A randomised trial evaluating bevacizumab as adjuvant therapy following resection of AJCC stage IIB, IIC and III cutaneous melanoma: an update.

At present, there are no standard therapies for the adjuvant treatment of malignant melanoma. Patients with primary tumours with a high-Breslow thickness (stages IIB and IIC) or with resected loco-regional nodal disease (stage III) are at high risk of developing metastasis and subsequent disease-related death. Given this, it is important that novel therapies are investigated in the adjuvant melanoma setting. Since angiogenesis is essential for primary tumour growth and the development of metastasis, anti-angiogenic agents are attractive potential therapeutic candidates for clinical trials in the adjuvant setting. Therefore, we initiated a phase II trial in resected high-risk cutaneous melanoma, assessing the efficacy of bevacizumab versus observation.In the interim safety data analysis, we demonstrate that bevacizumab is a safe therapy in the adjuvant melanoma setting with no apparent increase in the surgical complication rate after either primary tumour resection and/or loco-regional lymphadenectomy.

Resistance to a triple combination of broad-spectrum anthelmintics in naturally-acquired Ostertagia circumcincta infections in sheep.

AIM: To measure the efficacy of two macrocyclic lactone-levamisole-benzimidazole combination drenches against naturally-acquired abomasal nematode infections on a sheep farm in the North Island, New Zealand. METHODS: Eighteen lambs carrying naturally-acquired worm burdens were removed from pasture and randomly allocated to one of three equal-sized groups, consisting of an untreated control group and two treatment groups. One treatment group was given a single oral dose of a triple-combination anthelmintic administered at the manufacturer's recommended dose rate of 0.2 mg/kg ivermectin, 7.5 mg/kg levamisole and 5.0 mg/kg albendazole. The other treatment group received a similar dose of another triple-combination drench consisting of 0.2 mg/kg abamectin, 8.0 mg/kg levamisole and 4.5 mg/kg oxfendazole. Worm counts were carried out post mortem on the abomasa of all animals in all groups, 10 days after treatment. RESULTS: While the abamectin-levamisole-oxfendazole combination was highly effective against all three abomasal nematode species present, the ivermectin-levamisole-albendazole combination was not. In the latter instance, a reduction of only 78% was achieved against infections of Ostertagia (=Teladorsagia) circumcincta. CONCLUSIONS: These results provide evidence of resistance to an ivermectin-levamisole-albendazole combination drench by O. circumcincta. CLINICAL RELEVANCE: Besides representing the first confirmed report of resistance to a combination drench consisting of three broad-spectrum anthelmintics, the present results provide further evidence of the continuing escalation of multiple anthelmintic resistance in sheep nematodes in New Zealand.

Pharmacological knock-down of the presenilin 1 heterodimer by a novel gamma -secretase inhibitor: implications for presenilin biology.

Intramembranous cleavage of the beta-amyloid precursor protein by gamma-secretase is the final processing event generating amyloid-beta peptides, which are thought to be causative agents for Alzheimer's disease. Missense mutations in the presenilin genes co-segregate with early-onset Alzheimer's disease, and, recently, a close biochemical linkage between presenilins and the identity of gamma-secretase has been established. Here we describe for the first time that certain potent gamma-secretase inhibitors are able to interfere with the endoproteolytic processing of presenilin 1 (PS1). In addition, we identified a novel gamma-secretase inhibitor, [1S-benzyl-4R-[1-(5-cyclohexyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3(R,S)-ylcarbamoyl)-S-ethylcarbamoyl]-2R-hydroxy-5-phenyl-pentyl]-carbamic acid tert-butyl ester (CBAP), which not only physically interacts with PS1, but upon chronic treatment produces a "pharmacological knock-down" of PS1 fragments. This indicates that the observed accumulation of full-length PS1 is caused by a direct inhibition of its endoproteolysis. The subsequent use of CBAP as a biological tool to increase full-length PS1 levels in the absence of exogenous PS1 expression has provided evidence that wild-type PS1 endoproteolysis is not required either for PS1/gamma-secretase complex assembly or trafficking. Furthermore, in cell-based systems CBAP does not completely recapitulate PS1 loss-of-function phenotypes. Even though the beta-amyloid precursor protein cleavage and the S3 cleavage of the Notch receptor are inhibited by CBAP, an impairment of Trk receptor maturation was not observed.

