A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.

Radiology volunteers to support a breast cancer screening program in Peru: Description of the project, preliminary results, and impressions.

Breast cancer is the second most common cancer in Peruvian women. Due to limitations in national breast cancer screening programs, especially in rural areas, more than 50% of cases of breast cancer in Peru are diagnosed in advanced stages. In collaboration with a local clinic registered as a nongovernmental organization (CerviCusco), RAD-AID International aims to create a sustainable diagnostic structure to improve breast cancer screening in Cuzco. With the support of local, national, and international partners that have collaborated in analyzing radiological resources, raising awareness in the population, acquiring equipment, training clinical staff, and building referral networks, our teams of radiologists, included in the RAD-AID team, have participated in training CerviCusco staff in breast ultrasound, thus enabling additional training for radiology residents through a regulated international collaboration.

Radiology volunteers to support a breast cancer screening program in Peru: description of the project, preliminary results, and impressions. / Voluntariado radiológico para apoyar un programa de detección precoz del cáncer de mama en Perú: descripción del proyecto, presentación de los primeros resultados e impresiones.

Breast cancer is the second most common cancer in Peruvian women. Due to limitations in national breast cancer screening programs, especially in rural areas, more than 50% of cases of breast cancer in Peru are diagnosed in advanced stages. In collaboration with a local clinic registered as a nongovernmental organization (CerviCusco), RAD-AID International aims to create a sustainable diagnostic structure to improve breast cancer screening in Cuzco. With the support of local, national, and international partners that have collaborated in analyzing radiological resources, raising awareness in the population, acquiring equipment, training clinical staff, and building referral networks, our teams of radiologists, included in the RAD-AID team, have participated in training CerviCusco staff in breast ultrasound, thus enabling additional training for radiology residents through a regulated international collaboration.

Differentiating limb tissue affects neurite growth in spinal cord cultures.

Limb bud mesenchyme enhances and directs the growth of tadpole spinal cord nerve fibers in tissue culture. This effect on elongating neurites may involve alterations in nerve-substratum interactions by the presence of undifferentiated target tissues. The relationship between nerve fibers and their potential innervation sites can explain directed nerve growth to the developing limb.

Histogram analysis versus region of interest analysis of dynamic susceptibility contrast perfusion MR imaging data in the grading of cerebral gliomas.

BACKGROUND AND PURPOSE: Histogram analysis can be applied to dynamic susceptibility contrast (DSC) perfusion MR imaging datasets and can be as effective as traditional region-of-interest (ROI) measurements of relative cerebral blood volume (rCBV), an operator-dependent method. We compare the routine ROI method with histogram analysis in the grading of glial neoplasms. MATERIALS AND METHODS: Ninety-two patients underwent conventional and DSC MR imaging. Routine rCBV (rCBVmax) measurements were obtained from ROIs of the maximal abnormality within the glioma. Histogram analysis rCBVT was performed with an ROI drawn around the maximal tumor diameter. Spearman rank correlations measured associations among glioma grade, rCBVmax, and histogram measures. Mann-Whitney tests compared grade with respect to rCBV and histogram measures. Logistic regression and McNemar test compared the utility of rCBVmax and histogram measures for detecting high grade gliomas. RESULTS: Routine rCBVmax analysis showed significant correlation with grade (r = 0.734, P < .001). Histogram rCBVT metrics showed significant correlation with grade (P < .008); the 3 highest were rCBVT SD, SD50, and mean25 (r = 0.718, 0.684, and 0.683, respectively). Grade could be predicted by rCBVmax (P < .001) as well as rCBV(T) (P < .008). Three rCBVT histogram measures (SD, SD25, and SD50) detected high-grade glioma with significantly higher specificity than rCBVmax when the diagnostic tests were constrained to have at least 95% sensitivity. CONCLUSION: rCBVT histogram analysis is as effective as rCBVmax analysis in the correlation with glioma grade. Inexperienced operators may obtain perfusion metrics using histogram analyses that are comparable with those obtained by experienced operators using ROI analysis.

Trends in cancer incidence and mortality in the United States, 1969-76.

