HDL lipid composition is profoundly altered in patients with type 2 diabetes and atherosclerotic vascular disease.

BACKGROUND AND AIMS: We have previously shown that the anti-inflammatory and anti-oxidant functions of HDL are impaired in T2D patients. In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD). METHODS AND RESULTS: HETEs and HODEs on HDL were determined by LC-MS/MS in 40 non-diabetic controls (ND), 40 T2D without CVD (D⁺CVD⁻) and 38 T2D with known history of CVD (D⁺CVD⁺). HDL oxidant index was evaluated by a cell-free assay using dichlorofluorescein. Twenty-six randomly selected subjects from the three groups underwent coronary calcium score evaluation (CAC). Major cardiovascular risk factors were similar among the groups. HETEs and HODEs content were significantly increased in HDL from D⁺CVD⁺ when compared to D⁺CVD⁻ and ND patients. HDL oxidant index was not different among the three groups; however, it was significantly higher in patients with CAC score >100 when compared to patients with CAC score <100. CONCLUSION: Patients with D⁺CVD⁻ and D⁺CVD⁺ are characterized by a severe, graded enrichment of oxidized fatty acids on HDL. In the present study, a loss of HDL function (as estimated by the HDL oxidant index) is observed only in patients with more advanced atherosclerosis.

A novel framework for ketamine-assisted couple therapy.

Intimate relationship distress is prevalent and is associated with poorer health, mental health, and mortality outcomes. Evidence-based couple therapies target cognitive, behavioral, and emotional processes that underlie relationship dysfunction. Increasing research and clinical evidence supports the efficacy of ketamine-assisted psychotherapy (KAP) for addressing clinical mental health concerns, including depression, anxiety disorders, posttraumatic stress disorder, and more. The purported mechanisms of KAP are also likely to improve psychosocial and relational functioning for patients and may be useful for supporting change mechanisms in couple therapy. This paper reviews the current evidence for therapeutic ketamine and KAP and outlines how the mechanisms of ketamine therapy may also augment the cognitive, behavioral, and emotional interventions in the most commonly used evidence-based couple therapies. Key mechanisms include increased neuroplasticity, changes in functional connectivity, adaptive dissociation, decreased inhibition, and reduced avoidance. Given the reciprocal interaction between relationship dysfunction and mental health problems, ketamine may also help alleviate relationship distress by directly treating clinical mental health symptoms. We then outline a proposed framework for ketamine-assisted couple therapy, addressing the application of KAP preparation, dosing, and integration to a dyadic intervention framework in a way that can be applied to different couple therapy modalities. This clinical framework for couples' KAP may be useful for clinicians and researchers working to improve the efficacy of couple therapy, particularly when one or both partners has accompanying mental health concerns.

MDMA-assisted brief cognitive behavioral conjoint therapy for PTSD: Study protocol for a pilot study.

Background: Posttraumatic Stress Disorder (PTSD) impacts both individual and relational functioning. Veteran couples are at increased risk of relationship distress due to military stressors such as deployment, family reintegration, and traumatic stress. Although both Cognitive-Behavioral Conjoint Therapy (CBCT) and its brief version (bCBCT) consistently have large effects on reducing PTSD symptoms, these treatments have more variable effects on relational outcomes. Given the impact of relationship functioning on the overall health of veterans, improving the effect of PTSD treatments on relationship functioning is an essential area of research. One promising path is the role of MDMA (3,4-methylenedioxymethamphetamine)-assisted therapy in augmenting the relational impact of established therapeutic interventions such as bCBCT. Method/Design: This is a single site, open-label study assessing the preliminary efficacy, safety, and acceptability of MDMA-assisted therapy in combination with bCBCT in 8 veterans with PTSD and their intimate partners (N = 16). Therapy teams trained in bCBCT and MDMA-assisted therapy will deliver bCBCT combined with two MDMA sessions and two couple emotion focused integration sessions. PTSD symptom severity and relationship functioning outcomes will be evaluated. Conclusion: This is the first study to examine the efficacy of MDMA-assisted bCBCT for improving PTSD and relationship functioning among a sample of U.S. military veterans and their partners. This project could provide an opportunity to pilot a scalable model of treating PTSD within the Veterans Affairs healthcare system and leverage the benefits of MDMA for veterans with PTSD, as well as the downstream benefits to their partner on both individual and relationship functioning. ClinicalTrials.gov Identifier: NCT05979844.

Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population.

BACKGROUND AND AIMS: This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). METHODS: Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. RESULTS: 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p<0.001). CONCLUSIONS: High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps >5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.

