L-817,818

Expression and function of a CP339,818-sensitive K(+) current in a subpopulation of putative nociceptive neurons from adult mouse trigeminal ganglia.[Pubmed:25652918]

J Neurophysiol. 2015 Apr 1;113(7):2653-65.

Trigeminal ganglion (TG) neurons are functionally and morphologically heterogeneous, and the molecular basis of this heterogeneity is still not fully understood. Here we describe experiments showing that a subpopulation of neurons expresses a delayed-rectifying K(+) current (IDRK) with a characteristically high (nanomolar) sensitivity to the dihydroquinoline CP339,818 (CP). Although submicromolar CP has previously been shown to selectively block Kv1.3 and Kv1.4 channels, the CP-sensitive IDRK found in TG neurons could not be associated with either of these two K(+) channels. It could neither be associated with Kv2.1 channels homomeric or heteromerically associated with the Kv9.2, Kv9.3, or Kv6.4 subunits, whose block by CP, tested using two-electrode voltage-clamp recordings from Xenopus oocytes, resulted in the low micromolar range, nor to the Kv7 subfamily, given the lack of blocking efficacy of 3 muM XE991. Within the group of multiple-firing neurons considered in this study, the CP-sensitive IDRK was preferentially expressed in a subpopulation showing several nociceptive markers, such as small membrane capacitance, sensitivity to capsaicin, and slow afterhyperpolarization (AHP); in these neurons the CP-sensitive IDRK controls the membrane resting potential, the firing frequency, and the AHP duration. A biophysical study of the CP-sensitive IDRK indicated the presence of two kinetically distinct components: a fast deactivating component having a relatively depolarized steady-state inactivation (IDRKf) and a slow deactivating component with a more hyperpolarized V1/2 for steady-state inactivation (IDRKs).

Re-interventions following laparoscopic surgery for colorectal cancer: data from 818 individuals from the Dutch surgical colorectal audit.[Pubmed:25376001]

J Laparoendosc Adv Surg Tech A. 2014 Nov;24(11):751-5.

BACKGROUND: The surgical procedure of choice for the resection of colorectal cancer has shifted in favor of laparoscopic surgery. Although increasing data prove advantages of elective laparoscopic surgery, less is known about the results in acute indications such as surgical re-interventions following colorectal resections. This study aims to assess the clinical benefits in recovery following laparoscopic re-interventions compared with open re-interventions following laparoscopic colorectal cancer surgery. SUBJECTS AND METHODS: We performed an analysis of data from the Dutch Surgical Colorectal Audit from January 2010 to December 2012. All patients requiring surgical re-intervention after initial laparoscopic colorectal surgery were analyzed. RESULTS: Out of 27,448 patients, 11,856 underwent laparoscopic surgery. Following laparoscopic surgery, 159 patients (1.3%) had a laparoscopic re-intervention, and 659 patients (5.6%) had an open re-intervention. In a multivariable analysis adjusting for patients' demographics and risk factors, the length of hospital stay was 17 days (interquartile range, 11-16 days) for the laparoscopic group and 23 days (interquartile range, 14-37 days) for the open group (odds ratio [OR]=0.74; 95% confidence interval [CI], 0.65-0.84). In the laparoscopic group the intensive care unit admission rate was 39% compared with 66% in the open group. The 30-day mortality rate was 7 (4%) in the laparoscopic group compared with 89 (14%) in the open group (OR=0.31; 95% CI, 0.13-0.73). CONCLUSIONS: Laparoscopic re-intervention following laparoscopic surgery for colorectal cancer is feasible in selected patients. Because of the unknown extent of selection bias, prospective studies are needed to define the exact position and benefits of laparoscopic re-interventions.

Prospective Comparison of Age- and Sex-related Differences in Quantifiable 10-S Grip and Release and 10-S Step Test Results for Diagnosis of Cervical Spondylotic Myelopathy in 454 Patients With Cervical Spondylotic Myelopathy and 818 Asymptomatic Subjects.[Pubmed:27513225]

Spine (Phila Pa 1976). 2017 Apr 15;42(8):578-585.

