Efficacité thérapeutique de l’autologous conditioned plasma (ACP™) : analyse de sa composition cellulaire et revue de la littérature

Purpose

To analyze the platelet counts of autologous conditioned plasma (ACP™) in a group of patients compared to that of whole blood and to determine the value of ACP™ based on a literature review.

Methods

In 2011, a prospective study was performed in a continuous series of patients presenting with chronic tendinopathies. Three 9 μL venous blood samples were obtained from each patient: the first to perform a full blood count and the second and third to prepare two doses of ACP™, one which was injected into the patient and the other which underwent biological testing. A bibliographic search was performed on PubMed with the key words “autologous conditioned plasma”. All studies both clinical and experimental, in English and in French, were included.

Results

The series included 14 male patients mean age 39 ± 14 years. The mean platelet count was 230,538.5 ± 23,663/μL in whole blood and 377,153.8 ± 69,169.9/μL in ACP™, P = 0.00015. The mean “ACP™ platelet count/whole blood platelet count” ratio was 1.64 ± 0.30. The number of red and white blood cells was below the detection thresholds. The systematic review identified eight studies: three in animals and five in human of which two clinical studies.

Conclusion

The preparation technique for ACP™ was rapid and easy to use. ACP™ had a platelet count that was significantly higher than that of whole blood and did not contain any red or white blood cells. The review of the literature did not clearly confirm the therapeutic efficacy of ACP™. Randomized clinical studies comparing ACP™ to placebo are needed.

Level of evidence

IV.     

Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5′ CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often, but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI− tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2′-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.     

Appetitive and Consummatory Behaviors in the Control of Ethanol Consumption: A Measure of Ethanol Seeking Behavior

Models of ethanol self-administration in animals have demonstrated that ethanol can reinforce a variety of behaviors, independent of ethanol's caloric or fluid properties. However, the processes that control self-administration remain unclear. Determining factors related to ethanol seeking behavior, independent of consumption, Is central to the concepts of intake regulation. The model described in this article proposes a method to separate the initial appetitive (seeking) behavior from the following consummatory (drinking) behavior to assess each behavior type. Rats were trained to lever press to gain access to a drinking tube connected to a fluid bottle containing either 10Y0 ethanol or 3% sucrose for 20 min. When the response requirement to obtain access to the tube was increased, it was found that both solutions supported the same amount of responding (breakpoint was at approximately a fixed ratio 32 requirement), indicating equal reinforcer strength. However, regardless of the response requirement, if access to the fluids occurred, intakes were not changed. This suggests that factors besides those of reinforcer efficacy are important in controlling the size of the consummatory bout. Based on these findings, we believe that this model will be useful in determining factors related to seeking behaviors and the control of drinking bout size.     

The relationship between urban environment and the inflammatory bowel diseases: a systematic review and meta-analysis

ABSTRACT: BACKGROUND: The objective of this study was to conduct a systematic review with meta-analysis of studies assessing the association between living in an urban environment and the development of the Crohn's disease (CD) or ulcerative colitis (UC). METHODS: A systematic literature search of MEDLINE (1950-Oct. 2009) and EMBASE (1980-Oct. 2009) was conducted to identify studies investigating the relationship between urban environment and IBD. Cohort and case-control studies were analyzed using incidence rate ratio (IRR) or odds ratio (OR) with 95 % confidence intervals (CIs), respectively. Stratified and sensitivity analyses were performed to explore heterogeneity between studies and assess effects of study quality. RESULTS: The search strategy retrieved 6940 unique citations and 40 studies were selected for inclusion. Of these, 25 investigated the relationship between urban environment and UC and 30 investigated this relationship with CD. Included in our analysis were 7 case-control UC studies, 9 case-control CD studies, 18 cohort UC studies and 21 cohort CD studies. Based on a random effects model, the pooled IRRs for urban compared to rural environment for UC and CD studies were 1.17 (1.03, 1.32) and 1.42 (1.26, 1.60), respectively. These associations persisted across multiple stratified and sensitivity analyses exploring clinical and study quality factors. Heterogeneity was observed in the cohort studies for both UC and CD, whereas statistically significant heterogeneity was not observed for the case-control studies. CONCLUSIONS: A positive association between urban environment and both CD and UC was found. Heterogeneity may be explained by differences in study design and quality factors.     

