Antiamebic activity of new acridinic derivatives against Naegleria and Acanthamoeba species in vitro

In vitro antiamebic activity of selected acridine derivatives has been investigated against Naegleria and Acanthamoeba species. The most active compounds belong to the 9-thioacridanone and the 1,2,3,4-tetrahydro-9-thioacridanone series. In addition, some structure-activity relationships are proposed.     

Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta-analysis of randomized controlled trials

Context  The US Food and Drug Administration (FDA) has issued warnings that use of antidepressant medications poses a small but significantly increased risk of suicidal ideation/suicide attempt for children and adolescents. Objective  To assess the efficacy and risk of reported suicidal ideation/suicide attempt of antidepressants for treatment of pediatric major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and non-OCD anxiety disorders. Data Sources and Study Selection  PubMed (1988 to July 2006), relevant US and British regulatory agency reports, published abstracts of important scientific meetings (1998-2006), clinical trial registries, and information from authors. Studies were published and unpublished randomized, placebo-controlled, parallel-group trials of second-generation antidepressants (selective serotonin reuptake inhibitors, nefazodone, venlafaxine, and mirtazapine) in participants younger than 19 years with MDD, OCD, or non-OCD anxiety disorders. Data Extraction  Information was extracted on study characteristics, efficacy outcomes, and spontaneously reported suicidal ideation/suicide attempt. Data Synthesis  Twenty-seven trials of pediatric MDD (n = 15), OCD (n = 6), and non-OCD anxiety disorders (n = 6) were selected, and risk differences for response and for suicidal ideation/suicide attempt estimated by random-effects methods. Pooled risk differences in rates of primary study-defined measures of responder status significantly favored antidepressants for MDD (11.0%; [95% confidence interval {CI}, 7.1% to 14.9%]), OCD (19.8% [95% CI, 13.0% to 26.6%), and non-OCD anxiety disorders (37.1% [22.5% to 51.7%]), corresponding to a number needed to treat (NNT) of 10 (95% CI, 7 to 15), 6 (4 to 8), and 3 (2 to 5), respectively. While there was increased risk difference of suicidal ideation/suicide attempt across all trials and indications for drug vs placebo (0.7%; 95% CI, 0.1% to 1.3%) (number needed to harm, 143 [95% CI, 77 to 1000]), the pooled risk differences within each indication were not statistically significant: 0.9% (95% CI, –0.1% to 1.9%) for MDD, 0.5% (–1.2% to 2.2%) for OCD, and 0.7% (–0.4% to 1.8%) for non-OCD anxiety disorders. There were no completed suicides. Age-stratified analyses showed that for children younger than 12 years with MDD, only fluoxetine showed benefit over placebo. In MDD trials, efficacy was moderated by age, duration of depression, and number of sites in the treatment trial. Conclusions  Relative to placebo, antidepressants are efficacious for pediatric MDD, OCD, and non-OCD anxiety disorders, although the effects are strongest in non-OCD anxiety disorders, intermediate in OCD, and more modest in MDD. Benefits of antidepressants appear to be much greater than risks from suicidal ideation/suicide attempt across indications, although comparison of benefit to risk varies as a function of indication, age, chronicity, and study conditions.      

The heterogeneity of type IIA von Willebrand's disease: studies with protease inhibitors

The absence of large von Willebrand factor (vWF) multimers from plasma is a characteristic of Type IIA von Willebrand's disease (vWD) and is thought to contribute to the clinical expression of this disorder. Recently, three IIA patients have been reported in whom intermediate and large multimers could be restored if blood were collected in 5 mm EDTA, 6 mmol/L N-ethylmaleimide, and 1 mmol/L leupeptin. This suggested that absence of large multimers resulted from in vitro proteolysis. We have now collected blood from ten Type IIA vWD patients in these inhibitors but were not able to detect large multimers in the plasma of any of them. In addition, intermediate-sized multimers were reduced or completely absent in all. The inclusion of inhibitors in the citrate anticoagulant, as compared to citrate alone, was found to increase the relative proportion of intermediate multimers in some patients but had no effect in others, and in none did it restore large multimers to plasma. The results with platelet vWF were more varied. Four patients showed an absence or decrease of large multimers, whereas in seven patients large multimers were present. When compared with citrate anticoagulant alone, the inclusion of inhibitors in the anticoagulant had little or no effect on the platelet multimeric pattern. 1-Deamino-8- D-Arginine Vasopressin (DDAVP) was administered to six patients from five families. Two patients from one family showed complete correction and a third patient showed almost complete correction of her bleeding time. Two patients showed minimal correction and one showed no detectable correction. An increase in multimer size after DDAVP tended to be associated with correction of the bleeding time. However, in no case did the largest multimers appear in plasma even in patients with complete bleeding time correction. The presence or absence of inhibitors in the anticoagulant had little or no effect on the multimeric pattern after DDAVP. These results indicate that Type IIA vWD is a heterogeneous disorder in which absence of largest and intermediate multimers is an in vivo phenomenon.     

