Newborn Screening for Severe Combined Immunodeficiency: Analytic and Clinical Performance of the T Cell Receptor Excision Circle Assay in France (DEPISTREC Study).

Severe combined immunodeficiency (SCID) is characterized by a major T cell deficiency. Infants with SCID are asymptomatic at birth but die from infections in the first year of life if not treated. Survival rates are better for early treatment. SCID therefore meets criteria for newborn screening (NBS). T cell receptor excision circle (TREC) quantification is a reliable marker of T cell deficiency and can be performed using Guthrie cards. The DEPISTREC project was designed to study the feasibility, clinical utility, and cost-effectiveness of generalized SCID screening in France. About 200,000 babies from all over the country were screened at birth with a commercial kit. We determined assay performance and proposed a cutoff for classification of results. Our findings suggest that, given clearly established validation rules and decision-making procedures, the TREC assay is a suitably specific and sensitive method for high-throughput SCID screening. Clinical Trials: NCT02244450.

Both active and sham low-frequency rTMS single sessions over the right DLPFC decrease cue-induced cravings among pathological gamblers seeking treatment: A randomized, double-blind, sham-controlled crossover trial.

Background Craving is a core symptom of addictive disorders, such as pathological gambling for example. Over the last decade, several studies have assessed the efficacy of repetitive transcranial magnetic stimulation (rTMS) in the addiction field, which triggers the dorsolateral prefrontal cortex (DLPFC) to decrease craving. The STIMJEU study investigated whether a single session of low-frequency (LF, i.e., 1 Hz) rTMS applied to the right DLPFC reduced cue-induced gambling craving in a sample of treatment-seeking pathological gamblers. Methods Thirty patients received both active and sham rTMS in random order and were blinded to the condition in a within-subject crossover design. Outcome measures included self-reported gambling craving (Visual Analog Scale and Gambling Craving Scale) and physiological measures (heart rate and blood pressure). Results The rTMS sessions were associated with a significant decrease in the gambling urge, regardless of whether the session was active or sham. When controlling cue-induced craving levels, no effects were observed on craving for active rTMS. Overall, rTMS was well-tolerated, and the credibility of the sham procedure was assessed and appeared to be appropriate. Conclusions We failed to demonstrate the specific efficacy of one session of LF rTMS to decrease cue-induced craving in pathological gamblers. A strong placebo-effect and rTMS parameters may partly explain these results. Yet, we are convinced that rTMS remains a promising therapeutic method. Further studies are required to examine its potential effect.

Do abused young children feel less pain?

The objective of this study was to investigate whether acute pain in abused children was under recognized by doctors and nurses compared to children evaluated for accidental injuries. We hypothesize that an abused child's reaction to physical pain could be an additional symptom of this challenging diagnosis. For the observational prospective case control study in an emergency department, children were eligible when: younger than six years old, the reported trauma occurred within the previous seven days, the trauma comprised a bone injury or burn, and the child was able to express his or her pain. The case group comprised children for whom the medical team reported their abuse suspicions and supporting information to a court, and whose cases of abuse were subsequently confirmed. The control group consisted of children with a plausible cause for their injury and no obvious signs of abuse. The children were matched according to their age and type of trauma. The pain was assessed by doctors and nurses before analgesic administration using a certified pain scale. Among the 78 included children, pain was significantly less recognized in the abused children vs. the controls (relative risk=0.63; 95% CI: 0.402-0.986; p=0.04). We observed a discrepancy between the nurses' and doctors' scores for the pain assessments (Kappa coefficient=0.59, 95% CI: 0.40-0.77). Our results demonstrate that pain expression in abused children is under recognized by medical staff. They also suggest that abused children may have reduced pain expression after a traumatic event. Paying particular attention to the pain of abused children may also optimize the analgesic treatment.

Buprenorphine prescription compliance: an original observational and longitudinal study.

INTRODUCTION: Buprenorphine is one of the main opioid dependence treatments, especially in France, where it has been widely prescribed since 1996. But it can easily be misused and its prescription has to be followed up. In the literature, we found several studies on buprenorphine, but we did not find long-term ecological follow-up studies on buprenorphine prescription and compliance. MATERIAL AND METHOD: The main purpose of this study was to define stability or instability of the prescription of buprenorphine to opiate-addicted patients. We carried out a forecast study on prescription of buprenorphine over a 10-year period, using software collecting prescription data. We performed statistical analysis of the conditions and transitions of opiate-addicted patients treated with buprenorphine along appointments. DISCUSSION/CONCLUSION: We showed that 70% of buprenorphine prescriptions are stable; we assumed that our results correspond to buprenorphine compliance. The retention in treatment was associated with a positive evolution of prescription stability. Prior criminal records were the only factor linked to instability. We showed that collecting precise prescription data in face to face appointments using software, including legal prescription rules that guide practitioners in following buprenorphine prescription compliance, seemed to be a useful method to measure buprenorphine compliance.

Short communication: Paraoxonase 1 (PON1) in French HIV-infected patients under antiretroviral therapy: relationship with the metabolic syndrome and inflammation.

