Frequency and clinical significance of the S1235R mutation in the cystic fibrosis transmembrane conductance regulator gene: results from a collaborative study.

More than 900 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been reported to the cystic fibrosis (CF) consortium. A missense mutation, S1235R, was originally reported in a CF patient with a second mutation (G628R) on the same chromosome. The clinical significance of S1235R was not clear. S1235R is not among the commonly reported mutations, and it is not routinely screened for in most laboratories. However, we have detected the S1235R allele at a frequency that is significantly higher than that of many other CF mutations. Among more than 3,000 patients tested for either a possible diagnosis of CF or to determine CF carrier status, we identified 51 patients heterozygous for S1235R. No patients were homozygous for S1235R. Five patients were compound heterozygotes for a second CFTR mutation: two cases (one family) were N1303K/S1235R and three unrelated cases were deltaF508/S1235R. Our data suggest that S1235R, when combined with a second CF mutation, may be pathogenic, although phenotypic manifestations appear to be variable. The possibility that this represents a rare polymorphism cannot be discounted completely. Genetic counseling is difficult when S1235R is identified, even in the presence of a second known mutation, especially in prenatal cases.

Potentiation of butyrate-induced differentiation in human colon tumor cells by deoxycholate.

Human colon adenocarcinoma cells, treated with deoxycholate for 24 h prior to exposure to 1 mM butyrate, exhibited dose-dependent increases in the activities of three markers of colonic differentiation (alkaline phosphatase, lactase and CEA). Treatment with deoxycholate alone, for 24 h or longer, did not increase the secretion of CEA or the activities of either of the brush border-associated enzyme activities. Increases in differentiation markers were found to be bile acid-specific. Pretreatment with either dehydrocholic acid or cholic acid, even at cytotoxic concentrations, led to no significant butyrate-induced increases in brush-border associated hydrolase activities. The addition of a bacterial superoxide dismutase decreased the short-term cytotoxicity of deoxycholate and increased the maturation-potentiating effects of the bile acid in HCT-116 DO cells. The results of these studies demonstrate that bile acids, which are commonly thought to have tumor promoting activities in vivo, may also have physiological effects which serve to limit carcinogenic processes in the human colon by potentiating tumor cell differentiation.

A case of intussusception and lymphoid hyperplasia in a patient with AIDS.

Idiopathic intussusception in adults is rare. In tropical climates, enteric infection is causally implicated. Three cases of intussusception in AIDS patients have been reported, two of which were associated with enteric infection. We report the fourth case of ileocolonic intussusception in an AIDS patient in whom lymphoid hyperplasia of the terminal ileum was found but no infection documented. The relationship between lymphoid hyperplasia and intussusception is discussed. The previous cases of AIDS and intussusception are reviewed. Idiopathic intussusception may become more prevalent as the number of AIDS cases increases, and must be considered in the differential diagnosis of abdominal pain in AIDS patients.

Failure of rectal ornithine decarboxylase to identify adenomatous polyp status.

Rectal mucosal ornithine decarboxylase (ODC) activity has been reported to distinguish between patients with and without adenomatous polyps (AP). In the present investigation, ODC activity has been measured in 28 patients with AP and 34 patients without AP. To assess the intraindividual variation in ODC activity, repeat biopsies were performed on 11 patients. In addition, the effect of postbiopsy sample handling was investigated by storage of samples on either dry or wet ice during transport to the laboratory. The mean rectal mucosal ODC activity in patients with AP was 196.0 +/- 195.5, whereas that in AP negative patients was 182.2 +/- 320.5. The rectal mucosal ODC activity in patients with colorectal cancer was 388.2 +/- 581. Repeat samples in individuals were generally within the same range as the original samples. The method of sample transport did not significantly affect the level of ODC measured in a particular biopsy. Because of high variability in rectal mucosal ODC activity within the population, there was wide overlap in ODC values between those patients with and without AP in an unselected general population. Thus, the measurement of flat rectal mucosal ODC activity is not a good predictor of the presence or absence of AP. Additional studies of the factors affecting mucosal ODC activity are necessary before the potential clinical utility of the method can be realized in the general population.

Taurine deficiency after intensive chemotherapy and/or radiation.

Taurine, a nonessential amino acid (AA), is the most abundant free AA in the intracellular space. We measured plasma AA concentrations in 36 patients 7-28 d after intensive chemotherapy and/or radiation. Plasma taurine concentrations were uniformly low in all patients (20.0 +/- 6.4 mumol/L, mean +/- SD). Plasma taurine in 11 healthy volunteer control subjects was 45.0 +/- 20.3 mumol/L (P less than 0.001). Other AA concentrations, specifically those of precursor AAs methionine and cystine, were normal. We prospectively measured plasma AA concentrations in 12 patients before starting and 6-10 d after completing intensive cytotoxic treatment. Values before treatment were 37.2 +/- 11.6, 109.6 +/- 30.7, and 18.5 +/- 4.8 for taurine, cystine, and methionine, respectively, and were 24.3 +/- 6.0, 111.2 +/- 23.8, and 24.0 +/- 14.5 after treatment. Pretreatment plasma taurine correlated directly with the magnitude of decrease in plasma taurine during cytotoxic treatment (n = 12, r = 0.85, P less than 0.01). Intensive cytotoxic chemotherapy and/or radiation leads to a reduction in plasma taurine concentrations without any change in its precursor AAs, methionine and cystine. The clinical relevance of plasma taurine depletion will need further study.

