Analysis of somatic molecular changes, clinicopathological features, family history, and germline mutations in colorectal cancer families: evidence for efficient diagnosis of HNPCC and for the existence of distinct groups of non-HNPCC families.

OBJECTIVE: To analyse somatic molecular changes, clinicopathological features, family history, and germline mutations in families with colorectal cancer (CRC). METHODS: Molecular changes (K-ras and beta-catenin mutations, chromosome 18q allele loss (LOH), APC LOH, microsatellite instability (MSI), and expression of beta-catenin and p53) were examined in four series of CRC patients with proven or probable hereditary disease: hereditary non-polyposis colon cancer (HNPCC); MYH associated polyposis (MAP); multiple (>5) colorectal adenomas without familial adenomatous polyposis (FAP); and other families/cases referred to family cancer clinics (FCC series). HNPCC was diagnosed using a combination of germline mutation screening and tumour studies. A series of unselected CRC patients was also studied. RESULTS: There was overlap between genetic pathways followed by each type of CRC, but significant differences included: increased frequency of K-ras mutation and reduced frequency of APC LOH in cancers from MAP, but not from multiple adenoma patients; reduced frequency of LOH in HNPCC CRCs; and increased MSI in CRCs from HNPCC, but not from FCC or multiple adenoma patients. HNPCC was apparently detected efficiently by combined germline and somatic analysis. Cancers from the FCC, unselected, and multiple adenoma series shared similar molecular characteristics. In the FCC and multiple adenoma series, hierarchical cluster analysis using the molecular features of the cancers consistently identified two distinct groups, distinguished by presence or absence of K-ras mutation. CONCLUSIONS: While K-ras mutation status is known to differentiate hereditary bowel cancer syndromes such as MAP and FAP, it may also distinguish groups of non-HNPCC, FCC patients whose disease has different, as yet unknown, genetic origins.

Functional evidence of novel tumor suppressor genes for cutaneous malignant melanoma.

Losses of heterozygosity involving chromosomes 9 and 10 are frequent events in the development and progression of cutaneous malignant melanoma. To investigate whether specifically deleted chromosomal regions encode tumor suppressor genes (TSGs), we introduced normal chromosome 10 into the tumorigenic human metastatic melanoma cell line UACC-903 by microcell fusion. In addition, two chromosome 9 derivatives that were microdeleted in the region of the p16INK4A/p15INK4B locus were transferred to determine whether an additional melanoma TSG or TSGs reside on chromosome 9p, as indicated by previous melanoma allele loss studies. In comparison to parental cells, microcell hybrids generated with chromosomes 9 (microdeleted) and 10 displayed reduced anchorage-independent growth in soft agar and markedly reduced tumorigenicity in athymic (nu/nu) mice. These data define a TSG or TSGs that function independently of p15/p16 on chromosome 9 and provide evidence for a TSG (or TSGs) on chromosome 10 that may be important in melanoma development.

Potentially predictive and manipulable blood serum correlates of aging in the healthy human male: progressive decreases in bioavailable testosterone, dehydroepiandrosterone sulfate, and the ratio of insulin-like growth factor 1 to growth hormone.

A cross-sectional survey was made in 56 exceptionally healthy males, ranging in age from 20 to 84 years. Measurements were made of selected steroidal components and peptidic hormones in blood serum, and cognitive and physical tests were performed. Of those blood serum variables that gave highly significant negative correlations with age (r > -0.6), bioavailable testosterone (BT), dehydroepiandrosterone sulfate (DHEAS), and the ratio of insulin-like growth factor 1 (IGF-1) to growth hormone (GH) showed a stepwise pattern of age-related changes most closely resembling those of the age steps themselves. Of these, BT correlated best with significantly age-correlated cognitive and physical measures. Because DHEAS correlated well with BT and considerably less well than BT with the cognitive and physical measures, it seems likely that BT and/or substances to which BT gives rise in tissues play a more direct role in whatever processes are rate-limiting in the functions measured and that DHEAS relates more indirectly to these functions. The high correlation of IGF-1/GH with age, its relatively low correlation with BT, and the patterns of correlations of IGF-1/GH and BT with significantly age-correlated cognitive and physical measures suggest that the GH-IGF-1 axis and BT play independent roles in affecting these functions. Serial determinations made after oral ingestion of pregnenolone and data from the literature suggest there is interdependence of steroid metabolic systems with those operational in control of interrelations in the GH-IGF-1 axis. Longitudinal concurrent measurements of serum levels of BT, DHEAS, and IGF-1/GH together with detailed studies of their correlations with age-correlated functional measures may be useful in detecting early age-related dysregulations and may be helpful in devising ameliorative approaches.

