Peripheral and central nervous system inhibition of 11ß-hydroxysteroid dehydrogenase type 1 in man by the novel inhibitor ABT-384.

ABT-384 is a potent, selective inhibitor of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD-1). One milligram of ABT-384 daily fully inhibited hepatic HSD-1. Establishing the dose that fully inhibits central nervous system (CNS) HSD-1 would enable definitive clinical studies in potential CNS indications. [9,11,12,12-(2)H4] cortisol (D4 cortisol), a stable labeled tracer, was used to characterize HSD-1 inhibition by ABT-384. D4 cortisol and its products were measured in the plasma and cerebrospinal fluid (CSF) of healthy male volunteers during D4 cortisol infusions, for up to 40 h after five daily doses of 1-50 mg ABT-384. Similar procedures were conducted in control subjects who received no ABT-384. Peripheral HSD-1 inhibition was calculated from plasma levels of D4 cortisol and its products. CNS HSD-1 inhibition was characterized from plasma and CSF levels of D4 cortisol and its products. ABT-384 regimens ≥2 mg daily maintained peripheral HSD-1 inhibition ≥88%. ABT-384 1 mg daily maintained peripheral HSD-1 inhibition ≥81%. No CNS formation of D3 cortisol (the mass-labeled product of HSD-1) was detected following ABT-384 ≥2 mg daily, indicating full CNS HSD-1 inhibition by these regimens. Partial CNS HSD-1 inhibition was associated with 1 mg ABT-384 daily. CNS HSD-1 inhibition was characterized by strong hysteresis and increased with maximum post-dose plasma concentration of ABT-384 and its active metabolites. ABT-384 has a wide potential therapeutic window for potential indications including Alzheimer's disease and major depressive disorder. Stable labeled substrates may be viable tools for measuring CNS effect during new drug development for other enzyme targets.

Residential mobility and risk of childhood acute lymphoblastic leukaemia: an ecological study.

We conducted an ecological analysis of childhood acute lymphoblastic leukaemia-incidence data from children or=$5000 as potential predictors. Incidence was lower among black boys (rate ratio (RR)=0.5) and black girls (RR=0.4) than among other children of the same sex; no other significant racial differences were detected. Incidence was elevated among males (but not females) residing in counties where >or=50% of the population relocated (RR=1.5) and among females (but not males) residing in counties where <6% of the households had incomes <$5000 (RR=1.5). These sex differences in risk factors were unexpected.

Urbanisation and incidence of acute lymphocytic leukaemia among United States children aged 0-4.

Acute lymphocytic leukaemia (ALL) incidence among children under 5 years of age was examined, utilising data from 24 United States cancer registries. County-based incidence rates among white children were compared across four levels of urbanisation: large and small metropolitan counties, and adjacent and nonadjacent rural counties. In metropolitan areas, the incidence of ALL was lower among blacks (rate ratio (RR)=0.38, confidence interval (CI)=0.33-0.44) and among Asians/Pacific Islanders (RR=0.78, CI=0.63-0.97) than among whites. Among white children, the incidence of ALL decreased across the four strata of urbanisation, from 67 to 62 to 65 to 54 cases per million person-years at-risk (two-sided trend P=0.009), such that rates were significantly lower in the most remote rural counties than in the most populous metropolitan counties (RR=0.80, 95% CI=0.70-0.91).

Medically recorded allergies and the risk of childhood acute lymphoblastic leukaemia.

Data on five allergic conditions were abstracted from the medical records of 180 cases of childhood acute lymphoblastic leukaemia (ALL) and 718 matched controls. Odds Ratios (OR) and 95% Confidence Intervals (CI) were estimated for composite variables and for individual allergies using conditional logistic regression modelling. Allergies were divided into late and early diagnoses (those made within the year before the matched case's ALL diagnosis and those made earlier, respectively). Among the early diagnoses, atopy or hives was significantly associated with ALL (OR=2.20; 95% CI: 1.16-4.16). Significant associations were found for late diagnoses of atopy or hives (OR=3.78; 95% CI: 1.00-14.29) and of asthma (OR=3.10; 95% CI: 1.39-6.95). None of the other allergic conditions were associated with ALL. These results are contrary to those of prior studies of childhood ALL and allergy.