Trends in cancer incidence and mortality in the United States were analyzed over the period 1969 through 1976. The greatest increase in incidence among whites occurred for lung cancer among females (almost 9%/yr), whereas the incidence of cancer of the uterine corpus increased 6% per year. Cancer of the cervix showed the greatest decrease in incidence, an average of 6% per year. Stomach cancer incidence and mortality showed a substantial decline for each sex, and rectal cancer incidence increased for each sex whereas mortality declined. The incidence of cancer of the female breast increased 1.8% per year without inclusion of the rates for 1974 and 1975, when an unusually large increase occurred. Cancer mortality data were presented for the total United States on the basis of data from the National Center for Health Statistics. Emphasis was focused on the comparability of cancer incidence data over the time period studied, given the fact that cancer incidence was measured by the Third National Cancer Survey for the period 1969-71 and by the Surveillance, Epidemiology, and End Results Program for the period 1973-76. Each survey covered approximately 10% of the U.S. population but had four geographic areas in common. Investigation of the comparability of these two surveys revealed that the incidence rates for whites were sufficiently comparable to permit an analysis of trends in cancer incidence over the entire period 1969-1976. Such comparability was not found for blacks. Therefore, cancer incidence data are presented only for whites, but cancer mortality data are presented for both whites and blacks.

Cancer patient survival: Surveillance, Epidemiology, and End Results Program, 1973-79.

Data from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were used in the evaluation of cancer patient survival experience for almost 10% of the U.S. population. This first report contains actuarial (life table) survival analysis on 368,263 patients with first primary cancer diagnosed in 1973-79 from nine SEER areas: the entire States of Connecticut, Iowa, New Mexico, Utah, and Hawaii and the metropolitan areas of Atlanta, Detroit, San Francisco, and Seattle. Both observed and relative survival rates were shown for whites and blacks, sex, age, primary site, and time period (each yr, 1973-78). The largest racial difference in survival was for cancer of the corpus uteri: 87% 5-year relative survival rate for white females versus only 54% for black females. Survival rates varied considerably by primary site. For most sites, as age increased the relative and observed survival rates decreased. Analysis of relative survival rates by ech year of diagnosis, 1973-78, and for each year following diagnosis suggested increasing rates for cancers of the colon, lung, and prostate gland, whereas there were no definite increases for cancers of the female breast and corpus uteri. A dramatic increase in survival from acute lymphocytic leukemia was found for children under 15 years of age, with the 4-year relative survival rate increasing from 51% among those diagnosed in 1973-75 to 65% for those diagnosed in 1976-78.

Cancer patient survival among ethnic groups in the United States.

Data from the Surveillance, Epidemiology and End Results Program of the National Cancer Institute were used in the evaluation of cancer patient survival experience for 8 racial-ethnic groups in the U.S. population--Anglos, Hispanics, blacks, American Indians, Chinese, Japanese, Filipinos, and Hawaiians. This report contains an actuarial (life table) survival analysis on 402,752 patients with first primary cancer diagnosed in 1973-79 and followed through December 31, 1981. Relative and observed survival rates are shown for each sex separately by primary site. Survival rates for females exceeded those for males for each primary site except for gallbladder and urinary bladder. The primary site having the highest survival rate among each group studied was the thyroid gland with a 5-year relative rate of 91% for all races combined. Rates were uniformly low among each group for cancers of the esophagus, liver, and pancreas. Survival rates for Hispanics were almost identical to those for Anglos; the largest differences were found for bladder (73% for Anglos vs. 64% for Hispanics), Hodgkin's disease (70% for Anglos vs. 61% for Hispanics), and ovary (35% for Anglos vs. 42% for Hispanics). For many primary sites Japanese experienced the highest survival rates and American Indians the lowest. In comparison to Anglos, Japanese had higher survival for cancers of the stomach, colon, prostate gland, and breast. The higher survival for stomach and breast cancers persisted even when controlling for age of patient and stage of disease at diagnosis. Survival rates for blacks were much lower than those for whites for cancers of the corpus uteri and urinary bladder. Survival rates for Chinese and Hawaiians were roughly comparable to those for Anglos, whereas survival rates for Filipinos tended to be similar to those for blacks.

Incidence of testicular cancer in the United States related to marital status, histology, and ethnicity.

Analyses were made of the marital status of 3,346 patients with the diagnosis of testicular cancer. Among whites, blacks, and Puerto Rico Hispanics, the risk was greater among single than married men. Among whites and both Puerto Rico and New Mexico Hispanic groups, the elevated risk was apparent for histologic types other than seminoma. Among single white men, this excess risk began after 25-29 years of age. During the 10 years 1973 through 1982, incidence increased among single men under age 45, but little increase in incidence was found for married men. There was a striking increase among single men ages 30-44. These data confirm that single men are more susceptible to non-seminoma testicular cancer than are married men after the age of 30. Testicular cancer is increasing fastest among single men of ages 30-44.

