Gastrointestinal malacoplakia in children

Four children, whose ages ranged from 1 to 13 years, with malacoplakia of the gastrointestinal tract were treated at King Faisal Specialist Hospital between 1979 and 1983. All patients had either a preceding or a coexisting chronic illness. In one patient, malacoplakia was an incidental finding, while the remaining three patients presented with bloody diarrhea, abdominal pain, recurrent fever, and severe malnutrition. Colonoscopy in two patients revealed markedly inflamed and friable mucosa with focal ulceration alternating with patches of normal mucosa and pseudopolyposis. They were treated with antibiotics and cholinergic agonists. Three patients responded favorably, while one patient continued to have extensive active disease. Although the response to therapy is unpredictable, patients may respond if the treatment is continued on a long-term basis.     

Effects of atrial natriuretic peptide and sodium nitroprusside on epidermal growth factor-stimulated wound repair in rabbit corneal epithelial cells

PURPOSE: Treatment of rabbit corneal epithelial cells (RCEC) with epidermal growth factor (EGF) stimulates cell proliferation and wound repair in a cell culture model system. Studies have also shown that atrial natriuretic peptide (ANP) and sodium nitroprusside (SNP), a nitric oxide-generating agent, inhibit proliferation of a variety of cell types. The aim of the present work was to examine whether ANP or SNP has any effect on EGF-stimulated proliferation of RCEC involved in wound repair. METHODS: The SV-40 immortalized RCEC were cultured in 24-well plates until they became confluent. Wounds of uniform size (8 mm diameter) were created and the cells allowed to grow in the presence and absence of EGF and/or other agents. At prescribed time intervals, the cells were stained by Giemsa and the wound areas digitized and quantified by Sigma Image Scan System. The cGMP contents in RCEC, treated with or without ANP or SNP, were measured by radioimmunoassay. RESULTS: Addition of EGF (1-100 ng/ml) to RCEC stimulated cell proliferation which significantly reduced the time required for wound closure. Addition of ANP (1 nM to 10 microM) or SNP (10 microM to 1 mM), in the presence of EGF, dose-dependently inhibited the growth factor-stimulated wound closure in RCEC. When added alone to the cells, ANP or SNP increased cGMP accumulation in a dose-dependent manner. Addition of ANP (1 microM) or SNP (1 mM) to primary corneal epithelial cells, in the presence and absence of EGF, also inhibited the wound closure with a corresponding increase in cGMP contents. Treatment of the cells with ODQ (10 nM to 10 microM), a soluble guanylate cyclase inhibitor, dose-dependently decreased the SNP-induced accumulation of cGMP, and reversed the inhibitory effect of SNP on EGF-stimulated wound closure. Addition of membrane-permeable cGMP analog, 8-bromo-cGMP, to RCEC inhibited the EGF-stimulated wound closure in a dose-dependent manner. Treatment of RCEC with mitomycin C (5 microM) exerted a marked inhibitory effect on wound closure in the presence and absence of EGF, and also abrogated the inhibitory effect of 8-bromo-cGMP on wound closure in the EGF-treated and untreated cells. CONCLUSIONS: The results demonstrate that ANP and SNP inhibit the EGF-stimulated wound repair in RCEC. The effect of these agents is mediated via activation of guanylate cyclases that generate cGMP. Cyclic GMP appears to exert its inhibitory effect at the level of cell proliferation and not cell migration. The data suggest an important role for cGMP-dependent protein kinase in proliferation of RCEC stimulated by EGF.     

Significance of beta-blockers in the perioperative period

Beta-blockers have emerged as one of the key therapeutic agents that can decrease cardiac morbidity and mortality. Advances in cardiac beta-adrenergic receptor physiology and pharmacology have provided new insights into the beneficial effects of beta-blockers in cardiovascular medicine. Although significant advances have been made, many specific questions still remain to be answered. We will review some of these developments and the current role of beta-blockers in peri-operative medicine.     

Co-delivery of an antisense oligonucleotide and 5-fluorouracil using sustained release poly (lactide-co-glycolide) microsphere formulations for potential combination therapy in cancer

Antisense oligonucleotides (AODNs) can selectively inhibit oncogene expression by Watson-Crick hybridisation to target mRNA and are being increasingly considered for use in combination with conventional drugs for potential anticancer therapy. Combination therapy of AODNs and cytotoxic agents using biodegradable polymeric delivery systems potentially offers several advantages including site-specific or organ-directed targeting, protection from digesting enzymes, and improved pharmacokinetics/pharmacodynamics resulting from sustained delivery of the entrapped drugs. Using a model AODN targeting the epidermal growth factor receptor (that is over-expressed in several cancers including breast and brain cancer) and the commonly used cytotoxic agent, 5-fluorouracil (5-FU), we have examined the use of poly (lactide-co-glycolide) (P(LA-GA)) microsphere formulations for co-delivery of these agents. Both agents were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations and release profiles determined in vitro. Using a double emulsion method for preparing the P(LA-GA) microspheres suitable entrapment and sustained release over 35 days was observed in both types of formulation. Release of AODN and 5-FU from all formulations appeared to be biphasic. However, the release rates of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Electrophoretic mobility shift assays suggested that this might be, in part, due to an interaction of 5-FU with the oligodeoxynucleotide (ODN). Further, our data suggest that by mixing individual formulations of 5-FU and ODNs at different mass ratios allowed greater flexibility in achieving the desired release profile as well as avoiding potential drug-drug interactions. Thus, co-administration of individual P(LA-GA) microsphere formulations of AODNs and 5-FU, at appropriate mass ratios, appears worthy of further investigation for the potential co-delivery of these anti-cancer agents in vivo.     

