Plasma or serum 5-hydroxyindoleacetic acid can be used interchangeably in patients with neuroendocrine tumours.

5-hydroxyindole acetic acid, a metabolite of serotonin, is used in the diagnosis and monitoring of patients with neuroendocrine tumours, in particular patients with small intestinal neuroendocrine tumours associated with the carcinoid syndrome. Analysis of 5-hydroxyindole acetic acid was commonly performed in urine, but blood-based assays are now becoming available. The objective of this study was to assess how 5-hydroxyindole acetic acid compares in plasma and serum as a biochemical marker of neuroendocrine tumours. Twenty-four-hour urine, plasma and serum samples were obtained from 80 patients with neuroendocrine tumours and 30 healthy volunteers. We developed a liquid chromatography tandem mass spectrometry assay for plasma and serum 5-hydroxyindole acetic acid. Comparison was made between them, and their cut-off was determined using a receiver-operating characteristic curve. A close correlation was shown between plasma and serum 5-hydroxyindole acetic acid. At a cut-off of 135 nmol/l, a sensitivity of 91.2% with a specificity of 61.9% was obtained for both compared to the urinary assay. A statistically significant agreement was shown when plasma and serum 5-hydroxyindole acetic acid were compared with the currently used urine assay in patients with neuroendocrine tumours; κ = 0.675 (95% CI 0.49 to 0.86), p < 0.001 and healthy volunteers; 0.967 (95% CI 0.828 to 0.999), p = <0.001. In conclusion, 5-hydroxyindole acetic acid in plasma and serum were comparable, hence either sample type can be used interchangeably.

A Combined Experimental and Theoretical Investigation of Arene-Supported Actinide and Ytterbium Tetraphenolate Complexes.

Modular tetraphenolate ligands tethered with a protective arene platform (para-phenyl or para-terphenyl) are used to support mononuclear An(IV) (An = Th, U) complexes with an exceptionally large and open axial coordination site at the metal. The base-free complexes and a series of neutral donor adducts were synthesized and characterized by spectroscopies and single-crystal X-ray diffraction. Anionic Th(IV) -ate complexes with an additional axial aryloxide ligand were also synthesized and characterized. The para-phenyl-tethered mononuclear complexes exhibit rare An(IV)-arene interactions, and the An(IV)-arene distance broadly increases with axial donor strength. The para-terphenyl-tethered complexes have almost no interaction with the arene base, isolating the central metal cation. Computational analysis of the mononuclear complexes and their reduced analogues, and Yb(III) congeners, as well as the effect of additional donor ligand binding, seek to elucidate the electronic structure of the metal-arene interactions and establish whether they, or their reduced or oxidized counterparts, could function as molecular qubits.

Impact of intraoperative parathyroid hormone monitoring on the management of patients with primary hyperparathyroidism.

BACKGROUND/OBJECTIVE: Intraoperative parathyroid hormone (IOPTH) monitoring during surgery for primary hyperparathyroidism (PHPT) could improve cure rate and simplify current care pathways. This study assesses the performance of US, MIBI and IOPTH monitoring and their impact on outcomes and perioperative strategy. DESIGN: This is a retrospective study of a prospectively maintained database of patients who underwent parathyroidectomy guided by preoperative US, MIBI and IOPTH monitoring. Test performance (sensitivity, specificity, PPV, NPV, accuracy) and IOPTH added value (percentage of patients in whom test contributed to achieving cure) were calculated. RESULTS: A total of 617 patients (median age 59 years, 75% females), 603 (97.7%) of them cured, were included in analysis. Sensitivity of US was higher than MIBI (78.2% vs 70%, P < 0.05), but both were inferior to IOPTH (98.6%, P < 0.05). US and MIBI were more sensitive at detecting single gland disease (SGD) than multigland disease (MGD) (85% vs 55% and 77.5% vs 45.5%, respectively, P < 0.05), while IOPTH performed well in both situations (98.8% vs 96.7%, P > 0.05). In 41 patients with incorrect US predictions, MIBI gave correct result only in 12 (29.3%) cases, while IOPTH gave correct predictions in all but one patient (97.6%). Minimally invasive parathyroidectomy (MIP) was completed in 409 patients, with a similar completion rate regardless whether both or one scan was positive. IOPTH added value was significant in whole cohort (14%) and in subgroups of patients with concordant vs discordant scans, minimally invasive vs conventional surgery, and initial vs reoperative surgery. CONCLUSIONS: Intraoperative parathyroid hormone monitoring is more accurate at predicting cure than US and MIBI are at identifying abnormal glands in patients undergoing parathyroidectomy for PHPT and significantly contributes to cure rate in range of clinical scenarios. This implies that its routine use could facilitate successful surgery in patients with single positive imaging and increase number of MIPs while maintaining high cure rate.

