Injury to endothelial cells by phagocytosing polymorphonuclear leukocytes and modulatory role of lipoxygenase products.

Phagocytosis of microorganisms by polymorphonuclear leukocytes (PMN) is accompanied by inadvertent extracellular release of microbicidal products; this could result in tissue damage. We investigated whether PMN damages endothelial cells when phagocytosis of Staphylococcus aureus occurs on the endothelial surface and how this damage might be modulated. Damage was assayed by the measurement of cell detachment or cell lysis of cultured endothelial cells that were radiolabeled with 51Cr. Uptake of bacteria was accompanied by nonlytic detachment of endothelial cells from the monolayer. This effect was inhibited by alpha-1-antitrypsin but remained unaffected by scavengers of toxic oxygen species. During phagocytosis, PMN adhered to the endothelial cells. Adherence could be prevented by inhibition of the lipoxygenase pathway of arachidonic acid metabolism of the PMN with nordihydroguaiaretic acid. This inhibition also resulted in a marked decrease of the detaching activity of the PMN. The addition of exogenous leukotriene B4 during phagocytosis greatly enhanced the damage to the endothelial monolayer. These results indicate that phagocytosis of staphylococci by PMN is accompanied by injury to endothelial cell monolayers due to released lysosomal proteases and that products of the lipoxygenase pathway of PMN play a modulatory role in this injury.     

Correction of hypokalemia in Bartter's syndrome by enalapril

Seven patients with Bartter's syndrome were investigated before and after 3 months' treatment by enalapril. Serum potassium rose from 2.4 +/- 0.5 to 3.9 +/- 0.6 mmol/L. In all patients, serum magnesium rose and bicarbonate fell. Hormonal changes were as suspected: a further stimulation of renin and a decline in aldosterone. The BP sensitivity to angiotensin II normalized in the five patients in whom the test was performed. Clearance studies during maximal water diuresis, performed in four patients, were compatible with a high proximal fractional tubular sodium reabsorption and a relatively low distal fractional sodium reabsorption. Fractional free water excretion after furosemide was also low, confirming the concept of a primary sodium reabsorption defect in the furosemide-insensitive part of the nephron in Bartter's syndrome. The only consistent change after enalapril was a further decline in distal fractional sodium reabsorption. Initiation of therapy produced a BP fall in each subject. Clinical important hypotension associated with oliguria was seen twice, but these reactions were short-lasting. The BP rose to pretreatment values within 72 hours, despite continuation of converting-enzyme inhibition. Renal function recovered, though a moderate fall in function persisted. No other side effects were noticed. We conclude that converting-enzyme inhibition improves the potassium metabolism of patients with Bartter's syndrome, without ameliorating the abnormal renal sodium handling.     

Characterization of the alpha-MSH-like immunoreactivity in blood and cerebrospinal fluid of the rat

We have investigated the nature of the alpha-melanocyte stimulating hormone-like immunoreactivity (alpha-MSH-LI) in blood and cerebrospinal fluid (CSF) of the rat. Blood and CSF from intact animals were subjected to high pressure liquid chromatography (HPLC) followed by a radioimmunoassay (RIA) specific for the C-terminal part of the alpha-MSH molecule. It appeared that in both body fluids the predominant alpha-MSH-LI co-migrated with synthetic alpha-MSH and not with its des-acetyl or di-acetyl analogues. We conclude that alpha-MSH is the predominant form of alpha-MSH-LI circulating in plasma and CSF of rats from our Wistar strain.     

Identifying the barriers to conducting outcomes research in integrative health care clinic settings - a qualitative study

Background  

Integrative health care (IHC) is an interdisciplinary blending of conventional medicine and complementary and alternative medicine (CAM) with the purpose of enhancing patients' health. In 2006, we designed a study to assess outcomes that are relevant to people using such care. However, we faced major challenges in conducting this study and hypothesized that this might be due to the lack of a research climate in these clinics. To investigate these challenges, we initiated a further study in 2008, to explore the reasons why IHC clinics are not conducting outcomes research and to identify strategies for conducting successful in-house outcomes research programs. The results of the latter study are reported here.     