Radiographic features of central nervous system vasculitis.

Central nervous system (CNS) vasculitis refers to primary and secondary disorders of the CNS vasculature. Most authorities agree that CNS vasculitis is a potentially serious disorder; therefore, prompt diagnosis and initiation of therapy are high priorities in treatment. Remarkable progress has been made in the diagnosis, evaluation, and treatment of this disorder. This article examines many aspects of the radiographic evaluation of CNS vasculitis.

Nutritional issues in nursing home care.

The most common nutritional problems in nursing home residents are weight loss and concomitant protein energy undernutrition. Although the causes of weight loss in these patients can usually be treated, they are rarely identified in the nursing home. Depression and adverse drug effects are the most common causes of weight loss. We discuss the appropriate use of feeding tubes in the nursing home and the early use of enteral feeding to prevent the development of severe protein energy undernutrition. Vitamin deficiencies, especially folate and pyridoxine deficiencies, frequently develop in nursing home residents. Hip fractures are often associated with vitamin D deficiency. Trace mineral deficiencies (for example, zinc deficiency) can aggravate immune deficiency and slow wound healing. Inadequate fluid intake leads to dehydration, hypotension, and, in persons with diabetes mellitus, hyperosmolarity. Finally, food intake itself can cause postprandial hypotension (which in turn may precipitate falls), produce electrolyte shifts, and result in aspiration pneumonia. Physical activity programs are an important component of nursing home care that may have an effect on nutritional status, and simple, cost-effective programs may be as beneficial as high-technology programs. Careful attention to the nutritional intake of nursing home residents is both a clinical and a quality-of-life issue.

Angiotensin II and fluid ingestion in old rats.

Fluid ingestion was studied in Fischer 344/Brown Norway F1 rats aged 3, 12, 20, and 24 months of age. There was an age-related decrease in fluid ingestion when fluid intake was measured over 24 h. After water deprivation, 24- and 20-month-old rats drank less than 3- and 12-month-old rats. Twelve, 20-, and 24-month-old rats had less fluid intake associated with food deprivation than did 3-month-old rats. Three month old rats drank more fluid after angiotensin II than did 12-, 20-, and 24-month-old rats when expressed as fluid intake per kg body weight. These studies confirm that the rat is a reasonable model to study age-related hypodipsia.

The malnourished older patient: when and how to intervene.

Several factors place older patients at increased risk for malnutrition. The physiologic effects of aging itself are considered risk factors, as are systemic diseases such as Parkinson's disease, diabetes, infection, and cancer; depression, and other psychiatric disorders; abnormal chemical values; and effects of various medications. Many of these factors are reversible if recognized and assessed early. Cholesterol and albumin measurements may help confirm the diagnosis of malnutrition. Nutrition-promoting interventions that you can recommend include increasing exercise, raising levels of fluid and nitrogen intake, avoiding constipation through dietary and lifestyle changes, and recommending routine dental examinations.

Effect of aging on body fat.