A Phase 2 study of L‐asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL‐SA2‐2008 study

Purpose : The GRASPALL/GRAALL‐SA2‐2008 Phase II trial evaluated the safety and efficacy of L‐asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome‐negative acute lymphoblastic leukemia. Findings : Thirty patients received escalating doses of GRASPA^® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti‐asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L‐asparaginase activity. Complete remission rate was 70%. With a median follow‐up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. Conclusions : The addition of GRASPA^®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. ( clinicaltrials.gov identifier NCT01523782). Am. J. Hematol. 90:811–818, 2015. © 2015 Wiley Periodicals, Inc.     

Comparison between published clinical success of direct resin composite restorations in vital posterior teeth in 1995–2005 and 2006–2016 periods

Composites are increasing in popularity as restorative materials. This growing role indicates the necessity of studies on their clinical outcome. In this study, clinical studies published on the performance of posterior composite restorations were included except those of less than a 24‐month assessment period. Results of non‐vital, anterior or primary teeth and cervical single‐surface restorations were also excluded. Records about composite type, number of final recall restorations, failure/survival rate, assessment period and failure reasons were analysed for each decade. Overall survival/failure rates for studies in 1995–2005 were 89.41%/10.59% and for 2006–2016 were 86.87%/13.13%, respectively. In 1995–2005, the reasons for failure were secondary caries (29.47%) and composite fracture (28.84%) with low tooth fracture (3.45%) compared with reasons of failure in 2006–2016, which were secondary caries (25.68%), composite fracture (39.07%), and tooth fracture (23.76%). An increase in incidence of composite fracture, tooth fracture and need for endodontic treatment as failure reasons was noted in the latter decade in addition to a decrease in secondary caries, postoperative sensitivity, unsatisfactory marginal adaptation and wear. The overall rates of failure showed little difference, but the causes showed a notable change. This is believed to be a reflection of increased use of composites for larger restorations and possibly changes of material characteristics.     

Deficient total cell content of CR3 (CD11b) in neonatal neutrophils

Neonatal neutrophils (PMN) show a well-documented defect in chemotaxis that is associated with several abnormalities of PMN structure and function, including deficient surface expression of CR3 (CD11b), a critical adhesion molecule, on chemoattractant-activated PMN. After activation of PMN with additional stimuli including calcium ionophores, we also found deficient surface CR3 (but normal CR1) expression on neonatal PMN suggesting that abnormal signaling mechanisms are not likely to explain the deficient CR3 expression on activated neonatal PMN. Therefore, we hypothesized that deficient surface expression of CR3 on stimulated neonatal neutrophils is caused by a deficiency in total cell content of CR3. We tested this hypothesis using three different methods to compare the total quantity of CR3 in neonatal versus adult PMN. Western blotting of serial twofold dilutions of PMN lysates from five adult and neonatal pairs, using a monoclonal antibody (MoAb) against CR3 (21PM19C), consistently showed diminished CR3 content in neonatal PMN. A sandwich enzyme-linked immunosorbent assay, in which the CR3 heterodimers in PMN lysates were captured by MoAb to the beta-chain, CD18 (R15.7), then detected with a biotinylated MoAb to the alpha-chain, CD11b (anti-Mac-1), showed that neonatal PMN lysates contain about 66% of adult PMN levels of CR3 (P < 0.03; n = 6). PMN fixed with paraformaldehyde and permeabilized with saponin were studied by immunofluorescence flow cytometry to determine total (surface plus intracellular) CR3 content using phycoerythrin-conjugated MoAb to CR3 (anti-Leu15). Mean total cell CR3 content (in relative fluorescence units) was 58 +/- 14 for adult PMN and 27 +/- 6 for neonatal PMN (n = 5; P = 0.013). In each method, total cell content of CR1 was equivalent for neonatal versus adult PMN. We conclude that neonatal PMN are markedly deficient in total cell CR3 content compared with adult PMN. This result provides a primary explanation for deficient CR3 surface expression on activated neonatal PMN that, in turn, may be important in the chemotactic defect of these cells.     

