Effect of age on sensitivity to pain and brain opiate receptors

Age-related differences in sensitivity to pain as induced by heat and electrical shock were seen among groups of rats; 2-3, 6-12, and 24 months of age. These are differences were at least partially obliterated by naloxone treatment, suggesting that changes may occur in the endogenous opioid system during aging. In contrast to higher pain thresholds in older animals, however, are decreased concentrations of opiate receptors in the frontal poles, striatum and hippocampus. Anterior cortex and amygdala exhibit a trend toward decreased concentration with increased age, but this is not significant. No age changes in binding affinity occur in any of the brain regions examined. Possible explanations for the apparent discrepancy between altered receptors and response include: higher endogenous opioid levels in aged rats, mediation of pain sensitivity by brain regions other than those examined, difficulties inherent in attempting to localize age changes at a single step in such a complex process, and possibly differential spinal pathways mediating the various types of pain.     

Reuniting overnutrition and undernutrition,macronutrients, and micronutrients

Over‐nutrition and its late consequences are a dominant theme in medicine today. In addition to the health hazards brought on by over‐nutrition, the medical community has recently accumulated a roster of health benefits with obesity, grouped under “obesity paradox.” Throughout the world and throughout history until the 20^th century, under‐nutrition was a dominant evolutionary force. Under‐nutrition brings with it a mix of benefits and detriments that are opposite to and continuous with those of over‐nutrition. This continuum yields J‐shaped or U‐shaped curves relating body mass index to mortality. The overweight have an elevated risk of dying in middle age of degenerative diseases while the underweight are at increased risk of premature death from infectious conditions. Micronutrient deficiencies, major concerns of nutritional science in the 20^th century, are being neglected. This “hidden hunger” is now surprisingly prevalent in all weight groups, even among the overweight. Because micronutrient replacement is safe, inexpensive, and predictably effective, it is now an exceptionally attractive target for therapy across the spectrum of weight and age. Nutrition‐related conditions worthy of special attention from caregivers include excess vitamin A, excess vitamin D, and deficiency of magnesium.     

The cost of hospitalization in Crohn's disease

OBJECTIVE: The aim of this study was to evaluate the demographics, resource use, and costs associated with hospitalization of Crohn's disease patients. METHODS: All patients hospitalized at our institution from 7/1/96 to 6/30/97 with a primary diagnosis of "Crohn's Disease" were analyzed using a computerized database. Data are presented "per hospitalization." RESULTS: A total of 175 hospitalizations (147 patients) were identified. Mean patient age was 36.5 yr; 61% were female; 82% Caucasian. Payer mix was most commonly contracted (57%), commercial (21%), or Medicare (13%). 57% of hospitalizations had a primary surgical procedure; the remainder were medical. Average length of stay was 8.7 days (surgical, 9.6 days; medical, 7.5 days). The average cost of hospitalization, excluding physician fees, was $12,528 (surgical, $14,409; medical, $10,020), whereas average charges were $35,378 (surgical, $46,354; medical, $20,744), including physician fees, which averaged $7,249 (surgical, $11,217; medical, $1,959). Mean reimbursements were $21,968 (surgical, $28,946; medical, $12,666) with average weighted reimbursement rates of 60.17% of hospital charges, 69.57% of physician fees. The distribution of costs across subcategories was: Surgery (39.6%), Pharmacy (18.6%), Laboratory (3.8%), Radiology (2.1%), Pathology (0.8%), Endoscopy (0.3%), and Other Hospital Costs (34.9%). Of the hospitalizations, 87% included treatment with steroids, 23% with immunomodulators, and 14% with aminosalicylates; 27% included the administration of total parenteral nutrition, which accounted for 63% of the total pharmacy costs. CONCLUSIONS: Surgery accounts for the majority of hospitalizations, nearly 40% of their total costs, and 75% of overall charges and reimbursements. Therapy that decreases the number of surgical hospitalizations should substantially reduce inpatient Crohn's disease costs, as well as overall costs.     

Polytrauma induces increased expression of pyruvate kinase in neutrophils

Polytrauma (PT) leads to systemic activation of polymorphonuclear neutrophils (PMNs). Organ damage commonly found in these patients is ascribed to respiratory bursts of activated PMNs. With the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis, PMN extracts from PT patients were found to contain a clear protein band not seen in control PMNs from healthy volunteers. This band was identified by amino acid sequencing and Western blotting as pyruvate kinase (PK). Enzymatic assays revealed a 600-fold increase in PK activity in PMNs of PT patients, with the highest levels occurring between the fifth and seventh posttraumatic day. In lymphocytes, no such increase was detectable. As PK is a major regulatory enzyme in glycolysis, glucose-dependent lactate production in PMNs from PT patients was assayed. These cells showed a higher glycolytic lactate production than controls. It was additionally demonstrated that acute activation of respiratory burst activity depends mainly on breakdown of glucose to lactate via the pentose-phosphate pathway and glycolysis. In PMNs from PT patients, this glucose-dependent respiratory burst activity was more than twofold higher than in controls. The increase in expression and activity of PK in PMNs from PT patients may contribute to the high glucose-dependent respiratory burst activity seen in these cells.     

