Genome-wide analysis of canine oral malignant melanoma metastasis-associated gene expression.

Oral malignant melanoma (OMM) is the most common canine melanocytic neoplasm. Overlap between the somatic mutation profiles of canine OMM and human mucosal melanomas suggest a shared UV-independent molecular aetiology. In common with human mucosal melanomas, most canine OMM metastasise. There is no reliable means of predicting canine OMM metastasis, and systemic therapies for metastatic disease are largely palliative. Herein, we employed exon microarrays for comparative expression profiling of FFPE biopsies of 18 primary canine OMM that metastasised and 10 primary OMM that did not metastasise. Genes displaying metastasis-associated expression may be targets for anti-metastasis treatments, and biomarkers of OMM metastasis. Reduced expression of CXCL12 in the metastasising OMMs implies that the CXCR4/CXCL12 axis may be involved in OMM metastasis. Increased expression of APOBEC3A in the metastasising OMMs may indicate APOBEC3A-induced double-strand DNA breaks and pro-metastatic hypermutation. DNA double strand breakage triggers the DNA damage response network and two Fanconi anaemia DNA repair pathway members showed elevated expression in the metastasising OMMs. Cross-validation was employed to test a Linear Discriminant Analysis classifier based upon the RT-qPCR-measured expression levels of CXCL12, APOBEC3A and RPL29. Classification accuracies of 94% (metastasising OMMs) and 86% (non-metastasising OMMs) were estimated.

Treatment of acute myocardial infarction and 30-day mortality among women and men.

BACKGROUND: Previous studies have suggested that women with acute myocardial infarction receive less aggressive therapy than men. We used data from the Cooperative Cardiovascular Project to determine whether women and men who were ideal candidates for therapy after acute myocardial infarction were treated differently. METHODS: Information was abstracted from the charts of 138,956 Medicare beneficiaries (49 percent of them women) who had an acute myocardial infarction in 1994 or 1995. Multivariate analysis was used to assess differences between women and men in the medications administered, the procedures used, the assignment of do-not-resuscitate status, and 30-day mortality. RESULTS: Among ideal candidates for therapy, women in all age groups were less likely to undergo diagnostic catheterization than men. The difference was especially pronounced among older women; for a woman 85 years of age or older, the adjusted relative risk was 0.75 (95 percent confidence interval, 0.68 to 0.83). Women were somewhat less likely than men to receive thrombolytic therapy within 60 minutes (adjusted relative risk, 0.93; 95 percent confidence interval, 0.90 to 0.96) or to receive aspirin within 24 hours after arrival at the hospital (adjusted relative risk, 0.96; 95 percent confidence interval, 0.95 to 0.97), but they were equally likely to receive beta-blockers (adjusted relative risk, 0.99; 95 percent confidence interval, 0.95 to 1.03) and somewhat more likely to receive angiotensin-converting-enzyme inhibitors (adjusted relative risk, 1.05; 95 percent confidence interval, 1.02 to 1.08). Women were more likely than men to have a do-not-resuscitate order in their records (adjusted relative risk, 1.26; 95 percent confidence interval, 1.22 to 1.29). After adjustment, women and men had similar 30-day mortality rates (hazard ratio, 1.02; 95 percent confidence interval, 0.99 to 1.04). CONCLUSIONS: As compared with men, women receive somewhat less aggressive treatment during the early management of acute myocardial infarction. However, many of these differences are small, and there is no apparent effect on early mortality.

Report from the 1995 Core Indicators for Peritoneal Dialysis Study Group.

The 1995 Peritoneal Dialysis Core Indicators Study was conducted by the Health Care Financing Administration to ascertain standard practices and outcomes in chronic peritoneal dialysis patients. Data from 1,202 patients who did not receive hemodialysis but who were on chronic ambulatory peritoneal dialysis (CAPD) for at least part of the 6-month period between November 1, 1994, and April 30, 1995, are reported. The mean serum albumin level for this cohort was 3.5 g/dL by the bromcresol green method and 3.2 g/dL by the bromcresol purple method. Data sufficient to calculate a weekly Kt/V(urea) or weekly creatinine clearance were available for only 34% of patient submissions. In these patients, the median weekly Kt/V(urea) was 1.7 using a fixed value for V of 0.58 x body weight and was 2.0 using the Watson equation to calculate V; the median weekly creatinine clearance was 60.7 L/wk/1.73 m2. The mean hematocrit for this cohort was 32% and the average weekly recombinant human erythropoietin (rHmEPO) dose was 115 u/kg. Hematocrit values < or = 30% were found in 50% of black patients and 31% of white patients. The average blood pressure among peritoneal dialysis patients was 139/80 mm Hg, with 29% of patients having a systolic blood pressure exceeding 150 mm Hg and 18% a diastolic blood pressure greater than 90 mm Hg. In summary, serum albumin levels were significantly lower in peritoneal dialysis patients than in hemodialysis patients. Approximately one third of peritoneal dialysis patients did not have an adequacy measure obtained during the 6-month observation period. A significant minority of patients had either inadequately treated anemia of chronic renal disease or hypertension. There is an opportunity to substantially improve the medical care provided to chronic peritoneal dialysis patients.