Haemophilus influenzae type b vaccine formulation and risk of childhood leukaemia.

Incidence of childhood leukaemia was studied among subjects of a vaccine trial in Finland comparing the polysaccharide-diptheria toxoid conjugate and oligosaccharide-CRM197 conjugate Haemophilus influenzae type b conjugate vaccine formulations. Eighty cases of childhood leukaemia were detected: 35 among children on the polysaccharide-diptheria toxoid conjugate arm, and 45 among children on the oligosaccharide-CRM197 conjugate arm, which was not statistically significant.

Haemophilus influenzae type b serology in childhood leukaemia: a case-control study.

Antibody to Haemophilus influenzae type b (Hib) polysaccharide (PRP) was measured in 42 children with acute lymphoblastic leukaemia (ALL) and 42 non-leukaemic hospital controls. Modelling anti-PRP concentrations as a function of age revealed that the slopes of the trend lines differed significantly between cases and controls (P = 0.05); anti-PRP concentrations were lower among younger cases, and higher among older cases, than among controls of the same ages.

Haemophilus influenzae type b vaccination and risk of childhood leukemia in a vaccine trial in finland.

PURPOSE: To compare the incidence of childhood leukemia among children who received multiple early vaccine doses versus a single late dose in the context of a clinical trial in Finland during 1986 and 1987.METHODS: The trial was offered to the parents of all 114,000 children born in Finland between October 1, 1985 and August 31, 1987; 98% of the eligible children were enrolled. The vaccine consisted of heat-sized capsular polysaccharide of Haemophilus influenzae type b (Hib) coupled to diptheria toxoid (PRP-D). Children with odd birth dates received four doses of the vaccine at the ages of 3, 4, 6, and 14 months; children with even birth dates received only one dose, at the age of 24 months. The numbers of boys and girls with even and odd birth dates during the window of eligibility who remained alive during the follow-up period were obtained from the Finnish Population Registry. Numbers of leukemia cases diagnosed through 1996 among children with even and odd birth dates during the window of eligibility were obtained from the Finnish Cancer Registry. Poisson regression analysis of leukaemia incidence rates was conducted using the number of cases as the outcome variable and the natural logarithm of number of children at risk as an offset term. For comparison of the early and late vaccination groups, a binary variable based on odd or even date of birth was used.RESULTS: Among the 114,000 subjects, a total of 77 cases of childhood leukaemia were diagnosed: 33 in the early-vaccination group and 44 in the late-vaccination group. The incidence of childhood leukaemia was lower in the early-vaccination group (relative risk 0.72, 95% confidence interval 0.46-1.13) than in the late-vaccination group, but the difference did not reach statistical significance.CONCLUSIONS: Our results suggest that early vaccination against Hib may reduce the incidence of childhood leukaemia, but confirmatory studies are needed.

Haemophilus influenzae type B vaccination and risk of childhood leukaemia in a vaccine trial in Finland.

Incidence of childhood leukaemia was studied among subjects of a trial comparing administration of several doses of a conjugate vaccine against Haemophilus influenzae type b (Hib) starting at an early age (three months) with a single dose given at the age of two years. Among 114 000 subjects, a total of 77 cases of childhood leukaemia were detected. The incidence of childhood leukaemia was lower in the early vaccination arm (relative risk 0.72, 95% confidence interval 0.46-1.13) than late vaccination arm, but the difference did not reach statistical significance. Our results suggest that early immunization against Hib may reduce the incidence of childhood leukaemia, but confirmatory studies are needed.

Cancer surveillance series: non-Hodgkin's lymphoma incidence by histologic subtype in the United States from 1978 through 1995.