Hepatocellular adenoma: an excellent indication for laparoscopic liver resection

Objectives

Laparoscopic resection for benign liver disease has gained wide acceptance in recent years and hepatocellular adenoma (HA) seems to be an appropriate indication. This study aimed to discuss diagnosis and treatment strategies, and to assess the feasibility, safety and outcomes of pure laparoscopic liver resection (LLR) in a large series of patients with HA.

Methods

Of 88 patients who underwent pure LLR, 31 were identified as having HA. Diagnosis was based on radiological evaluation and resections were performed for lesions measuring >5.0 cm.

Results

The sample included 29 female and two male patients. Their mean age was 33.2 years. A total of 27 patients had a single lesion, one patient had two and one had four lesions. The two remaining patients had liver adenomatosis. Mean tumour size was 7.5 cm. Three right hepatectomies, 17 left lateral sectionectomies and 11 wedge resections or segmentectomies were performed. There was no need for blood transfusion or conversion to open surgery. Postoperative complications occurred in two patients. Mean hospital stay was 3.8 days.

Conclusions

Hepatocellular adenoma should be regarded as an excellent indication for pure LLR. Pure LLR is safe and feasible and should be considered the standard of care for the treatment of HA when performed by surgeons with experience in liver and laparoscopic surgery.     

Follow-up intervals in patients with Cushing’s disease: recommendations from a panel of experienced pituitary clinicians

Purpose

Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing’s disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course.

Methods

The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after (“second round”) an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: “agreement” if no more than two responses were outside a 2 week window around the median response; “disagreement” if more than two responses were outside a 2 week window around the median response. Recommendations were developed based on second round results.

Results

Panel agreement was 65.9% before and 88.6% after the in-person discussion. The panel recommended follow-up within 8 weeks for patients in remission on glucocorticoid replacement and within 1 year of surgery; within 4 weeks for patients with uncontrolled persistent or recurrent disease; within 8–24 weeks in post-radiotherapy patients controlled on medical therapy; and within 24 weeks in asymptomatic patients with stable plasma ACTH concentrations after bilateral adrenalectomy.

Conclusions

With a high level of consensus using the Delphi process, panelists recommended regular follow-up in most patient scenarios for this chronic condition. These recommendations may be useful for assessment of CD care both in research and clinical practice.

     

Screening for impaired fasting glucose and diabetes using available health plan data

AimsTo develop and validate prediction equations to identify individuals at high risk for type 2 diabetes using existing health plan data.MethodsHealth plan data from 2005 to 2009 from 18,527 members of a Midwestern HMO without diabetes, 6% of whom had fasting plasma glucose (FPG) ≥ 110 mg/dL, and health plan data from 2005 to 2006 from 368,025 members of a West Coast-integrated delivery system without diabetes, 13% of whom had FPG ≥ 110 mg/dL were analyzed. Within each health plan, we used multiple logistic regression to develop equations to predict FPG ≥ 110 mg/dL for half of the population and validated the equations using the other half. We then externally validated the equations in the other health plan.ResultsAreas under the curve for the most parsimonious equations were 0.665 to 0.729 when validated internally. Positive predictive values were 14% to 32% when validated internally and 14% to 29% when validated externally.ConclusionMultivariate logistic regression equations can be applied to existing health plan data to efficiently identify persons at higher risk for dysglycemia who might benefit from definitive diagnostic testing and interventions to prevent or treat diabetes.     