Improvement in adequacy of delivered dialysis for adult in-center hemodialysis patients in the United States, 1993 to 1995.

The objective of this review is to describe the adequacy of delivered dialysis provided to in-center hemodialysis patients in the United States and to compare the findings with published guidelines. The medical records of random samples of 6,138, 6,919, and 6,861 patients in hemodialysis facilities were studied from all Medicare-eligible adult in-center hemodialysis patients alive on December 31, 1993, 1994, and 1995, respectively. The main clinical measure used was the urea reduction ratio (URR), the mean of which was 0.63 in 1993, 0.64 in 1994, and 0.66 in 1995. The proportion of patients with URR > or = 0.65, as recommended by the Renal Physicians Association and a National Institutes of Health Consensus Development Conference Statement, increased from 43% in 1993 to 49% in 1994 and 59% in 1995. In each of these 3 years, women were more likely than men to have a URR > or = 0.65 (1993: 54% v 31%, odds ratio 2.6; 1994: 61% v 38%, odds ratio 2.5; and 1995: 70% v 50%, odds ratio 24), as were older patients (65+ years) compared with younger patients (18 to 44 years) (1993: 47% v 37%, odds ratio 1.4; 1994: 54% v 45%, odds ratio 1.5; and 1995: 65% v 53%, odds ratio 1.6) and white patients compared with black patients (1993: 46% v 36%, odds ratio 1.5; 1994: 53% v 43%, odds ratio 1.5; and 1995: 63% v 54%, odds ratio 1.4). There was also substantial geographic variation in the proportion of patients receiving hemodialysis with a URR > or = 0.65. In conclusion, marked differences existed in 1993, 1994, and 1995 between observed practice and consensus guidelines for the delivery of adequate dialysis. Nevertheless, notable improvement occurred during this time period. A system to monitor further improvements in hemodialysis care in the United States is in place.

Nephrotoxic effects of primary immunosuppression with FK-506 and cyclosporine regimens after liver transplantation.

OBJECTIVE: We conducted a treatment trial to determine the relative toxicity of FK-506 and cyclosporine A (CSA) in liver transplant recipients. DESIGN: Between October 1990 and October 1991, 37 patients were enrolled in an open-labeled, randomized study of two immunosuppressive regimens after liver transplantation. MATERIAL AND METHODS: Of the 23 men and 14 women, 20 received FK-506 plus prednisone, and 17 received CSA plus prednisone and azathioprine. Renal function was assessed before and after transplantation (day 1, month 1, month 4, and month 12) by measurements of serum creatinine (SCr) and glomerular filtration rate (GFR) as determined by urinary iothalamate or creatinine clearance (or both). FK-506 trough plasma levels (enzyme immunoassay) were to be maintained between 0.2 and 5.0 ng/mL, and CSA trough blood levels (whole blood high-performance liquid chromatography) were to be maintained between 250 and 400 ng/mL. Severe nephrotoxicity was defined as sudden decreases in urine output to less than 10 mL/h or rapid increases in SCr (more than 0.5 mg/dL daily) that necessitated withdrawal of study medication for more than 48 hours. Mean patient age and values for SCr and GFR were comparable between the two groups at entry. RESULTS: Both study groups demonstrated a similar deterioration in renal function during a 12-month follow-up, although patients who received FK-506 had a significantly (P < 0.05) lower GFR when measured at 12 months than did patients treated with CSA (45 +/- 4 versus 64 +/- 6 mL/min per body surface area). Mild nephrotoxicity that responded to decreased drug doses was noted in 9 CSA-treated patients (53%) and 10 FK-506-treated patients (50%). Severe nephrotoxicity that necessitated drug withdrawal occurred in only four patients, all of whom were in the FK-506 group. These severe nephrotoxic reactions to FK-506 occurred early after transplantation, often during intravenous administration of the drug, and were not associated with poor liver allograft function or drug levels outside the therapeutic range. CONCLUSION: Both FK-506 and CSA are significantly nephrotoxic in liver transplant recipients. In this trial, however, we observed an early development of severe nephrotoxic reactions only in some patients who received FK-506.