[Transition from pediatric to adult care: experience of a cystic fibrosis care center]. / Passage de l'enfant à l'adulte: l'exemple d'un centre de ressources et de compétences pour la mucoviscidose.

BACKGROUND AND OBJECTIVE: Even though patients with cystic fibrosis (CF) are continuously improving their life expectancy, guidelines for transition to adult services have not been clearly determined yet. The aim of this study was to analyze the management of this transition in the CF care center of Angers, France. PATIENTS AND METHOD: From their medical files, we analyzed the transfer of 22 patients with CF from pediatric to adult care. The perceptions of patients and caregivers regarding this transition were evaluated using anonymous questionnaires. RESULTS: The initial objective was to transfer patients around 18 years of age, offering them 3 or 4 joint consultations with a pediatrician and adult lung specialist. The median age of transfer was 22 years and the median duration of the transition period was 9 months. Half of the patients had only 1 joint transfer consultation during transition. The patient reaching the age of 18 and maturity were the most common criteria mentioned for transfer. All highlighted problems leaving the pediatric team they had grown attached to and its familiar environment. Caregivers described the transfer as a success, whereas half of the patients were dissatisfied with it, with both patients and caregivers indicating that the transition was too short without enough joint consultations. CONCLUSIONS: This study shows that this period is a major life event for the patient with CF. The transition process must be organized with the patient and independent behaviors should be encouraged. Adult and pediatric teams need to cooperate. Based on this experience and former medical data, we suggest a transition program for patients with CF.

Endothelin increases [Ca2+]i in rat pancreatic acinar cells by intracellular release but fails to increase amylase secretion.

In individual fura-2 loaded cells of rat pancreatic acini endothelin-1 (ET-1) (10-50 nM) induced sustained oscillations in [Ca2+]i. At higher concentrations a larger, but transient increase in [Ca2+]i was observed, which was largely unaffected by removal of extracellular Ca2+. ET-1 induced the release of Ca2+i from the same store as cholecystokinin (CCK), but with less potency. At concentrations of endothelin which transiently increased Ca2+, ET-1 increased the accumulation of inositol phosphates. Specific binding sites for 125I-endothelin were demonstrated on rat pancreatic acini. A single class of binding sites was identified with an apparent Kd 108 +/- 12 pM and Bmax of 171 +/- 17 fmol/mg for ET-1. The relative potency order for displacing [125I]ET was ET-1 greater than ET-2 greater than ET-3. In contrast to CCK and the non-phorbol ester tumour promoter Thapsigargin (TG) which induce both transient and sustained components of [Ca2+]i elevation, ET-1 failed to increase amylase release over the range 100 pM-1 microM.

High-density lipoprotein loses its anti-inflammatory properties during acute influenza a infection.

BACKGROUND: Viruses have been identified as one of a variety of potential agents that are implicated in atherogenesis. METHODS AND RESULTS: C57BL/6J mice were killed before or 2, 3, 5, 7, or 9 days after intranasal infection with 10(5) plaque-forming units (pfu) of Influenza A strain WSN/33. Peak infectivity in lungs was reached by 72 hours, and it returned to baseline by 9 days. No viremia was observed at any time. The activities of paraoxonase and platelet-activating factor acetylhydrolase in HDL decreased after infection and reached their lowest levels 7 days after inoculation. The ability of HDL from infected mice to inhibit LDL oxidation and LDL-induced monocyte chemotactic activity in human artery wall cell cocultures decreased with time after inoculation. Moreover, as the infection progressed, LDL more readily induced monocyte chemotaxis. Peak interleukin-6 and serum amyloid A plasma levels were observed at 2 and 7 days after inoculation. HDL apoA-I levels did not change. ApoJ and ceruloplasmin levels in HDL peaked 3 days after infection. Ceruloplasmin remained elevated throughout the time course, whereas apoJ levels decreased toward baseline after the third day. CONCLUSIONS: We conclude that alterations in the relative levels of paraoxonase, platelet-activating factor acetylhydrolase, ceruloplasmin, and apoJ in HDL occur during acute influenza infection, causing HDL to lose its anti-inflammatory properties.

[Knowledge of adolescents with inflammatory bowel disease: Results of a multicenter cross-sectional survey]. / Connaissances des adolescents atteints de maladie inflammatoire chronique intestinale : résultats d'une enquête transversale multicentrique.