Improved vascular endothelial function after oral B vitamins: An effect mediated through reduced concentrations of free plasma homocysteine.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for coronary heart disease (CHD). Dietary supplementation with B vitamins lowers plasma homocysteine by up to 30%. However, little is known about the potential beneficial effects of homocysteine lowering on vascular function in patients with CHD. METHODS AND RESULTS: We investigated 89 men with CHD (aged 56 [range 39 to 67] years). Brachial artery flow-mediated dilatation (endothelium dependent) and nitroglycerin-induced dilatation (endothelium independent) were measured before and 8 weeks after treatment with either (1) folic acid (5 mg) and vitamin B(12) (1 mg) daily (n=59) or (2) placebo (n=30). Total, protein-bound, and free plasma homocysteine, serum folate, and vitamin B(12) were measured at baseline and at 8 weeks. Flow-mediated dilatation improved after treatment with B vitamins (2.5+/-3.2% to 4.0+/-3.7%, P:=0.002) but not placebo (2.3+/-2.6% to 1.9+/-2.6%, P:=0.5). Vitamin therapy lowered plasma concentrations of total homocysteine (from 13.0+/-3.4 to 9.3+/-1.9 micromol/L, P:<0.001), protein-bound homocysteine (from 8.7+/-2.8 to 6.2+/-1.4 micromol/L, P:<0.001), and free homocysteine (from 4.3+/-1.2 to 3.0+/-0.6 micromol/L, P:<0.001) and raised concentrations of serum folate (from 10.3+/-4.3 to 31.2+/-10.8 ng/mL, P:<0.001) and vitamin B(12) (from 314+/-102 to 661+/-297 pg/mL, P:<0.001). In regression analysis, improved flow-mediated dilatation correlated closely with the reduction in free plasma homocysteine (r=-0.26, P:=0.001), independent of changes in protein-bound homocysteine, folate, and vitamin B(12). Nitroglycerin-induced dilatation was unchanged after both B vitamins and placebo. CONCLUSIONS: Folic acid and vitamin B(12) supplementation improves vascular endothelial function in patients with CHD, and this effect is likely to be mediated through reduced concentrations of free plasma homocysteine concentrations. Our data support the view that lowering homocysteine, through B vitamin supplementation, may reduce cardiovascular risk.

Peripherin/rds influences membrane vesicle morphology. Implications for retinopathies.

Peripherin/rds is an integral membrane glycoprotein found in the rim regions of vertebrate photoreceptor cell discs. Natural mutations of the encoding gene result in degenerative retinal disorders, such as retinitis pigmentosa. The retinal degeneration slow (rds) phenotype, observed in mice, is considered to be an appropriate model for peripherin/rds-mediated retinitis pigmentosa. Associated abnormalities in the outer segment of photoreceptor cells have implicated peripherin/rds in some aspect of disc morphology, yet it remains unclear whether such morphological effects are the cause or the result of this condition. Here we present the first direct evidence to support a role for peripherin/rds in maintaining the flattened vesicle morphology characteristic of photoreceptor outer segments. In vitro expression yields a 36-kDa immunoreactive species, which is inserted into membranes and undergoes N-glycosylation, inter- and intramolecular disulfide bonding, and dimerization. Electron microscopy reveals that peripherin/rds flattens microsomal vesicles. This effect appears to be dependent on disulfide bond formation but not N-glycosylation. The inability of two pathogenic peripherin/rds mutants (P216L and C165Y) to flatten membrane vesicles implicates such mutations as the primary cause of the retinal degeneration observed in retinitis pigmentosa.

Are newspapers a viable source for intentional injury surveillance data?