Mutations in the protein kinase-binding domain of the NS5A protein in patients infected with hepatitis C virus type 1a are associated with treatment response

An interaction of the hepatitis C virus (HCV) NS5A protein with the interferon (IFN)-alpha-inducible double-stranded RNA-activated protein kinase (PKR) was demonstrated in vitro. The clinical correlation between amino acid mutations within the HCV NS5A region and response to antiviral treatment is controversial. Thirty-two patients chronically infected with HCV-1a, who were treated with IFN-alpha with or without ribavirin, were studied. The carboxy-terminal half of HCV NS5A was sequenced and was investigated by phylogenetic and conformational analyses. Eight patients achieved a sustained virologic response. An end-of-treatment response but relapse thereafter was observed among 8 patients, whereas 16 patients were nonresponders. The median number of mutations within the PKR-binding domain but not within the previously described IFN sensitivity-determining region was significantly higher for patients with sustained (3 mutations [range, 1-5]) or end-of-treatment (4 mutations [range, 1-5]) virologic response than for nonresponders (2 mutations [range, 0-3]) (P=.0087). Phylogenetic and conformational analyses of NS5A sequences allowed no differentiation between sensitive and resistant strains.     

Primary angioplasty with routine stenting compared with thrombolytic therapy in elderly patients with acute myocardial infarction

Background

Prior studies have yielded conflicting data on the advantage of primary angioplasty compared with thrombolysis in elderly patients with acute myocardial infarction (AMI). These studies, however, were performed before the contemporary widespread use of intracoronary stents and glycoprotien IIb/IIIa antagonists.

Methods

We prospectively compared the outcome of 130 consecutive elderly patients (aged ≥70 years) with ST-elevation AMI who were admitted to 2 similar neighboring medical centers. Patients were assigned to receive either thrombolytic therapy with accelerated tissue-type plasminogen activator (center I) or primary angioplasty with routine stenting (center II).

Results

Of the patients assigned to receive primary angioplasty, 91% underwent stenting. At 6 months, patients treated with primary angioplasty, compared with those treated with thrombolytic therapy, had a lower incidence of reinfarction (2% vs 14%, P = .053) and revascularization for recurrent ischemia (9% vs 61%, P < .001) and a significant reduction in the prespecified combined end point of death, reinfarction, or revascularization for recurrent ischemia (29% vs 93%, P < .01). Primary angioplasty remained an independent predictor of the triple combined end point after controlling for potential covariables (relative risk 0.63, 95% CI 0.38-0.84). Major bleeding complications were also significantly reduced in the primary angioplasty group (0% vs 17%, P = .03).

Conclusions

Compared with thrombolysis, primary angioplasty with routine stenting in elderly patients with AMI is associated with better clinical outcomes and a lower risk of bleeding complications.     

Follow-up of hemorheological parameters and platelet aggregation in patients with acute coronary syndromes

Pathologic hemorheological parameters and increased platelet aggregation in association with other risk factors significantly increase the possibility of the development of myocardial ischemia. Hemorheological parameters and platelet aggregation were investigated in 157 patients (mean age: 65+/-12 years) with acute coronary syndromes and in 68 healthy subjects (mean age: 36+/-6 years). Plasma fibrinogen, plasma and whole blood viscosity, red blood cell aggregation and filterability and platelet aggregation were measured in the hospital phase (after admission, on 2nd and 6th days) and monitored after discharge (at 1, 6 and 12 months). After admission all these parameters were significantly higher in patients than in control subjects (p<0.01) and almost all of them remained in the pathologic range at discharge. Some of the rheologic parameters showed a slight improvement after 1 month, but hematocrit and whole blood viscosity were higher than those after admission and of control subjects (p<0.05). After 6 and 12 months these parameters showed a small, but significant increase. Pathologically altered hemorheological parameters could be observed in patients with classical cardiovascular risk factors and significant improvement was found after elimination of them. Antiplatelet therapy was efficient in about half of the treated patients after admission; and despite a significant improvement, the proportion of ineffectively treated patients was still considerable during the follow-up. Our results support the role of abnormal hemorheological parameters in the development of myocardial ischemia and draw attention to the rheologic risk of these patients. The results of platelet aggregation measurements show the insufficiency of antiplatelet therapy at some cases and confirm the importance of guided secondary prevention.     

Post-feeding hyperammonaemia in patients with transjugular intrahepatic portosystemic shunt and liver cirrhosis: role of small intestinal ammonia release and route of nutrient administration