OBJECTIVE: To examine the effects of aging on body fat. DESIGN: Cross-sectional comparison by age and gender. SETTING: Community health fairs, medical school, and a Department of Veterans Affairs Nursing Home Care Unit. PARTICIPANTS: Five hundred and fourteen individuals between the ages of 29-96 attending three different community health fairs; 62 first year medical students; and 121 male residents of a nursing home. INTERVENTION: None MEASUREMENTS: All underwent measurements of weight, height, and percentage body fat using the RJL Spectrum Bodycomp II Bioelectrical Impedance machine. RESULTS: Percentage body fat increased slightly between ages 20 to 39 years and 40 to 84 years. There were no significant differences noted in percentage body fat among the age groups 40-64, 65-74 and 75-84 in either males or females. There were also no significant differences noted in percentage body fat between any age groups when age-matched for body mass index. Patients over the age of 85 had significantly lower percentage body fat compared with all other age groups. Finally, nursing home patients were more likely to have a lower percentage body fat compared with the ambulatory population. CONCLUSIONS: The percentage body fat does not appear to increase significantly after the age of 40 years. In addition, the major reason for the increase in body fat in older persons appears to be weight gain rather than a true age-related increase in percentage body fat. Previous studies suggesting a marked increase in percentage body fat with advancing age have failed to correct for the presence of an increased body mass index that commonly occurs at middle age.

Effects of peripheral hormones on memory and ingestive behaviors.

This article explores the mechanisms by which peripheral gastrointestinal hormones produce central nervous system effects on memory and feeding. Cholecystokinin produces its satiety effects and memory-enhancing effects by stimulating ascending vagal fibers. Hyperglycemia has been demonstrated to be a cause of memory dysfunction in persons with diabetes mellitus. A number of other hormones, such as amylin and bombesin, modulate both memory processing and feeding. The causes of the anorexia of aging are briefly reviewed.

Role of the opioid system in the hypodipsia associated with aging.

OBJECTIVE: To compare the effects of the opioid antagonist, naloxone, on fluid ingestion in young and older males, in order to estimate the role of the opioid system in hypodipsia of older men. DESIGN: Single-blinded, randomized, cross-over, placebo-controlled study. SETTING: Outpatient Department of Veterans Affairs. STUDY PARTICIPANTS: Sixteen young subjects (aged 23 to 39) and eight older subjects (aged 69 to 75). All subjects were healthy, community-dwelling, non-smoking men, on no medications. INTERVENTION: Subjects were randomized to receive either placebo or naloxone on day one. Whichever substance the subject did not receive was given on day two with days one and two separated by at least a 2-week washout period. MAIN OUTCOME MEASURES: Fluid intake after overnight food and fluid deprivation, with placebo or naloxone injected in the morning. RESULTS: After overnight fluid deprivation, older individuals consumed 29% less fluid in 2 hours compared with younger individuals (ns). After overnight fluid deprivation and injection with naloxone 100 micrograms/kg, fluid intake was diminished by 42% (P less than 0.05) in young subjects compared with placebo, but only by 7% (ns) in older subjects. Subjective ratings did not differ significantly between young and old subjects. CONCLUSIONS: These preliminary data suggest that the opioid system plays a role in the drinking response in young subjects while failing to alter fluid intake in older subjects. Hypodipsia in older individuals may be due to a deficit in the opioid drinking drive.

Effect of aging on fluid ingestion in mice.

The amount of fluid consumed by C57BL/6Nnia male mice 3, 12, and 25 months of age under various paradigms was studied. The old mice consumed less water during the dark cycle but not during the light cycle (12 h lights off; 12 h lights on). When thirst was induced by providing dry food pellets or after overnight fluid deprivation, old mice consumed significantly less water than younger mice over a one-hour period. When thirst was induced by administration of hypertonic saline, there were no age-related effects. Naloxone 7.5 mg/kg IP significantly suppressed drinking in 3- and 12-month-old mice, while 25-month-old mice did not show suppression. Dehydration-induced thirst is impaired in old mice, as it is in older humans. This may be related to the alteration in opioid mechanisms modulating thirst.

The effect of recombinant human growth hormone on malnourished older individuals.