BACKGROUND: Previous researchers have reported that newspapers were useful adjuncts to unintentional injury surveillance efforts in a nearby southern state. The current study sought to determine whether newspaper accounts of intentional injuries could provide a reliable source of primary or secondary surveillance data. METHODS: Newspaper accounts of assaults, homicides, suicides, and rapes occurring in Jefferson County, Alabama, between January 1, 1991, and December 31, 1991, were compared with similar data from official governmental agencies whose responsibility it is to investigate and/or document the occurrence, details, and characteristics of violent events resulting in death or injury. RESULTS: Newspapers greatly underreported suicides, rapes, and assaults, and reported firearms-related incidents in numbers that substantially exceeded their actual occurrence. CONCLUSIONS: Much information of potential value for injury surveillance purposes appears to be excluded from newspapers by editorial process and policy. Thus, newspapers are neither a valid nor reliable source for intentional injury surveillance purposes.

Factors associated with life satisfaction among a sample of persons with neurotrauma.

Factors were examined that are associated with life satisfaction one year post-discharge for persons with a spinal cord (SCI) or traumatic brain injury (TBI). Findings show persons with SCI or TBI should be considered as two distinct groups with regard to factors affecting life satisfaction. Different strategies might be considered to affect either group. Three psychosocial variables significantly increased life satisfaction for persons with SCI: closeness to family, the level of family activities, and blaming oneself for the injury. For persons with TBI, total family satisfaction, blaming oneself for the injury, being employed, being married, and having memory and bowel independence significantly increased life satisfaction. For persons with TBI, there was a difference in the number of factors affecting life satisfaction dependent on whether the persons blamed themselves or not. Those who do not blame themselves show a greater number of functional activities as indicators for their self-satisfaction.

Factors influencing failure to return to work due to traumatic brain injury.

About 63% of all traumatic brain injuries (TBI) occur in teenagers and adults aged 15-64 years, the primary working population. Since reports of failure to return to work (FTRTW) vary, understanding the factors that influence FTRTW is key to improving work outcomes for this primarily working-age population. Our study sample consists of 343 previously employed persons who were hospitalized following TBI and had either returned to work at 1 year or had failed to return to work because of their injury (injury-related FTRTW). Medical records were reviewed and participants were interviewed by telephone at 1 year post-discharge. Individuals with injury-related FTRTW were far more likely to report dependence or modified independence on the Functional Independence Measure (FIM) than those who were employed at 1 year. The joint distribution of motor and cognitive items suggests that, for a given level of cognitive function, the addition of a motor limitation will result in greater injury-related FTRTW. In addition as motor function declines, FTRTW is further increased. Injury-related FTRTW is also associated with being unmarried and not completing high school. While the importance of behavioural, economic, and psychosocial factors should not be minimized, services aimed at improving function can be expected to have an impact on RTW after TBI.

Barriers to return to work among persons unemployed due to arthritis and musculoskeletal disorders.

OBJECTIVE: To identify barriers to return to work (RTW) among persons likely to be seen in a clinician's practice who are unemployed due to arthritis and musculoskeletal disorders. METHODS: Two hundred eighteen persons unemployed due to arthritis and musculoskeletal disorders were interviewed at baseline and followed up for 1 year, at which time their work status was ascertained. Backward stepwise logistic regression was used to determine the association of baseline clinical, sociodemographic, and work-related factors to their work status at 1 year of followup. RESULTS: Fifty-one (24%) of 216 initially unemployed subjects had returned to permanent paid employment of > or = 20 hours/week after 1 year. Having rheumatoid arthritis, Social Security Disability Insurance (SSDI) status, a high pain level, older age, and lower education were barriers to reemployment. CONCLUSION: This study establishes the importance of chronic pain and having rheumatoid arthritis as factors independently associated with failure to RTW among persons unemployed due to arthritis and musculoskeletal disorders. The importance of SSDI beneficiary status, age, and education level in RTW is further confirmed. Duration of unemployment or previous work factors were not predictors of RTW in this group.

