MNK1 and MNK2 mediate adverse effects of high-fat feeding in distinct ways.

The MAP kinase-interacting kinases (MNK1 and MNK2) are non-essential enzymes which are activated by MAP kinases. They are implicated in controlling protein synthesis. Here we show that mice in which the expression of either MNK1 or MNK2 has been knocked out (KO) are protected against adverse effects of high-fat feeding, and in distinct ways. High-fat diet (HFD)-fed MNK2-KO show less weight gain than wild-type animals, and improved glucose tolerance, better insulin sensitivity and markedly diminished adipose tissue inflammation. This suggests MNK2 plays a role in adipogenesis and/or lipogenesis and in macrophage biology. MNK1-KO/HFD mice show better glucose tolerance and insulin sensitivity, but gain weight and show similar adipose inflammation to WT animals. These data suggest MNK1 participates in mediating HFD-induced insulin resistance. Our findings reveal distinct roles for the MNKs in a novel area of disease biology, metabolic dysfunction, and suggests they are potential new targets for managing metabolic disease.

A novel use of reticulated hyaluronic acid (Healaflow) for hypotony eyes in patients with uveitis.

Persistent ocular hypotony is a complex and ongoing challenge faced in ophthalmology. It can result in early ocular phthisis and associated visual decline, pain and deformity. We present the first case series, in which repeated intracameral injections of highly reticulated hyaluronic acid (Healaflow) have successfully prevented the complications of ocular hypotony in the long term. We believe it is a viable management option that can bring about a significant improvement to the quality of life in this subgroup of patients while avoiding frequent intervention.

Pegfilgrastim administered in an abbreviated schedule, significantly improved neutrophil recovery after high-dose radiation-induced myelosuppression in rhesus macaques.

Conventional daily administration of filgrastim is effective in reducing the duration of severe neutropenia and enhancing survival following lethal radiation, myelosuppressive cytotoxic therapy or myeloablation and stem cell transplantation. A sustained-duration form of filgrastim, pegfilgrastim has significantly simplified scheduling protocols after chemotherapy-induced neutropenia to a single injection while maintaining the therapeutic effectiveness of daily administration of filgrastim. We examined the ability of a single or double (weekly) administration of pegfilgrastim to significantly improve neutrophil recovery in a rhesus macaque model of severe radiation-induced myelosuppression. Animals were exposed to potentially lethal 6 Gy total-body X radiation. After irradiation all animals received supportive care and were administered either pegfilgrastim at 300 µg/kg on day 1 or day 1 and day 7 post exposure, or filgrastim at 10 µg/kg/day initiated on day 1 post exposure and continued daily through neutrophil recovery. Pharmacokinetic parameters and neutrophil-related values for duration of neutropenia, neutrophil nadir, time to recovery to an absolute neutrophil count ≥500/µL or ≥2000/µL, and days of antibiotic support were determined. Effective plasma concentrations of pegfilgrastim were maintained in neutropenic animals until after the onset of hematopoietic recovery, which is consistent with neutrophil-dependent properties of elimination. Administration of pegfilgrastim at day 1 and day 7 was most effective at improving neutrophil recovery compared to daily administration of filgrastim or a single injection of pegfilgrastim on day 1, after severe, radiation-induced myelosuppression in rhesus macaques.

Impact of 5-HT3 receptor blockade on colonic haemodynamic responses to ischaemia and reperfusion in the rat.

5-HT(3) receptor antagonists are clinically available for treating patients with irritable bowel syndrome (IBS) but their use is restricted because of a link with some episodes of ischaemic colitis. However, the role of 5-HT3 receptors in regulating colonic blood flow has not been systematically investigated. Thus, we examined acute and chronic treatment with alosetron, a potent and selective antagonist of the 5-HT3 receptor, on baseline colonic blood flow and haemodynamic responses during occlusion and reactive hyperaemia in the pentobarbitone-anaesthetized rat. Colonic haemodynamics were assessed using ultrasonic recordings of superior mesenteric blood flow (MBF) and laser Doppler recordings of colonic vascular perfusion (VP). Blood pressure (BP) was also monitored and in some experiments tissue oxygen was detected polarographically. Alosetron (10, 30, 100 microg kg(-1), i.v.) had no effect on baseline haemodynamics nor responses to nitric oxide synthase inhibition with N(omega)-nitro-l-arginine methyl ester (l-NAME) (16 mg kg(-1)). Arterial occlusion (5 min) reduced MBF (-98.6 +/- 0.6%) and VP (-70.7 +/- 5.4%) followed by a post-occlusion reactive hyperaemia (MBF = +94.5 +/- 19.1%; VP = +60.0 +/- 22.3%) the magnitude of which was unchanged following acute (30 microg kg(-1)) or chronic alosetron administration (0.5 mg kg(-1) twice daily, 5 days). Alosetron did not significantly alter baseline colonic blood flow in the anaesthetized rat; nor did it interfere with vascular control mechanisms activated during occlusion and reactive hyperaemia.

Activation of the cannabinoid 2 (CB2) receptor inhibits murine mesenteric afferent nerve activity.

