Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Cai

Summary Chromatographic analysis of 3,5-cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the cytosol of human neutrophils shows the predominant presence of PDE IV (cAMP specific) and PDE V (cGMP specific). PDE IV is characterized by (1) cAMP selectivity, (2) a K_M for cAMP of 1.2 M and (3) a typical rank order of IC ₅₀-values for PDE inhibitors: 0.13, 0.17, 47 and 9.5 M for PDE IV selective rolipram, PDE III/IV selective zardaverine, PDE III selective motapizone and unselective 3-isobutyl-l-methylxanthine (IBMX), respectively. Functions of polymorphonuclear leukocytes (PMN) such as N-formylmethionyl-leucyl-phenylalanine (fMLP)-stimulated superoxide release and fMLP/thimerosal elicited leukotriene (LT) biosynthesis are inhibited by these PDE inhibitors with the same rank order and even lower IC₅₀-values. Measurements of changes in cytosolic Ca_i in Fura-2 loaded PMN demonstrate a transient Ca_i increase after stimulation with 0.1 M fMLP and an additional sustained elevation of Ca_i levels in the presence of thimerosal. PDE inhibitors suppress this sustained phase of Ca_i release with the same rank order of IC₅₀-values as LT biosynthesis. The correlation between fMLP/thimerosal-induced LT biosynthesis and Ca_i levels reveal a Ca_i threshold of 150 nM for arachidonic acid metabolism. cAMP levels in PMN were elevated by PDE inhibitors alone by less than 2-fold. In the presence of fMLP however, cAMP was increased up to 10-fold and the efficacy of PDE inhibitors to increase cAMP paralleled their potency to inhibit PDE IV. It is concluded that (1) suppression of PMN functions is achieved by PDE IV inhibition, (2) necessary cAMP elevations are within 50% increase, (3) superoxide release was affected by cAMP/protein kinase A (PKA) directly whereas (4) for inhibition of LT biosynthesis a cAMP related reduction of Ca-influx is involved. Send offprint requests to Ch. Schudt at the above address     

Low vitamin D status is associated with low cord blood levels of the immunosuppressive cytokine interleukin-10

The cytokine interleukin-10 (IL-10) plays a pivotal regulatory role in tolerizing exogenous antigens. Experimental data indicate that low cellular availability of the vitamin D hormone 1,25-dihydroxyvitamin D [1,25(OH)2D] results in a down-regulation of IL-10 concentrations. The tissue production of an adequate amount of 1,25(OH)2D depends on a high circulating 25-hydroxyvitamin D (25-OHD) level. The present study was thus aimed at evaluating the associations between season of birth, vitamin D status, and the allergy risk markers IL-10 and total immunoglobulin (IgE) in newborns. Cord blood was obtained from 49 infants born during the summer half year (mid-April to mid-October, geographic latitude 51 degrees N) and from 47 infants born during the winter half year (mid-October to mid-April, geographic latitude of 51 degrees N). Serum levels of 25-OHD were 99% higher, and IL-10 levels were 43% higher in the summer half year compared with the winter half year (p < 0.001 and p = 0.018). Moreover, the ratio of IL-10 to total IgE was 124% higher in the summer half year compared with the winter half year (p = 0.039). Serum levels of 25-OHD were correlated with IL-10 levels (r = +0.22; p < 0.05). Mothers' age, gestational ages, birth weights and serum 1,25(OH)2D levels did not differ between study groups. We conclude that the low vitamin D status of infants born in winter may at least in part adversely affect biomarkers of allergy risk.     

