Current and future treatment of pulmonary hypertension

Pulmonary hypertension is a disorder characterized by an increase in mean pulmonary arterial pressure (mPAP > 25 mmHg), which is responsible for the transport of blood from the heart to the lungs. Increased pressure leads to decreased flow of blood through the lungs and decreased oxygen deliverance throughout the body. The disorder causes right ventricular hypertrophy and can quickly lead to death, especially with the severe forms of pulmonary hypertension. Symptoms include fatigue, shortness of breath, dizziness and peripheral edema in the lower extremities. Symptoms are usually delayed in appearance and progress slowly, which leads to a late diagnosis and often a poor prognosis. Despite large advances in the last 10 years, there is still about a 15% annual mortality for diagnosed patients. Despite the number of medications available, there are still no cures for this fatal disease. Current therapies include endothelin receptor antagonists, prostacyclin agonists and cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5) inhibitors or combinations. Recent strategies have shown promise in animal models to prevent the onset of pulmonary hypertension when it is induced. However, few of them show a sustained benefit in clinical trials. Strategies for the cure of this debilitating disease should be the focus of future research.     

Colonic Manometry Catheter Placement with Primary Fluoroscopic Guidance

The purpose of this paper is to describe our experience with a new technique of colonic manometry catheter placement using fluoroscopic guidance. Between 2000 and 2004, 44 colonic manometry catheters were placed with primary fluoroscopic guidance in 38 patients (25 males; median age, 7 years; range, 0.4–31 years) with severe defecation disorders. Fourteen colonoscopic placements were reviewed to compare the different procedures. Manometry catheters were inserted through the rectum (16 patients), cecostomy (9), ileostomy (2), and colostomy (17). Placements through diverted colons were successful in 24 of 28 (86%). Insertion through the rectum was successful in 10 of 16 (63%) fluoroscopic-guided placements vs. 12 of 14 (86%) colonoscopic placements (P=0.23). Significantly longer fluoroscopic exposure was required for fluoroscopic compared to colonoscopic placement (P=0.004). In conclusion, placement of colonic manometry catheters with primary fluoroscopic guidance is feasible in children. An important disadvantage of the fluoroscopic methodology is the prolonged fluoroscopic exposure time.     

Fine-needle aspiration diagnosis of squamous cell carcinoma in a lymph node involved with small lymphocytic lymphoma: case report and review of the literature

Diagnosis of two distinct malignant entities existing concurrently and at the same location (synchronous malignancy) by fine- needle aspiration (FNA) is unusual but may occur. Small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) in particular is associated with an increased incidence of secondary tumor, likely due to associated immunodeficiency. Co-occurrence of some carcinomas such as squamous cell carcinoma (SCC), may show especially aggressive behavior. A 57-year-old Caucasian male presented with recurrent upper extremity lymphedema and diffuse lymphadenopathy of the axillary and cervical regions. FNA of a large cervical lymph node was diagnostic for both atypical lymphocytic proliferation and SCC. Flow cytometric analysis showed the atypical lymphocytic proliferation to be positive for CD5, CD23, CD19, CD20, HLA-DR, CD38, and the population was kappa light chain restricted. These cells were negative for CD-10 and FMC-7 antigens, suggesting a phenotype of B-cell SLL/CLL. We report a rare occurrence of metastatic SCC to a lymph node infiltrated by SLL/CLL. The diagnosis was achieved by a combination of cytomorphologic examination of FNA smears, immunohistochemical staining of cell block material, and flow cytometry on the sample obtained by FNA. To the best of our knowledge, only three cases of SCC metastasis to SLL/CLL diagnosed by FNA have been reported in the English literature. Though rare, awareness of such a possibility and careful cytological examination under the appropriate clinical conditions is warranted.     

Volume therapy with colloid solutions preserves intestinal microvascular perfusion in endotoxaemia

Colloid solutions have been suggested to improve microvascular perfusion due to their anti-inflammatory properties. Whether this also applies for the gut, an important immunological organ vulnerable to hypoperfusion is unknown. This study investigated intestinal microcirculation of endotoxaemic rats after volume therapy with colloid solutions such as hydroxyethyl starch (HES) and gelatin or isotonic saline (NaCl). In addition intestinal oxygenation and morphology as well as mesenteric leukocyte-endothelium interaction were quantified. Rats were anaesthetised with urethane and ketamine, mechanically ventilated, and monitored haemodynamically. Normotensive endotoxaemia was induced by a continuous intravenous infusion of Escherichia coli lipopolysaccharide (LPS, 1.5 mg kg(-1) h(-1)). After 1 h of LPS infusion either 6% HES (16 ml kg(-1)), 4% gelatin (16 ml kg(-1)) or 0.9% NaCl (64 ml kg(-1)) were infused for 1 h. Using intravital microscopy, functional capillary density (FCD) and red blood cell velocity (RBCV) were measured in the mucosa of the terminal ileum at baseline and 3 h after volume therapy. In another set of animals, mesenteric leukocyte-endothelium interaction was determined 3 h after volume therapy. In all animals intestinal lactate/pyruvate ratio and intestinal morphology were assessed. Three hours after volume therapy, FCD decreased in NaCl (808 [749/843] cm(-1); median [quartiles] P<0.05 versus baseline) but not in HES (995 [945/1036] cm(-1)) and gelatin (988 [867/1193] cm(-1)) groups. RBCV, lactate/pyruvate ratio and intestinal morphology did not differ among groups. Also mesenteric leukocyte-endothelium interaction was not significantly influenced by either treatment. In conclusion, early volume therapy with HES or gelatin, but not with NaCl, preserved gut microvascular perfusion during endotoxaemia but did not have a significant effect on tissue oxygenation nor morphological appearance in this experimental model. An anti-inflammatory effect of colloid solutions was not seen and fails to explain the changes in intestinal microcirculation.     