Are Signs of Central Sensitization in Acute Low Back Pain a Precursor to Poor Outcome?

Central sensitization is considered to have a pathophysiological role in chronic low back pain (LBP). Whether individuals with increased central sensitization early in their condition are more likely to develop persistent pain or whether it increases over time is unclear. This study aimed to determine whether sensory profiles during acute LBP differ between individuals who did and did not recover by 6 months and to identify subgroups associated with outcomes. Individuals with acute LBP (<2 weeks of onset; N = 99) underwent pain threshold (heat/cold/pressure) and conditioned pain modulation testing after completing questionnaires related to pain/disability, sleep, and psychological status. Sensory measures were compared during the acute phase (baseline) and longitudinally (baseline/6 months) between unrecovered (greater or unchanged pain and disability), partially recovered (improved but not recovered pain and/or disability), and recovered (no pain and disability) participants at 6 months. We assessed baseline patterns of sensory sensitivity alone, and with psychological and sleep data, using hierarchical clustering and related the clusters to outcome (pain/disability) at 3 and 6 months. No sensory measure at either time point differed between groups. Two subgroups were identified that associated with more (“high sensitivity”) or less (“high sensitivity and negative psychological state”) recovery. These data seem to suggest that central sensitization during the acute phase resolves for many patients, but is a precursor to the transition to chronicity when combined with other psychological features.PerspectiveCentral sensitization signs during early acute LBP does not necessarily precede poor outcome, but may be sustained in conjunction with other psychological factors and facilitate pain persistence.     

Influence of social factors on weight-related behaviors according to gender in the French adult population

Although the prevalence of obesity is higher in low socioeconomic position (SEP), the relationship between SEP and body mass index (BMI) differs according to gender. The purpose of this study is to investigate the relationships between BMI and SEP according to gender and explore the weight-related behaviors. In a cross-sectional survey, 1646 French adults were weighed and answered a questionnaire about eating behavior (DEBQ), SEP markers, ideal weight perception, physical activity and smoking. Our study showed that BMI was inversely correlated with SEP score in women only, independently of other BMI-associated factors (age, restrained eating, smoking status, TV viewing and physical activity). The SEP gradient was the same in both genders for some weight-related behaviors, such as restrained eating, physical activity and TV viewing, but differs for others, such as smoking and weight consciousness. There was an interaction between the SEP score and the actual BMI on the ideal BMI in women only, thus the difference in ideal body weight according to SEP is mainly due to difference in obese women. Our study concluded that gender differences in the relationship between BMI and SEP could be mainly due to the subjects' perception of weight appropriateness and their weight-related behaviors.     

Balloon catheter dilation of severe pulmonary restenosis 11 years after surgical valvulotomy

A young girl who underwent repair of an atrial septal defect and pulmonary valvulotomy when 6 years of age, presented with clinical and haemodynamic signs of pulmonary restenosis 11 years later: right ventricular systolic pressure (RVSP) of 130 mmHg with a systolic RV/PA pressure gradient of 105 mmHg. Pulmonary valvuloplasty was performed using a balloon catheter (20 mm X 40 mm). Two inflations were necessary to correct the hour glass deformity of the balloon caused by the stenosis. After valvuloplasty the RVSP was 75 mmHg and the RV/PA gradient 55 mmHg. The calculated pulmonary valve surface area increased from 0.36 cm2 to 0.72 cm2. Angiography performed immediately after dilatation showed improved valvular mobility but here was persistant severe infundibular hypertrophy. The intensity of the pulmonary systolic murmur decreased. The good result obtained in this case shows that percutaneous valvuloplasty may be considered when restenosis occurs several years after surgical valvulotomy. Control catheterisation performed two months after dilatation confirmed the good initial haemodynamic result.     

Antibody seronegative human T-lymphotropic virus type III (HTLV-III)- infected patients with acquired immunodeficiency syndrome or related disorders

The human T-lymphotropic virus type III (HTLV-III) is the primary cause of the acquired immunodeficiency syndrome (AIDS) and related disorders (ARC). Prior studies have reported that nearly all symptomatic patients with AIDS or ARC manifest antibody to HTLV-III. This observation has engendered efforts to screen for HTLV-III, especially prior to blood donation, with assays for antibody to HTLV-III. We report the first two cases, one with AIDS and one with ARC, that are HTLV-III virus positive but antibody negative. Accurate diagnosis of HTLV-III infection in some cases may require direct virus culture or tests for antigen. In addition, lack of HTLV-III antibody may indicate an atypical clinical course of AIDS.