Advancing equity,diversity, and inclusion in the American College of Neuropsychopharmacology (ACNP): advances,challenges, and opportunities to accelerate progress

It is increasingly accepted that higher levels of excellence and innovation in research can be achieved by organizations that promote equity, diversity, and inclusion across several domains including ethnicity and gender. The purpose of this commentary is to provide an overview of the methods used to increase diversity within ACNP, as well as recommendations for accelerating progress. Annual membership surveys confirm increases in female membership and leadership positions, slower but encouraging signals for “Asian” and “Hispanic” members, and less progress for African American and other ethnic populations. Meetings have become visibly more diverse, due in part to ethnic minority travel awards and apparently increasing diversity among guest attendees. Evidence of increasing inclusion includes well-attended networking events and minority-relevant programming, active communications about diversity-related events and resources, and strong statements by ACNP leadership that embrace diversity as a core value and support collaboration among key committees and task forces to identify and implement pro-inclusion and diversity-enhancing efforts. We believe ACNP can accelerate progress with more scientifically valid approaches to assessing diversity and inclusion. The current membership survey includes five outmoded ethnic options and postmeeting surveys that are not designed to assess inclusion efforts and consequences. Measures should be developed that better characterize diversity and assess efforts to reduce the barriers that exist for potential non-White populations (e.g., annual membership and meeting attendance costs). Increased collaboration with NIH and other organizations that are committed to these same goals may also contribute to acceleration of progress by ACNP and other scientific organizations.Subject terms: Medical research, Neuroscience     

Disorganised Memory after Right Dorsolateral Prefrontal Damage

Neurophysiological and functional brain imaging studies suggest the importance of dorsolateral area 9/46 for modality-independent working memory. However, the behavioural manifestations following isolated damage to this area have not been clearly outlined. Here, we describe the dramatic derangement of pragmatic memory after circumscribed lesion of the right area 9/46. A 52 year-old woman had suffered a traumatic brain injury 13 years ago and sought help for what she thought was a severe memory disorder. She regularly missed appointments and had gradually lost all her friends. She had tried different strategies to compensate for her memory problem, such as writing notes on her wrist or using electronic organizers. Intelligence, attention, verbal long-term memory, and executive functions were normal. Furthermore, experimental exploration demonstrated intact time estimation, attribution of memories to ongoing reality, and anticipation of outcomes. However, she failed to rehearse and manipulate information in working memory (n-back task), confirming the findings of functional imaging studies that the mid-dorsolateral prefrontal cortex is involved in mental manipulation of information. This case exemplifies that an isolated lesion of the right area 9/46 may induce severe failure to schedule actions and memory retrieval, a disorder leading to severely disorganised behaviour and disability.     

Is prevention of atopic eczema with hydrolyzed formulas cost-effective? A health economic evaluation from Germany

To cite this article: Mertens J, Stock S, Lüngen M, Berg AV, Kr?mer U, Filipiak-Pittroff B, Heinrich J, Koletzko S, Grübl A, Wichmann H-E, Bauer C-P, Reinhardt D, Berdel D, Gerber A. Is Prevention of Atopic Eczema with Hydrolyzed Formulas Cost-Effective? A Health Economic Evaluation from Germany. Pediatr Allergy Immunol 2012: 23: 597-604. ABSTRACT: Objective: The German Infant Nutritional Intervention (GINI) trial, a prospective, randomized, double-blind intervention, enrolled children with a hereditary risk for atopy. When fed with certain hydrolyzed formulas for the first 4?months of life, the risk was reduced by 26-45% in PP and 8-29% in intention-to-treat (ITT) analyses compared with children fed with regular cow's milk at age 6. The objective was to assess the cost-effectiveness of feeding hydrolyzed formulas. Patients and Methods: Cost-effectiveness was assessed with a decision tree model programmed in TreeAge. Costs and effects over a 6-yr period were analyzed from the perspective of the German statutory health insurance (SHI) and a societal perspective at a 3% effective discount rate followed by sensitivity analyses. Results: The extensively hydrolyzed casein formula would be the most cost-saving strategy with savings of 478?€ per child treated in the ITT analysis (CI95%: 12?€; 852?€) and 979?€ in the PP analysis (95%CI: 355?€; 1455?€) from a societal perspective. If prevented cases are considered, the partially whey hydrolyzed formula is cost-saving (ITT -5404?€, PP -6358?€). From an SHI perspective, the partially whey hydrolyzed formula is cost-effective, but may also be cost-saving depending on the scenario. An extensively hydrolyzed whey formula also included into the analysis was dominated in all analyses. Conclusions: For the prevention of AE, two formulas can be cost-effective or even cost-saving. We recommend that SHI should reimburse formula feeding or at least the difference between costs for cow's milk formula and the most cost-effective formula.     