Cancer incidence among American Indians and Alaska Natives, 1980 through 1987.

OBJECTIVES: This study uses Indian Health Service inpatient data to estimate cancer incidence among American Indians and Alaska Natives. METHODS: Hospital discharge data for 1980 through 1987 were used to identify cases of cancer for 21 sites in women and 18 sites in men. Estimates of incidence were directly standardized to data from the Surveillance, Epidemiology, and End Results Program for the same time frame. RESULTS: Cancers of the gallbladder, kidney, stomach, and cervix show generally high rates among many American Indian and Alaska Native communities, and cancers of the liver and nasopharynx are high in Alaska. Of the relatively common cancers in Whites, American Indians and Alaska Natives experience lower rates for cancers of the breast, uterus, ovaries, prostate, lung, colon, rectum, and urinary bladder and for leukemia and melanoma. Variation among geographic areas and among tribal groups is observed for many important cancer sites. CONCLUSIONS: This study demonstrates significant variations of cancer rates among American Indians and Alaska Natives, with important implications for Indian Health Service cancer control programs. The study also supports the potential use of hospital discharge data for estimating chronic disease among diverse American Indian and Alaska Native communities.

Clinical hypertension and its interaction with diabetes among American Indians and Alaska Natives. Estimated rates from ambulatory care data.

OBJECTIVE: To estimate the prevalence of clinical hypertension and describe the coexistence with diabetes in American Indian and Alaska Native communities. RESEARCH DESIGN AND METHODS: A cross-sectional study of outpatient visits for hypertension and diabetes over a 1-yr period (1 October 1986 to 30 September 1987) in IHS facilities was conducted. RESULTS: The 1987 estimated age-adjusted prevalence of diagnosed hypertension for this group was 10.9/100 for people > or = 15 yr of age. Thirty-seven percent of diabetic patients were diagnosed with hypertension. The relative risk of hypertension in the diabetic populations compared with the nondiabetic population varied from 4.7 to 7.7 among the different IHS areas. CONCLUSIONS: Despite high rates of diabetes and obesity, hypertension rates were relatively low among American Indians and Alaska Natives when compared with other ethnic groups in the U.S.

Cerebral white matter and cognition in hydrocephalic children.

Although children with hydrocephalus frequently show poor development of nonverbal cognitive skills relative to verbal skills, little is known about the neuropathologic correlates of these discrepancies. In this study, cerebral white-matter structures and lateral ventricles were measured from the magnetic resonance images of age-matched children with meningomyelocele, meningocele, and aqueductal stenosis and normal subjects. The volume of each lateral ventricle and the cross-sectional area of the corpus callosum and internal capsules were correlated with concurrent measures of verbal and nonverbal cognitive skills. The corpus callosum in the meningomyelocele and aqueductal stenosis groups was smaller. The lateral ventricles were larger, and the internal capsules were smaller, in all patient groups than in normal subjects. There were no differences in the size of the centra semiovale. Although verbal and nonverbal measures correlated positively with the size of the corpus callosum, the correlation was higher for nonverbal measures. Nonverbal measures correlated with the right, but not the left, lateral ventricle and with the area of the right and left internal capsules. Verbal measures correlated with the left, but not right, lateral ventricle and with the left, but not right, internal capsule. These results show a relationship between the corpus callosum and cognitive skills that is also influenced by hydrocephalus-related changes in the lateral ventricles and other cerebral white-matter tracts.

The combination of prednisone and colchicine in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis is a cholestatic liver disease characterized by inflammation and fibrosis of the biliary tract. The cause of the disease is unknown, and no effective medical treatment exists. In this study, 12 patients received a combination of low-dose prednisone (10 mg/day) and colchicine (0.6 mg bid). Their course was compared with that of a group of concurrent historical controls. At 6 and 12 months, there was significantly more improvement in liver test results over baseline values in patients receiving prednisone and colchicine than in the untreated controls. At 24 months, however, no significant differences in biochemical tests were appreciated between treated and untreated patients. Analysis of serial liver biopsies showed no differences in histologic change in the two groups. During the 2 yr of follow-up, there were two deaths in the control group but none in the treated group. Four untreated patients developed ascites; gastrointestinal bleeding developed in three untreated patients, one of whom developed ascites. In contrast, in the treated group, ascites and bleeding developed in only one patient. We conclude that the combination of colchicine and prednisone does not retard histologic progression or progression of standard liver tests after 2 yr of therapy. There is a trend toward less clinical deterioration and improved survival after 2 yr of treatment. On the basis of these findings, we would not advocate empiric use of these drugs for patients with primary sclerosing cholangitis, but suggest that, if they are to be used at all in PSC, they be evaluated in a controlled clinical trial as treatment for this as yet incurable disease.