STUDY DESIGN: A prospective comparison. OBJECTIVE: The purpose of this prospective study was to verify the clinical effectiveness of the 10-s grip and release (G&R) and 10-s step quantitative tests for assessing the severity of cervical spondylotic myelopathy (CSM) and to compare age- and sex-related differences in the results between large cohorts of CSM patients and asymptomatic subjects. SUMMARY OF BACKGROUND DATA: To determine the severity of CSM, objective and reproducible means of measuring patient disability are essential. No studies have evaluated differences in quantitative test results between a large series of CSM patients and healthy subjects. METHODS: Four hundred fifty-four CSM patients and 818 asymptomatic subjects were included. The Japanese subjects were in their 40s to 70s and were divided according to their age by decade. The 10-s G&R and 10-s step tests were used to quantitatively assess performance. The severity of myelopathy before surgery was evaluated according to a scoring system proposed by the Japanese Orthopaedic Association for cervical myelopathy (JOA score) in the CSM patients. RESULTS: In the CSM patients, the 10-s G&R and step test results significantly correlated with the JOA score (P < 0.0001). The number of the 10-s G&R and step tests significantly decreased with age in both groups. There was a difference in the 10-s G&R and step test results between males and females. In the asymptomatic subjects, the number of the 10-s G&R and step tests in the females was less than that in the males. The numbers in the 10-s G&R and step tests were significantly lower in CSM patients than those in asymptomatic subjects in each decade (P < 0.01). CONCLUSION: The 10-s G&R and 10-s step tests were useful for quantitatively assessing CSM severity, and age and sex differences in results should be considered in screening. LEVEL OF EVIDENCE: 2.

Identification and characterization of subtype selective somatostatin receptor agonists.[Pubmed:11087999]

J Physiol Paris. 2000 May-Aug;94(3-4):211-5.

High affinity, subtype selective non-peptide agonists of somatostatin receptor subtypes 1-5 were identified in combinatorial libraries constructed based on molecular modeling of known peptide agonists. Simultaneous traditional chemical synthesis yielded an additional series of somatostatin subtype-2 receptor (SSTR2) selective agonists. These compounds have been used to further define the physiological functions of the individual somatostatin receptor subtypes. In vitro experiments demonstrated the role of the SSTR2 in inhibition of glucagon release from mouse pancreatic alpha-cells and the somatostatin subtype-5 receptor (SSTR5) as a mediator of insulin secretion from pancreatic beta-cells. Both SSTR2 and SSTR5 regulated growth hormone release from the rat anterior pituitary gland. In vivo studies performed with SSTR2 receptor selective compounds demonstrated effective inhibition of pulsatile growth hormone release in rats. The SSTR2 selective compounds also lowered plasma glucose levels in normal and diabetic animal models. The availability of high affinity, subtype selective non-peptide agonists for each of the somatostatin receptors provides a direct approach to defining their physiological function both peripherally and in the central nervous system.

Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: an in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice.[Pubmed:10614629]

Endocrinology. 2000 Jan;141(1):111-7.

Somatostatin (SST) potently inhibits insulin and glucagon release from pancreatic islets. Five distinct membrane receptors (SSTR1-5) for SST are known, and at least two (SSTR2 and SSTR5) have been proposed to regulate pancreatic endocrine function. Our current understanding of SST physiology is limited by the receptor subtype selectivity of peptidyl SST analogs, making it difficult to assign a physiological function to an identified SST receptor subtype. To better understand the physiology of SSTRs we studied the in vitro effects of potent subtype-selective nonpeptidyl SST analogs on the regulation of pancreatic glucagon and insulin secretion in wild-type (WT) and in somatostatin receptor 2 knockout (SSTR2KO) mice. There was no difference in basal glucagon and insulin secretion between islets isolated from SSTR2KO and WT mice; however, potassium/arginine-stimulated glucagon secretion was approximately 2-fold higher in islets isolated from SSTR2KO mice. Neither SST nor any SSTR-selective agonist inhibited basal glucagon or insulin release. SST-14 potently inhibited stimulated glucagon secretion in islets from WT mice and much less effectively in islets from SSTR2KO mice. The SSTR2 selective analog L-779,976 inhibited glucagon secretion in islets from WT, but was inactive in islets from SSTR2KO mice. L-817,818, an SSTR5 selective analog, slightly reduced glucagon release in both animal groups, whereas SSTR1, -3, and -4 selective analogs were inactive. SST and L-817,818 inhibited glucose stimulated insulin release in islets from WT and SSTR2KO mice. L-779,976 much less potently reduced insulin secretion from WT islets. In conclusion, our data demonstrate that SST inhibition of glucagon release in mouse islets is primarily mediated via SSTR2, whereas insulin secretion is regulated primarily via SSTR5.

Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry.[Pubmed:9784130]

Science. 1998 Oct 23;282(5389):737-40.

Nonpeptide agonists of each of the five somatostatin receptors were identified in combinatorial libraries constructed on the basis of molecular modeling of known peptide agonists. In vitro experiments using these selective compounds demonstrated the role of the somatostatin subtype-2 receptor in inhibition of glucagon release from mouse pancreatic alpha cells and the somatostatin subtype-5 receptor as a mediator of insulin secretion from pancreatic beta cells. Both receptors regulated growth hormone release from the rat anterior pituitary gland. The availability of high-affinity, subtype-selective agonists for each of the somatostatin receptors provides a direct approach to defining their physiological functions.