote westernized conceptrs. Medical care in Peru is by large directed to the needs of the middle class, and the middle class by and large dictates the type of medical care available.


Making the post-MDG global health goals relevant for highly inequitable societies: findings from a consultation with marginalized populations in Guatemala.
The United Nations presented a set of Millennium Development Goals that aimed to improve social and economic development and eradicate poverty by 2015. Most low and middle-income countries will not meet these goals and today there is a need to set new development agenda, especially when it comes to health. The paper presents the findings from a community consultation process carried out within the Goals and Governance for Global Health (GO4Health) research consortium in Guatemala, which aims to identify community needs and expectations around public policies and health services. Through a participative and open consultation process with experts, civil society organizations and members of the research team, the municipalities of Tectitan and Santa Maria Nebaj were selected. A community consultation process was undertaken with community members and community leaders. Group discussions and in-depth interviews were conducted and later analyzed using thematic analysis, a qualitative method that can be used to analyze data in a way that allows for the identification of recurrent patterns that can be grouped into categories and themes, was used. Following the Go4Health framework's domains for understanding health-related needs, the five themes identified were health, social determinants of health, essential health needs and their provision, roles and responsibilities of relevant stakeholders and community participation in decision-making. Participants reported high levels of discrimination related to ethnicity, to being poor and to living in rural areas. Ethnicity played a major role in how community members feel they are cared for in the health system. Achieving health goals in a context of deep-rooted inequality and marginalization requires going beyond the simple expansion of health services and working with developing trusting relationships between health service providers and community members. Involving community members in decision-making processes that shape policies will contribute to a larger process of community empowerment and democratization. Still, findings from the region show that tackling these issues may prove complicated and require going beyond the health system, as this lack of trust and discrimination has permeated to all public policies that deal with indigenous and rural populations.


Emerging content in nursing: an analysis of dissertation abstracts and titles: 1976-1982.
This study describes the distribution of content in nursing doctoral program dissertations over a six-year period (1976-1982). Dissertation abstracts were requested from the 25 nursing doctoral programs that admitted students in the fall of 1982. A total of 319 dissertations first were grouped as either studies of clinical nursing or studies of social issues in nursing or studies of social issues in nursing and then coded for all subcategories that described the content of the study. Of the dissertations included in this analysis 78.4% pertained to clinical nursing; 21.6% were studies of social issues in nursing. Further analysis of subcategories and most frequently occurring combinations of study variables showed significant differences in dissertation content when analyzed by program age, geographic region of the country, and type of degree program.


Interaction analysis between genetic polymorphisms and pharmacodynamic effect in patients treated with adjunctive cilostazol to dual antiplatelet therapy: results of the ACCEL-TRIPLE (Accelerated Platelet Inhibition by Triple Antiplatelet Therapy According to Gene Polymorphism) study.
Compared with standard dual antiplatelet therapy, adjunctive cilostazol to dual antiplatelet therapy ('triple antiplatelet therapy') has a potential to reduce ischemic event occurrence after percutaneous coronary intervention. The pharmacokinetic and pharmacodynamic effects of clopidogrel have been significantly influenced by the enzyme activity of the ABCB1 C3435T and the CYP2C19 system. • For the pharmacokinetics of cilostazol, genetic polymorphisms of the CYP3A5 and CYP2C19 have been associated with the substantial interindividual variability in healthy volunteers. Loss-of-function polymorphism of the CYP2C19 gene, but not the ABCB1 C3435T and CYP3A5*3 genes, affects the antiplatelet effect of triple antiplatelet therapy. Most of extensive and intermediate East Asian metabolizers (0 or 1 CYP2C19 loss-of-function allele) show adequate platelet inhibition when treated with triple antiplatelet therapy after percutaneous coronary intervention. However, carriage of 2 CYP2C19 loss-of-function alleles is still associated with the risk of high platelet reactivity (defined by by 5 µM ADP-induced maximal platelet aggregation >46%), which clinical impact needs to be validated in future clinical trials. AIMS Although adjunctive cilostazol to dual antiplatelet therapy can reduce the risks of clinical events after percutaneous coronary intervention (PCI), whether genetic polymorphism can influence the pharmacodynamics of this regimen has not been evaluated. One hundred and twenty-seven patients treated with PCI and taking triple antiplatelet therapy (≥1 month) were enrolled. Platelet reactivity was assessed by conventional aggregometry and the VerifyNow P2Y12 assay. High on-treatment platelet reactivity (HPR) was defined as 5 µm ADP-induced maximal platelet reactivity (Agg(max) ) >46%. CYP3A5*3, CYP2C19*2/*3 and ABCB1 3435C > T were genotyped. CYP3A5*3 and ABCB1 3435C > T variants did not affect the antiplatelet effect of triple antiplatelet therapy. For non-carriers, one and two carriers of the CYP2C19 loss-of-function (LOF) allele, Agg(max) consecutively increased after the addition of 5 µm[mean (95% confidence intervals): 24.6% (20.8 to 28.5%) vs. 28.7% (25.4 to 32.0%) vs. 32.3% (25.8 to 38.7%), P = 0.062, respectively] and 20 µm ADP [34.2% (29.3 to 39.0%) vs. 41.7% (37.8 to 45.6%) vs. 44.9% (37.9 to 51.9%), P = 0.007, respectively]. Likewise, late platelet reactivity and P2Y12 reaction units proportionally changed according to the number of CYP2C19 LOF alleles. HPRs were observed in 9.2% of subjects: 6.3%, 7.4% and 20.0% with 0, 1 and 2 carriers of CYP2C19 LOF allele(s) (P = 0.099). In multivariate analysis, carriage of two CYP2C19 LOF alleles was a significant predictor for the prevalence of HPR (odds ratio 5.78, 95% CI 1.21, 27.78, P = 0.028). Among PCI-treated patients, the effect of triple antiplatelet therapy is influenced by the CYP2C19 LOF allele. Its clinical benefit needs to be validated according to the CYP2C19 metabolic phenotype in future clinical trials. [Adjunctive Cilostazol Versus High Maintenance dose ClopidogrEL in Acute Myocardial Infarction Patients According to CYP2C19 Polymorphism (ACCEL-AMI-2C19), NCT00915733 and Adjunctive Cilostazol Versus High Maintenance-dose Clopidogrel According to Cytochrome 2C19 Polymorphism (ACCEL-2C19), NCT01012193].