Stomach and colorectal cancers in Puerto Rican-born residents of New York City.

Colorectal cancer incidence and mortality rates for Puerto Rican-born residents in New York City (PR-NYC) for 1975-79 were about two times those for Puerto Ricans living in Puerto Rico (PR-PR) and one-half to almost two-thirds those for other whites in New York City. From 1958 to 1979, colon cancer mortality rates for PR-NYC increased dramatically (i.e., 212% in males and 54% in females), whereas in PR-PR, male rates increased only slightly and female rates remained constant. For stomach cancer, incidence rates for male and female PR-NYC were slightly, but not significantly, higher than those for male and female PR-PR. In contrast, stomach cancer mortality rates for PR-NYC were lower than those for PR-PR throughout the survey period, and mortality decreased substantially in all racial-ethnic groups in New York City and Puerto Rico from 1958 to 1979. Results of this study indicated that the changes in colorectal and stomach cancer incidence and mortality in Puerto Rican-born residents after migration to New York City, although not as dramatic as in migrants from Japan and Eastern Europe, were comparable to those observed for Hispanic migrants to New Mexico and Los Angeles.

Incidence of prostate cancer and marital status.

Analyses were made of the marital status of 48,106 men with adenocarcinoma of the prostate, who were reported to the Surveillance, Epidemiology, and End Results program of the National Cancer Institute during the 9 years ending in 1981. The hypothesis tested was that widowers and possibly divorced men were at higher risk for developing this cancer than were married men. Age- and marital-specific incidence rates were calculated for 4 age groups (45-54, 55-64, 65-74, and greater than or equal to 75 yr) for U.S. white, black, and Puerto Rico Hispanic men. Risks for other marital status groups were calculated relative to "married." Among the 45-54 age group, all ethnic groups had an excess risk for widowed as compared to the risk for married men [whites, relative risk (RR) = 1.7; blacks, RR = 1.5; Hispanics, RR = 2.5]. These excesses were not significantly different from unity. In the other 3 age groups and among each ethnic group, among whom 97.3% of all prostate cancers occurred, there was no suggestion of an excess risk for the development of prostate cancer among widowed men relative to married men. Unexpected findings were significant deficits in risk for single, separated, and divorced white men as compared to the risk for married men. Thus this study does not support an association between widowerhood and an increased risk for the development of prostate cancer. Additional studies are required to investigate a suggestion of decreased risk for older, separated, and divorced men.

Serum cholesterol and colon cancer incidence in Hawaiian Japanese men.

A prospective study of cancer and coronary heart disease (CHD) in 8,006 Hawaiian Japanese men, aged 45-68 years, showed that serum cholesterol levels below 180 mg/dl predicted low rates of CHD and high rates of colon cancer. Men with colon cancer had lower mean serum cholesterol levels than did other members of the cohort, including those with cancer at other sites. The lowest serum cholesterol levels were obtained from men who died as a result of colon cancer. The lack of such an association with other cancers and the persistence of this inverse association in colon cancer patients diagnosed 5-9.9 years after examination suggest that the low serum cholesterol was not due to preexisting disease. Right colon tumors showed the strongest inverse association with serum cholesterol. The differences between CHD and colon cancer in respect to serum cholesterol indicate that different subsets of the westernized Japanese population are affected.

Ethnic patterns of Hodgkin's disease incidence among children and adolescents in the United States, 1973-82.

The descriptive epidemiologic findings were summarized on 1,109 patients (white, black, and Hispanic) under 20 years of age who were diagnosed with Hodgkin's disease as reported to the Surveillance, Epidemiology, and End Results ("SEER") Program of the National Cancer Institute from 1973 to 1982. Across all ethnic strata, incidence rates increased with advancing age at diagnosis, with white adolescents 15-19 years old exhibiting the highest rates (male, 3.67; female, 4.18). Gender difference among children 0-14 years of age was most evident in blacks (male:female ratio: 4.0 for blacks, 1.0 for whites). Highest adolescent:childhood ratios of incidence rates were noted for females (5.81 for whites and 8.29 for New Mexico Hispanics) and lowest, for Hispanic males (1.25, New Mexico; 2.15, Puerto Rico). Whites exhibited the highest percentage of the nodular sclerosis histologic subtype (65%) and Hispanics, the lowest (45%). Conversely, Hispanics had higher rates of histologic types associated with a poorer prognosis (mixed cellularity and lymphocyte depletion). These differing age and histologic patterns were consistent with previously described international patterns of disease occurrence. Analysis of secular trends for whites from 1969 to 1982 revealed relatively stable rates for youngest ages and male adolescents. Rates increased over time for white female adolescents, but the trend was not statistically significant.