Abstract Cannabinoid 2 (CB2) receptors have both antinociceptive and antihypersensitivity effects, although the precise mechanisms of action are still unclear. In this study, the modulatory role of CB2 receptors on the mesenteric afferent response to the endogenous immunogenic agent bradykinin (BK) was investigated. Mesenteric afferent recordings were obtained from anaesthetized wild-type and CB2(-/-) mice using conventional extracellular recording techniques. Control responses to BK were obtained in all experiments prior to administration of either CB2 receptor agonist AM1241, or AM1241 plus the CB2 receptor antagonist AM630. Bradykinin consistently evoked activation of mesenteric afferents (n = 32). AM1241 inhibited the BK response in a dose dependent manner. In the presence of AM630 (10 mg kg(-1)), however, AM1241 (10 mg kg(-)1) had no significant effect on the BK response. Moreover, AM1241 had also no significant effect on the BK response in CB2(-/-) mice. Activation of the CB2 receptor inhibits the BK response in mesenteric afferents, demonstrating that the CB2 receptor is an important regulator of neuroimmune function. This may be a mechanism of action for the antinociceptive and antihypersensitive effects of CB2 receptor agonists.

Is admission for epistaxis more common in Caucasian than in Asian people? A preliminary study.

OBJECTIVES: Epistaxis is a common ENT complaint. Although casual observation suggested that it is more common in Caucasian, compared with Asian people, a literature search failed to find any studies investigating ethnicity and epistaxis. The aim of this study was to identify any differences in emergency admission rates for epistaxis between Asian and Caucasian people. DESIGN: Retrospective observational study using hospital computerised data (HISS). SETTING: Large University Hospital accepting ENT emergencies. PARTICIPANTS: All Asian and Caucasian patients admitted under ENT care as an emergency (1 January 2000 to 30 November 2005), split into two groups: one composed of epistaxis patients, the other of all other ENT emergency admissions. MAIN OUTCOMES MEASURES: The proportions of Asian and Caucasian patients among the two patient groups, either epistaxis admissions or other ENT emergency admissions. RESULTS: The proportions of Asian and Caucasian patients in the group admitted with emergency epistaxis were 7.1% (100/1410) and 92.9% (1310/1410) respectively. However, the proportions of Asian and Caucasian patients in the group composed of any other ENT emergency were 13.2% (729/5515) and 86.8% (4786/5515), respectively (chi-squared P < 0.01). CONCLUSIONS: Caucasian people form an unexpectedly large, and Asians a smaller proportion of emergency epistaxis admissions. The possibility of an ethnic risk factor for epistaxis warrants further investigation.

Subintimal recanalisation and stenting of a common iliac artery occlusion by a left axillary and an ipsilateral femoral retrograde approach using modified gooseneck grab aided by balloon dilatation of "dissection port".

The technique of recanalisation using deliberate subintimal dissection of an occluded iliac artery is being increasingly used and practised via ipsilateral and or contralateral approaches. There remains, however, a fair proportion of cases where, in spite of using gooseneck snares, the wire manipulation to traverse the occlusion can prove unsuccessful resulting in failed de-obliteration of the occlusion. We describe a technique to aid successful re-establishment of the patency using balloon dilatation of the dissection "entry port" with modified gooseneck snare grab.

Pegfilgrastim, a sustained-duration form of filgrastim, significantly improves neutrophil recovery after autologous marrow transplantation in rhesus macaques.

Daily administration of filgrastim decreases the duration of severe neutropenia in the clinical setting. A sustained-duration form of filgrastim, pegfilgrastim, significantly reduces scheduling protocols to a single injection per chemotherapy cycle while maintaining therapeutic efficiency. We examined the ability of a single injection of pegfilgrastim to significantly improve neutrophil recovery following autologous bone marrow transplantation (AuBMT) in rhesus macaques. On day 1, postmyeloablation (920 cGy x-irradiation) and AuBMT, animals received either 0.1% autologous serum for 18 consecutive days (n=13), or single doses of pegfilgrastim via the subcutaneous (s.c.) or intravenous (i.v.) route (300 or 100 micro g/kg), or a single dose of filgrastim at 300 micro g/kg via the s.c. or i.v. route, or filgrastim at 10 micro g/kg via the s.c. route (n=4) on a daily basis (range=days 12-17). Pharmacokinetic parameters and neutrophil recovery were assessed. A single dose of pegfilgrastim via the i.v. or s.c. route was as effective as daily filgrastim administration, resulting in significant improvement of neutrophil recovery after myeloablation and ABuMT. Effective pegfilgrastim plasma concentrations were maintained in neutropenic animals until after the onset of hematopoietic recovery. Enhanced pharmacokinetics in AuBMT cohorts are consistent with self-regulating, neutrophil-mediated clearance.

Survey of flexible fibreoptic bronchoscopy in the United Kingdom.