Our goal was to determine if paraoxonase 1 (PON1) activity relates to the presence of metabolic syndrome (MS) and inflammation in HIV patients treated with highly active antiretroviral therapy (HAART). This was a prospective, multicenter study including 269 patients receiving HAART for at least 1 year and a maximum of 4 years. PON1 and inflammatory markers [C reactive protein (CRP), interleukin-6 (IL-6), serum amyloid A (SAA), and soluble tumor necrosis factor receptors 2 (sTNF-R2)] were compared between patients with or without MS and the association between inflammatory markers and PON1 was assessed by logistic regression analyses. MS was found in 18.2% of the patients. Inflammatory markers, with the exception of sTNF-R2, were significantly higher, while PON1 activity was significantly lower in the presence of metabolic syndrome. PON1 activity was significantly related to apolipoprotein C3, CD4 count, and sTNF-R2. It may be concluded that PON1 appears to be a marker for the metabolic syndrome in HIV-infected subjects. PON1 activity is related to dyslipidemia and the immunological status of the patients but is not fully determined by inflammation.

Suitability of POC lactate methods for fetal and perinatal lactate testing: considerations for accuracy, specificity and decision making criteria.

BACKGROUND: Point of care (POC) testing for fetal scalp blood lactate is a more user friendly and more successful approach compared to scalp pH for intrapartum fetal monitoring. The aim of this study was to assess the analytical specificity and clinical reliability of three POC lactate methods. METHODS: The analytical performance of three POC lactate methods was compared to Cobas 6000 (Roche Diagnostics) laboratory reference method: Lactate Pro from Arkray, GEM 4000 from Instrumentation Laboratory and StatStrip Lactate from Nova Biomedical. The clinical performance and influences on accuracy and decision making criteria for the three POC methods was assessed with umbilical cord samples and compared to the laboratory reference method. The influence of varying ranges of hemoglobin, pH and partial oxygen pressure (pO(2)) on the accuracy of results was assessed. RESULTS: Although all three POC methods showed good correlation with the reference method for the umbilical cord sample population (r=0.989, 0.973 and 0.980, respectively), Lactate Pro and Gem 4000 showed a significant negative bias compared to the reference method. The degree of bias meant a significant readjustment of decision making criteria was required for fetal lactate use. The accuracy of the Lactate Pro results was affected by hemoglobin and to a lesser extent pH. CONCLUSIONS: The three electrochemical POC devices can measure fetal lactate reliably. StatStrip Lactate showed a closer correlation and concordance to our laboratory reference method. The results of this study indicate the requirement for predetermining the reliability of POC lactate methods before use present in fetal and perinatal settings.

Clinical profiles as a function of level and type of impulsivity in a sample group of at-risk and pathological gamblers seeking treatment.

Level and type of impulsivity are essential variables to be taken into consideration during the initial evaluation of a pathological gambler. The aim of this study was to measure the score for 4 impulsivity-related traits (Urgency, (lack of) Premeditation, (lack of) Perseverance and Sensation seeking) in a sample group of at-risk and pathological gamblers, and to highlight any links with certain elements of clinical data. The UPPS Impulsive Behaviour Scale was administered to 84 problem gamblers seeking treatment. The severity of gambling disorders was evaluated using the diagnostic criteria of the DSM-IV. Psychiatric and addictive comorbidities were also explored. The results indicated that the score for the Urgency facet had a positive correlation with the severity of gambling disorders. It appeared that participants displayed different clinical profiles according to the level and type of impulsivity. Several of the UPPS scales were identified as risk factors for mood disorders, risk of suicide, alcohol use disorders, and Attention Deficit/Hyperactivity Disorder (ADHD). The results confirm both the complexity of the multi-dimensional concept of impulsivity and the reason why the UPPS is of interest for a more in-depth study of the subject.

Relevance of both individual risk factors and occupational exposure in cancer survival studies: the example of intestinal type sinonasal adenocarcinoma.

OBJECTIVES/HYPOTHESIS: Wood dust is a well-established risk factor for intestinal type sinonasal adenocarcinoma. The 5-year overall survival has varied from 20% to 80% according T1-T4 stages; 5-year survival according to histologic subtype has varied from 20% to 50%. To date, no study has evaluated whether environmental, occupational, and personal risk factors have any impact on both overall and cancer-specific survival. We aimed to determine whether exposure to carcinogenic risk factors besides wood exposure can influence the survival of patients with sinonasal ethmoid carcinoma. STUDY DESIGN: Retrospective cohort study of the association of survival data and occupational and personal carcinogenic risk factors. METHODS: All patients hospitalized for ethmoid adenocarcinoma at the Nantes University Hospital between 1988 and 2004 were included . Data concerning TNM classification, histology, type and quality of tumor resection at the macro- and microscopic level, and occupational and personal exposure to carcinogens were collected. Statistical analysis was conducted using univariate and multivariate linear regression. RESULTS: A total of 98 patients were included with a response rate of 98%. Data showed 86% of patients had been exposed to wood dust. The 5-year survival was 62%. We first identified four factors that independently influenced overall survival: diplopia (P = .0159), spread to the orbit (P = .0113), bilateral involvement (P = .0134), TNM stage (P < .001). When the analysis included all occupational environmental factors (wood dust, solvent, and metals exposure) as well as personal risk factors, the length of exposure to metals (P = .0307) and tobacco exposure (P = .0031) also were found to influence 5-year overall survival. We identified high prevalence of colon cancer (4%) and double cancer (18%). CONCLUSIONS: We showed exposure to both environmental (tobacco) and occupational (metal dust) factors could influence survival in the diagnosis of a cancer. Our study suggests that screening for colon cancer should be offered to wood dust workers. A prospective multicentric study should be necessary to confirm our results.

