A major mechanism by which the heart adapts to intracellular acidosis during ischemia and recovers from the acidosis after reperfusion is through the sodium-hydrogen exchanger (NHE). There are at least 5 NHE isoforms thus-far identified with the NHE-1 subtype representing the major one found in the mammalian myocardium. This 110 kDa glycoprotein extrudes protons concomitantly with Na influx in a 1:1 stoichiometric relationship rendering the process electroneutral. Although NHE is critical for the maintenance of intracellular pH during acid loading conditions such as ischemia, there is convincing evidence that it also plays a pivotal role in mediating tissue injury during ischemia and reperfusion. The mechanism for this paradoxical deleterious role of NHE reflects the fact that under conditions of tissue stress, including ischemia, Na-K adenosine triphosphate (ATP)ase is inhibited thereby limiting Na extrusion resulting in an elevation in intracellular Na concentrations. The latter effect, in turn, will increase intracellular Ca concentrations via Na-Ca exchange. In addition, NHE-1 expression in the diseased myocardium is increased suggesting that elevated production of the antiporter represents a long-term adaptive process in an attempt by the cardiac cell to regulate intracellular pH which, paradoxically, contributes to cardiac pathology. Extensive studies using NHE inhibitors such as amiloride or its analogs, or more specific compounds including3-methylsulphonyl-4-piperidinoloenzoyl-guanidine methanesulphonate (HOE 694) or 4-isopropyl-3-methylsulphonylbenzcyl-guanidine meth-ane sulphonate (HOE 642) have consistently shown protective effects against ischemic and reperfusion injury in a large variety of experimental models and animal species particularly in terms of attenuating contractile dysfunction. Such studies have contributed greatly to the overwhelming evidence that NHE activation mediates ischemic and reperfusion injury. Indeed, HOE 642 (Cariporide) is currently undergoing clinical evaluation in high risk cardiac patients. Moreover, there is now emerging evidence that NHE may be involved in mediating cardiotoxicity directly produced by various ischemic meta-bolites such as lipid amphiphiles or reactive oxygen species. In this regard, we have demonstrated that NHE inhibitors can effectively attenuate the cardiac injury produced by lysophosphatidylcholine and hydrogen peroxide. In addition, it now appears that NHE inhibition reduces apoptosis in the ischemic myocardium, a process which may be of importance in the subsequent development of postinfarction heart failure. In conclusion, NHE represents an important adaptive process in response to intracellular acidosis resulting in a paradoxical contribution to cardiac tissue injury.

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The HMGI proteins, a subfamily of the high mobility group (HMG) proteins, play an im-portant role in the regulation of gene expression. They bind to AT-rich DNA sequences and alter DNA conformation to modulate the binding affinity of transcription factors to their cognate sites. They are expressed almost exclusively during embryogenesis and Hmgi-c null mice have the mouse pygmy phenotype. Studies have revealed the disruption of HMGI family genes in a variety of mesenchymal-derived benign tumors. Therefore, the HMGI genes function in the coordination of cell proliferation and differentiation during mammalian development.

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Using the method of vector autoregressive modeling (VAR) analysis of frequently sampled oral glucose tolerance test (OGTT) results, we evaluated abnormalities in the feedback relationships between plasma glucose and insulin in gastrectomized patients to assess insulin secretion capacity and insulin resistance following gastrectomy. VAR modeling analysis was applied to the plasma glucose and insulin level data from the frequently-sampled 75g-OGTT results of 38 subjects who had under-gone total or subtotal gastrectomy and 977 controls without gastrectomy. After gastrectomy, the pre-dicted response of insulin to a glucose challenge was excessive in normal subjects and those with slightly impaired glucose tolerance. Furthermore, the glucose response to insulin was clearly positive in gastrectomized subjects with moderately to severely impaired glucose tolerance, i.e., diabetics, indi-cating strong insulin resistance. The insulin resistance in this situation cannot be explained by decreased peripheral glucose disposal. Our results suggest that the lowered glucose tolerance which follows gastrectomy results from disturbance of the hormonal relationship between pancreas and intestine (entero-insular axis), which causes increased intestinal glucose absorption, and the insulin resistance which occurs in response to hyperinsulinemia in patients with normal fasting plasma glucose. Disturbance of the entero-insular axis may cause not only increased glucose absorption but also hyperglucagonemia, both of which contribute to hyperglycemia in diabetic patients after gastrectomy.

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Activities of daily living (ADL), mental function, spontaneity, emotion and problematic behaviors were compared in elderly patients with hip fracture, hemiplegia, hemiparesis, senile demen-tia of Alzheimer type and multi-infarct dementia. Osteoarthropathy patients with normal intelligence served as a control group. ADL was most strongly affected by spontaneity, then, by intelligence. The contributions of emotion and problematic behaviors were not very marked.

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The time course of oxidative stress following cerebral ischemia and reperfusion has been obscure, although oxygen-derived free radicals have been postulated to play an important role in the progression of reperfusion injury. We have examined the time profile of hydrogen peroxide (H₂O₂) generation in the rat cortex following incomplete forebrain ischemia and reperfusion. We used 20 male Sprague-Dawley rats anesthetized with a-chloralose and urethane. A closed cranial window was created in the temporoparietal skull, and 2'-7'-dichlorofluorescein (DCF), a sensitive fluorescent probe for H₂O₂, was loaded intracellularly by the superfusion technique. We simultaneously monitored DCF fluorescence and reflectance from the cortex with an in vivo fluoromicroscope having two photo-multiplier tubes, and subtracted the hemodynamic artifact from DCF fluorescence. Incomplete fore-brain ischemia was induced by temporal ligation of both common carotid arteries combined with hypotension. The results showed that corrected DCF fluorescence remained unchanged during ische-mia, but increased following reperfusion, indicating enhanced H₂O₂ generation. Pretreatment by intraperitoneal injection of catalase attenuated H₂O₂ generation significantly. Our in vivo study veri-fied that H₂O₂ generation is mainly enhanced following reperfusion.

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This manuscript will highlight the major elements of the recently published sixth Joint National Committee (JNC-6) report.¹ First, a 3-tiered classification of overall cardiovascular risk is provided as a guide to the institution of therapy with either lifestyle modifications or antihypertensive drugs. Second, the need for prevention is stressed. Third, guidelines for the effective use of appropriate lifestyle modifications are provided. Fourth, a 3-pronged pathway for the choice of critical therapy is provided: one for uncomplicated hypertensive; another for those with “compelling” indications for specific drugs, including the presence of diabetic nephropathy, congestive heart failure, post-myocardial infarction or systolic hypertension in the elderly; the third for those with concomitant con-ditions that may be either favorably or unfavorably affected by specific types of drugs. In addition, the report emphasizes the need to achieve the goal of less than 140/90mmHg by a progressive process of therapy and, if necessary, referral to a hypertension specialist. Recommendations are made for improved adherence to therapy, therapy of resistant hypertension and hypertensive crises.

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