Prevention of colon cancer in primary care practice.

Colorectal cancer is a common disease with a high mortality rate. Surgical resection in early stages is the only effective treatment, therefore, recent attention is focused on diagnosing early colon cancer by screening asymptomatic subjects. Principles and current technology supporting early detection of colorectal cancer are critically evaluated. Current guidelines for screening average risk asymptomatic subjects and high-risk groups are discussed.

Colorectal cancer. Scope of the problem.

The extent of the problem of colorectal cancer is discussed. The need for early identification of the disease for cure is emphasized. The need for research into markers for early detection of disease as well as research into therapy for patients with established nonresectable cancer are also emphasized.

Clinical features, evaluation, and detection of colorectal cancer.

The most common presentation of colorectal carcinoma is in the symptomatic patient, most often with complaints of rectal bleeding, abdominal pain, or change in bowel habits. Symptomatic patients often have advanced disease and, because surgical resection is the only effective therapy at present, their chance for cure is poor. Until effective treatment is available, therefore, we must identify patients at high risk for lifelong screening. In addition, more effective means of surveillance of the general population need to be developed in order to diagnose patients at risk for sporadic colorectal cancer, given that this represents the majority of patients with disease. Tumor markers also would be useful to find residual disease while it is still resectable in patients who have undergone surgery for curative resection.

Relationship of hormones and growth factors to colon cancer.

The role of hormones and growth factors in the pathogenesis and therapy of colon cancer is biologically intricate and medically important. The effects of the previously described hormones and growth factors on normal and neoplastic colonic growth and development suggest the mechanisms by which hormonal alteration might either enhance or suppress the cancer process. The high degree of association between the specific endocrine-related processes (breast cancer, acromegaly, hyperparathyroidism, gastrin sensitivity of colon cancer, and cancer cell lines) suggests a significant role for hormones in colonic carcinogenesis. The relationship between the specific hormones and cancers is often unclear. This is the result of many factors: the variable presence of specific hormone receptors on the surface of the tumor or cell line; the inconsistent response to exogeneous hormone administration in vivo and in vitro; and the occasional failure of specific hormone-blocking agents to affect cell proliferation. The relationship between growth factors and cancers is also unclear. The following questions must be resolved in order to understand the significance of growth factors and the neoplastic process: (1) Is a growth factor significant in either an autocrine or a paracrine capacity? (2) Are combinations of growth factors rather than individual growth factors more biologically significant? (3) Do structural alterations of the immunologically similar, but functionally different growth factors modify their effect on the neoplastic tissue? The potential for manipulation of hormones and growth factors in the prevention and treatment of colon cancer is evidence to date suggesting that such efforts are indeed justified.

Colonoscopic polypectomy.

Since the advent of fiberoptic endoscopy and the introduction of colonoscopic polypectomy, a simple and cost-effective procedure has been available to deal with an exceedingly common problem, the colonic polyp. Although polyps in the gastrointestinal tract have a varied natural history, there is strong evidence that adenomatous colonic polyps have a potential for malignant degeneration and that virtually all colorectal cancers arise from adenomatous polyps. This article will review some basic features of the endoscopic approaches and problems associated with polypectomy.

Life after colectomy.

Animal and epidemiologic studies have raised hopes that effective chemoprevention of colorectal cancer in very high-risk patients may be possible in the future, but at present, the only established effective way to prevent colorectal cancer in very high-risk patients is colectomy. Advances in surgical techniques, improvements in stomal appliances, and medical advances in dealing with complications of colorectal surgery (such as impotence) have contributed to substantial improvements in the quality of life of patients who have had prophylactic colectomies.

Strategies for the control of colorectal cancer.

An overview of this issue is presented, with a discussion of its application to control of colorectal cancer. A brief update on new findings in molecular and genetic aspects is also given. Finally, strategies for control of colorectal cancer are discussed.

Biochemical markers in colorectal cancer: diagnostic and therapeutic implications.

Markers that are now in use, including CEA and CA-19-9, are not specific or sensitive enough to detect early colorectal cancer. Newer tumor markers such as polyamines, ornithine decarboxylase, and altered blood group carbohydrate antigens may have a potential as future tumor markers. Additional studies of these markers as well as the development of new biochemical markers are warranted in the future to enhance the sensitivity and specificity of diagnosis of early colorectal cancer and those at risk for developing cancer. Finally, understanding events involved in abnormal cell proliferation (that is, elevated polyamines and ODC in colorectal cancer) may help direct future chemotherapy and possibly chemoprevention in high-risk groups such as adenomatous polyposis coli.