Incidence of Legionella pneumophila infections among Oklahoma pulmonary disease patients.

Prior studies by the authors suggested high levels of Legionella pneumophila in the recreational and water supply reservoirs in central Oklahoma. This high exposure potential was supported by a relatively high prevalence of seropositive, asymptomatic infections among healthy blood donors in the area. In contrast, the present 9-month laboratory-based study confirmed only one clinical Legionella infection among 117 unidentified pulmonary disease patients admitted to the Oklahoma City Veterans Administration Medical Center. Comparison with the reports of others and with reported legionellosis in Oklahoma indicates that differences in cohort definition and variations in utilization and interpretation of clinical analyses leads to wide variations in the reported incidence of legionellosis.

Primary sclerosing cholangitis: natural history, prognostic factors and survival analysis.

The natural history of primary sclerosing cholangitis was assessed in 174 patients; 37 were asymptomatic and 137 had symptoms related to underlying liver disease. At the time of diagnosis, the mean age was 39.9 years, 66% of the primary sclerosing cholangitis patients were male and 71% had associated inflammatory bowel disease, most commonly chronic ulcerative colitis. Long-term follow-up (mean: 6.0 years; range: 2.7 to 15.5 years) was available in all patients. During follow-up, 59 (34%) of the patients died: 55 in the symptomatic group and four in the asymptomatic group. Median survival from the time of diagnosis of primary sclerosing cholangitis at the Mayo Clinic was 11.9 years. Survival in the asymptomatic group was significantly decreased compared with that in a control population matched for age, race and sex. Multivariate analysis (Cox proportional hazards regression modeling) revealed that age, serum bilirubin concentration, blood hemoglobin concentration, presence or absence of inflammatory bowel disease and histologic stage on liver biopsy were independent predictors of high risk of dying. The development of a multivariate statistical survival model is a major step in identifying individual primary sclerosing cholangitis patients at low, moderate and high risk of dying. Such models will be useful for stratifying patients in therapeutic trials, in patient counseling and in patient selection and timing of liver transplantation.

Extrahepatic malignancy following long-term immunosuppressive therapy of severe hepatitis B surface antigen-negative chronic active hepatitis.

To determine the frequency, predisposing factors and consequences of extrahepatic malignancy following long-term immunosuppressive therapy of severe HBsAg-negative chronic active hepatitis, 149 patients who had received prednisone (20 mg daily) or prednisone (10 mg daily) in combination with azathioprine (50 mg daily) for at least 6 months were evaluated systematically for 109 +/- 5 months (range: 7 to 223 months). Seven neoplasms involving cervix (2), lymphatic tissue (1), breast (1), bladder (1), soft tissue (1) and unknown site (1) developed in seven patients after 116 +/- 23 months (range: 18 to 164 months). The incidence of extrahepatic neoplasm was 1 per 194 patient-years of surveillance, and the probability of tumor occurrence was 3% after 10 years. Tumor frequency was similar in men and women and the risk was 1.4-fold greater than that in an age- and sex-matched normal population (95% confidence interval, 0.6- to 2.9-fold normal). Patients with extrahepatic malignancy were not distinguished by age, sex, treatment regimen, cumulative duration of treatment (42 +/- 9 vs. 60 +/- 4 months, p = 0.7) or individual features of the liver disease. Five of the seven patients survived during 48 +/- 25 months of follow-up, including two patients who have lived for at least 5 years after the diagnosis of malignancy. We conclude that extrahepatic malignancy develops infrequently during long-term immunosuppressive therapy. Its occurrence is not related to the type or duration of treatment, and long-term survival after tumor detection is possible. The low but probably increased risk of extrahepatic neoplasm does not militate against the use of immunosuppressive therapy in these patients.

Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis.