[Disputed optical correction].
Problems arising from eyeglasses prescriptions can be due either to a fautive prescription (over correction of hyperopia, of astigmatism, ...), either to a fautive writing of the prescription (inversion of axis or sign of a cylinder, inversion of the value RE/LE, ...) or to a poor work by the optician (decentered glasses ...)


Direct detection of polarization multiplexed single sideband signals with orthogonal offset carriers.
We propose a novel direct detection (DD) scheme for polarization division multiplexed (PDM) single sideband (SSB) signals with two orthogonal carriers located at the opposite sides. Polarization diversity is realized with a pair of optical filters that are used to suppress the unwanted orthogonal carrier component. A PDM-SSB DD receiver is thus constructed without polarization de-rotation. The intra-polarization signal-signal beat interference (SSBI) can be mitigated by Kramers-Kronig detection or iterative SSBI cancellation. For inter-polarization SSBI mitigation, we propose a joint iterative SSBI cancellation method. The proposed PDM-SSB DD scheme is validated with a principle experiment of 40Gbaud PDM-SSB 16-ary quadrature amplitude modulation (16-QAM) signals. After 80km standard single-mode fiber (SSMF) transmission, the bit-error rates (BERs) achieve 20% hard-decision forward error correction (HD-FEC) threshold of 1.5 × 10-2. The performance of iterative SSBI cancellation, Kramers-Kronig detection, and joint iterative SSBI cancellation are evaluated for PDM-SSB signals with different carrier-to-signal ratios (CSPRs) through numerical simulations. Moreover, a multi-input-multi-output (MIMO) equalization scheme is proposed and validated with numerical simulation, which can suppress the linear inter-polarization crosstalk and relax the sharpness requirement of optical filter edges.


Macrolide-treated Pseudomonas aeruginosa induces paradoxical host responses in the lungs of mice and a high mortality rate.
Accumulating data have demonstrated that macrolide antibiotics suppress Pseudomonas aeruginosa virulence, which may explain the efficacy of macrolides in clinical settings. We examined the virulence of macrolide-treated bacteria in vivo. P. aeruginosa PAO-1 was grown for 24 h on agar containing sub-MIC antibiotics, and then mice were challenged intranasally with 10(7) cfu of bacteria. The mortality rate of mice inoculated with bacteria grown in the presence of clarithromycin (10 mg/L), erythromycin (10 mg/L) or azithromycin (5 mg/L) was 80%, 80% and 100%, respectively. In contrast, none of the mice inoculated with non-treated bacteria or bacteria treated with other antibiotics died. Lung weight and protein concentration in bronchoalveolar lavage fluid (BALF) were significantly higher in the clarithromycin group between 3 and 9 h. Moreover, we detected higher levels of tumour necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) in the BALF of these mice. These data demonstrate that macrolide-treated P. aeruginosa induced paradoxically strong responses, such as elevation of TNF-alpha, NO and permeability in the lungs.


[Effect of haloperidol and clozapine on the bioelectric activity of the human cerebral cortex].
A study of spatial synchronization of the cortical biopotentials of man by multi-channel registration (leads from 48 points) made it possible to elucidate the common and specific characteristics of the action of typical (haloperidol) and atypical (clozapine) neuroleptics. The study was conducted on 10 subjects with the normal bioelectrical activity of the brain. Common for both drugs is their capacity to decrease the activity of the anterior cortical portions. They are different in that haloperidol, reducing the activity of the left hemisphere, perverts the inter-hemispherical relationships existing before its intake whereas clozapine does not change the nature of the inter-hemispherical relationships. These data may serve as the neurophysiological basis of the sedative and antipsychotic effects of typical and atypical neuroleptics.


A comparison of the digestion of nuclei and chromatin by staphylococcal nuclease.
We have followed the kinetics of staphylococcal nuclease digestion of duck reticulocyte nuclei and chromatin from early stages to the digestion limit. We confirm that partial digestion of nuclei produces discrete DNA bands which are multiples of a monomer, 185 base pairs in length. The multimers are shown to be precursors of the monomer, which is next digested to a homogeneous, 140 base pair fragment. This fragment in turn gives rise to an array of nuclear limit digest DNA bands, which is almost identical with the limit digest pattern of isolated chromatin. As in the case of chromatin, half the DNA of nuclei is acid soluble at this limit. While the DNA limit digest patterns of nuclei and chromatin are similar, the large multimeric structures present as intermediates in nuclear digestion are absent in chromatin digestion. Alternate methods of chromatin gel preparation appear to leave more of the higher order structure intact, as measured by the production of these multimeric bands. Our results are consistent with the "beads on a string" model of chromatin proposed by others.