Aminoglycoside nephrotoxicity in obstructive jaundice.

PURPOSE: Although it is known that liver disease predisposes to aminoglycoside nephrotoxicity, specific features of such disease that may predispose to aminoglycoside-induced renal injury have not been identified. We sought to identify such features. PATIENTS AND METHODS: We undertook a retrospective review of the charts of 42 consecutive patients with biliary obstruction and/or cholangitis who had received more than three doses of an aminoglycoside. RESULTS: Comparison of patients in whom aminoglycoside nephrotoxicity did and did not develop revealed no differences in age, race, sex, dose, and duration of aminoglycoside therapy; mean peak and trough aminoglycoside levels; initial pre-treatment levels of serum creatinine, aspartate transaminase, alkaline phosphatase, or albumin; or prothrombin time. The initial pre-treatment serum bilirubin level was higher in the patients in whom aminoglycoside nephrotoxicity developed (12.2 +/- 8.8 mg/dl versus 3.4 +/- 3.2 mg/dl, p less than 0.01). Aminoglycoside nephrotoxicity occurred in eight patients (19 percent): in seven of 15 patients (47 percent) with an initial bilirubin value greater than 5.0 mg/dl, but in only one of 27 patients (4 percent) with an initial bilirubin value below 5.0 mg/dl (p less than 0.01). The pre-treatment bilirubin level correlated with the change in creatinine during aminoglycoside therapy (n = 42, r = 0.66, p less than 0.01). CONCLUSION: Aminoglycosides should probably be avoided in patients with biliary obstruction and a high serum bilirubin level.

A direct relationship between ionized calcium and arterial pressure among patients in an intensive care unit.

Serum ionized calcium (Ca+2), creatinine, magnesium, phosphate, and arterial pH were measured in patients on admission to the medical ICU (MICU). Patients were classified into three groups: a) hypotensive (n = 38), those who received vasopressor support for frank hypotension; b) hypertensive (n = 21), those who required vasodilator therapy; and c) normotensive (n = 53), those who required neither vasopressor nor vasodilator therapy. Analysis of variance revealed that only Ca+2, creatinine, and arterial pH differed among the three groups. The difference in Ca+2 persisted when analysis of variance was repeated with creatinine as a covariate. Hypotensive patients had a significantly (p less than .05) lower mean Ca+2 (1.04 +/- 0.13 mmol/L) than normotensive patients (1.13 +/- 0.10 mmol/L), who in turn had a significantly (p less than .05) lower Ca+2 than hypertensive patients (1.18 +/- 0.09 mmol/L). Ca+2 correlated with mean arterial pressure at the time of serum collection (n = 118; r = .43; p less than .01), independent of any other variable. Vasopressor support was required in 41% of hypocalcemic patients in comparison to 14% of normocalcemic patients (p less than .01). Vasodilator therapy was required for 34% of normocalcemic patients, compared to 7.5% of hypocalcemic patients (p less than .01). There appears to be a clinically significant association between hypotension and hypocalcemia. This association may or may not be causal.

Prevalence and clinical implications of hypocalcemia in acutely ill patients in a medical intensive care setting.

The incidence and the clinical implications of hypocalcemia were evaluated in acutely ill patients admitted to the Medical Intensive Care Unit of the Detroit Receiving Hospital. Total and ionized calcium levels were prospectively evaluated upon admission for all patients over a three-month interval. A high proportion of patients (62 of 88, 70 percent) were found to have decreased levels of both total and ionized calcium. Known causes of hypocalcemia could be identified in only 28 patients (45 percent). These included hypomagnesemia (17, 28 percent), renal insufficiency (five, 8 percent), alkalosis (four, 6 percent), and acute pancreatitis (two, 3 percent). In the remaining 34 patients (55 percent), no readily identifiable cause could be found. These 34 patients had a lower mean albumin level than did the 23 normocalcemic patients (p less than 0.01), but there were no differences in age, pH, serum creatinine, magnesium, or phosphate between the two groups. Serum albumin correlated directly with ionized calcium levels (n = 82, r = 0.33, p less than 0.01), as well as with total calcium levels (n = 76, r = 0.70, p less than 0.01). There was a strong association between sepsis and hypocalcemia. Patients who survived the hospitalization had higher mean ionized calcium, total calcium, and albumin values than did nonsurvivors, but there were no differences in age, serum creatinine, magnesium, and phosphate between the two groups. The mortality of the hypocalcemic patients (44 percent) was significantly greater (p less than 0.05) than the mortality of the normocalcemic patients (17 percent). These findings suggest that hypocalcemia is a very common abnormality in acutely ill patients and is associated with a poor prognosis.

Hypocalcemia and hypophosphatemia in acutely ill patients.

Hypocalcemia and hypophosphatemia have recently been recognized as common metabolic complications in acutely ill patients. The diagnostic and therapeutic approaches to these abnormalities are described in this article.