Safety and efficacy of dexmedetomidine in children with heart failure.

This retrospective observational study aimed to evaluate the safety and efficacy of dexmedetomidine (DEX) for children with heart failure. The study was conducted in the cardiovascular intensive care unit (CVICU) of a single, tertiary care, academic children's hospital. A retrospective review of the charts for all children (up to 18 years of age) with signs and symptoms consistent with congestive heart failure who received DEX in our CVICU between April 2006 and April 2011 was performed. The patients were divided into two groups for study purposes: the DEX group of 21 patients, who received a DEX infusion together with other conventional sedation agents, and the control group of 23 patients, who received conventional sedation agents without the use of DEX. To evaluate the safety of DEX, physiologic data were collected including heart rate, mean arterial pressure (MAP), and inotrope score. To assess the efficacy of DEX, the amount and duration of concomitant sedation and analgesic infusions in both the DEX and control groups were examined. The numbers of rescue boluses for each category before the initiation of sedative infusion and during the sedative infusion also were examined. The baseline characteristics of the patients in the two groups were similar. There was no effect of DEX infusion on heart rate, MAP, or inotrope score at the termination of infusion. The daily amount of midazolam administered was significantly less during the last 24 h of DEX infusion in the DEX group than in the control group (p = 0.04). The daily amount of morphine infusion did not differ between the DEX and control groups during any period. The numbers of sedation and analgesic rescue boluses were lower in DEX group throughout the infusion. No other significant side effects were noted. Two patients in the DEX group had a 50 % or greater drop in MAP compared with baseline in the first 3 h after initiation of DEX infusion, whereas one patient had a 50 % or greater drop in heart rate compared with baseline in the first 3 h after initiation of DEX infusion. Administration of DEX for children with heart failure appears to be safe but should be used cautiously. Furthermore, DEX use is associated with a decreased opiate and benzodiazepine requirement for children with heart failure.

Reversal of endothelial progenitor cell dysfunction in patients with type 2 diabetes using a conditioned medium of human embryonic stem cell-derived endothelial cells.

BACKGROUND: The potential clinical application of bone marrow or peripheral blood-derived progenitor cells for cardiovascular regeneration in patients with diabetes mellitus (DM) is limited by their functional impairment. We sought to determine the mechanisms of impaired therapeutic efficacy of peripheral blood-derived progenitor cells in type 2 DM patients and evaluated the use of cell-free conditioned medium obtained from human embryonic stem cell-derived endothelial-like cells (ESC-ECs) to reverse their functional impairment. METHODS: The angiogenic potential of late outgrowth endothelial cells (OECs) and cytokine profile of the conditional medium of proangiogenic cells (PACs) derived from peripheral blood-mononuclear cells of healthy control and DM patients and ESC-ECs was compared by in vitro tube formation assay and a multiplex bead-based immunoassay kit, respectively. The in vivo angiogenic potential of ESC-ECs derived conditioned medium in rescuing the functional impairment of PB-PACs in DM patients was investigated using a hindlimb ischemia model. RESULTS: Human ESC-ECs had similar functional and phenotypic characteristics as OECs in healthy controls. Cytokine profiling showed that vascular endothelial growth factor, stromal cell-derived factor 1 and placental growth factor were down-regulated in PACs from DM patients. Tube formation assay that revealed functional impairment of OECs from DM patients could be rescued by ESC-ECs conditioned medium. Administration of ESC-ECs conditioned medium restored the therapeutic efficacy of PB-PACs from DM patients in a mouse model of hindlimb ischemia. CONCLUSIONS: Our results showed that peripheral blood-derived progenitor cells from DM patients have impaired function because of defective secretion of angiogenic cytokines, which could be restored by supplementation of ESC-ECs conditioned medium.