Cancer incidence and mortality trends among whites in the United States, 1947-84.

Cancer incidence trends from the late 1940s to 1983-84 were assessed among white residents of five geographic areas (Atlanta, Connecticut, Detroit, Iowa, San Francisco-Oakland) by means of data derived from several National Cancer Institute surveys, the Connecticut Tumor Registry, and the Surveillance, Epidemiology, and End Results Program. Incidence trends were compared with mortality trends for the entire United States and for the same five study areas. This study documented rising incidence and mortality rates for four cancers: lung cancer, melanoma of the skin, multiple myeloma, and non-Hodgkin's lymphomas. Increases in lung cancer continued through the early 1980s, but the rate of increase has been moderating during recent years, particularly among males and at younger ages for whom recent declines are evident. Overall, lung cancer incidence rates increased more than 220 and 400% among males and females, respectively. Although much rarer than lung cancer, melanoma of the skin and multiple myeloma increased greatly until the early 1980s among both males and females. The overall rate of increase in melanoma incidence among males was greater than that for lung cancer, and the rate of increase in multiple myeloma mortality among females was exceeded only by that for lung cancer. Increases of 70-120% were observed for non-Hodgkin's lymphomas. Increases in incidence and mortality rates for pancreatic cancer were apparent during the early years but less conspicuous in recent years. Laryngeal and kidney cancer rates generally increased substantially, although the changes were not remarkable for laryngeal cancer mortality among males and kidney cancer mortality among females. The rates for cancers of the mouth and pharynx increased among females but not males. Prostate, colon, and bladder cancer incidence rates increased more than 65% among males, whereas mortality rates changed only moderately. The incidence of thyroid cancer increased more than 75% among both sexes until the late 1970s, but mortality rates have declined during the period of study. Breast cancer incidence increased 30%, whereas mortality rates remained remarkably constant. The incidence of corpus uteri cancer increased dramatically during the mid-1970s and decreased substantially thereafter; these changes were not reflected in the mortality rates, which continually declined during the entire time period. The incidence of testicular cancer increased more than 90% and that of Hodgkin's disease did not change greatly; however, mortality rates for both cancers declined more than 50% since the late 1960s and early 1970s.(ABSTRACT TRUNCATED AT 400 WORDS)

Comparative effects of methylphenidate and thioridazine in hyperkinetic children. I. Clinical results.

The effects of three pharmacological treatments, methylphenidate hydrochloride, thioridazine hydrochloride, a methylphenidate/thioridazine combination, and placebo were studied in outpatient hyperkinetic children rated hyperactive both in school and at home or clinic. Active treatment lasted 12 weeks; placebo lasted four weeks. Significant clinical improvement was obtained in a variety of settings--all treatments were superior to placebo on ratings filled out by parents, teachers, and clinic staff. Though initially the combination of methylphenidate and thioridazine tended to produce greater clinical improvement, it was not superior to methylphenidate alone after 12 weeks of treatment. Methylphenidate alone and the methylphenidate/thioridazine combination were more effective than thioridazine alone. The salient side effects with methylphenidate treatment were decrease in appetite, difficulty in falling asleep, and increased mood sensitivity. In contrast, thioridazine administration was associated with appetite increase and enuresis.

Morphological response of extending spinal neuritic growth cones to peripheral target tissue.

Nerve fibers extend from spinal cord explants of larval frog in an enhanced and directed manner when cocultured with limb mesenchyme target tissue. In order to gain a better understanding of the events involved in target directed neurite extension, a detailed examination of the nerve growth cone was undertaken. The growth cones of spinal neurites that had elongated in the presence or absence of target tissue were examined by light and electron microscopy. Scanning electron microscopy revealed that growth cones of cord+limb cultures were elaborate in form with numerous and long filopodia, while those cultured in the absence of the target tissue appeared relatively simple with few, short filopodia. A morphological parallel existed between those growth cones that were cultured without the target and those in cord+limb cultures but which grew from the side of the cord explant away from the mesenchyme tissue. When examined with the transmission electron microscope, growth cones under target influence were organelle-rich in contrast to target-deprived growth cones, which lacked the extensive array of vesicles, endoplasmic reticulum, and filaments. When the attachment substratum of polylysine was substituted by collagen, the dramatic differences in growth cones were not realized, although enhanced, oriented growth still occurred in the presence of limb target tissue. It appears that growth cone morphology is a dynamic reflection of the growth effects elicited by a target tissue factor that in turn may be mediated by the nature of the extracellular environment.