BACKGROUND: Hyperammonaemia is a pathogenetic factor for hepatic encephalopathy that may be augmented after a transjugular intrahepatic portosystemic shunt (TIPS). Experimental data suggest that hyperammonaemia may be caused to a large extent by metabolism of small intestinal enterocytes rather than colonic bacteria. AIMS: To evaluate if ammonia release and glutamine metabolism by small intestinal mucosa contribute to hyperammonaemia in vivo in patients with liver cirrhosis. METHODS: Using TIPS to examine mesenteric venous blood, we measured mesenteric venous-arterial concentration differences in ammonia and glutamine in patients with liver cirrhosis before, during, and after enteral (n = 8) or parenteral (n = 8) isonitrogenous infusion of a glutamine containing amino acid solution. RESULTS: During enteral nutrient infusion, ammonia release increased rapidly compared with the post-absorptive state (65 (58-73) v. 107 (95-119) micromol/l after 15 min; mean (95% confidence interval)) in contrast with parenteral infusion (50 (41-59) v. 62 (47-77) micromol/l). This resulted in a higher portal ammonia load (29 (21-36) v. 14 (8-21) mmol/l/240 minutes) and a higher degree of systemic hyperammonaemia (14 (11-17) v. 9 (6-12) mmol/l/240 minutes) during enteral than parenteral infusion. The mesenteric venous-arterial concentration difference in glutamine changed from net uptake to release at the end of the enteral infusion period (-100 (-58 to -141) v. 31 (-47-110) micromol/l) with no change during parenteral nutrition. CONCLUSIONS: These data suggest that small intestinal metabolism contributes to post-feeding hyperammonaemia in patients with cirrhosis. When artificial nutrition is required, parenteral nutrition may be superior to enteral nutrition in patients with portosystemic shunting because of the lower degree of systemic hyperammonaemia.     

Studies of aging in ames dwarf mice: Effects of caloric restriction

Ames dwarf mice, which are small and deficient in growth homone (GH), prolactin (PRL), and thyroid stimulating hormone (TSH) live much longer (1–1.25 years) than their normal siblings. It was of interest to examine the response of these animals to caloric restriction (CR) because of the possibility that dwarf mice are voluntarily caloric restricted. We are testing the hypothesis that this possible natural caloric restriction will negate any benefits of an imposed CR on lifespan. Male and female Ames dwarf mice and their normal counterparts have been fed ad libitum (AL) or a 30% CR diet for 25–29 months. Animals were monitored daily and weighed weekly. At 12–15 months of age, CR mice weighed significantly less than their AL fed counterparts (normal females: −42%, normal males: −23%, dwarf females: −18.8%, and dwarf males: −22.2%). Only in dwarf females has this significant difference disappeared with age. At one year of age, a comparison of daily food consumption revealed that female dwarf mice consume significantly more food per gram body weight than normal females and a similar tendency is evident for males. Although they received 30% less food, CR mice ate the same amount as AL mice per gram body weight. On measures of total locomotor activity, CR mice were significantly more active than their AL-fed counterparts. On an inhibitory avoidance learning task, 18–21 month old dwarf mice exhibited significantly better retention than their age-and diet-matched normal counterparts. Histopathological analysis in aging dwarf versus normal mice suggested that the incidence of tumors does not differ between the two groups but tumors appear to develop later in dwarf than in normal mice. After 2.25 years on the study 27% of AL normals, 52% of CR normals, 74% of AL dwarfs, and 87% of CR dwarfs are still alive. We conclude that Ames dwarfs are not CR mimetics although they share many characteristics. It remains to be determined whether CR will delay aging and cause a further life extension in Ames dwarf mice.     

X-ray densitometry for the measurement of regional myocardial perfusion

The evaluation of regional myocardial blood flow (RMBF) during cardiac catheterization is of particular diagnostic interest. The purpose of this investigation was to validate x-ray densitometric parameters for the evaluation of RMBF. In five anesthetized dogs, arterial flow in the circumflex coronary artery was measured continuously with an electromagnetic flowmeter, and RMBF was determined by colored microspheres. Five different perfusion levels were created by mechanical obstruction of the coronary artery or by intravenous infusion of adenosine. At each steady-state perfusion level, digital subtraction coronary angiograms were obtained for densitometric analysis. Results documented a close correlation between the related time parameters 1/Mean Transit Time (1/MTT, r² = 0.969), and 1/Rise Time (1/RT, r² = 0.965) and RMBF over a wide range between 0.36 ml/(min · g) and 11.16 ml/(min · g). Maximum myocardial contrast density (Imax) also showed a good, but inverse correlation (r² = 0.889) with RMBF and, therefore, did not reflect vascular volume. Contrast medium Appearance Time (AT) showed no correlation to RMBF (r² = 0.017). Repeat densitometric measurements for different perfusion levels revealed a good reproducibility for MTT (accuracy: 0.001 s; precision: 0.447 s or 6.7%) and RT (accuracy: 0.014 s; precision: 0.202 s or 10.4%), while AT (accuracy: 0.072 s; precision: 0.420 s or 68.5%) and Imax (accuracy: 0.022 GL; precision: 1.197 GL or 44.5%) showed substantial variation. Myocardial perfusion reserve (MPR) calculated from RT (r² = 0.90) or MTT (r² = 0.94) showed better correlations to RMBF reserve than MPR calculated from AT (r² = 0.04). In conclusion, only 1/MTT and 1/RT showed a good reproducibility and a close correlation to RMBF. Therefore, only these parameters can be recommended for calculations of RMBF and its reserve under clinical conditions. Received: 2 November 1999, Returned for revision: 5 January 2000, Revision received: 1 February 2000, Accepted: 6 February 2000