Prevalence and risk factors for diabetes-related foot complications in Translating Research Into Action for Diabetes (TRIAD)

AimsThe objective was to describe the prevalence of diabetes-related foot complications in a managed care population and to identify the demographic and biological risk factors.MethodsWe assessed the period prevalence of foot complications on 6992 patients using ICD-9 diagnosis codes from health plan administrative data. Demographic and biological variables were ascertained from surveys and medical record reviews. We defined four mutually exclusive groups: any Charcot foot, DFU with debridement, amputation ± DFU and debridement, and no foot conditions.ResultsOverall, 55 (0.8%) patients had Charcot foot, 205 (2.9%) had DFU with debridement, and 101 (1.4%) had a lower-extremity amputation. There were 6631 patients with no prevalent foot conditions. Racial/ethnic minorities were less likely to have Charcot foot (OR = 0.21; 95% CI: 0.10, 0.46) or DFU (OR = 0.61; 95% CI: 0.44, 0.84) compared to non-Hispanic Whites, but there were no racial/ethnic differences in amputation. Histories of micro- or macrovascular disease were associated with a two- to four-fold increase in the odds of foot complications.ConclusionIn managed care patients with uniform access to health care, we found a relatively high prevalence of foot complications, but attenuation of the racial/ethnic differences of rates reported in the literature.     

Neuregulin and dopamine modulation of hippocampal gamma oscillations is dependent on dopamine D4 receptors

The neuregulin/ErbB signaling network is genetically associated with schizophrenia and modulates hippocampal γ oscillations-a type of neuronal network activity important for higher brain processes and altered in psychiatric disorders. Because neuregulin-1 (NRG-1) dramatically increases extracellular dopamine levels in the hippocampus, we investigated the relationship between NRG/ErbB and dopamine signaling in hippocampal γ oscillations. Using agonists for different D1- and D2-type dopamine receptors, we found that the D4 receptor (D4R) agonist PD168077, but not D1/D5 and D2/D3 agonists, increases γ oscillation power, and its effect is blocked by the highly specific D4R antagonist L-745,870. Using double in situ hybridization and immunofluorescence histochemistry, we show that hippocampal D4R mRNA and protein are more highly expressed in GAD67-positive GABAergic interneurons, many of which express the NRG-1 receptor ErbB4. Importantly, D4 and ErbB4 receptors are coexpressed in parvalbumin-positive basket cells that are critical for γ oscillations. Last, we report that D4R activation is essential for the effects of NRG-1 on network activity because L-745,870 and the atypical antipsychotic clozapine dramatically reduce the NRG-1-induced increase in γ oscillation power. This unique link between D4R and ErbB4 signaling on γ oscillation power, and their coexpression in parvalbumin-expressing interneurons, suggests a cellular mechanism that may be compromised in different psychiatric disorders affecting cognitive control. These findings are important given the association of a DRD4 polymorphism with alterations in attention, working memory, and γ oscillations, and suggest potential benefits of D4R modulators for targeting cognitive deficits.     

Structure-function analysis of pneumococcal DprA protein reveals that dimerization is crucial for loading RecA recombinase onto DNA during transformation

Transformation promotes genome plasticity in bacteria via RecA-driven homologous recombination. In the Gram-positive human pathogen Streptococcus pneumoniae, the transformasome a multiprotein complex, internalizes, protects, and processes transforming DNA to generate chromosomal recombinants. Double-stranded DNA is internalized as single strands, onto which the transformation-dedicated DNA processing protein A (DprA) ensures the loading of RecA to form presynaptic filaments. We report that the structure of DprA consists of the association of a sterile alpha motif domain and a Rossmann fold and that DprA forms tail-to-tail dimers. The isolation of DprA self-interaction mutants revealed that dimerization is crucial for the formation of nucleocomplexes in vitro and for genetic transformation. Residues important for DprA-RecA interaction also were identified and mutated, establishing this interaction as equally important for transformation. Positioning of key interaction residues on the DprA structure revealed an overlap of DprA-DprA and DprA-RecA interaction surfaces. We propose a model in which RecA interaction promotes rearrangement or disruption of the DprA dimer, enabling the subsequent nucleation of RecA and its polymerization onto ssDNA.