Hemodynamic effects of dexmedetomidine in critically ill neonates and infants with heart disease.

The primary objective of this study was to evaluate the hemodynamic effects of dexmedetomidine (DEX) infusion on critically ill neonates and infants with congenital heart disease (CHD). The secondary objective of the study was to evaluate the safety and efficacy profile of the drug in this patient population. A retrospective observational study was conducted in the cardiovascular intensive care unit (CVICU) of a single tertiary care university children's hospital. The charts of all neonates and infants who received DEX in the authors' pediatric CVICU between August 2009 and June 2010 were retrospectively reviewed. The demographic data collected included age, weight, sex, diagnosis, and Risk Adjustment in Congenital Heart Surgery (RACHS-1) score. To evaluate the hemodynamic effects of DEX, physiologic data were collected including heart rate, mean arterial pressure (MAP), inotrope score, near-infrared spectroscopy, and central venous pressure (CVP). To assess the efficacy of DEX, the amount and duration of concomitant sedation and analgesic infusions over a period of 24 h were examined together with the number of rescue boluses. The potential side effects evaluated in this study included nausea, vomiting, abdominal distension, dysrhythmias, neurologic abnormalities, seizures, and signs and symptoms of withdrawal. During the study period, 50 neonates and infants received DEX for a median period of 78 h (range, 40-290 h). These patients had an average age of 3.53 ± 2.64 months and a weight of 4.85 ± 1.67 kg. Whereas 34 patients (68%) received DEX after surgery for CHD, 15 patients (30%) received DEX after heart transplantation. Of these 50 infants, 10 (20%) had a single-ventricle anatomy, whereas 13 (26%) had a risk adjustment score (RACHS-1) in the category of 4-6. The median CVICU stay was 29 days (range, 8-69 days). Despite a significant decrease in heart rate, MAP, inotrope score, and CVP, all the patients remained hemodynamically stable during DEX infusion. There was no substantial difference in major hemodynamic variables between neonates and infants, single- and two-ventricle repair, RACHS 4-6 and RACHS 1-3 categories for patients undergoing surgery, or patients undergoing heart transplantation and patients undergoing other surgical procedures. Dexmedetomidine infusion for neonates and infants with heart disease is safe from a hemodynamic standpoint and can reduce the concomitant dosing of opioid and benzodiazepine agents. Furthermore, DEX infusion may be useful for reducing vasopressor agent dosing in children with catecholamine-refractory cardiogenic shock.

Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice.

BACKGROUND: Aging and aging-related disorders impair the survival and differentiation potential of bone marrow mesenchymal stem cells (MSCs) and limit their therapeutic efficacy. Induced pluripotent stem cells (iPSCs) may provide an alternative source of functional MSCs for tissue repair. This study aimed to generate and characterize human iPSC-derived MSCs and to investigate their biological function for the treatment of limb ischemia. METHODS AND RESULTS: Human iPSCs were induced to MSC differentiation with a clinically compliant protocol. Three monoclonal, karyotypically stable, and functional MSC-like cultures were successfully isolated using a combination of CD24(-) and CD105(+) sorting. They did not express pluripotent-associated markers but displayed MSC surface antigens and differentiated into adipocytes, osteocytes, and chondrocytes. Transplanting iPSC-MSCs into mice significantly attenuated severe hind-limb ischemia and promoted vascular and muscle regeneration. The benefits of iPSC-MSCs on limb ischemia were superior to those of adult bone marrow MSCs. The greater potential of iPSC-MSCs may be attributable to their superior survival and engraftment after transplantation to induce vascular and muscle regeneration via direct de novo differentiation and paracrine mechanisms. CONCLUSIONS: Functional MSCs can be clonally generated, beginning at a single-cell level, from human iPSCs. Patient-specific iPSC-MSCs can be prepared as an "off-the-shelf" format for the treatment of tissue ischemia.

