Ineffective esophageal motility assessment in patients with and without pathological esophageal acid reflux

Ineffective esophageal motility (IEM), defined as minor esophageal motility disorder, is also the most common esophageal motility disorder. The relationship between gastro-esophageal reflux disease is still controversial. Our aim in this study is to evaluate whether there are differences in terms of demographic, endoscopic, or motility findings between IEM patients with pathological esophageal acid reflux and physiological reflux.Patients diagnosed with IEM according to the Chicago classification v3 with high-resolution manometry (HRM) before acid monitoring constituted the study group of our investigation. The patients were divided into 2 groups as patients with pathological esophageal reflux and patients with physiological reflux according to 24-hour acid monitoring. Demographic data, endoscopic findings, and HRM findings were compared between 2 groups.A total of 62 patients who were diagnosed with IEM according to the Chicago classification v3 were included in the study. Patients in the physiological reflux group were 7 years younger on average than the pathological reflux group. Esophagitis rates were significantly higher in the pathological reflux group (P = .033). Lower esophageal sphincter resting pressure, integrated relaxation pressure, and the presence of hernia were found to be similar in the 2 groups (P = 392, P = 182, P = 657, respectively). The rate of severe IEM was also similar between the 2 groups (P = .143).The fact that the physiological reflux patient group is younger may suggest that the IEM develops in the early period and then reflux accompanies the picture with advancing age.     

Anti-cancer activity of withaferin A in B-cell lymphoma

Withaferin A (WA), a withanolide from the plant, Ashwagandha (Withania somnifera) used in Ayurvedic medicine, has been found to be valuable in the treatment of several medical ailments. WA has been found to have anticancer activity against various solid tumors, but its effects on hematological malignancies have not been studied in detail. WA strongly inhibited the survival of several human and murine B cell lymphoma cell lines. Additionally, in vivo studies with syngeneic-graft lymphoma cells suggest that WA inhibits the growth of tumor but does not affect other proliferative tissues. We demonstrate that WA inhibits the efficiency of NF-κB nuclear translocation in diffuse large B cell lymphomas and found that WA treatment resulted in a significant decrease in protein levels involved in B cell receptor signaling and cell cycle regulation. WA inhibited the activity of heat shock protein (Hsp) 90 as reflected by a sharp increase in Hsp70 expression levels. Hence, we propose that the anti-cancer effects of WA in lymphomas are likely due to its ability to inhibit Hsp90 function and subsequent reduction of critical kinases and cell cycle regulators that are clients of Hsp90.     

Association of paraoxonase activity and coronary collateral flow

OBJECTIVES: Paraoxonase is a high-density lipoprotein-bound antioxidant enzyme that inhibits atherosclerosis and endothelial dysfunction. Coronary collateral flow is a crucial clinical entity with significant impact on the cardiovascular morbidity and mortality. This study sought to determine the relationship between the degree of angiographically visible coronary collateral circulation and serum paraoxonase activity. METHODS: The study population included 98 patients (mean age=57.9+/-10.1 years, 65 men) with angiographically documented total occlusion in one of the major coronary arteries. Development of collaterals was classified by Rentrop's method. Patients were defined as having poorly developed collaterals for Rentrop grades 0 and 1 or well-developed collaterals for Rentrop grades 2 and 3. Serum paraoxonase and arylesterase activities were measured spectrophotometrically. RESULTS: Statistically significant differences between well and poorly developed collateral groups in respect to serum low-density lipoprotein cholesterol level (P=0.046), and serum paraoxonase (P=0.001), and arylesterase (P=0.014) activities were present. Serum low-density lipoprotein cholesterol level (chi=4.15, beta=-0.347, P=0.032) and serum paraoxonase activity (chi=10.43, beta=0.008, P=0.022) were independent predictors of well-developed coronary collateral flow. Serum paraoxonase activity gradually increased from collateral grade 0 to collateral grade 3 (analysis of variance P=0.003). Serum paraoxonase (r=0.362 and P<0.001) and arylesterase (r=0.245 and P=0.015) activities were both correlated with collateral flow grade. CONCLUSION: Findings of this study suggest that serum paraoxonase activity is independently associated with the degree of coronary collateral flow and reduced serum paraoxonase activity might represent a biochemical marker of impaired coronary collateral flow.     