AIM: To assess knowledge acquired by adolescents about their inflammatory bowel disease (IBD). METHODS: An anonymous questionnaire was given during consultation to adolescents followed for IBD by pediatricians from 13 hospitals between 1 September 2012 and 1 July 2013. After parental consent, these physicians completed a form at the inclusion of each patient, in which the characteristics of IBD were detailed. The patients mailed back their questionnaire. RESULTS: A total of 124 patients from 12 to 19 years of age were included with a response rate of 82% (all anonymous); 23% of the patients thought that diet was a possible cause of IBD and 22% that one of the targets of their treatment was to cure their disease for good. Of the patients reported having Crohn disease, 46% knew the anoperineal location and 14% knew that Crohn disease can affect the entire digestive tract. Twenty-five percent of the patients were able to name one side effect of azathioprine (88% had already received this treatment), 24% were able to name one side effect of infliximab (54% had already received this treatment), 70% of the adolescents knew that smoking worsens Crohn disease, 68% declared they had learned about their IBD from their pediatrician, and 81% said they would like to receive more information. CONCLUSION: Adolescents with IBD have gaps in their general knowledge and the different treatments of their disease. Their main source of information is their pediatrician, warranting the implementation of customized patient education sessions.

Calcium induces rapid changes in protein phosphorylation in permeabilized pancreatic acini.

Calcium is an important mediator of pancreatic stimulus-secretion coupling, and in streptolysin O-permeabilized acini maximal amylase release can be induced by 1 microMCa2+. Two-dimensional analysis of acinar phosphoproteins using 32P-labeled acini showed that 1-min stimulation of permeabilized acini with 1 microMCa2+ induced a number of rapid protein phosphorylation and dephosphorylation events similar to previously observed effects of secretagogues acting on intact acini. The rapid Ca2+ effects on protein phosphorylation correlated well with the earliest detectable onset of amylase release after 1 min of incubation with Ca2+. Our findings indicate that some of the agonist-induced changes in protein phosphorylation are mediated by Ca2+ and also provide evidence for the possible involvement of Ca(2+)-mediated dephosphorylation in acinar stimulus-secretion coupling.

Hyperthermia, inducing pancreatic heat-shock proteins, fails to prevent cerulein-induced stress kinase activation.

The dually phosphorylated c-jun kinase and p38 mitogen-activated protein (MAP) kinase, also termed stress kinases, are members of the MAP kinase family. They are activated early during cerulein pancreatitis induction and have been proposed as regulators during pancreatitis development by us and others. We recently showed that hyperthermia preconditioning induces expression of pancreatic heat-shock proteins (HSP) and protects against cerulein pancreatitis. Because it was further reported that HSP70 can prevent activation of stress kinases in lymphoid tumor cells, we investigated whether hyperthermia preconditioning might reduce hyperstimulation-mediated activation of pancreatic stress kinases. Pancreatic HSP expression was induced by whole-body hyperthermia preconditioning. Without prior HSP induction, cerulein led to a rapid and dose-dependent increase in serum lipase and amylase levels, pancreatic wet weight through edema formation, and activation of pancreatic MAP kinases. Hyperthermia preconditioning, although strongly inducing HSP70 and almost completely preventing edema formation, as well as the increase of serum amylase and lipase, did not reduce cerulein-mediated stress kinase activation. This indicates that in the pancreas, cerulein can strongly activate MAP kinases even when pancreatitis development is greatly inhibited, and that pancreatic HSPs do not inhibit activation of pancreatic stress kinases in vivo.

Treatment of hepatic hydrothorax and reduction of chest tube output with octreotide.

Hepatic hydrothorax is a dreaded complication in patients with liver cirrhosis. Placement of chest tubes can alleviate respiratory distress, but patients often succumb due to excessive fluid and protein loss via the open drain. Our case illustrates that high-dose octreotide can strongly reduce hepatic hydrothorax drainage volume. This allows removal of the chest tube, which would otherwise not have been possible.

Stress kinase inhibition modulates acute experimental pancreatitis.