Attention deficit hyperactivity disorder among pathological and at-risk gamblers seeking treatment: a hidden disorder.

BACKGROUND: The links between attention deficit hyperactivity disorder (ADHD) and substance use disorders have been the subject of numerous papers. Few studies, however, have focused specifically on the relationship between ADHD and behavioural addictions. The aim of this study was to (i) examine the frequency of pathological and at-risk gamblers having a previous history of ADHD; (ii) give details of the characteristics of this association, and (iii) identify risk factors for a history of ADHD. METHODS: 84 pathological and at-risk gamblers were assessed about socio-demographic, gambling and clinical characteristics. RESULTS: Over 25% of the subjects had a history of ADHD. They were characterized as having more severe gambling problems and a higher level of gambling-related cognitions, a higher frequency of psychiatric comorbidities and an elevated risk of suicide. Finally, they differed in their level and type of impulsivity. Among pathological and at-risk gamblers, a high level of impulsivity, or a history of anxiety disorders, constitute risk factors for a comorbidity with ADHD. CONCLUSION: The association 'ADHD-problem gambling' therefore appears to be not only frequent, but also linked to factors that are known to worsen the prognosis. Researching this relationship is therefore important to adapt strategies for effective future therapy.

Gene expression profiling in sinonasal adenocarcinoma.

BACKGROUND: Sinonasal adenocarcinomas are uncommon tumors which develop in the ethmoid sinus after exposure to wood dust. Although the etiology of these tumors is well defined, very little is known about their molecular basis and no diagnostic tool exists for their early detection in high-risk workers. METHODS: To identify genes involved in this disease, we performed gene expression profiling using cancer-dedicated microarrays, on nine matched samples of sinonasal adenocarcinomas and non-tumor sinusal tissue. Microarray results were validated by quantitative RT-PCR and immunohistochemistry on two additional sets of tumors. RESULTS: Among the genes with significant differential expression we selected LGALS4, ACS5, CLU, SRI and CCT5 for further exploration. The overexpression of LGALS4, ACS5, SRI, CCT5 and the downregulation of CLU were confirmed by quantitative RT-PCR. Immunohistochemistry was performed for LGALS4 (Galectin 4), ACS5 (Acyl-CoA synthetase) and CLU (Clusterin) proteins: LGALS4 was highly up-regulated, particularly in the most differentiated tumors, while CLU was lost in all tumors. The expression of ACS5, was more heterogeneous and no correlation was observed with the tumor type. CONCLUSION: Within our microarray study in sinonasal adenocarcinoma we identified two proteins, LGALS4 and CLU, that were significantly differentially expressed in tumors compared to normal tissue. A further evaluation on a new set of tissues, including precancerous stages and low grade tumors, is necessary to evaluate the possibility of using them as diagnostic markers.

Binding activities and antitumor properties of a new mouse/human chimeric antibody specific for GD2 ganglioside antigen.

PURPOSE: We previously generated a mouse monoclonal antibody (mAb) specific for the tumor-associated GD2 ganglioside antigen. Here, we describe the development of a chimeric anti-GD2 mAb for more effective tumor immunotherapy. EXPERIMENTAL DESIGN: We cloned the cDNA encoding the immunoglobulin light and heavy chains of the 60C3 anti-GD2 mAb, and constructed chimeric genes by linking the cDNA fragments of the variable regions of the murine light and heavy chains to cDNA fragments of the human kappa and gamma1 constant regions, respectively. RESULTS: The resultant chimeric anti-GD2 mAb, c.60C3, showed identical binding affinity and specificity to that of its murine counterpart. Both c.60C3 and 60C3 were rapidly internalized by tumor cells at 37 degrees C. When human serum and human natural killer cells were used as effectors in complement-mediated cytotoxicity and antibody-dependent cell cytotoxicity, respectively, c.60C3 was more effective in killing GD2-expressing tumor cells. However, c.60C3 was ineffective at inducing cell death by apoptosis, although binding of 60C3 induced apoptotic death in vitro. In an in vivo, GD2-expressing, syngeneic tumor model, i.v. injection of c.60C3, but not of 60C3, significantly suppressed tumor growth in mice (P<0.0005). CONCLUSION: Immune effector functions mediated by this antibody and its potentially reduced immunogenicity make chimeric c.60C3 a promising therapeutic agent against neuroectodermic tumors.