Salviae miltiorrhizae radix and puerariae lobatae radix herbal formula improves circulation, vascularization and gait function in a peripheral arterial disease rat model.

ETHNOPHARMACOLOGICAL RELEVANCE: DG is a herbal formula, containing the root of Salvia miltiorrhiza Bunge (Danshen) and the root of Pueraria lobate (Willd.) Ohwi (Gegen), has a history of usage in China for cardiovascular protection and anti-atherosclerosis. AIM OF THE STUDY: The present study aims to determine the beneficial effect of DG on the hind-limb ischemia rat model which mimics peripheral arterial disease (PAD) and its vasodilative effect on isolated femoral artery. MATERIALS AND METHODS: The vasodilatory effects were assessed by contractile responses to DG in the isolated femoral artery and its underlying mechanisms were evaluated by the involvement of endothelium, potassium channel and calcium channel. For hind-limb ischemia study, treatment outcomes were assessed by evaluating hind-limb blood flow, functional limb recovery, muscle histology and angiogenesis. RESULTS: Our results demonstrated positive dose-dependent vasodilatory response to DG via an endothelium-independent mechanism that involved inwardly rectifying K+ channels and Ca2+ channels. We also demonstrated significant improvement in blood perfusion and micro-vessel density in the ischemic limb and positive effects in functional limb recovery. CONCLUSION: In conclusion, our study supported the potential use of DG as a novel treatment for symptomatic PAD.

Single-incision laparoscopically assisted colectomy using standard laparoscopic instrumentation.

BACKGROUND: A prospective case series of transumbilical single-incision laparoscopic colectomies using conventional laparoscopic trocars and instruments is described. METHODS: Seven selected patients with colonic neoplasm underwent transumbilical SIL colectomy between November 2008 and March 2009. Three trocars via a single small umbilical incision were used. The bowel was mobilized and the vessels ligated intracorporeally with an extracorporeal anastomosis. RESULTS: This series of seven patients (6 men and 1 woman) had no conversion to standard multiport laparoscopy or open surgery. Six of the patients had pathology in the right colon, and one had a carcinoma at the splenic flexure. The patients had an average age of 71 years (range, 63-83 years) and an average body mass index (BMI) of 24.3 kg/m(2) (range, 21-28 kg/m(2)). The average operating time was 89 min (range, 75-115 min). No significant blood loss or complications occurred. The average length of hospital stay was 5.4 days (range, 4-11 days). The average incision length was 3.1 cm (range, 2.5-4.5 cm). Histopathology showed adequate tumor excision margins and an average lymph node yield of 15 nodes (range, 7-26 nodes). CONCLUSIONS: Single-incision laparoscopic surgery for colectomy is feasible. It can be performed without specialized instrumentation and at no extra cost. Further evaluation is required.

Metallacyclic actinide catalysts for dinitrogen conversion to ammonia and secondary amines.

Chemists have spent over a hundred years trying to make ambient temperature/pressure catalytic systems that can convert atmospheric dinitrogen into ammonia or directly into amines. A handful of successful d-block metal catalysts have been developed in recent years, but even binding of dinitrogen to an f-block metal cation is extremely rare. Here we report f-block complexes that can catalyse the reduction and functionalization of molecular dinitrogen, including the catalytic conversion of molecular dinitrogen to a secondary silylamine. Simple bridging ligands assemble two actinide metal cations into narrow dinuclear metallacycles that can trap the diatom while electrons from an externally bound group 1 metal, and protons or silanes, are added, enabling dinitrogen to be functionalized with modest but catalytic yields of six equivalents of secondary silylamine per molecule at ambient temperature and pressure.

