Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose

BACKGROUND: Increasing plasma glucose levels improves memory in patients with Alzheimer disease (AD). Increasing plasma glucose levels also increases endogenous insulin levels, raising the question of whether memory improvement is due to changes in insulin, independent of hyperglycemia. We address this question by examining memory and counterregulatory hormone response during hyperglycemia when endogenous insulin was suppressed by concomitant infusion of the somatostatin analogue octreotide (Sandostatin). METHODS: Twenty-three patients with AD and 14 similarly aged healthy adults participated in 4 metabolic conditions on separate days: (1) hyperinsulinemia (538 pmol/L) with fasting glucose (5.6 mmol/L [100 mg/dL]), achieved by insulin and variable dextrose infusion; (2) hyperglycemia (12.5 mmol/L [225 mg/dL]) with fasting insulin (57 pmol/L), achieved by dextrose and somatostatin (octreotide) infusion (150 mg/h); (3) placebo with isotonic sodium chloride solution (saline) infusion (fasting insulin and glucose); and (4) an active control condition in which somatostatin alone was infused (150 mg/h). Declarative memory (story recall) and selective attention (Stroop interference test) were measured during steady metabolic states. RESULTS: Patients with AD showed improved memory during hyperinsulinemia relative to placebo (P = .05) and relative to hyperglycemia (P<.005). Memory did not improve during hyperglycemia when insulin was suppressed. Somatostatin analogue infusion alone also improved memory for patients with AD (P<.05). Hyperinsulinemia increased cortisol levels in subjects with AD, whereas somatostatin alone lowered cortisol concentrations. CONCLUSIONS: These results confirm that elevated insulin without hyperglycemia enhances memory in adults with AD, and indicate that insulin is essential for hyperglycemic memory facilitation. These results also suggest a potential therapeutic role for somatostatin in AD.     

Serotonin (5-HT) release in the dorsal raphé and ventral hippocampus: Raphé control of somatodendritic and terminal 5-HT release

Summary Somatodendritic and terminal release of serotonin (5-HT) was investigated by simultaneously measuring extracellular concentrations of 5-HT, 5-hydroxyindole-3-acetic acid (5-HIAA) and homovanillic acid (HVA) in the dorsal raphé and ventral hippocampus in freely moving rats. Perfusion of tetrodotoxin (TTX, 1M and 10M) into the dorsal raphé simultaneously decreased dorsal raphé and hippocampal 5-HT release. However, following TTX perfusion into the hippocampus (10M), hippocampal 5-HT release was profoundly reduced but dorsal raphé 5-HT remained unchanged.Systemic injections with the 5-HT_1a agonist, buspirone (1.0–5.0mg/kg, i.p.) decreased 5-HT and 5-HIAA and increased HVA concentrations in the dorsal raphé and in the hippocampus. The decreases in raphé and hippocampal 5-HT induced by systemic buspirone were antagonized in rats pretreated with 1.OmM (–) pindolol, locally perfused into the dorsal raphé. Local dorsal raphé perfusion of (–) pindolol alone (0.01–1.0mM) increased dorsal raphé 5-HT and concomitantly induced a small increase in hippocampal 5-HT. Buspirone perfusion into the dorsal raphé did not change (10 nM, 100nM), or produced a small increase (1.0mM) in raphé 5-HT, without changing hippocampal 5-HT.These data provide evidence that 5-HT release in the dorsal raphé is dependent on the opening of fast activated sodium channels and that dorsal raphé 5-HT_1a receptors control somatodendritic and hippocampal 5-HT release.     

Breast cancer in Argentina: case-control study with special reference to meat eating habits

An exploratory case-control study of the role of diet in the etiology of breast cancer was conducted in Buenos Aires, Argentina, where the mortality rate for this disease is high and the consumption of meat, mainly beef, is unusually elevated (76.2 kilograms per head were reported for 1987). One hundred and ninety-six women with breast cancer admitted to the Institute of Oncology "Angel H. Roffo" and 205 controls were interviewed to obtain information on demographic, socio-economic and reproductive variables, on frequency of consumption of 40 food items, and on methods of cooking. Special emphasis was given to different kinds of meat. After controlling for other risk factors for breast cancer the major dietary associations observed were a statistically insignificant trend of increasing risk with amount of beef consumed, an increase in risk in women who ate more than 3 eggs per week, and an increase in risk in women who ate a variety of fried foods.     

Cytoprotective influence of ZVAD-fmk and glycine on gel-entrapped rat hepatocytes in a bioartificial liver

BACKGROUND: This study was designed to determine if an anti-necrotic compound, glycine, and/or an anti-apoptotic agent, ZVAD-fmk, improved the viability and function of hepatocytes in a bioartificial liver. METHODS: Isolated rat hepatocytes were entrapped in collagen gel (1.0-10.0 x 10(6) cells/mL) and cultured in serum-free medium (1:10 ratio of gel:media) supplemented with glycine alone, ZVAD-fmk alone, or glycine and ZVAD-fmk. The cytoprotective effects of glycine and ZVAD-fmk on gel-entrapped rat hepatocytes (GERH) were determined after anoxic exposure (0-20 hours). Cell functionality (measured by urea production), cell viability (quantitated by vital staining with fluorescein diacetate:ethidium bromide [FDA:EB]), and the mechanism of cell death (verified by electron microscopy and DNA fragmentation studies) were determined for each condition. RESULTS: The viability of GERH declined gradually and then stabilized 12 hours after hepatocyte isolation. The rate of urea production by GERH was directly proportional to the number of viable hepatocytes. Apoptotic death predominated at low cell density, and necrotic cell death became significant at high cell density. Hepatocyte necrosis became more significant after exposure to longer periods of anoxia (4, 8, 12, and 20 hours). ZVAD-fmk provided dose-dependent cytoprotection to GERH with an optimum benefit at a concentration of 60 mumol/L. After anoxic exposure or under high cell density culture, glycine demonstrated a maximum benefit of inhibiting necrosis at a concentration of 3 mmol/L. The beneficial effects of glycine and ZVAD-fmk were additive. CONCLUSIONS: The metabolic activity of a hepatocyte bioartificial liver may benefit from the use of cytoprotective agents such as ZVAD-fmk and glycine.     

Beckwith-Wiedemann syndrome and virilizing cortical adrenal tumor in a child

The authors report a case of a virilizing adrenal tumor that developed in a 2-year-old child with Beckwith-Wiedemann syndrome (BWS). He had a fetal diagnosis of omphalocele and a history of neonatal adrenal cysts. The importance of prenatal diagnosis of BWS and postnatal follow-up of tumors is discussed. The differential diagnosis of adrenal pathologies occurring in BWS also is reviewed.     

An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

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