Musculoskeletal disability, employment, and rehabilitation.

OBJECTIVE: To determine which, if any, baseline social and disease characteristics can be used to identify persons with musculoskeletal disabilities accepted for state-federal vocational rehabilitation services who are most likely to return to work. METHODS: A database of case closures from the Alabama Vocational Rehabilitation Service was analyzed using segmentation modelling. This included all persons (n = 4093) with musculoskeletal disability who were accepted by the Alabama Vocational Rehabilitation Agency in 1987-91. Demographics, income, type of disability, severity of disability, medical insurance, similar benefits, benefit status, and referral source were independent variables. Outcome (dependent) variable was work status at end of agency services. RESULTS: Overall, 71% of persons with arthritis and musculoskeletal disorders who were accepted for vocational rehabilitation services in 1987-91 returned to work at the end of agency services. Segmentation modelling created a tree in which certain baseline characteristics formed subgroups with differing rates of successful rehabilitation. Social Security Disability Insurance (SSDI) status was the single best predictor of rehabilitation. Seventy-three percent of nonbeneficiaries were rehabilitated compared to 55% of beneficiaries (p < 0.00001). For non-SSDI beneficiaries, education level > or = grade 12 was associated with better rehabilitation outcome (p < 0.00001). SSDI beneficiaries with nonback disorders fared better than those with back disorders (p < 0.05). Disease severity, assessed by Federal Special Programs criteria, was not associated with rehabilitation outcome at any level of the tree. CONCLUSION: Simple baseline social and disease characteristics can be used to identify groups of persons accepted for vocational rehabilitation services with musculoskeletal disability with differing rates of vocational rehabilitation. Disability benefit status and education level are important predictors of return to work after agency services. These findings can lead to the development of strategies to improve the efficacy of vocational rehabilitation services.

Homicide among black males in Jefferson County, Alabama 1978-1989.

This study examined 1505 of 1573 (96%) homicides occurring in Jefferson County, Alabama, between 1978 and 1989, that were investigated by the Coroner/Medical Examiners' Office. During this 12 year period, Jefferson County's average annual homicide rate was 18.9 per 100,000 compared to an 11.3 per 100,000 State of Alabama's rate and a 9.3 per 100,000 US rate. In Jefferson County, the average annual homicide rate among blacks (41.4) was almost six times the rate among whites (7.1). The highest average annual race-specific homicide rate was in black males (75.9), followed by black females (12.4), white males (10.4) and white females (4.1). Black males in the 25-34 year age group had the highest rate (159.7), followed by black males in the 35-44 year age group (151.7) and then by black males in the 15-24 year age group (96.2). These rates ranged from almost eight to over eleven times the rates of similarly aged, black females or white males and were over 33 times higher than the rates for white females of the same age. Our results emphasize the high rates of black male on black male violence, the acquaintance of the black male victim and perpetrator, and the importance of arguments as an inciting event. Moreover, we determined that while the raw numbers and rates for black homicides were and are staggering, the average annual homicide rate for black males was actually declining at a greater rate than for all other race-sex groups. Further, our results suggest that a number of hypothesized determinants commonly believed to be associated with the increase in the homicide rate among black males between 15 and 24 years of age, such as drug use, increased availability of firearms and increased child abuse were not, in fact, major determinants of the change in homicide rates.

Social and physical factors in the referral of people with traumatic brain injuries to rehabilitation.

Using standardized data abstracted from a representative sample of hospitals in north-central Alabama, we analyze significant social and physical factors in acute care discharge referral patterns for 756 people with traumatic brain injury (TBI). When a Physical Medicine and Rehabilitation specialist is involved in the referral, patients receive more formal rehabilitation care following discharge, even after controlling for the relevant social and physical characteristics of the patient. Other significant variables predicting the level of rehabilitation care include presence of injury-related complications, abnormal computed tomography scan, longer length of acute care stay, being unmarried, older, and having an unintentional injury. Patients not seen by rehabilitation medicine specialists and/or those whose injuries provide less clinical evidence (implying greater uncertainty of diagnosis) are less likely to be referred to more formal rehabilitation. Thus, social and demographic factors may be significant in referral patterns when diagnostic uncertainty is present. Results suggest the importance of increasing availability of rehabilitation medicine consultation for TBI patients, while informing acute care providers about formal rehabilitation as a management option.