Percutaneous endoscopic cecostomy (introducer method) in chronic intestinal pseudo‐obstruction: Report of two cases and literature review

We report on two patients with recurrent episodes of chronic intestinal pseudo‐obstruction (CIPO). A 50‐year‐old woman with severe multiple sclerosis and an 84‐year‐old man with Parkinson's disease and dementia had multiple hospital admissions because of pain and distended abdomen. Radiographic and endoscopic findings showed massive dilation of the colon without any evidence of obstruction. Conservative management resolved symptoms only for a short period of time. As these patients were poor candidates for any surgical treatment we carried out percutaneous endoscopic colostomy by placing a 20‐Fr tube in the cecum with the introducer method. The procedure led to durable symptom relief without complications. We present these two cases and give a review through the existing literature of the procedure in CIPO.     

Quantitative susceptibility mapping and 23Na imaging‐based in vitro characterization of blood clotting kinetics

Blood clotting is a fundamental biochemical process in post‐hemorrhagic hemostasis. Although the varying appearance of coagulating blood in T₁‐ and T₂‐weighted images is widely used to qualitatively determine bleeding age, the technique permits only a rough discrimination of coagulation stages, and it remains difficult to distinguish acute and chronic hemorrhagic stages because of low T₁‐ and T₂‐weighted signal intensities in both instances. To investigate new biomedical parameters for magnetic resonance imaging‐based characterization of blood clotting kinetics, sodium imaging and quantitative susceptibility mapping (QSM) were compared with conventional T₁‐ and T₂‐weighted imaging, as well as with biochemical hemolysis parameters. For this purpose, a blood‐filled spherical agar phantom was investigated daily for 14 days, as well as after 24 days at 7 T after initial preparation with fresh blood. T₁‐ and T₂‐weighted sequences, a three‐dimensional (3D) gradient echo sequence and a density‐adapted 3D radial projection reconstruction pulse sequence for ²³Na imaging were applied. For hemolysis estimations, free hemoglobin and free potassium concentrations were measured photometrically and with the direct ion‐selective electrode method, respectively, in separate heparinized whole‐blood samples along the same timeline. Initial mean susceptibility was low (0.154 ± 0.020 ppm) and increased steadily during the course of coagulation to reach up to 0.570 ± 0.165 ppm. The highest total sodium (NaT) values (1.02 ± 0.06 arbitrary units) in the clot were observed initially, dropped to 0.69 ± 0.13 arbitrary units after one day and increased again to initial values. Compartmentalized sodium (NaS) showed a similar signal evolution, and the NaS/NaT ratio steadily increased over clot evolution. QSM depicts clot evolution in vitro as a process associated with hemoglobin accumulation and transformation, and enables the differentiation of the acute and chronic coagulation stages. Sodium imaging visualizes clotting independent of susceptibility and seems to correspond to clot integrity. A combination of QSM and sodium imaging may enhance the characterization of hemorrhage.     

Targeted tissue engineering:hydrogels with linear capillary channels for axonal regeneration after spinal cord injury

正Spinal cord injury(SCI)frequently results in the permanent loss of function below the level of injury due to the failure of axonal regeneration in the adult mammalian central nervous system(CNS).The limited intrinsic growth capacity of adult neurons,a lack of growth-promoting factors and the multifactorial inhibitory microenvironment around the lesion site contribute to the lack of axonal