Malnutrition in the elderly is often unrecognized and untreated. Reduced secretion of growth hormone (GH) has been suggested as a cause of decreased muscle and bone mass with aging. This pilot study characterized the nutritional response of elderly malnourished subjects to recombinant human GH (rhGH). Subjects were included if they were over 60 years of age, if weight was more than 20% below average body weight (ABW), and if serum albumin concentration was less than 3.8 g/dL. Subjects were divided into two groups: one received 100 micrograms/kg rhGH (Protropin, Genentech) intramuscularly (IM) daily for 21 days; the other received a daily control injection of normal saline (Controls -C) (0.1 mL/kg IM) for the same period of time. During the 3-week period, mid-arm muscle circumference (MAMC) increased an average of 0.6 cm in GH patients but fell in C subjects. There was a non-significant trend to a decreased caloric intake in the control group. Weight increased an average of 4.95 lbs (2.2 kg) in the GH treated group, and decreased an average of 4.9 lbs (2.2 kg) in C subjects (P less than 0.05). Urinary nitrogen retention occurred only in the growth hormone treated subjects (P less than 0.05). Somatomedin C (IGF-1) rose significantly in those treated with GH (P less than 0.05), while there was no change in the control group. There was a significant association between weight change and IGF 1 concentration (r = 0.837, P less than 0.05). Neither clinical edema nor hyperglycemia was noted. These findings suggest that GH may be an effective way of maintaining and enhancing weight in malnourished older individuals.

Secondary hypogonadism in older men: its relation to impotence.

The relation of the reproductive endocrine system to impotence in older men was examined by measuring the concentrations of testosterone (T), bioavailable testosterone (BT), LH, and PRL and body mass index (BMI) in 57 young controls (YC), 50 healthy potent older controls attending a health fair (HF), and 267 impotent patients (SD). The SD and HF had markedly reduced mean T and BT values compared to YC. When adjusted for age and BMI there was no difference in BT between potent and impotent older men. The percent BT was much higher in YC than in the older groups. While the percent BT rose significantly with increased T in YC, it was inversely related to T in the older subjects, suggesting that increased sex hormone-binding globulin binding was a primary event leading to a low BT. Forty-eight percent of HF and 39% of SD were hypogonadal, as defined by a mean BT of 2.5 SD or more below the mean of YC (less than or equal to 2.3 nmol/L). Ninety percent of these had LH values in the normal range, suggesting hypothalamic-pituitary dysfunction. Thirty-four SD and six each of YC and older control volunteers (OC) underwent GnRH testing. Older subjects showed impaired responsiveness to GnRH compared to YC. A low basal LH level correlated very highly with hyporesponsiveness to GnRH. Thus, secondary hypogonadism and impotence are two common, independently distributed conditions of older men.

Aging and risks for dehydration.

The elderly are at increased risk for dehydration and associated fluid and electrolyte imbalances. Changes in functional and mental status, medication effects, and changes in the aging renal system all may be factors. Furthermore, hypodipsia, or insensibility to thirst, may be a physiologic process of aging. These and other risk factors are presented, along with a guide to the management of dehydration in the elderly.

Do peptide-induced changes in feeding occur because of changes in motivation to eat?

The usual paradigm in which peptides are tested for their effect on food intake involves measuring intake of readily available food. In the lever press apparatus, the subjects must "work" to get food. Such work has traditionally been used as a means of measuring motivation. Mice were trained to press a lever for milk reinforcement. After achieving a stable level of performance, we tested the effects of gastrin-related peptide (GRP), bombesin (BBS) and cholecystokinin octapeptide (CCK-8) on lever pressing. All three peptides suppressed lever pressing for milk reinforcement. Prefeeding mice with milk increased the suppression of lever pressing to a greater extent in peptide-treated mice than in saline-treated mice. As the duration of prefeeding increased, lever pressing decreased. When mice were required to make more lever presses to obtain milk, both saline- and CCK-8-treated mice increased their lever pressing. However, saline-treated mice pressed at a higher rate than CCK-8-treated mice. Unlike the results obtained with saline and CCK-8, administration of a known gustatory adversant, lithium chloride, suppressed lever pressing to the same degree in mice fed or not fed prior to training. The results are consistent with the hypothesis that these peptides act as satiety agents.