Age-related inflammatory cytokines and disease

Aging is associated with chronic low-grade increases in circulating levels of inflammatory markers. A wide range of environmental factors, including smoking, infections, and obesity, genetic factors, and the declining function of sex hormones may contribute to systemic low-grade inflammatory activity in older individuals. Age-associated disease may exacerbate this phenomenon. The multifunctional cytokines TNF-alpha and IL-6 have been associated with morbidity and mortality in the elderly. Evidence supports the direct role of TNF-alpha in the pathogeneses of atherosclerosis, type 2 DM, and AD in older individuals. Age-related increases in systemic levels of TNF-alpha could provide a unifying basis for these disorders. Furthermore, TNF-alpha induces a catabolic state that causes frailty. Circulating levels of IL-6 seem to be a strong risk factor for frailty in the elderly, which could reflect its association with increased production of TNF-alpha. IL-6 also may be a risk factor for thromboembolic complications. In healthy, elderly populations, high circulating levels of TNF-alpha and IL-6 predict mortality, independent of comorbidity, indicating that TNF-alpha and IL-6 cause morbidity and mortality. In cohorts of frail, older individuals, TNF-alpha and IL-6 also act as disease markers. Circulating levels of TNF-alpha seem to be the best predictor of mortality in frail, elderly populations with a high mortality rate, whereas IL-6 seems to be the strongest risk marker in healthy, elderly populations. This finding could reflect that in relatively healthy old populations the increase in circulating levels of IL-6 represent a systemic response to local proinflammatory activities; however, when age-related inflammatory diseases progress, levels of TNF-alpha increase in the circulation and become gradually a stronger risk marker than IL-6. In conclusion low-grade elevations in levels of circulating cytokines are strong independent risk factors of morbidity and mortality in the elderly, and lifestyle factors and comorbidities may modulate these levels. Exercise and dietary interventions may be possible strategies to decrease inflammatory activity and improve the health status of the elderly.     

Multiple telomeric aberrations in a telomerase-positive leukemia patient

Bone marrow samples from a pancytopenia/leukemia patient were routinely analyzed at first and second admission. At the first presentation, the karyotype was normal, whereas 17 months later several chromosome aberrations were recognized including presumed additions to the short arms of chromosomes 1 and 16 in all cells, and numerous other aberrations in subpopulations of cells. From the predominance of aberrations at chromosome ends, we suspected insufficient telomere maintenance as an underlying mechanism behind the karyotype changes, in particular as an interstitial deletion in the region harboring the gene for the RNA component (hTERC) of the telomerase enzyme was also noticed; however, while molecular cytogenetic investigation confirmed the terminal aberrations, we found the malignant cells positive for telomerase activity and the presence of an hTERC gene on both chromosomes 3. A presumed chromosome 1 addition turned out to reflect an amplification of a tandemly repeated sequence element. Labeling of multiple tandem repeat sequences in situ by a novel multicolor primed in situ hybridization showed no evidence of instability of other repeated DNA elements.     

99mTc-aprotinin scintigraphy in amyloidosis.

Changes in the amount and distribution of amyloid lesions have been difficult to monitor because they can usually be demonstrated only by evident symptoms or from a biopsy. The recent progress in the treatment of amyloidosis stresses the need for an early diagnosis and the need for noninvasive monitoring during the course of treatment. To validate (99m)Tc-aprotinin scintigraphy, we studied 23 consecutive patients with known or suspected amyloidosis. METHODS: (99m)Tc-Aprotinin (500-700 MBq) was injected intravenously and whole-body scans, regional images, and SPECT tomograms were obtained 90 min after tracer injection. RESULTS: Focal accumulations of (99m)Tc-aprotinin were seen in different organs of 22 patients with a total of 90 lesions, of which 20 were confirmed by biopsy or autopsy. Scintigraphy revealed "silent" amyloid deposits in at least 5 patients who later developed clinical symptoms. Physiologic uptake or excretion in liver and kidneys could not be differentiated from pathologic lesions in those organs. CONCLUSION: (99m)Tc-Aprotinin scintigraphy appears to be a fairly sensitive and specific diagnostic modality in patients with suspected amyloidosis. The technique is noninvasive, and it entails a minimal stress to the patient and is useful for detection of a wide range of lesions.     

Episodes of care: an overview of legal and regulatory issues

The use of managed care, with its chief goal of delivering cost-efficient health coverage, predominates the American health benefit arena. Though the advent of managed care unquestionably has saved billions of dollars since the late 1980s, patients raised on a diet of unfettered treatment have seen choices decrease and care diminish. "Episodes of care," in which teams of professionals contract to provide an entirety of health care services involved with a given procedure in exchange for a fixed, global fee, allows for broader choices for patients at competitive costs for insurers.     

Long-term combined supplementations with alpha-tocopherol and vitamin C have no detectable anti-inflammatory effects in healthy men

Inflammatory and oxidative stresses play a pivotal role in atherogenesis. Vitamin E and vitamin C are the two most important dietary antioxidants; moreover, vitamin E has anti-inflammatory effects. Combined supplementations with vitamin E and vitamin C twice daily for 3 y reduced lipid peroxidation and retarded the progression of common carotid atherosclerosis in healthy men in the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study. To further elucidate the underlying mechanisms that retarded the progression of atherosclerosis in the ASAP study, we investigated the effect of a combined intake of vitamin E and vitamin C on inflammatory markers in vivo. Circulating levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and C reactive protein (CRP) were measured in 45- to 69-y-old men from the ASAP study with cholesterol >5.0 mmol/L before and after treatment with either placebo (n = 52) or a combined supplementation with 91 mg (136 IU) alpha-tocopherol and 250 mg of slow-release vitamin C twice a day (n = 55) for 3 y. Antioxidant treatment for 36 mo had no effect on circulating levels of TNF-alpha, IL-6 or CRP. In conclusion, long-term combined supplementations with alpha-tocopherol and vitamin C in reasonable doses have no detectable systemic anti-inflammatory effects in a healthy population of men with slight hypercholesterolemia and no overt signs of inflammation.     

Muscle-derived interleukin-6: possible biological effects

Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the increase in plasma IL-6 during exercise. The production of IL-6 during exercise is related to the intensity and duration of the exercise, and low muscle glycogen content stimulates the production. Muscle-derived IL-6 is released into the circulation during exercise in high amounts and is likely to work in a hormone-like fashion, exerting an effect on the liver and adipose tissue, thereby contributing to the maintenance of glucose homeostasis during exercise and mediating exercise-induced lipolysis. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as tumour necrosis factor α. The latter cytokine is produced by adipose tissue and inflammatory cells and appears to play a pathogenetic role in insulin resistance and atherogenesis.     

Clinically unsuspected pheochromocytomas. Experience at Henry Ford Hospital and a review of the literature

Thirty-two histopathologically confirmed pheochromocytomas were diagnosed at Henry Ford Hospital, Detroit, between 1951 and 1982. Eleven (34%) of these cases were clinically unsuspected exhibiting none of the typical symptoms of palpitation, diaphoresis, or headache, and only five were hypertensive. These pheochromocytomas may be discovered during computed tomography of the abdomen while evaluating multiple endocrine neoplasia, abdominal pain, and abdominal masses, or they may present at autopsy, at surgery, or as a mass lesion without paroxysmal symptoms or hypertension. Before 1962, 53% of these tumors were undiagnosed before surgery or autopsy; however, since 1962 only 18% of pheochromocytomas have remained clinically unsuspected. By maintaining a higher index of suspicion and using newer biochemical and imaging techniques, the incidence of clinically unsuspected pheochromocytomas should be reduced.