Phagocytosis of herpes simplex virus by human granulocytes and monocytes

Summary Polymorphonuclear leukocytes (PMN) can mediate cytotoxic reactions against virus infected targets cells. We observed very efficient binding of PMN to HSV-infected fibroblasts when loaded with HSV-specific antibodies. Using electron microscopy, infected fibroblasts were found to be totally surrounded by PMN and the phagocytosis of virions and fragments of infected cells was demonstrated. To quantify and study this phenomenon, and to compare PMN with monocytes, we developed radiometric and fluorometric phagocytosis assays. Leukocytes were mixed with [³H]glucosamine- or FITC-labeled virus and incubated at 37°C. PMN associated radioactivity or fluorescence per cell as measured by flow cytometry was determined. PMN phagocytosis was dependent on the presence of specific anti-HSV antibodies and could be enhanced by addition of complement. Monocytes were also able to phagocytize virions; however, the rate of uptake was less than that for PMN. Under optimal conditions the total amount of herpes simplex particles that could be associated with one PMN or monocyte was about 10,000.PMN and monocytes are capable of phagocytosis of HSV. This may be an important factor in preventing the spread of infection in vivo.     

Developments in buccal drug delivery

The buccal mucosa offers excellent possibilities for the (long-term) delivery of suitable drugs, especially for metabolically unstable drugs, such as peptides. A review is given of the present knowledge about buccal drug absorption and drug delivery devices. The structure and physiology of the oral mucosae are described, as well as interspecies differences with respect to tissue permeability. Methods to determine mucosal drug absorption, either in vivo or in vitro, are discussed, as well as absorption pathways, mechanisms, and enhancement. Technological strategies to control transbuccal drug absorption comprise the design of mucoadhesive devices in order to shorten diffusion pathways and prolong administration, and structural and chemical modulation of the device with the aim of shifting the rate-limiting transport step from the tissue to the device. Finally, examples of buccally administered drugs are given and devices currently used in local therapy are described.     

The Nasal Mucociliary Clearance: Relevance to Nasal Drug Delivery

Mucociliary clearance is an important physiological defense mechanism of the respiratory tract to protect the body against noxious inhaled materials. This process is responsible for the rapid clearance of nasally administered drugs from the nasal cavity to the nasopharynx, thereby interfering with the absorption of drugs following intranasal application. This review describes the mucociliary system and the methods used for its characterization. Examples are given of the effects of drugs and additives on its functioning. Further, possible approaches are presented for increasing the residence time of drugs in the nasal cavity, thereby improving intranasal drug delivery.     

Complementary practitioners' views of treatment for inflammatory bowel disease.

A substantial number of patients with inflammatory bowel disease use complementary therapies to manage their disease, including chiropractic and herbal therapies. The objective of this study was to explore whether providers of these therapies see patients with inflammatory bowel disease and recommend therapies, and to determine their opinions about the treatments that they recommend. The study sample comprised 66 chiropractors, 19 pharmacists, 16 herbalists and 15 health food store employees in Calgary, Alberta. A structured questionnaire containing two patient scenarios (a patient with active ulcerative colitis and a patient with inactive Crohn's disease) was completed either by an in-person interview or by a mailed questionnaire. Most respondents had seen patients with ulcerative colitis, and at least 80% of each group except pharmacists (only 10%) would treat these patients or recommend treatment. Almost all chiropractors used spinal manipulation, whereas herbalists and health food store employees suggested a wide range of different treatments. Chiropractors rated their treatment as moderately effective; herbalists and health food store employees viewed their recommendations as very effective. The results with respect to the second scenario were very similar. The wide range of treatment recommendations by practitioners, who differ greatly in terms of skills, knowledge and experience, has important implications for physician-patient communication, information provision and education regarding complementary and alternative therapies.