The practice of flexible bronchoscopy is not standardized. Current guidelines are concerned primarily with safety aspects of the procedure. In view of this, and the authors' own observations of individual variation in preparation and technique, a national survey of bronchoscopic procedure was performed to assess physicians' methods. A structured questionnaire was mailed to 547 consultant physicians in adult respiratory medicine. Physicians' routines of patient preparation, drug therapy, sampling methods, and experience of complications with the flexible bronchoscope were assessed. A 60% response (328 physicians) was obtained. Patient consent was obtained by a junior doctor in 31% of replies. 205 (63%) physicians gave benzodiazepine sedation, 46 (14%) used opioid, and 38 (12%) administered both. Ninety-four (29%) physicians prescribed an antimuscarinic agent, and 235 (74%) gave antibiotics to patients with mechanical heart valves. Only 22% of physicians monitored electrocardiogram and 10% monitored blood pressure during all procedures. Marked variance was noted in sampling routines of suspected lung tumours. Physicians who used fluoroscopic guidance for transbronchial lung biopsy reported a significantly lower incidence of pneumothorax requiring drain insertion over the previous 12 months compared to those who did not (2.68 of 1000 versus 9.17 of 1000, (p<0.03)), but no difference in the total incidence of pneumothorax. Only 87 (27%) of responders had performed transbronchial needle aspiration sampling over the previous 12 months. The preparation and practice of flexible bronchoscopy varies greatly for each physician. Use of radiographical screening for performing transbronchial lung biopsy was associated with a lower likelihood of pneumothorax requiring chest tube drainage.

Evaluation of a series of anticonvulsant 1,2,3,4-tetrahydroisoquinolinyl-benzamides.

SAR studies around a series of N-(tetrahydroisoquinolinyl)-2-methoxybenzamides, identified by high-throughput screening at the novel SB-204269 binding site, have provided compounds such as 13, 29-33 with high affinity and excellent anticonvulsant activity in animal models.

Choline acetyltransferase (ChAT) immunoreactivity in paraffin sections of normal and diseased intestines.

There is increasing interest in localizing nerves in the intestine, especially specific populations of nerves. At present, the usual histochemical marker for cholinergic nerves in tissue sections is acetylcholinesterase activity. However, such techniques are applicable only to frozen sections and have uncertain specificity. Choline acetyltransferase (ChAT) is also present in cholinergic nerves, and we therefore aimed to establish a paraffin section immunocytochemical technique using an anti-ChAT antibody. Monoclonal anti-choline acetyltransferase (1.B3.9B3) and a biotin-streptavidin detection system were used to study the distribution of ChAT immunoreactivity (ChAT IR) in paraffin-embedded normal and diseased gastrointestinal tracts from both rats and humans. Optimal staining was seen after 6-24 hr of fixation in neutral buffered formalin and overnight incubation in 1 microgram/ml of 1.B3.9B3, with a similar distribution to that seen in frozen sections. In the rat diaphragm (used as a positive control), axons and motor endplates were ChAT IR. Proportions of ganglion cells and nerve fibers in the intramural plexi of both human and rat gastrointestinal tracts were also ChAT IR, as well as extrinsic nerve bundles in aganglionic segments of Hirschsprung's disease. Mucosal cholinergic nerves, however, were not visualized. In addition, non-neuronal cells such as endothelium, epithelium, and inflammatory cells were ChAT IR. We were able to localize ChAT to nerves in formalin-fixed, paraffin-embedded sections. The presence of ChAT IR in non-neuronal cells indicates that this method should be used in conjunction with other antibodies. Nevertheless, it proves to be a useful technique for studying cholinergic neuronal distinction in normal tissues and pathological disorders.

The mast cell-nerve axis in wound healing: a hypothesis.

Beyond their classic roles in allergic reactions and defence against parasites, mast cells can now be viewed as key players in regulating connective tissue homeostasis. There is good evidence that mast cells are in close morphological and functional contact with the peripheral nervous system. Although substantial differences exist between mast cells of different tissues and different species, they produce a wide range of agents, including cytokines, growth factors, and other regulatory molecules, and they respond to an equally wide range of substances, including neuropeptides. At our current level of understanding wound healing, inflammation plays a central role in this process, with macrophages being central protagonists at the cellular level. There is now increasing evidence that mast cells are also involved in wound healing, in health and disease. They produce and secrete histamine, heparin, and multifunctional cytokines and growth factors, which represent important agents in the wound-healing process. Reviewing the recent literature supporting this hypothesis, we also outline the clinical importance of this work to help close the gap between basic research and clinical application.

Effects of Epoetin alfa on hemostasis in chronic renal failure.

Epoetin alfa is the cornerstone of anemia therapy in patients with end-stage renal disease. In addition to stimulating erythropoiesis, Epoetin alfa has been demonstrated to affect hemostasis. Such effects may be important because patients with chronic renal failure have a bleeding diathesis that is multifactorial in origin. Therefore, a computer literature search on the relationship between Epoetin alfa therapy for anemia in patients with end-stage renal disease and platelets, coagulation, coagulation inhibitors, and fibrinolysis was performed. All articles and abstracts reporting original data in the English language on Epoetin alfa and its effect on hemostasis were reviewed. The literature suggests that the effects of Epoetin alfa on the coagulation cascade are of minimal clinical importance. However, Epoetin alfa transiently increases the number of circulating platelets and improves platelet function, and these effects are associated with a return of the bleeding time towards normal.