AIM: To examine the role of p38 during acute experimental cerulein pancreatitis. METHODS: Rats were treated with cerulein with or without a specific JNK inhibitor (CEP1347) and/or a specific p38 inhibitor (SB203580) and pancreatic stress kinase activity was determined. Parameters to assess pancreatitis included trypsin, amylase, lipase, pancreatic weight and histology. RESULTS: JNK inhibition with CEP1347 ameliorated pancreatitis, reducing pancreatic edema. In contrast, p38 inhibition with SB203580 aggravated pancreatitis with higher trypsin levels and, with induction of acinar necrosis not normally found after cerulein hyperstimulation. Simultaneous treatment with both CEP1347 and SB203580 mutually abolished the effects of either compound on cerulein pancreatitis. CONCLUSION: Stress kinases modulate pancreatitis differentially. JNK seems to promote pancreatitis development, possibly by supporting inflammatory reactions such as edema formation while its inhibition ameliorates pancreatitis. In contrast, p38 may help reduce organ destruction while inhibition of p38 during induction of cerulein pancreatitis leads to the occurrence of acinar necrosis.

[Barrett's esophagus: screening and prognosis]. / Barrett-Osophagus, Screening und Prognose.

The diagnostic criteria for Barrett's disease have changed very considerably during the last 10 years. Classically, the definition asked for columnar epithelium in the lower esophagus extending for at least 3 cm proximally. Now, the diagnosis rests on the finding of specialised intestinal metaplasia, i.e. columnar epithelium with goblet cells, in the esophagus, regardless of the extension. This is important because it is this type of metaplasia that is associated with an increased risk for the development of esophageal adenocarcinoma and esophageal adenocarcinoma is the tumor with the fastest rising incidence in the western world in recent years. The criteria of the current definition of Barrett's esophagus are described in detail and the implications this change in definition carries for screening and surveillance of patients is discussed.

[Adolescent with anorexia nervosa: consequences on bone mineralization]. / Anorexie mentale de l'adolescent : conséquences sur la minéralisation osseuse.

INTRODUCTION: Anorexia nervosa is responsible for abnormalities in bone mineralization, which are well known and described in adults, but less well documented in adolescents. The aim of this research was to evaluate the frequency and severity and to determine predictive factors for these abnormalities in a population of adolescents with diagnosed anorexia nervosa. PATIENTS AND METHODS: This retrospective study involved 39 female adolescents with anorexia nervosa having undergone dual energy X-ray absorptiometry prior to the age of 18 years. Clinical (age, Tanner puberty stages, weight, body mass index [BMI] at different times during the anorexia phase and amenorrhea features), radiological (bone mineral density [BMD] in Z-score units and in absolute values), and biological (calcemia and vitamin D) parameters were collected. RESULTS: In total, 20 patients (51%) presented osteopenia (Z-score <-1 DS and >-2.5 DS) and 2 (5%) had osteoporosis (Z-score <-2.5 DS). Five (13%) exhibited a Z-score less than -2 DS. BMD expressed in Z-scores correlated with none of the parameters assessed. At univariate analysis, BMD in absolute values correlated with the age at disease onset, BMI, weight loss at the lowest weight achieved and BMI at the time of densitometry (P<0.01). At multivariate analyses, only the correlation with the age at disease onset persisted (P<0.05). CONCLUSION: Bone loss in anorexia nervosa is a complication that may be present as early as adolescence. It must be systematically searched for in all adolescents with severe malnutrition because, even if BMD correlated with nutritional parameters, no clinical predictor for osteoporosis or osteopenia could be identified in this study.

[Body composition analysis in patients with cystic fibrosis. Comparison of 3 methods: dual energy x-ray absorptiometry, bioelectrical impedance analysis, and skinfold measurements]. / Composition corporelle des patients mucoviscidosiques - comparaison de 3 techniques de mesure : anthropométrie, absorptiométrie biphotonique et impédancemétrie.

Nutritional status must be closely monitored in cystic fibrosis (CF) patients. This study compared three methods of measuring body composition in CF patients and then examined the relationships between two simple anthropometric markers of nutritional status - tricipital skinfold thickness (TSK) and arm muscular circumference (AMC) - and the results given by each method. Fifty-five patients with CF, 27 females and 28 males, participated in this study. The mean age at the time of the study was 14 ± 5 years, ranging from 4 to 29 years. The four skinfolds (SK) and arm circumference were measured in all patients and fat mass (FM) and AMC were calculated. Fifty patients underwent dual energy x-ray absorptiometry (DEXA) and 38 underwent bioelectrical impedance analysis (BIA). The values for FM as calculated by the three methods were highly correlated, as were the values for lean body mass (LM) (p<0.001). The LM assessed by anthropometry was overestimated by 8 ± 4% compared with DEXA and by 6 ± 7% compared with BIA. BIA overestimated LM by 4 ± 6% compared with DEXA (p<0.001). The LM values measured by SK, DEXA, and BIA were highly correlated with AMC (p<0.001) and FM calculated using these three techniques were highly correlated with TSK (p<0.001). The measurement of TSK and AMC are simple and rapid ways to evaluate body composition. The excellent correlation between the three methods used to measure body composition suggests that they are valid for use in patients with CF, but the results were not identical. The measurement from each technique must be interpreted according to its own norms and comparisons can only be made if the same technique is used in the same patient.