Effects of Helicobacter pylori infection on gastric epithelial cell kinetics in patients with chronic renal failure

AIM: To evaluate the effects of Helicobacter pylori infection on gastric epithelial cell kinetics in patients with chronic renal failure (CRF). METHODS: Forty-four patients were enrolled in this study and divided into four groups with respect to their Helicobacter pylori (H pylori) and CRF status. Groups were labeled as follows: la: normal renal function, H pylori negative (n=12), 1b: normal renal function, H pylori positive (n=11), 2a: CRF, H pylori negative (n=10), 2b: CRF, H pylori positive (n=11). Upper gastrointestinal endoscopy was done in all the patients involved in the study. During endoscopical investigation, antral biopsy specimens were taken from each patient. In order to evaluate the cell apoptosis and proliferation in gastric epithelial cells, Bax and proliferating cell nuclear antigen (PCNA) labeling indexes (LI) were assessed with immunohistochemical staining method. RESULTS: For groups 1a, 1b, 2a, and 2b, mean Bax LI was identified as 34.4±13.7, 44.1±16.5, 46.3±20.5, 60.7±13.8, respectively and mean PCNA LI was identified as 36.2±17.2, 53.6±25.6, 59.5±25.6, 67.2±22, respectively. When the one-way ANOVA test was applied, statistically significant differences were detected between the groups for both Bax LI (P=0.004 <0.01) and PCNA LI (P=0.009<0.01). When groups were compared further in terms of Bax LI and PCNA LI with Tukey's HSD test for multiple pairwise comparisons, statistically significant difference was observed only between groups 1a and 2b (P=0.006<0.01). CONCLUSION: In gastric epithelial cells, expression of both the pre-apoptotic protein Bax and the proliferation marker PCNA increase with H pylori infection. This increase is more evident in patients with uremia. These findings suggest that uremia accelerates apoptosis and proliferation in gastric epithelial cells.     

Relative oral efficacy and acute toxicity of hydroxypyridin-4-one iron chelators in mice [see comments]

The relationship between the oral efficacy and the acute toxicity of hydroxypyridin-4-one iron chelators has been investigated to clarify structure-function relationships of these compounds in vivo and to identify compounds with the maximum therapeutic safety margin. By comparing 59Fe excretion following oral or intraperitoneal administration of increasing doses of each chelator to iron-overloaded mice, the most effective compounds have been identified. These have partition coefficients (Kpart) above 0.3 in the iron-free form with a trend of increasing oral efficacy with increasing Kpart values (r = .6). However, this is achieved at a cost of increasing acute toxicity, as shown by a linear correlation between 59Fe excretion increase per unit dose and 1/LD50 (r = .83). A sharp increase in the LD50 values is observed for compounds with Kpart values above 1.0, suggesting that such compounds are unlikely to possess a sufficient therapeutic safety margin. Below a Kpart of 1.0, acute toxicity is relatively independent of lipid solubility. All the compounds are less toxic by the oral route than by the intraperitoneal route, although iron excretion is not significantly different by these two routes. At least five compounds (CP51, CP94, CP93, CP96, and CP21) are more effective orally than the same dose of intraperitoneal desferrioxamine (DFO) (P less than or equal to .02) or orally administered L1(CP20) (P less than or equal to .02).     

Human T-lymphocyte growth factor: regulation of growth and function of T lymphocytes

The discovery of T-cell growth factor (TCGF) has made it possible to now routinely grow in tissue culture normal and neoplastic human T cells for long periods and in large amounts. TCGF has been recently purified. It is a small protein released by a subset of mature T cells following lectin-antigen activation, which in turn acts upon other T- cell subsets that have developed specific receptors for TCGF after lectin-antigen stimulation. Thus, release of TCGF and development of receptors for it appear to be obligatory for the clonal expansion of all activated T cells. Unlike normal T cells, neoplastic T cells respond directly to TCGF, requiring no prior in vitro lectin-antigen activation. This has led to the development of several new cell lines from patients with T-cell leukemias and lymphomas. In some cases, these cells become independent of exogenous TCGF by producing their own growth factor, implying a role for TCGF in the continuous proliferation of these cells. These developments necessitate a reevaluation of some concepts of immunoregulation of T-cell activities in terms of production and response to TCGF. In addition, this information has clinical implications. Recent results have shown that a major defect of the athymic nude mouse is the inability to produce TCGF and that some immunosuppressive agents, such as glucocorticosteroids and cyclosporin- A, exert their effects on T cells by disrupting the TCGF-T-cell interaction. Some human immune deficiencies might be due to a failure to respond to or to produce TCGF, which in some cases might be corrected by exogenous TCGF.     

