Differences in proximal （cardia） versus distal （antral） gastric carcinogenesis via retinoblastoma pathway

AIM: Disruption of cell cycle regulation is a critical event in carcinogenesis, and alteration of the retinoblastoma (pRb) tumour suppressor pathway is frequent. The aim of this study was to compare alterations in this pathway in proximal and distal gastric carcinogenesis in an effort to explain the observed striking epidemiological differences. METHODS: Immunohistochemistry was performed to investigate expression of p16 and pRb in the following groups of both proximal (cardia) and distal (antral) tissue samples: (a) biopsies showing normal mucosa, (b) biopsies showing intestinal metaplasia and, (c) gastric cancer resection specimens including uninvolved mucosa and tumour. RESULTS: In the antrum there were highly significant trends for increased p16 expression with concomitant (and in the group of carcinomas inversely proportional) decreased pRb expression from normal mucosa to intestinal metaplasia to uninvolved mucosa (from cancer resections) to carcinoma. In the cardia, there were no differences in p16 expression between the various types of tissue samples whereas pRb expression was higher in normal mucosa compared with intestinal metaplasia and tissue from cancer resections. CONCLUSION: Alterations in the pRb pathway appear to play a more significant role in distal gastric carcinogenesis. It may be an early event in the former location since the trend towards p16 overexpression with concomitant pRb underexpression was seen as early as between normal mucosa and intestinal metaplasia. Importantly, the marked differences in expression of pRb and p16 between the cardia and antrum strongly support the hypothesis that tumours of the two locations are genetically different which may account for some of the observed epidemiological differences.     

Comparative rates of nucleotide sequence variation in the hypervariable region of E1/E2 and the NS5b region of hepatitis C virus in patients with a spectrum of liver disease resulting from a common source of infection

The association of the severity of liver disease and the molecular evolution of hepatitis C virus (HCV) during chronic infection remains unclear and controversial. To address this we have studied the interpatient variability in the nucleotide sequence of two regions of the HCV genome, E1/E2, which contain the hypervariable region 1 and the nonstructural NS5b region, in a cohort of Irish female patients who were all recipients of a single source of HCV genotype 1b-contaminated anti-D immunoglobulin in 1977 and 1978 and who over the subsequent 20 years developed a spectrum of liver disease. In addition, quasispecies analysis was used to evaluate intrapatient variability in the E1/E2 region in four patients with mild and four with severe disease. Phylogenetic and evolutionary rate analyses of the nucleotide sequences demonstrated that there was no significant difference between those who developed mild disease and those who had progressed to severe disease or cirrhosis. These findings suggest that other factors, either additional viral or host, may be important in the pathogenesis and clinical outcome of chronic hepatitis C virus infection.     

Caspase 3 expression in benign prostatic hyperplasia and prostate carcinoma

BACKGROUND: Apoptotic resistance to androgen ablation represents a significant problem in the treatment of prostate cancer. Over expression of antiapoptotic proteins such as Bcl-2 and mutations in p53 contribute to this resistance. The caspase family of proteases are central executioners of the cell death pathway. They are expressed in normal prostate secretory epithelial cells. Altered expression may represent an additional component leading to cell resistance. The aim of this study was to determine by immunohistochemistry caspase 3 expression in benign prostatic hyperplasia and prostate cancers. METHODS: Twenty-two patients with histologically determined prostate cancer and benign prostatic hyperplasia (BPH) were investigated. All specimens were obtained from patients undergoing surgical resection of the prostate. Immunohistochemical analysis was performed on formalin fixed paraffin embedded sections to assess caspase 3 expression. RESULTS: Caspase 3 was expressed in 18/22 (81.1%) samples, with high expression in BPH which demonstrated staining in both basal and secretory epithelial cells. Increasing grades of prostatic cancer showed a significant loss of expression in secretory epithelial layers and little staining in epithelial cells in high-grade prostatic carcinoma. CONCLUSIONS: Altered caspase 3 expression may represent an additional mechanism of apoptotic resistance to androgen ablation. Prostate 47:183-188, 2001.     

Herbal Remedies Used by Selected Migrant Farmworkers in El Paso, Texas

CONTEXT: Little is known about the use of complementary and alternative medicine among the approximately 1.6 million migrant farmworkers in the United States. PURPOSE: To evaluate the use of medicinal plants and natural remedies among a convenience sample of 100 migrant farmworkers living temporarily in a migrant worker center in El Paso, Texas. METHODS: A structured interview instrument was designed to elicit information about reasons for medicinal herb use, form in which herbs were ingested, serious side effects experienced, location of purchase, effectiveness of treatment, and use of allopathic medications. FINDINGS: The majority of workers used herbal remedies or other natural products because they believed them to be more effective than pharmaceuticals and because of tradition. Most learned about herbal remedies from a relative, primarily from their mother, and the majority who used herbal remedies believed them to be very helpful in treating specific illnesses. No adverse reactions to any herbal remedy were reported. The majority of participants did not inform their physician about their use of herbal remedies. According to the literature, potential adverse interactions between herbal remedies used and allopathic medications included gastrointestinal irritation, renal toxicity, and hypoglycemia. CONCLUSIONS: Health care providers must be knowledgeable about the use of herbal remedies among migrant farmworkers. By showing an understanding of and sensitivity to the use of these remedies, health care providers will be able to conduct more comprehensive health assessments of migrant workers and their families and provide them with more culturally competent care.     