Author Correction: Metallacyclic actinide catalysts for dinitrogen conversion to ammonia and secondary amines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The brain-penetrating, orally bioavailable, ghrelin receptor agonist HM01 ameliorates motion-induced emesis in Suncus murinus (house musk shrew).

BACKGROUND AND PURPOSE: HM01, a novel, orally bioavailable, brain-penetrating agonist of ghrelin receptors, ameliorates emesis in Suncus murinus. This study compared HM01's activity against motion sickness with that of the less brain-penetrating ghrelin receptor agonist, HM02. EXPERIMENTAL APPROACH: The potential of HM01 and HM02 to relax isolated mesenteric arteries and to increase feeding was investigated. Radio telemetry was used to record gastric slow waves and body temperature. Plethysmography was used to measure respiratory function. HM01 and HM02 were administered p.o. 1 hr prior to provocative motion, and c-Fos expression in brain sections was assessed. KEY RESULTS: HM01 and HM02 both relaxed precontracted arteries, yielding EC50 values of 2.5 ± 0.5 and 3.5 ± 0.4 nM respectively. HM01 increased feeding, but HM02 did not. Both compounds caused hypothermia and bradygastria. Motion induced 123 ± 24 emetic events. HM01, but not HM02, reduced motion-induced emesis by 67.6%. Motion increased c-Fos expression in the nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMNV), medial vestibular nucleus (MVe), central nucleus of the amygdala, and paraventricular hypothalamic nucleus (PVH). HM01 alone increased c-Fos expression in the area postrema, NTS, DMNV, PVH, and arcuate hypothalamic nucleus; HM02 had a similar pattern except it did not increase c-Fos in the PVH. Both compounds antagonized the motion-induced increases in c-Fos expression in the MVe. CONCLUSIONS AND IMPLICATIONS: HM01 is more effective than HM02 in preventing motion-induced emesis. The difference in potency may relate to activation of ghrelin receptors in the PVH.

Does indocyanine green improve the evaluation of perfusion during laparoscopic colorectal surgery with extracorporeal anastomosis?

BACKGROUND: There has been recent interest in indocyanine green (ICG) to assess anastomotic perfusion in colorectal surgery. We describe our experience using ICG when performing laparoscopic segmental colorectal resections with extracorporeal anastomotic technique and a highly standardized approach for clinically assessing blood flow. METHODS: We recruited 20 consecutive patients to undergo segmental laparoscopic resection and determined an appropriate point to transect mesentery proximally confirming pulsatile arterial flow at this level. Once confirmed, we did a further perfusion study using ICG to ascertain if this would change intraoperative decision-making. RESULTS: Twenty segmental colonic resections were assessed in nine female and 11 male patients aged 26-91 years. ICG administration was safe with no adverse outcomes documented. ICG demonstrated anastomotic perfusion in all cases. We observed no cases wherewith pulsatile blood flow at the cut edge of the mesentery, ICG showed inadequate perfusion at this level. We did find in 25% of cases ICG showed perfusion beyond the cut edge of the mesentery to a distance of up to 2.5 cm. CONCLUSION: ICG perfusion is safe and straightforward to carry out. However, when pulsatile arterial bleeding is demonstrated clinically it does not add anything to assessment of perfusion in our study. Furthermore, in 25% of cases perfusion can be demonstrated beyond the cut edge of the mesentery up to a distance of 2.5 cm. This raises the possibility that an organ well perfused with ICG may have less than ideal blood flow when assessing for this with a view to constructing an anastomosis.

Mechanisms of the dilator action of cryptotanshinone on rat coronary artery.

In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.

Dihydrotanshinone, a lipophilic component of Salvia miltiorrhiza (danshen), relaxes rat coronary artery by inhibition of calcium channels.

