Maternal Nutrition—Effect on Fetal Growth and Outcome of Pregnancy

During the first half of the 20th century, chronic energy undernutrition due to low dietary intake, repeated infections, and rapid succession of pregnancy were the factors most responsible for maternal undernutrition and consequent adverse outcomes of pregnancy. Efforts to improve dietary intake, treatment of infections, and provision of contraceptive care were the major focuses of intervention from 1950 to 1990. These interventions resulted in reduction in severe grades of undernutrition. However, there was no reduction in mild and moderate degrees of undernutrition and anemia during pregnancy and there was no significant improvement in the course and outcome of pregnancy, or in birth weight. During the 1990s, among the middle- and upper-income groups, there has been a progressive rise in obesity and consequent adverse effects. The advent of HIV infection in India in the 1980s will inevitably lead to increases in severe undernutrition associated with HIV infection in pregnancy and an adverse impact of maternal HIV infection on the fetus. Practicing physicians and nutritionists in the new millennium will therefore have to assess each person individually and provide appropriate advice regarding diet, exercise, fertility, and infection prevention and control in order to achieve optimum health and nutrition status during pregnancy and to prevent adverse pregnancy outcomes.     

Sequential expression of the neuropeptides substance P and somatostatin in granulomas associated with murine cysticercosis

Neurocysticercosis, a parasitic infection of the human central nervous system caused by Taenia solium, is a leading cause of seizures. Seizures associated with neurocysticercosis are caused mainly by the host inflammatory responses to dying parasites in the brain parenchyma. We previously demonstrated sequential expression of Th1 cytokines in early-stage granulomas, followed by expression of Th2 cytokines in later-stage granulomas in murine cysticercosis. However, the mechanism leading to this shift in cytokine response in the granulomas is unknown. Neuropeptides modulate cytokine responses and granuloma formation in murine schistosomiasis. Substance P (SP) induces Th1 cytokine expression and granuloma formation, whereas somatostatin inhibits the granulomatous response. We hypothesized that neuropeptides might play a role in regulation of the granulomatous response in cysticercosis. To test this hypothesis, we compared expression of SP and expression of somatostatin in murine cysticercal granulomas by using in situ hybridization and immunohistochemistry. We also compared expression with granuloma stage. Expression of SP mRNA was more frequent in the early-stage granulomas than in the late-stage granulomas (34 of 35 early-stage granulomas versus 1 of 13 late-stage granulomas). By contrast, somatostatin was expressed primarily in later-stage granulomas (13 of 14 late-stage granulomas versus 2 of 35 early-stage granulomas). The median light microscope grade of SP mRNA expression in the early-stage granulomas was significantly higher than that in the late-stage granulomas (P = 0.008, as determined by the Wilcoxon signed rank test). By contrast, somatostatin mRNA expression was higher at later stages (P = 0.008, as determined by the Wilcoxon signed rank test). SP and somatostatin are therefore temporally expressed in granulomas associated with murine cysticercosis, which may be related to differential expression of Th1 and Th2 cytokines.     

Pre-clinical Study of <Superscript>213</Superscript>Bi Labeled PAI2 for the Control of Micrometastatic Pancreatic Cancer

Purpose: The urokinase plasminogen activator (uPA) and its receptor (uPAR) are expressed by pancreatic cancer cells and can be targeted by the plasminogen activator inhibitor type 2 (PAI2). We have labeled PAI2 with ²¹³Bi to form the alpha conjugate (AC), and have studied its in vitro cytotoxicity and in vivo efficacy. Methods and Materials: The expression of uPA/uPAR on pancreatic cell lines, human pancreatic cancer tissues, lymph node metastases, and mouse xenografts were detected by immunohistochemistry, confocal microscopy, and flow cytometry. Cytotoxicity was assessed by the MTS and TUNEL assay. At 2 days post-cancer cell subcutaneous inoculation, mice were injected with AC by local or systemic injection. Results: uPA/uPAR is strongly expressed on pancreatic cancer cell lines and cancer tissues. The AC can target and kill cancer cells in vitro in a concentration-dependent fashion. Some 90% of TUNEL positive cells were found after incubation with 1.2 MBq/ml of AC. A single local injection of ~222 MBq/kg 2 days post-cell inoculation can completely inhibit tumor growth over 12 weeks, and an intraperitoneal injection of 111 MBq/kg causes significant tumor growth delay. Conclusions: ²¹³Bi-PAI2 can specifically target pancreatic cancer cells in vitro and inhibit tumor growth in vivo. ²¹³Bi-PAI2 may be a useful agent for the treatment of post-surgical pancreatic cancer patients with minimum residual disease.     

Heterogeneity of calcium channels in mast cells and basophils and the possible relevance to pathophysiology of lung diseases: A review

Calcium plays a critical role in the formation and secretion of a wide variety of chemical mediators. Calcium slow-channel blockers,e.g. nifedipine and verapamil, have been shown to inhibit the synthesis of SRS (SRS-A, leukotrienes) in human and guinea pig lung tissue, thromboxane A₂ formation in rat lung and platelet activating factor in human neutrophils. Verapamil and nifedipine also prevent the release of lysosomal enzymes from rabbit and human polymorphonuclear neutrophils. Calcium-channel blockers produce variable inhibitory effects on allergic and nonallergic histamine secretion. Ca⁺⁺-entry blockers also inhibit the Ca⁺⁺ uptake (influx) into mast cells. Many of these inhibitory effects of Ca⁺⁺ antagonists are antagonized by an increased extracellular Ca⁺⁺ ion concentration. The magnitude of the inhibitory influences of Ca⁺⁺-channel blockers on allergic and nonallergic release of chemical mediators appears to depend on the cell source, species, nature and the concentration of the secretory stimuli as well as on the composition and pH of buffers and the concentration of Ca⁺⁺-entry blockers used. The data summarized in this review suggest the existence of a functional heterogeneity of Ca⁺⁺ channels in leukocytes, mast cells and basophils. Interference with the Ca⁺⁺-dependent steps involved in the formation and/or release of chemical mediators appears to be the primary mode of action for Ca⁺⁺-channel blockers in these cells.The differential effects of Ca⁺⁺ antagonists on Ca⁺⁺-dependent activation of phospholipase A₂, 5-lipoxygenase, and calmodulin (or other intracellular Ca⁺⁺-binding proteins) in different cell types (mast cells, basophils, leukocytes, lung tissue, etc.) may explain the variation of their effectiveness in inhibiting the synthesis/release of chemical mediators and antagonizing bronchoconstriction in response to diverse stimuli.During the process of hypersensitization and in immediate hypersensitivity diseases, Ca⁺⁺ homeostasis (uptake, mobilization, distribution, relocation, etc.) may be altered in leukocytes (mast cells, basophils) and lung tissues. The altered Ca⁺⁺ homeostasis could be responsible for the induction of airway hyperreactivity in asthmatics and for hyperreleasability of chemical mediators from leukocytes, mast cells and other cell types.The development of drugs (Ca⁺⁺-channel blockers, antiallergic agents) that are capable of selectively altering Ca⁺⁺-dependent functions in leukocytes (mast cells, basophils, macrophages) and lung tissue in disease staes would offer an attractive alternative and an effective therapeutic approach for obstructive respiratory diseases,e.g. allergic asthma, exercise-induced asthma and a variety of other mediator-dependent allergic disorders.