Neuronal overload in the developing anuran lateral motor column in response to limb removal and thyroid hormone.

The lateral motor column (LMC) in the anuran spinal cord normally undergoes a dramatic reduction in motor neuron number during development. At least two factors influence this process: the limb target which is required for the progression of cell loss, and thyroid hormone, a requisite for metamorphosis. This study has examined the relative and combined effects of limb amputation and exogenous thyroxine, initiated at the onset of normal rapid cell loss in Rana pipiens tadpoles, in regulating neuron number in the lumbosacral LMC. Thyroxine treatment or unilateral limb amputation temporarily resulted in significantly more LMC neurons than in untreated controls. Extraordinary numbers of motor neurons persisted through metamorphic climax when both treatments were combined. Population sizes frequently exceeded the maximum number of neurons observed prior to the onset of natural cell loss. Moreover, thyroxine-treated tadpoles contained increased numbers of mitotic figures in the ventricular zone of the spinal cord and significantly more newly generated cells in the LMC, as revealed by 3H-thymidine autoradiography. These findings suggest that thyroxine-potentiated mitogenesis promotes greater numbers of new motor neurons to the LMC while, simultaneously, target removal delays the loss of extant cells. It is proposed that this interaction effectively maintains an immature state in the LMC so that neuronal "decisions" for survival and the consequent loss of target-deprived neurons are postponed far longer than previously reported.

Neurotropic influence of mesenchymal limb target tissue on spinal cord neurite growth in vitro.

Peripheral nerve fiber outgrowth from developing spinal cord is proposed to be under the influence of the limb bud target which, at the time of nerve fiber invasion, is in an essentially premuscular, mesenchymal condition. Thus, the true target for elongating spinal nerve fibers in early development is mesenchyme rather than differentiated skeletal muscle. Spinal cord explants derived from stage V larval Rana pipiens were cultured in a defined medium in the presence or absence of mesenchymal limb tissue or limb-conditioned medium (LCM). Analysis of quantified neuritic outgrowth under these conditions demonstrated a dependency on the target tissue for enhanced nerve fiber density and oriented growth. The characteristics of neuritic growth in the presence of limb mesenchyme or LCM changed from the relatively sparse and straight outgrowth of control cords to dense, wavy arborizations. Areas of the cord explants nearest the limb tissue exhibited the greatest increases in nerve fiber density and morphologic complexity. Additionally, an inverse relationship existed between growth enhancement and the cord-to-target distance. Regulation of directed nerve growth in vitro is suggested to result from a diffusible, target-originated growth factor that binds to the attachment substratum as a concentration gradient guidance pathway with implications for mechanisms of in vivo nerve growth.

Inferior vena cava interruption: a new indication?

Propagating illofemoral venous thrombosis that occurs despite adequate anticoagulation can be detected by the serial fibrinogen uptake test. Twenty-three patients who were receiving heparin sodium for confirmed iliofemoral thrombophlebitis underwent the serial fibrinogen uptake test. There was an increasing percentage of isotope uptake at the groin and the upper part of the thigh in eight of these patients, three of whom subsequently developed clinical signs, perfusion, and ventiliation lung scan findings compatible with the occurrence of pulmonary embolism. The remaining 15 patients had decreasing serial fibrinogen uptake during heparin therapy and no sequelas indicative of pulmonary embolism. Progressive thrombosis in adequately heparinized patients indicates failure of anticoagulation therapy and, when this occurs, we believe that interior vena cava interruption should be considered before a first, but potentially lethal, pulmonary embolus develops.

Target tissue control of nerve fiber growth rate and periodicity in vitro.

Spinal cord and dorsal root ganglion nerve fibers of tadpoles elongate in vitro at an increased rate in the presence of target tissue or target-conditioned medium. These neurites extend in a cyclic fashion with the period between the occurrence of maximal growth rates being under target influence. Rate parameters may be an important feature in the understanding of directed nerve growth during development and regeneration.