Cancer mortality, aging, and patterns of comorbidity in the United States: 1968 to 1986.

Cancer is often reported as contributing to the risk of noncancer causes of death. The age variation of these reports was studied using U.S. data on all causes of death listed on death certificates for 1968 to 1986. The occurrence of cancer as a nonunderlying cause of death increased with age and was higher for treatable and slowly growing tumor types. These patterns persisted even if the cancer manifested changes in occurrence. Nonunderlying occurrences were highest in the 85 to 94 age group and were correlated with cancer survival. This suggests increased importance of cancer as a cause of death and a comorbid condition among oldest-old persons. The high rate of occurrence as an associated cause of death suggests that if life expectancy increases due to declines in circulatory and other chronic disease mortality, cancer could become the preeminent cause of death in the United States.

Multivariate procedures to describe clinical staging of melanoma.

Analyzing multivariate clinical data to identify subclasses of patients being treated for a specific disease may improve patient management and increase understanding of the behavior of disease under clinical conditions. In some cases, patients have been classified on prognostic characteristics using standard risk assessment procedures (e.g., Cox' regression). This requires long term follow-up, differentiates patients only on attributes relevant to survival, and assumes that patients are sampled from a common population. Other approaches involve the use of clustering algorithms to classify patients into categories based on multiple clinical attributes. We illustrate the use of a multivariate statistical procedure to directly characterize patients on multiple clinical characteristics. The procedure is designed to analyze discrete response data with parameters representing individual differences within groups. Its use is illustrated for patients with Stage I melanoma in determining how age is related to treatment response in different patient groups.

Changes in health service use and mortality among U.S. elderly in 1980-1986.

Concern has emerged about the impact on quality of care of recent changes in Medicare reimbursement for acute hospital episodes (i.e., the introduction of the Prospective Payment System based on the Diagnosis Related Groups Reimbursement methodology). One aspect of those concerns is that very sick patients would be prematurely discharged to nursing homes in which the high level of medical care required would not be available. This was recently studied in terms of changes between 1981 and 1985 in the location of deaths (e.g., hospital, institutional) reported on U.S. death certificates. We analyzed the death certificate data for a longer period of time (1980 to 1986) and stratified the analysis by both age and cause of death--which we felt were important determinants of location of death. We also examined data from the 1982 and 1984 National Long Term Care Surveys linked to data on Medicare service use. In those analyses we could explicitly identify chronically disabled and institutionalized populations and study death rates in different locations within those populations. Our analyses showed little evidence of increased mortality rates due to premature hospital discharge. There were, however, significant changes in the patterns of service use. More home health agency (HHA) and skilled nursing facility (SNF) services were consumed though the rates of death per episode in those venues declined.

Multiple sclerosis in Key West, Florida.

In 1984, a press release by a Miami, Florida, neurologist described a possible cluster of persons with multiple sclerosis in Key West, Florida. The authors examined the cluster using prevalence rates, which are recognized as having a latitudinal gradient for multiple sclerosis, being generally high at high latitudes and low at low latitudes. Case ascertainment showed 32 definite or probable cases among residents of the study area (latitude, 24.5 degrees N) on September 1, 1985, a prevalence rate of 70.1/100,000 population--14 times the rate estimated for this latitude by modeling techniques based on US and international data, 7-44 times the rate for areas at similar latitudes (Mexico City, Mexico; Hawaii; New Orleans, Louisiana; and Charles County, South Carolina), and 2.5 times the expected rate for all US latitudes below 37 degrees N. This finding could not be explained by changes in diagnostic criteria, case ascertainment bias, immigration of people from high-risk areas, an unusual population structure, a large percentage of related cases, or better survival. Prevalent cases (n = 22) were more likely than general population controls (n = 76), matched by sex and 10-year age group, to have: lived longer in Key West, been a nurse, ever owned a Siamese cat, had detectable antibody titers to coxsackievirus A2 and poliovirus 2, and ever visited a local military base (Fleming Key). Key West has an unusually high prevalence of multiple sclerosis that may be related to these risk factors.