AIM OF THE STUDY: Dihydrotanshinone is a lipophilic component of the medicinal herb Salvia miltiorrhiza (danshen) belonging to the family of Labiatae. In this study, we have investigated the mechanisms of its relaxant effect on rat-isolated coronary artery. MATERIALS AND METHODS: Rat coronary artery rings were precontracted with 1 microM 5-hydroxytryptamine (5-HT). Involvement of endothelium-dependant mechanisms were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ,10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 10 mM). Involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. RESULTS: Dihydrotanshinone relaxed the 5-HT-precontracted coronary artery rings with an IC50 value of 10.39+/-1.69 microM. None of the above inhibitors or antagonists tested produced a significant change on the vasorelaxant effect of dihydrotanshinone, except ODQ caused a 50% reduction. Pre-incubation of the artery rings for 10 min with dihydrotanshinone (100 microM) abolished the CaCl(2)-induced vasoconstriction. CONCLUSIONS: These findings suggest that inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for the vasorelaxant effect of dihydrotanshinone, and it is independent of pathways involving the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase.

Analgesic and anti-arthritic effects of Lingzhi and San Miao San supplementation in a rat model of arthritis induced by Freund's complete adjuvant.

AIM OF STUDY: In this study, we have investigated the analgesic and anti-arthritic effects of a traditional Chinese medicine (TCM) combination of Lingzhi and San Miao San (SMS) in a rat model of arthritis induced by Freund's complete adjuvant (FCA). MATERIALS AND METHODS: Sprague-Dawley rats were induced with monoarthritis by single unilateral injection of FCA into the knee joint. The TCM combination was administered to the rats daily by intraperitoneal injection (50mg/(kgday)) or via oral administration (500mg/(kgday)) for 7 days before induction of arthritis and 7 days after. Extension angle that provoked struggling behavior, and size and blood flow of the rat knees were measured to give indexes of allodynia, edema, and hyperemia, respectively. The extent of cell infiltration, tissue proliferation, and erosions of joint cartilage provided additional indexes of the arthritis condition. RESULTS: FCA injection produced significant allodynia, edema, hyperemia, immune cell infiltration, synovial tissue proliferation, and erosions of joint cartilage in the ipsilateral knees compared with the contralateral saline-injected knees. Intraperitoneal injection of the TCM combination (50mg/(kgday)) suppressed allodynia, edema, and hyperemia in the inflamed knees, and oral administration (500mg/(kgday)) suppressed edema and hyperemia. Histological examination showed that the TCM administered by either route reduced immune cell infiltration and erosion of joint cartilage. CONCLUSIONS: These findings suggest the Lingzhi and SMS formulation has analgesic and anti-inflammatory effects in arthritic rat knees, and concur to previous clinical studies that showed the TCM combination reduced pain in rheumatoid arthritis patients, and extends its possible benefit to suppression of inflammatory symptoms in these patients.

Radiotherapy for anal squamous cell carcinoma: must the upper pelvic nodes and the inguinal nodes be treated?

BACKGROUND: Loco-regional failure is the predominant cause of death in anal squamous cell carcinoma. We assessed patterns of loco-regional recurrence to determine the impact of radiotherapy (RT) volumes on patient outcome. METHODS: Retrospective clinical study, including patients treated curatively with RT or chemo-radiotherapy between 1994 and 2007. RT fields/volumes were reviewed and compared with patterns of failure. Patients were classified as having whole pelvic radiotherapy (WPRT) if RT extended to L5/S1 or lower pelvic radiotherapy (LPRT) if it extended to the lower sacroiliac joints or below. Patients with negative inguinal nodes either underwent prophylactic inguinal radiotherapy (PIRT) or had inguinal observation (IO). Patterns of failure were compared. RESULTS: Twenty-seven patients (53%) had WPRT and 24 (47%) had LPRT. Forty-two patients had negative inguinal nodes: 29 (69%) had PIRT and 13 (31%) had IO. Median follow-up was 5.8 years. Twelve regional failures occurred in eight patients: three pelvic, one inguinal and four pelvic and inguinal. All patients with regional failure died of disease. Pelvic nodal failure was 7.7% in N0 and 33% in N1-3 patients (P = 0.012). There was no difference in pelvic regional failure between WPRT and LPRT (11% versus 16%, P = 0.64). There was only one possible regional failure above LPRT in this group (4%). Inguinal failure was 0% in the PIRT group compared with 23% in IO group (P = 0.009). CONCLUSION: There was no difference in pelvic regional failure between WPRT and LPRT. LPRT is likely to be safe in N0 patients. Inguinal nodes should be treated in all patients.