The value of enhanced magnetic resonance imaging in the evaluation of endocochlear disease.

BACKGROUND: Gadolinium-enhanced magnetic resonance imaging (GdMRI) is routinely used in the evaluation and management of suspected retrocochlear pathology such as vestibular schwannoma. However, its value in the evaluation and diagnosis of cochlear pathology associated with sensorineural hearing loss (SNHL) has been less clear. STUDY DESIGN: Retrospective review of case histories and imaging studies of patients with SNHL and cochlear enhancement on GdMRI diagnosed between 1998 and 2000. RESULTS: Five patients with SNHL who required gadolinium administration to establish the diagnosis of endocochlear disease were identified. Diagnosed lesions included an intralabyrinthine schwannoma, intracochlear hemorrhage, radiation-induced ischemic change, autoimmune labyrinthitis, and meningogenic labyrinthitis. In these illustrative cases, the GdMRI demonstrated intrinsic high signal or contrast enhancement within the cochlea and labyrinth in the absence of a retrocochlear mass. In one patient with meningogenic labyrinthitis, cochlear enhancement on MRI led to prompt cochlear implantation before the potential development of cochlear ossification. CONCLUSION: Our experience suggests that GdMRI plays a crucial role in the diagnosis of cochlear pathology associated with sensorineural hearing loss and may directly impact patient management.     

Long-term treatment with growth hormone in Noonan's syndrome

Five children (four boys, one girl) with Noonan's syndrome were treated with growth hormone for a mean of 2.9 (range 1.8 to 4.6) years. Treatment was commenced at a mean age of 3.9 (range 2.5 to 6.0) years. After one year of treatment, height velocity SDS increased from a mean of -2.1 (range -4.1 to - 0.3) to a mean of +3.1 (range +2.0 to +3.5). Subsequently, height SDS increased significantly from -3.3(range -4.2 to -2.2)to -2.4(range -3.3 to - 1.6). Although in all patients a marked decrease in height velocity was observed in the following years of treatment, compared to the first year, height SDS continued to improve in comparison to pretreatment (mean height SDS in the third year for four patients was -2.1) (range -3.1 to - 1.4). In the four patients who had completed their second year of treatment, height SDS for bone age had increased from -1.8 (range - 2.8 to - 09) to -1.2 (range - 1.6 to -0.6).     

Comparison of plasma and intraluminal amino acid profiles in man after meals containing a protein hydrolysate and equivalent amino acid mixture.

Plasma and intraluminal amino acid profiles were compared in normal subjects 30, 60, 120, 180 minutes after meals containing either a peptide-rich protein hydrolysate (H) or an equivalent free amino acid mixture (AA) as the nitrogen source. Except for asparagine (30 minutes) and glutamine (30 and 60 minutes), which were absorbed to a significantly (p less than 0.05) greater extent from the peptide mixture, there were no significant differences in the plasma increments of the remaining 13 amino acids at any time interval after the meals. Positive correlations (p less than 0.01 or less) between the amino acid composition of the hydrolysate and amino acid meals and both (1) the post-prandial increments in the individual plasma amino acids and (2) the residual intraluminal amino acid content suggested that the amino acid composition of ingested protein, rather than specialised free amino acid and peptide transport systems, dictated the pattern of amino acid absorption. The studies provide no evidence that peptides rather than free amino acids are the ideal nitrogen source in elemental diets.     

The role of intramuscular lipid in insulin resistance

There is interest in how altered lipid metabolism could contribute to muscle insulin resistance. Many animal and human states of insulin resistance have increased muscle triglyceride content, and there are now plausible mechanistic links between muscle lipid accumulation and insulin resistance, which go beyond the classic glucose-fatty acid cycle. We postulate that muscle cytosolic accumulation of the metabolically active long-chain fatty acyl CoAs (LCACoA) is involved, leading to insulin resistance and impaired insulin signalling or impaired enzyme activity (e.g. glycogen synthase or hexokinase) either directly or via chronic translocation/activation of mediators such as a protein kinase C (particularly PKC theta and epsilon ). Ceramides and diacylglycerols (DAGs) have also been implicated in forms of lipid-induced muscle insulin resistance. Dietary lipid-induced muscle insulin resistance in rodents is relatively easily reversed by manipulations that lessen cytosolic lipid accumulation (e.g. diet change, exercise or fasting). PPAR agonists (both gamma and alpha) also lower muscle LCACoA and enhance insulin sensitivity. Activation of AMP-activated protein kinase (AMPK) by AICAR leads to muscle enhancement (especially glycolytic muscle) of insulin sensitivity, but involvement of altered lipid metabolism is less clear cut. In rodents there are similarities in the pattern of muscle lipid accumulation/PKC translocation/altered insulin signalling/insulin resistance inducible by 3-5-h acute free fatty acid elevation, 1-4 days intravenous glucose infusion or several weeks of high-fat feeding. Recent studies extend findings and show relevance to humans. Muscle cytosolic lipids may accumulate either by increased fatty acid flux into muscle, or by reduced fatty acid oxidation. In some circumstances muscle insulin resistance may be an adaptation to optimize use of fatty acids when they are the predominant available energy fuel. The interactions described here are fundamental to optimizing therapy of insulin resistance based on alterations in muscle lipid metabolism.