BACKGROUND: Clinical investigations have shown prognostic heterogeneity within the non-Hodgkin's lymphomas (NHLs) according to histology, but few descriptive studies have considered NHLs by subgroup. Our purpose is to assess the demographic patterns and any notable increases in population-based rates of different histologic subgroups of NHL. METHODS: Using data collected by the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, we calculated incidence rates for the major clinicopathologic categories of NHL by age, race, sex, geographic area, and time period. RESULTS: Among the 60 057 NHL cases diagnosed during the period from 1978 through 1995, total incidence (per 100 000 person-years) was 17.1 and 11.5 among white males and females, respectively, and 12.6 and 7.4 among black males and females, respectively. However, rates for follicular NHLs were two to three times greater among whites than among blacks, with little sex variation. Blacks demonstrated much higher incidence than whites for peripheral T-cell NHL, with the incidence rates higher in males than in females. For other NHL subgroups, the incidence rates for persons less than 60 years of age were generally higher among males than among females, with little racial difference; at older ages, the rates were higher among whites than among blacks, with little sex difference. High-grade NHL was the most rapidly rising subtype, particularly among males. Follicular NHL increased more rapidly in black males than in the other three race/sex groups. Overall, the broad categories of small lymphocytic, follicular, diffuse, high-grade, and peripheral T-cell NHL emerged as distinct entities with specific age, sex, racial, temporal, and geographic variations in rates. CONCLUSIONS: Findings from our large, population-based study reveal differing demographic patterns and incidence trends according to histologic group. Future descriptive and analytic investigations should evaluate NHL risks according to subtype, as defined by histology and new classification criteria.

Infant vaccinations and risk of childhood acute lymphoblastic leukaemia in the USA.

Previous studies have suggested that infant vaccinations may reduce the risk of subsequent childhood leukaemia. Vaccination histories were compared in 439 children (ages 0-14) diagnosed with acute lymphoblastic leukaemia (ALL) in nine Midwestern and Mid-Atlantic states (USA) between 1 January 1989 and 30 June 1993 and 439 controls selected by random-digit dialing and individually matched to cases on age, race and telephone exchange. Among matched pairs, similar proportions of cases and controls had received at least one dose of oral poliovirus (98%), diphtheria-tetanus-pertussis (97%), and measles-mumps-rubella (90%) vaccines. Only 47% of cases and 53% of controls had received any Haemophilus influenzae type b (Hib) vaccine (relative risk (RR) = 0.73; 95% confidence interval (CI) 0.50-1.06). Although similar proportions of cases (12%) and controls (11%) received the polysaccharide Hib vaccine (RR = 1.13; 95% CI 0.64-1.98), more controls (41%) than cases (35%) received the conjugate Hib vaccine (RR = 0.57; 95% CI 0.36-0.89). Although we found no relationship between most infant vaccinations and subsequent risk of childhood ALL, our findings suggest that infants receiving the conjugate Hib vaccine may be at reduced risk of subsequent childhood acute lymphoblastic leukemia. Further studies are needed to confirm this association and, if confirmed, to elucidate the underlying mechanism.

Family history and risk of stomach cancer in Warsaw, Poland.

In a population-based case-control study of stomach cancer conducted in Warsaw, Poland, 464 cases and 480 controls were interviewed to evaluate the role of family history and other risk factors. A greater than threefold increase in risk was associated with a history of stomach cancer in a first degree relative (OR = 3.5; 95% Cl = 2.0-6.2), but no excess risk was seen with other forms of cancer. The risk associated with familial occurrence was not significantly modified by gender, age or ABO blood type, and did not vary with Laurén histologic classification. Our findings add to evidence for a familial predisposition to both diffuse and intestinal types of gastric cancer. Further studies are needed to identify the susceptibility genes and environmental exposures that may account for the familial tendency to stomach cancer.

Fusarium mycotoxins in corn and corn products in a high-risk area for gastric cancer in Shandong Province, China.

Consumption of fermented, but not unfermented, corn pancakes has been linked with elevated stomach cancer mortality rates in rural Linqu County in Shandong Province, China. Previous surveys of fungal contamination of corn in China have detected fumonisins, which are mycotoxins produced by Fusarium moniliforme. To determine whether mycotoxins might account for the increased risk of cancer among those consuming fermented pancakes, we obtained specimens of corn, cornmeal, unfermented and fermented pancake batter, and cooked fermented pancakes from each of 16 households in Linqu County for analysis by the U.S. Department of Agriculture. Fumonisins B1, B2, and B3 were detected (> or = 0.5 microgram/g) in 19, 25, and 6% of the corn specimens, respectively, as well as in various corn products. No type A trichothecenes were detected; however, the type B trichothecenes deoxynivalenol and 15-acetyldeoxynivalenol were detected (> or = 0.5 microgram/g) in 58 and 17% of the corn specimens, respectively, and zearalenone was detected (> or = 0.5 microgram/g) in 15% of the cornmeal specimens. The mycotoxins were detected only at low levels (< 10 micrograms/g), which did not increase with fermentation. These findings do not support the hypothesis that mycotoxin contamination increases the risk of gastric cancer among those who consume fermented Chinese pancakes.

