Clonidine and Dexmedetomidine Potently Inhibit Peristalsis in the Guinea Pig Ileum In Vitro

Background: Inhibition of intestinal peristalsis is a major side effect of drugs used for anesthesia or for analgesia and sedation of patients in the intensive care unit. This in vitro study examined the effect of clonidine and dexmedetomidine on intestinal peristalsis and analyzed some of their mechanisms of action.

Methods: In isolated segments of the guinea pig small intestine, peristalsis was triggered by a perfusion-induced rise of the intraluminal pressure. The peristaltic pressure threshold to elicit a peristaltic wave was used to quantify drug effects on peristalsis. Vehicle (Tyrode's solution), clonidine (10 nm-100 [mu]m), or dexmedetomidine (0.1-100 nm) were added extraserosally to the organ bath. In other series of experiments, clonidine or dexmedetomidine was administered after pretreatment with yohimbine, prazosin, apamin, naloxone, or vehicle. Clonidine was also tested after blockade of NO synthase with l-NAME and in the presence of the inactive enantiomer d-NAME.

Results: Clonidine and dexmedetomidine concentration-dependently increased peristaltic pressure threshold and inhibited peristalsis (clonidine: EC50 = 19.6 [mu]m; dexmedetomidine: EC50 = 12.0 nm). The inhibition caused by clonidine could be prevented by pretreatment with yohimbine, naloxone, and apamin, but not by prazosin, l-NAME, or d-NAME. Inhibition caused by dexmedetomidine was prevented by yohimbine only.     

Developmental patterns of intermediate filament gene expression in the normal hamster brain

We have examined the patterns of expression of the major intermediate filament (IF) protein mRNAs during development of the hamster brain. Quantitative northern blotting was used to examine changes in the levels of mRNAs for the low, middle and high molecular weight neurofilament proteins (NF-L, NF-M, NF-H) as well as peripherin, vimentin and glial fibrillary acidic protein (GFAP). Total RNA was isolated from hamster brains at embryonic (E) days 12 and 14 and postnatal (P) days 1, 3, 5, 7, 9, 11, 13, 15, 20, 28 and 60-90 (adult), and probed with specific IF cDNAs. Northern blotting revealed that NF-L and NF-M mRNAs were present at very low levels in embryonic brain and that significant expression of these genes only occurred postnatally when the levels increased dramatically until P28 and then declined again in the adult. Increases in NF-H mRNA levels were somewhat delayed relative to those of NF-L and NF-M. NF-H mRNA was not seen at embryonic stages and was expressed at very low levels prior to P9; after that time the levels increased rapidly until P28 and then declined in the adult. Two of the type III IF genes, peripherin and vimentin, followed a pattern of expression opposite that of the NF genes. Both peripherin and vimentin mRNAs were present in embryonic brain and were expressed at higher levels during early postnatal stages than at later times. The magnitude and rate of reduction in vimentin gene expression in the postnatal interval was much greater than that of peripherin. GFAP mRNA levels were extremely low prior to P9 after which a robust increase occurred, followed by a decline in the adult. We discuss the implication of the dramatic changes in IF isotype expression in brain to the pathways of both neuronal and glial development in vivo.     

International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study.

Nonmotor symptoms (NMS) of Parkinson's disease (PD) are not well recognized in clinical practice, either in primary or in secondary care, and are frequently missed during routine consultations. There is no single instrument (questionnaire or scale) that enables a comprehensive assessment of the range of NMS in PD both for the identification of problems and for the measurement of outcome. Against this background, a multidisciplinary group of experts, including patient group representatives, has developed an NMS screening questionnaire comprising 30 items. This instrument does not provide an overall score of disability and is not a graded or rating instrument. Instead, it is a screening tool designed to draw attention to the presence of NMS and initiate further investigation. In this article, we present the results from an international pilot study assessing feasibility, validity, and acceptability of a nonmotor questionnaire (NMSQuest). Data from 123 PD patients and 96 controls were analyzed. NMS were highly significantly more prevalent in PD compared to controls (PD NMS, median = 9.0, mean = 9.5 vs. control NMS, median = 5.5, mean = 4.0; Mann-Whitney, Kruskal-Wallis, and t test, P < 0.0001), with PD patients reporting at least 10 different NMS on average per patient. In PD, NMS were highly significantly more prevalent across all disease stages and the number of symptoms correlated significantly with advancing disease and duration of disease. Furthermore, frequently, problems such as diplopia, dribbling, apathy, blues, taste and smell problems were never previously disclosed to the health professionals.     