Dextran sodium sulphate-induced colitis perturbs muscarinic cholinergic control of colonic epithelial ion transport

1. Neuronal cholinergic input is an important regulator of epithelial electrolyte transport and hence water movement in the gut. 2. In this study, colitis was induced by treating mice with 4% (w v(-1)) dextran sodium-sulphate (DSS)-water for 5 days followed by 3 days of normal water. Mid-colonic segments were mounted in Ussing chambers and short-circuit current (Isc, indicates net ion movement) responses to the cholinergic agonist, carbachol (CCh; 10(-4) M)+/-tetrodotoxin, atropine (ATR), hexamethonium (HEX), naloxone or phenoxybenzamine were assessed. 3. Tissues from mice with DSS-induced colitis displayed a drop in Isc in response to CCh (-11.3+/-3.3 microA/cm(2)), while those from control mice showed a transient increase in Isc (76.3+/-13.0 microA/cm(2)). The DeltaIsc in colon from DSS-treated mice was tetrodotoxin-sensitive, atropine-insensitive and was reversed by hexamethonium (HEX+CCh=16.7+/-7.8 microA/cm(2)), indicating involvement of a nicotinic receptor. 4. CCh induced a drop in Isc in tissues from controls only when they were pretreated with the cholinergic muscarinic receptor blocker, atropine: ATR+CCh=-21.3+/-7.0 microA/cm(2). Nicotine elicited a drop in Isc in Ussing-chambered colon from both control and DSS-treated mice that was TTX-sensitive. 5. The drop in Isc evoked by CCh challenge of colonic tissue from DSS-treated mice or ATR+CCh challenge of control tissue was not significantly affected by blockade of opiate or alpha-adrenergic receptors by naloxone or phenoxybenzamine, respectively. 6. The data indicate that DSS-colitis reveals a nicotinic receptor that becomes important in cholinergic regulation of ion transport.     

Non-ahr gene susceptibility Loci for porphyria and liver injury induced by the interaction of 'dioxin' with iron overload in mice

Among the actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in mice is the induction of hepatic porphyria. This is similar to the most common disease of this type in humans, sporadic porphyria cutanea tarda (PCT). Evidence is consistent with the actions of dioxin being mediated through binding to the aryl hydrocarbon receptor (AHR) with different Ahr alleles in mouse strains apparently accounting for differential downstream gene expression and susceptibility. However, studies of dioxin-induced porphyria and liver injury indicate that the mechanisms must involve interactions with other genes, perhaps associated with iron metabolism. We performed a quantitative trait locus (QTL) analysis of an F(2) cross between susceptible C57BL/6J (Ahr(b1) allele) and the highly resistant DBA/2 (Ahr(d) allele) strains after treatment with dioxin and iron. For porphyria we found QTLs on chromosomes 11 and 14 in addition to the Ahr gene (chromosome 12). Studies with C57BL/6.D2 Ahr(d) mice confirmed that the Ahr(d) allele alone did not completely negate the response. SWR mice are syngenic for the Ahr(d) allele with the DBA/2 strain but are susceptible to porphyria after elevation of hepatic iron. Analysis of SWRxD2 F(2) mice treated with iron and dioxin showed a QTL on chromosome 11, as well as finding other loci on chromosomes 1 (and possibly 9), for both porphyria and liver injury. These findings show for the first time the location of genes, other than Ahr, that modulate the mechanism of hepatic porphyria and injury caused by dioxin in mice. Orthologous loci may contribute to the pathogenesis of human sporadic PCT.     

Oral medication-induced esophageal injury in elderly patients

SUMMARY: ABSTRACT Although oral medication induced esophageal injury (OMIEI), is a well-known and preventable condition, many cases are still missed, particularly in the elderly patients.OBJECTIVE To determine the frequency and outcome of oral medication-induced esophageal injury in elderly patients.METHODS Records of 390 patients aged over 65 years, with diagnoses of dysphagia, odynophagia, and noncardiac chest pain, over the period of 11 years, were selected for a retrospective review. Patients who had barium studies only, in whom endoscopy was not done or was unsuccessful, and those with incomplete data were excluded, leaving 250 patients for further review.RESULTS Diagnosis of OMIEI was made in 27% (68 of 250) patients. Fifty-one of 68 (75%) patients with OMIEI responded to conservative management, including H2 blockers, proton pump inhibitors, antacids, or sucralfate. The remaining 17 patients (25%) developed esophageal strictures requiring dilation.CONCLUSIONS A high index of clinical suspicion and low threshold for empiric treatment and diagnostic measures (endoscopy, barium swallow study), may be helpful, if indicated, for early diagnosis and prompt therapy of OMIEI.     

Serum immunoglobulin levels in neoplastic disorder of breast

Serum IgG, IgA and IgM were estimated in 42 cases of carcinoma and 12 cases of fibroadenoma of breast. The results were compared with 20 healthy female controls. Results showed increased levels of serum IgA in carcinoma breast cases. This increase was statistically significant (p = 0.001) when compared with healthy controls while IgG and IgM values were found to be insignificant. Values of IgG, IgA and IgM in cases of fibroadenoma breast when compared with the controls were found to be insignificant. Statistically significant increased value of IgA was also observed in medullary carcinoma and non-metastasizing tumours when viewed separately, suggestive of good prognostic index of serum IgA level estimation in the case of carcinoma breast.     

Inequalities in health: a comparative study between ethnic Norwegians and Pakistanis in Oslo, Norway

Background  

The objective of the study was to observe the inequality in health from the perspective of socio-economic factors in relation to ethnic Pakistanis and ethnic Norwegians in Oslo, Norway.