Risk of stomach cancer in relation to consumption of cigarettes, alcohol, tea and coffee in Warsaw, Poland.

To identify reasons for the high incidence rates of stomach cancer in Poland, we conducted a population-based case-control study in Warsaw. Cases were residents aged 21 to 79 years who were newly diagnosed with stomach cancer between March 1, 1994, and April 30, 1997. Controls were randomly selected from Warsaw residents registered at the nationwide Polish Electronic System of Residence Evidency, frequency-matched to cases by age and sex. Information on demographic characteristics; consumption of cigarettes, alcohol, tea and coffee; diet; medical history; family history of cancer; occupational history; and living conditions during adolescence was elicited by trained interviewers using a structured questionnaire. Included were 464 cases (90% of eligible) and 480 controls (87% of eligible). Among men, the risk of stomach cancer was significantly elevated among current smokers (OR = 1.7, 95% CI = 1.1-2.7) but not among former smokers. The excess risk was largely confined to long-term and heavy smokers, with significant 2-fold excess risk among men who smoked 40 or more pack-years. Among women, an 80% increase in risk was observed in both current and former smokers but dose-response trends were less consistent than among men. Alcohol consumption was not clearly related to risk, and no association was found for drinking regular coffee or herbal tea or using milk/cream in coffee or tea. A significant reduction in risk was linked to daily tea drinking among women, but not among men. Our findings confirm an association with cigarette smoking, which is estimated to account for approximately 20% of stomach cancers diagnosed among Warsaw residents during the study period.

Factorial trial of three interventions to reduce the progression of precancerous gastric lesions in Shandong, China: design issues and initial data.

In the fall of 1995, 3411 subjects in 13 rural villages in Linqu County, Shandong Province, China, began participating in a blinded, randomized 23 factorial trial to determine whether interventions can reduce the prevalence of dysplasia and other precancerous gastric lesions. One intervention is treatment for infection by Helicobacter pylori with amoxicillin and omeprazole. A second is dietary supplementation with capsules containing vitamin C, vitamin E, and selenium. A third is dietary supplementation with capsules containing steam-distilled garlic oil and Kyolic aged garlic extract. Investigators will evaluate histopathologic endpoints after gastroscopies with biopsies from seven standard sites in 1999. Initial data from pill counts and sampled blood levels of vitamin E, vitamin C, and S-allylcysteine indicate excellent compliance. Subjects have tolerated all interventions well, although 3.1% of those assigned to amoxicillin and omeprazole developed rashes, compared to 0.3% to those in the control group. Preliminary breath tests demonstrate substantial reductions in gastric urease activity, an indication of infection by Helicobacter pylori, among those assigned to amoxicillin and omeprazole.

Waldenström's macroglobulinemia: incidence patterns in the United States, 1988-1994.

BACKGROUND: There are few data describing the epidemiologic aspects of Waldenström's macroglobulinemia (WM), a rare lymphoplasmaproliferative disorder. METHODS: The authors evaluated the incidence of WM reported in 11 population-based cancer registries in the U.S. RESULTS: A total of 624 cases were diagnosed between January 1, 1988 (when WM became reportable) and December 31, 1994. Age-adjusted incidence rates for WM (per 1 million person-years at risk) were 3.4 among males and 1.7 among females. The rates increased sharply with age, from 0.1 at age < 45 years to 36.3 at age 75+ years (males) and from 0.1 at age < 45 years to 16.4 at age 75+ years (females). The rates for WM were comparable to those for hairy cell leukemia, but considerably lower than those for multiple myeloma or chronic lymphocytic leukemia. Some geographic variation was evident, with age-adjusted rates among white males ranging from 2.2-7.8 across registries. There was no significant change in rates over the 7-year study period (P > 0.05). The markedly higher rates for WM among whites than blacks stand in contrast to multiple myeloma, which occurs twice as often among blacks. CONCLUSIONS: This survey provides new data regarding the incidence patterns of WM in the U.S. However, further epidemiologic studies with biomarkers are needed to define the environmental, genetic, immunologic, and viral determinants of this rare but distinctive disorder.