Differentiation of rat lens epithelial cells in tissue culture--IV. Some characteristics of the process, including possible in vitro models for pathogenic processes in cataractogenesis

In this paper a number of our observations on cultured rat lens epithelial cells are discussed, and some parallels are drawn with some other systems. Several stages of differentiation of rat lens epithelial cells in tissue culture are outlined along with the criteria used to define them. The effects of several factors including cell density, medium and hormonal factors such as cyclic AMP on differentiation are discussed. The behaviour of primary cells in culture, seen on a time-lapse video tape available from the authors, is outlined. Actin and tubulin both appear to be involved in the elongation stage of primary cells in culture. Cold shock appeared to induce γ-crystallin protein detectable by immunofluorescence in a cell line, RLE-R, obtained by treatment of primary cultures with Rous Sarcoma virus. A second cell-line, RLE-MM, obtained after similar treatment with murine leukemia and murine sarcoma cells is reported. A number of possibilities for modelling various aspects of the globular degeneration occurring in cataracts is reported, including globules formed in old 16-day-embryo cultures, globules formed in primary cells after treatment with cytochalasin D, and in the cell-line RLE-R following cold shock. Glucose toxicity to cells of the line RLE-R, which may also be a contributing factor in diabetic cataracts, was relieved by vitamins E and C which appeared to act additively. Several problems remaining are discussed.     

Effects of dietary saturated,monounsaturated and polyunsaturated fats on plasma lipids and lipoproteins in diabetic rats*

The effects of altering the type of dietary fat on plasma lipid and lipoprotein levels were investigated in streptozotocin‐diabetic rats fed non‐purified diets containing corn oil, olive oil, cod‐liver oil, sheep tallow and lard. After 32 days of experimental feeding, plasma levels of glucose, triglycerides, total cholesterol, low density and high density lipoprotein cholesterol were determined. Body weights and food intake were also measured. In neither animal group did the type of fat in the diet affect significantly the plasma levels of lipids and lipoproteins and their calculated ratios, and plasma glucose, body weight change or accumulative food intakes. In all studied diabetic rats, significant correlations were observed between body weight change and the following plasma variables: total cholesterol level (r = —0.37, P < 0.03), low density lipoprotein cholesterol level (r = —0.38, P<0.03) and triglycéride concentration (r = —0.36, P < 0.04). A significant positive correlation (r = 0.60, P < 0.0003) was also found between plasma levels of glucose and triglycérides. No significant correlations were noticed between accumulative food intakes and any of the studied variables. It is concluded that, in uncontrolled hyperglycemia in diabetes, the type of fat in the diet exerts little or no influence on plasma lipid and lipoprotein concentrations.     

The potential therapeutic effect of melatonin in gastro-esophageal reflux disease

Background  

Gastro-Esophageal Reflux Disease (GERD) defined as a condition that develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Many drugs are used for the treatment of GERD such as omeprazole (a proton pump inhibitor) which is a widely used antiulcer drug demonstrated to protect against esophageal mucosal injury. Melatonin has been found to protect the gastrointestinal mucosa from oxidative damage caused by reactive oxygen species in different experimental ulcer models. The aim of this study is to evaluate the role of exogenous melatonin in the treatment of reflux disease in humans either alone or in combination with omeprazole therapy.     

Recurrent cerebral infarction and the antiphospholipid syndrome: effect of intravenous gammaglobulin in a patient with systemic lupus erythematosus.

A 23 year old woman with systemic lupus erythematosus and antiphospholipid syndrome developed severe thrombocytopenia (5-10 X 10(9)/l) and cerebral infarction. Treatment with high doses of corticosteroids and cytostatic drugs was not effective. The condition was successfully treated only when three courses of intravenous gammaglobulin at 400 mg/kg daily was added. A clear relation was found between the immunoglobulin infusions and rising platelet counts, whereas an effect on the levels of anticardiolipin antibodies could not be recorded. The findings suggested that the mechanisms responsible may be modification and solubilisation of immune complexes or interference with anticardiolipin binding to platelet membranes, or both.