Specific immunotherapeutic strategy for myasthenia gravis: targeted antigen-presenting cells

The pathogenesis of myasthenia gravis (MG) involves a T cell-dependent antibody-mediated autoimmune response directed against acetylcholine receptors (AChR). Inactivation of AChR-specific T cells should interrupt the immune response, resulting in therapeutic benefit. Since each individual's repertoire of T cells responds to a heterogeneous and unique spectrum of AChR epitopes presented in association with self-major histocompatibility complex (MHC) class II, an individualized approach is required to target all relevant AChR-specific T cells. The individual's own antigen-presenting cells (APC) can be used for this purpose, since they process and present the antigen appropriately, and express the correct MHC class II. A novel method of binding AChR to surface immunoglobulin with a heterobifunctional antibody conjugate allows us to use all B cells as APC. Conjugate-plus-AChR-treated B cells (AChR-APC) effectively targeted AChR-specific T cells, stimulating vigorous proliferative responses in a rat cell culture system. If APCs are 'fixed' with cross-linking reagents, they induce long-lasting or permanent 'anergy' of the specific T cells. We prepared AChR-APC, allowed them to process AChR in vitro, and fixed them with paraformaldehyde. Pre-culture of these fixed AChR-APC with AChR-specific T cells induced anergy: when restimulated with fresh AChR-APC, the T cells exhibited markedly reduced proliferative responses and IL-2 production, compared with responses of T cells pre-cultured with control fixed B cells. Implications for the design of antigen-specific therapeutic strategies for MG and other immune disorders will be discussed.     

Inter- and intraobserver variability in the histopathological diagnosis of medullary carcinoma of the breast,and its prognostic implications

Summary One hundred thirty-one breast carcinomas with medullary features, registered in the Danish Breast Cancer Cooperative Group from 1977–1982, have been histopathologically reviewed by two senior pathologists and classified as typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), and non-medullary carcinoma (NMC). Diagnostic criteria were based on those put forward by Ridolfiet al. and Fisheret al. The procedure was repeated with an interval of about one year by both pathologists. The diagnostic interobserver agreement was 72% with a Kappa of 0.55. The intraobserver agreement was 77% and 63% with Kappa values of 0.64 and 0.44, respectively. To see whether the observed inter- and intraobserver variability had any prognostic implications, diagnostic subgroups for both pathologists were analyzed with Kaplan Meier plots for recurrence-free survival (RFS) and with log rank tests. In the first evaluation pathologist 1 segregated a group of TMC with a significantly better RFS than for the NMC group, and pathologist 2 segregated a group of TMC with a corresponding strong trend. These findings could not, however, be reproduced in the second evaluation. The study indicates that the criteria of TMC and AMC as proposed by Ridolfiet al. need to be sharpened and simplified in order to reduce inter-and intraobserver variability. Larger studies with a control group of infiltrating ductal carcinomas are mandatory to elucidate the clinical importance of the diagnoses of Typical and Atypical Medullary Carcinoma of the breast.     

Prospective evaluation of double RBC collection using three different apheresis systems.

BACKGROUND: Automated component collection systems offer the possibility of increasing blood supply and improving transfusion safety. DESIGN: 30 blood donors were randomly assigned to double RBC collection with either the Baxter Alyx (AX), the Haemonetics MCS Plus (MCS+), or the Gambro Trima Accel (TA). Procedures were prospectively evaluated focussing on yield, time, efficiency, citrate donor load, and in vitro quality. RESULTS: All units showed sufficient in vitro quality throughout 42 days of storage and complied with international requirements. Donor reactions were limited to mild citrate reactions. AX was the fastest and most efficient system* * (* *p approximately 0.001) attaining the highest yield* * from similar amounts of whole blood. The drawbacks were a higher RBC loss* (*p < 0.05) and accelerated citrate infusion* *. Due to lower collection rates* * * (* * *p < 0.001), MCS+ was slower than TA* * * but compensated with lower citrate load * * *. CONCLUSION: Double RBC apheresis was performed safely and efficiently with all three instruments. AX had advantages for most parameters evaluated.     

Surgical therapy in patients with active infective endocarditis: seven-year single centre experience in a subgroup of 255 patients treated with the Shelhigh stentless bioprosthesis

OBJECTIVE: We investigated outcomes after surgical therapy in patients with active infective endocarditis (AIE) with regard to survival in relation to surgical urgency, valve position, number of valves implanted and abscess formation. We aimed to identify independent risk factors for early mortality. METHODS AND RESULTS: Two hundred and fifty-five patients received Shelhigh bioprostheses between February 2000 and March 2007. A total of 74.1% had native and 25.9% prosthetic AIE. Surgery was regarded as urgent in 57.3% and as an emergency procedure in 38.4%. There was a highly significant difference in survival rate between patients who were operated on urgently versus in an emergency (p<0.0001), between single and double valve replacement (p=0.0206) and between patients with and without abscess formation (p=0.0245). There were two cases of early reinfection (0.78%) and six of late reinfection (2.35%) leading to re-operation. CONCLUSIONS: The survival of patients differs significantly in dependence on their surgical urgency. Better outcome could have been achieved if patients had been referred earlier for surgery and operated upon before heart failure or septic shock developed. Long-term survival was better in patients without abscess formation. The low reinfection rate of Shelhigh bioprostheses in AIE is promising and the early and mid-term results achieved need to be verified in the long-term course.