Comparison of two enzyme-linked immunosorbent assay tests for diagnosis of Helicobacter pylori infection in China.

An ELISA based on a pool of United States strains of Helicobacter pylori was compared with a newly developed ELISA based on a pool of Chinese strains. Both assays were tested using sera from 132 Chinese study subjects with biopsy-proven H. pylori infection. Using cutpoints designed to yield equal specificities of 94.9% in an uninfected control population, the sensitivity of the Chinese assay was 100.0%, compared to 97.7% for the United States assay (P = 0.25 by McNemar test). These results suggest that a H. pylori assay based on pooled antigens from United States strains will perform as well in the rural Chinese population as one based on antigens from Chinese strains.

Is there a 'cancer corridor' in Louisiana?

Cancer mortality rates in South Louisiana are higher than the national averages, leading to the area's designation as a "cancer corridor". This study was conducted to assess whether incidence data substantiate the reputation derived from mortality statistics. Age-adjusted cancer incidence rates for 1983-1987 were calculated for South Louisiana as a whole, for five regional divisions of it, and for the combined nine areas of the Surveillance, Epidemiology, and End Results (SEER) program. Significantly lower (p < 0.0001) incidence rates were found in South Louisiana among white females, black males, and black females for cancers of all sites combined; among women of both races for cancer of the breast; among men of both races for cancers of the colon and prostate; and among whites of both sexes for melanoma and rectal cancer. South Louisiana incidence rates were significantly higher than the SEER rates only for lung and larynx cancers in white males. The excess of lung cancer was statistically significant in four out of five regions while the laryngeal cancer excess was significant only in the New Orleans area. The excessive mortality rates reported for South Louisiana are not the result of excessive incidence. These results indicate poorer cancer prognosis in this region, a phenomenon that deserves more scrutiny by the health profession.

Patterns of occurrence of the leukaemias.

Despite a proliferation of epidemiological studies during the past two decades, aetiologies of the leukaemias remain poorly understood, and characterisation of descriptive patterns has been limited. Recent publications of international mortality and incidence data, along with the expanding U.S. database, make a comprehensive assessment of leukaemia patterns particularly timely. Total leukaemia mortality has dramatically declined among children and increased among the elderly, while incidence has declined somewhat (for Caucasian and African-American females) or remained stable (for African-American males) during the past two decades in the United States. Population-based 5-year relative survival for total leukaemia has risen substantially among children since the mid-1970s, and improved slightly among other age groups in the U.S., where survival is consistently higher among Caucasians than African-Americans, but differs little by gender. In a detailed assessment by leukaemia subtype, some important differences in geographic, racial/ethnic, age and trend patterns are identified, suggesting that the subtypes may have different aetiologic factors. Proven and suspected risk factors cannot explain more than a small fraction of the observed geographic and temporal variation in incidence. Several noteworthy subtype-specific characteristics or trends warrant further investigation: for acute lymphoid leukaemia (ALL), increasing incidence, with higher rates in Spanish and Latino populations; for chronic lymphoid leukaemia (CLL), declining incidence, with dramatically low rates among Asians; for acute myeloid leukaemia (AML), increasing incidence among African-American males; and for chronic myeloid leukaemia (CML), declining rates among Caucasian but not among African-Americans.

Epidemiology of human leukemia.

The leukemias show clear geographic, racial, ethnic, age, and gender variation in both incidence and mortality, and the patterns of occurrence differ among subtypes. Despite decades of epidemiologic study, the known and suspected risk factors for leukemia are insufficient to explain more than a small fraction of the observed variation in the occurrence of the leukemias. Important contributions to the literature in 1993 included studies further clarifying the role of known risk factors (ionizing radiation, certain chemotherapeutic agents, and specific occupational chemical exposures) and suspected risk factors (infectious agents, electromagnetic fields, cigarette smoking, other chemotherapeutic agents, and additional occupational chemical exposures) in leukemogenesis.

What the hand surgeon should know about workers' compensation.

It is important for surgeons treating work-related conditions to be knowledgeable of workers' compensation laws in their states. They should also work closely with the designated provider and/or employer to effect speedy recovery and return to work.