Sex chromosome homology and incomplete, tissue-specific X-inactivation suggest that monotremes represent an intermediate stage of mammalian sex chromosome evolution.

Female mammals have two X chromosomes and males have a single X and a smaller, male-determining Y chromosome. The dosage of X-linked gene products is equalized between the sexes by the genetic inactivation of one X chromosome in females. The characteristics of the mechanism of X-chromosome inactivation differ in eutherian and metatherian mammals, and it has been suggested that the metatherian system represents a more primitive stage. The present study of monotreme sex chromosomes and X-chromosome inactivation suggests that the prototherian mammals may represent an even more primitive stage. There is extensive G-band homology between the monotreme X and Y chromosomes, and differences in the patterns of replication of the two X chromosomes in females suggest that X inactivation is tissue specific and confined to the unpaired segment of the X. On the basis of these results, we propose a model for the differentiation of mammalian sex chromosomes and the evolution of the mechanism of X-chromosome inactivation. This model involves a gradual reduction of the Y chromosome and an accompanying gradual recruitment of (newly unpaired) X-linked loci under the control of a single inactivation center.

Karyotypic conservation in the mammalian order monotremata (subclass Prototheria).

The order Monotremata, comprising the platypus and two species of echidna (Australian and Nuigini) is the only extant representative of the mammalian subclass Prototheria, which diverged from subclass Theria (marsupials and placental mammals) 150-200 million years ago. The 2n = 63 male, 64 female karyotype (newly described here) of the Nuigini echidna is almost identical in morphology and G-band pattern to that of the Australian echidna, from which it diverged about a million years ago. The karyotype of the platypus (2n = 52) has several features in common with those of the echidna species; six pairs of large autosomes, many pairs of small (but not micro-) chromosomes, and a series of small unpaired chromosomes which form a multivalent at meiosis. Comparison of the G-band patterns of platypus and echidna autosomes reveals considerable homology. Chromomycin banding demonstrates GC-rich heterochromatin at the centromeres of many platypus and echidna chromosomes, and at the nucleolar organizing regions; some of this heterochromatin C-bands weakly in platypus (but not echidna) spreads. Late replication banding patterns resemble G-banding patterns and confirm the homologies between the species. Striking heteromorphism between chromosomes of some of the large autosomal pairs can be accounted for in the echidna by differences in amount of chromomycin-bright, late replicating heterochromatin. The sex chromosomes in all three species also bear striking homology, despite the difference in sex determination mechanism between platypus (XX/XY) and the echidna species (X1X1X2X2/X1X2Y). The platypus X and echidna X1 each represent about 5.8% of haploid chromosome length, and are G-band identical. Y chromosomes are similar between species, and are largely homologous to the X (or X1).

Evolution of mammalian X-chromosome inactivation: sex chromatin in monotremes and marsupials.

The inactive mammalian X-chromosome is always late-replicating, and in eutherian mammals it is heterochromatic and hypermethylated. We propose that this multistep system has evolved from a more primitive system, remnants of which may be found in marsupials and monotremes. The heterochromatic X (sex-chromatin body) is a distinctive feature of interphase cells of certain tissues in eutherian females but not males. Thus we have searched for a sex-specific chromatin body in these same tissues in marsupials (brush-tail possum, Trichosurus vulpecula) and monotremes (platypus, Ornithorynchus anatinus), using classical histological techniques. A female-specific chromatin body was observed at low frequency in nuclei of possum corneal epithelium, but not in any other tissues. No sex difference was observed in any monotreme tissue. These data suggest that stabilization of X-chromosome inactivation by heterochromatinization is tissue-specific in marsupials and absent in monotremes.