Transient elastography and portal hypertension in pediatric patients with cystic fibrosis Transient elastography and cystic fibrosis.

BACKGROUND: Esophageal varices (EV) are a complication of cystic fibrosis-associated liver disease. Esophagogastroduodenoscopy (EGD) is currently used to diagnose varices but is invasive for pediatric patients. The goal of this study was to explore the relationship between transient elastography (FibroScan®) and the presence of EV in patients with liver disease defined by clinical, laboratory, sonographic, and/or endoscopic criteria. METHODS: 18 patients with cystic fibrosis underwent EGD and transient elastography. 12 patients had EV. RESULTS: Patients with EV had higher FibroScan values than those without varices with median values of 22.4 kPa (14.4-30.4 kPa) vs. 7.9 kPa (4.4-13.7 kPa) (p=0.01). Using a threshold of 12 kPa, four of six patients without EV would not have needed EGD. CONCLUSIONS: Elastography should be recommended for all cystic fibrosis patients with liver disease to follow its progression. A prospective study is needed to define an elastography threshold value that predicts the presence of EV.

JAK and STAT proteins are expressed and activated by IFN-gamma in rat pancreatic acinar cells.

The development of acute pancreatitis (AP) is triggered by acinar events, but the subsequent extra-acinar events, particularly a distinct immune response, appear to determine its severity. Cytokines modulate this immune response and are derived not only from immunocytes but also from pancreatic acinar cells. We studied whether pancreatic acinar cells were also capable of responding to cytokines. The JAK/STAT-pathway represents the main effector for many cytokines. Therefore, expression and regulation of JAK and STAT proteins were investigated in rat pancreatic acinar cells. Western blotting showed expression of JAK1, JAK2, Tyk2, and STAT1, STAT2, STAT3, STAT5, STAT6. In addition, STAT1 was reversibly tyrosine-phosphorylated upon the procedure of acinar cell isolation. In contrast, STAT3-phosphorylation occurred spontaneously after pancreas removal and was not reversible within 8 h. STAT1 phosphorylation was also observed upon treatment with IFN-gamma but not upon EGF, TNF-alpha or IL-6, and inhibited by the JAK2-inhibitor AG-490. Immunohistochemistry revealed cytoplasmic expression of unphosphorylated STAT1 in untreated acinar cells and nuclear translocation of phosphorylated STAT1 following IFN-gamma-treatment. Interestingly, although CCK leads to the activation of multiple stress pathways in pancreatic acinar cells, we found no influence of CCK on phosphorylation of STAT1, STAT3, or STAT5 in the pancreas. In conclusion, our data provide further evidence that pancreatic acinar cells are able to interact with immune cells. Besides stimulating immune cells via cytokine secretion, acinar cells are in turn capable of responding to IFN-gamma via JAK2 and STAT1 which may have an impact on the development of AP.

Pancreatic zymogen granule membrane proteins: molecular details begin to emerge.

Regulated secretion and exocytosis require the controlled docking and fusion of secretory storage organelles with the plasma membrane. Proteins resident in secretory organelle membranes are, therefore, likely to have critical functions as a part of these processes. The exocrine pancreas with its secretory storage organelle, the zymogen granule, represents a classical model of regulated secretion and exocytosis. Until recently, however, little has been known of zymogen granule membrane protein structure and function. With the recent cloning of two zymogen granule membrane proteins, GP-2 and GP-3, and with the identification of the presence of low molecular weight guanosine triphosphate binding proteins, it is now possible to approach the role of the zymogen granule membrane proteins at the molecular level.

Low molecular weight GTP-binding proteins: molecular switches regulating diverse cellular functions.

Low molecular weight GTP-binding proteins (LMWG proteins) form a family of proteins that shows homology with Ras, are 18-30 kDa in mass, and bind and hydrolyze GTP. They act as molecular switches, being active when binding GTP. Their activity is regulated by other proteins that influence the dissociation of GDP and the rate of GTP hydrolysis. Roles are emerging for these proteins in regulation of membrane fusion and cytoskeletal organization and growth. In the gastrointestinal tract, the best studied physiological processes that may be regulated by LMWG proteins are digestive enzyme and gastric acid secretion.