The effect of proctocolectomy on the primary sclerosing cholangitis that frequently is associated with chronic ulcerative colitis in patients with both conditions is unknown. We have studied prospectively the progression of clinical, biochemical, cholangiographic, and hepatic histologic features in 45 patients with both primary sclerosing cholangitis and chronic ulcerative colitis to compare these variables in the 20 patients who had undergone proctocolectomy with the 25 who had not. The two groups were similar initially with regard to clinical, biochemical, cholangiographic, and hepatic histologic findings. All patients were followed for a minimum of 1 yr and overall duration of follow-up was similar in both groups (4.1 vs. 3.9 yr). Clinically, new onset of hepatomegaly, splenomegaly, esophageal varices, and ascites did not differ in patients with and without proctocolectomy. Biochemically, the serial changes in bilirubin, alkaline phosphatase, aspartate aminotransferase, prothrombin time, and albumin were similar. Histologic progression on liver biopsy did not differ between groups, nor did changes on serial cholangiograms. Proctocolectomy also had no effect on survival. We conclude that proctocolectomy for chronic ulcerative colitis has no beneficial effect on the primary sclerosing cholangitis in patients with both diseases.

Prospective trial of penicillamine in primary sclerosing cholangitis.

We evaluated the therapeutic efficacy of penicillamine in primary sclerosing cholangitis. In a randomized, prospective, double-blind trial, 39 patients received penicillamine (250 mg t.i.d.) and 31 received a placebo. The two groups were highly comparable at entry with regard to clinical, biochemical, radiologic, and hepatic histologic features. Although a predictable cupruresis and a decrease in levels of hepatic copper were achieved in patients taking penicillamine, there was no beneficial effect on disease progression within 36 mo or on overall survival. Progressive symptoms, deterioration in serial hepatic laboratory values, or histologic progression on sequential liver biopsy specimens were similar in both groups, occurring in greater than 80% of the entire study population. The development of major side effects led to the permanent discontinuation of penicillamine in 21% of the patients taking the drug. We conclude that the use of penicillamine in primary sclerosing cholangitis is not associated with a beneficial effect on disease progression or survival, and has considerable toxicity. The study also suggests that primary sclerosing cholangitis is a progressive disease in many patients.

Frequency and significance of serum alpha-fetoprotein elevation in severe hepatitis B surface antigen-negative chronic active hepatitis.

To determine the frequency and significance of alpha-fetoprotein elevation in severe hepatitis B surface antigen-negative chronic active hepatitis, 558 serum samples obtained from 83 patients were tested by an immunoenzymometric assay. All patients received corticosteroids and sampling occurred at 6-12-mo intervals during 96 +/- 6 mo of follow-up. Twenty-nine patients (35%) had an abnormal level. In 26 patients, the abnormality was at presentation. In 3 patients, the abnormality developed 11-127 mo later. Two of these patients had primary hepatocellular carcinoma. Serum aspartate aminotransferase levels were higher in patients with an alpha-fetoprotein elevation at presentation (p less than 0.02). After therapy, the alpha-fetoprotein level normalized and patients entering remission had lower levels than at entry (p less than 0.001). alpha-Fetoprotein levels, however, did not correlate closely with serum aspartate aminotransferase levels at entry nor did they distinguish patients with different patterns of histologic activity. Outcomes after therapy were similar in patients with and without alpha-fetoprotein elevation. Three patients (4%) developed primary hepatocellular carcinoma after 113 +/- 26 mo but only 2 had elevated alpha-fetoprotein levels. We conclude that elevation of the alpha-fetoprotein level occurs commonly at presentation. The abnormality frequently resolves after corticosteroid therapy and it does not have prognostic significance. An elevation that occurs after treatment suggests primary hepatocellular carcinoma.

Lymphocyte subsets in primary sclerosing cholangitis.

As an initial step in testing the hypothesis that immunoregulatory abnormalities are important in the pathogenesis of primary sclerosing cholangitis, we determined the number and percentage of lymphocyte subsets in the peripheral blood of 33 patients with primary sclerosing cholangitis. In these patients, when compared with normal and diseased controls, there was a significant reduction in the total number of circulating T cells because of a disproportionate decrease in Leu-2a (suppressor/cytotoxic) cells. This decrease resulted in a significantly increased ratio of Leu-3a to Leu-2a cells. Patients with cirrhosis had significantly higher Leu-3a/Leu-2a (helper/suppressor) ratios than did noncirrhotic patients; both disease groups, however, had ratios that were significantly higher than controls. The number and percentage of B cells were significantly increased. Alterations in the percentage of B cells correlated significantly with histologic stage and concentrations of gamma globulin, serum IgG, and bilirubin. We conclude that these abnormalities are suggestive of a defect in immunoregulation in primary sclerosing cholangitis, which is not secondary to advanced liver disease alone and appears to be independent of chronic ulcerative colitis or obstructive jaundice.