Pharmacological characterization of receptor types mediating the dilator action of anandamide on blood vessels of the rat knee joint.

This study investigates the actions of N-(2-hydroxyethyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (anandamide) on blood flow of the rat knee joint. Topical bolus administration of anandamide (10-1000 nmol) onto the exposed knee joint capsules produced dose-dependent increases in the knee joint blood flow. Various antagonists were tested on the vasodilator response to 100 nmol anandamide. Capsazepine (N-[2-(4-chlorophenyl)ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide), an antagonist of the transient receptor potential vanilloid type 1 (TRPV1) receptor, given at 10 and 100 nmol, suppressed the response by a maximum of 71%. A cannabinoid CB(1) receptor antagonist AM281 (10 nmol) and a CB(2) receptor antagonist AM630 (10 nmol) shortened its duration from 15 min to 5 min. O-1918 (1 nmol), an antagonist of the putative endothelial anandamide/abnormal-cannabidiol receptor, on its own or combined with capsazepine and the two cannabinoid receptor antagonists produced 38% and 24% inhibition on the peak vasodilator response to anandamide, respectively. URB597 (1 nmol), an inhibitor of fatty acid amide hydrolase (FAAH) suppressed the response by 40%, and an anandamide transporter inhibitor [N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide] (AM404; 1 nmol) or a cyclo-oxygenase (COX) inhibitor flurbiprofen (20 nmol) abolished the response. These findings suggest the vasodilator action of anandamide in the rat knee joint involved hydrolysis of the compound by FAAH, production of COX-derived eicosanoid(s), activation of TRPV1 receptors, and a small component involved activation of endothelial anandamide/abnormal-cannabidiol receptors; a minor delayed dilator response was mediated by activation of conventional cannabinoid receptors.

Relaxant effects of danshen aqueous extract and its constituent danshensu on rat coronary artery are mediated by inhibition of calcium channels.

In this study, we have investigated the actions of danshensu, an active, water-extractable component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the water-extractable fraction of the herb. Extraction of the water-soluble fraction from danshen (S. miltiorrhiza) provided yield of 17.5% (35 g/200 g). The amount of danshensu determined in the crude danshen herb and in its aqueous fraction was 0.45 mg/g (0.045%) and 3.28 mg/g (0.33%). The danshen aqueous extract was 13 times less potent than danshensu in relaxing 5-HT-precontracted coronary artery rings; IC50 values were 930.3+/-133.5 microg/ml and 71.5+/-11.0 microg/ml. Removal of the endothelium did not significantly affect their vasodilator potencies; IC50 values were 842.1+/-123.8 microg/ml and 84.8+/-8.8 microg/ml. On the other hand, a potassium channel inhibitor tetraethylammonium (TEA, 10 mM) shifted their concentration-response curves by 1.7 and 2.2 folds. The possible involvement of Ca2+ channels was investigated in artery rings incubated with Ca2+-free buffer and primed with 1 microM 5-HT or 60 mM KCl for 5 min prior to addition of CaCl2 to elicit contraction. In 5-HT-primed preparations, the CaCl2-induced vasoconstriction was abolished by 2 mg/ml danshen aqueous extract and 200 microg/ml danshensu, whereas, in KCl-primed preparations, 10 mg/ml danshen aqueous extract and 600 microg/ml danshensu were required to abrogate the vasoconstriction. These findings suggest the vasorelaxant actions of danshen aqueous extract and danshensu were produced by inhibition of Ca2+ influx in the vascular smooth muscle cells. The opening of K+ channels had a minor contribution to the response, but endothelium-dependent mechanisms were not involved.