Iron mobilization from hepatocyte monolayer cultures by chelators: the importance of membrane permeability and the iron-binding constant

A series of bidentate hydroxypyridinone iron chelators that have therapeutic potential as oral iron chelators, have been studied systematically to determine which properties are the most critical for the mobilization of hepatocyte iron. The relationship between lipid solubility of the free and complexed forms of each chelator and hepatocyte iron release has been investigated as well as the contribution of the binding constant for iron (III). Hydroxypyridin-4- ones that were approximately equally soluble in lipid and aqueous phases were the most active compounds, the partition coefficient of the free chelator appearing to be more critical in determining iron release than that of the iron-complexed form. Highly hydrophilic chelators did not mobilize intracellular iron pools, whereas highly lipophilic compounds were toxic to hepatocytes. The contribution of the binding constant for iron (III) to cellular iron release was assessed by comparing hydroxypyridin-4-ones (log beta 3 = 36) and hydroxypyridin-2- ones (log beta 3 = 32), which possess similar partition coefficients. The results show that the binding for iron (III) is particularly important at low concentrations of chelator (less than 100 mumol/L) and that at higher concentrations (greater than 500 mumol/L) iron mobilization is limited by the available chelatable pool. Measurement of iron release with other chelators confirms the importance of both the lipid solubilities and iron (III)-binding constants to iron mobilization. The most active hydroxypyridin-4-ones released more hepatocyte iron than did deferoxamine when compared at equimolar concentrations. The results suggest that the ability of an iron chelator to enter the cell is crucial for effective iron mobilization and that once within the cell the binding constant of the chelator for iron (III) becomes a dominant factor.     

Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate

The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.     

Hypothalamic-pituitary-gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism

OBJECTIVES: To investigate abnormalities of the hypothalamic-pituitary-gonadal (HPG) axis and cortisol concentrations in young women with primary fibromyalgia (FM); and to determine whether depression, fatigue, and sleep disturbance affect these hormones. METHODS: Follicle stimulating hormone (FSH), luteinising hormone (LH), oestradiol, progesterone, prolactin, and cortisol concentrations in 63 women with FM were compared with those in 38 matched healthy controls; all subjects aged <35 years. The depression rate was assessed by the Beck Depression Inventory (BDI) and patients with high and low BDI scores were compared. Additionally, patients were divided according to sleep disturbance and fatigue and compared both with healthy controls and within the group. RESULTS: No significant differences in FSH, LH, oestradiol, prolactin, and progesterone levels were found between patients with FM and controls, but cortisol levels were significantly lower in patients than in controls (p<0.05). Cortisol levels in patients with high BDI scores, fatigue, and sleep disturbance were significantly lower than in controls (p<0.05). Correlation between cortisol levels and number of tender points in all patients was significant (r = -0.32, p<0.05). CONCLUSION: Despite low cortisol concentrations in young women with FM, there is no abnormality in HPG axis hormones. Because fatigue, depression rate, sleep disturbance, and mean age of patients affect cortisol levels, these variables should be taken into account in future investigations.     

Heterogeneity of immunologic markers and surface morphology in childhood lymphoblastic lymphoma

The neoplastic cells from seven patients with childhood lymphoblastic lymphoma were studied for cell surface markers and surface morphology in the scanning electron microscope (SEM). The cells were studied for surface immunoglobulin (Slg), complement receptors (EAC), receptors for cytophilic antibody (IgGEA), and nonimmune rosette formation with sheep red blood cells (E). In one patient the cells exclusively bound E, suggesting a T-lymphocytic origin. In two patients the cells bound EAC, but demonstrated no other B-lymphocytic markers. In two patients no markers were detected, and in two patients receptors for both E and EAC were demonstrated. Additional studies in one of these patients permitted simultaneous demonstration of both markers on the same neoplastic cells. The neoplastic cells were also examined by SEM after fixation and critical point dehydration. No consistent surface morphology was observed. In four patients the cells were predominately smooth, whereas in two patients variable numbers of surface microvilli were present. A correlation of the surface features with membrane markers could not be established. A comparison of the surface markers with clinical and cytologic features revealed clinical homogeneity in spite of the heterogeneous immunologic markers. This heterogeneity was most likely a reflection of neoplastic alteration and disordered differentiation of the cells. The observation of complement receptors on the cells of four cases is a feature not previously reported in this disease and should be investigated in other presumed T-cell malignancies.