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Previous studies suggest that concurrent Lyme disease and babesiosis produce a more sever illness than either disease alone. The majority of babesiosis infections, however, are subclinical. Our objective was to characterize on the basis of a total-population survey of Nantucket Island, Massachusetts, whether coexposure to Lyme disease and babesiosis causes more severe illness or poorer long-term outcomes than Lyme disease alone. In this retrospective cohort study, residents indicating a history of Lyme disease were compared with randomly selected population controls on a standardized medical history, blinded physical examination, and serological studies for Borrelia burgdorferi and Babesia microti. Serological evidence of exposure to babesiosis was not associated with increased severity of acute Lyme disease. The groups did not differ with regard to the prevalence of constitutional, musculoskeletal, or neurological symptoms a mean of 6 years after acute Lyme disease. Prior Lyme disease and serological exposure to B. microti are not associated with poorer long-term outcomes or more persistent symptoms Lyme disease alone.

Objective: Endoscopic ultrasound (EUS) is accepted as the most accurate modality for T- and N-staging of esophageal cancer, but some malignant strictures prevent passage of the echoendoscope beyond the level of the tumor. This incomplete evaluation may decrease staging accuracy. Previous studies have yielded conflicting results regarding the safety and efficacy of esophageal dilation for EUS., Methods: We prospectively evaluated 267 consecutive patients undergoing EUS for esophageal carcinoma staging at our institution over a 66-month period to determine the number of patients requiring dilation for EUS examination, the success of dilation, safety of dilation, and clinical importance., Results: Among 267 endosonographic examinations of the esophagus, 81 (30.3%) required dilation to advance the echoendoscope beyond the level of the stricture. After dilation was performed, the echoendoscope could be passed through the stricture in 69 patients (85.2%), and in 63 of 67 of the patients dilated to > or = 14 mm (94.0%). No complications have occurred secondary to the dilations performed to permit completion of the endosonographic examination. Tumor staging by EUS after dilation was T2 (14.8%), T3 (56.8%), and T4 (21.0%), nodal staging N0 (14.6%) and N1 (75.3%); and M1 (9.9%)., Conclusions: We conclude that incremental, stepwise dilation of malignant strictures to 14 mm is safe and effective in permitting echoendoscope passage beyond the stenosis. The presence of a malignant stricture does not seem to diminish the utility of EUS staging of esophageal cancer.

Endopeptidase EC 3.4.24.15 (EP 24.15) is a thermolysin-like metalloendopeptidase which is expressed widely throughout the body, with the highest concentrations in the brain, pituitary and testis. While the precise role of EP 24.15 remains unknown, it is thought to participate in the regulated metabolism of a number of specific neuropeptides. Of the limited number of inhibitors described for EP 24.15, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-amino benzoate (CFP) is the most widely studied. CFP is a potent and specific inhibitor, but is unstable in vivo due to its cleavage between the alanine and tyrosine residues by the enzyme neprilysin (EP 24.11). The cpp-Ala-Ala N-terminal product of this cleavage is a potent inhibitor of angiotensin converting enzyme, which further limits the use of CFP in vivo. To generate specific inhibitors of EP 24.15 that are resistant to in vivo proteolysis by EP 24.11, beta-amino acids have been incorporated into the structure of CFP. We have prepared racemic mixtures of beta-amino acids containing proteogenic side chains, which are 9-fluorenylmethoxycarbonyl (Fmoc)-protected, and several analogues of CFP containing beta-amino acids have been synthesized by solid phase peptide synthesis. The results of stability and inhibitory studies of these new analogues show that the incorporation of beta-amino acids adjacent to the scissile bond can indeed stabilize the peptides against cleavage by EP 24.11 and still inhibit EP 24.15. The results obtained in these studies demonstrate the potential of these amino acids in the synthesis of peptidomimetics and in the design of new stable and specific therapeutics.

The closely related zinc metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16) cleave many common substrates, including bradykinin (BK). As such, there are few substrate-based inhibitors which are sufficiently selective to distinguish their activities. We have used BK analogues with either alanine or beta-amino acid (containing an additional carbon within the peptide backbone) substitutions to elucidate subtle differences in substrate specificity between the enzymes. The cleavage of the analogues by recombinant EP24.15 and EP24.16 was assessed, as well as their ability to inhibit the two enzymes. Alanine-substituted analogues were generally better substrates than BK itself, although differences between the peptidases were observed. Similarly, substitution of the four N-terminal residues with beta-glycine enhanced cleavage in some cases, but not others. beta-Glycine substitution at or near the scissile bond (Phe5-Ser6) completely prevented cleavage by either enzyme: interestingly, these analogues still acted as inhibitors, although with very different affinities for the two enzymes. Also of interest, beta-Gly8-BK was neither a substrate nor an inhibitor of EP24.15, yet could still interact with EP24.16. Finally, while both enzymes could be similarly inhibited by the D-stereoisomer of beta-C3-Phe5-BK (IC50 approximately 20 microM, compared to 8 microM for BK), EP24.16 was relatively insensitive to the L-isomer (IC50 12 approximately microM for EP24.15, >40 microM for EP24.16). These studies indicate subtle differences in substrate specificity between EP24.15 and EP24.16, and suggest that beta-amino acid analogues may be useful as templates for the design of selective inhibitors.

The apical plasma membrane (PM) is important in hyphal tip growth, where it may regulate tip extensibility via its association with an appropriate membrane skeleton (MS). By cell fractionation and immunocytochemistry we show that proteins with characteristics of actin, spectrin, and integrin are associated in a MS-like manner with the PM of Neurospora crassa hyphae. The spectrin-like protein in particular is highly concentrated at the PM in the region of maximum apical expansion. This protein shares with other spectrins immunoreactivity, molecular weight, PM association, and actin binding capacity. Its distribution in hyphae suggests that it is a dominant component of the MS in true fungi and is critical to hyphal tip growth.

Context: Skin cancer is the most common form of cancer in the United States, and it is one of the most preventable. Interventions for young children and their parents can help prevent future cases of skin cancer., Objective: To determine whether a skin cancer prevention program implemented at outdoor recreation sites improved children's sun-protection behaviors and site sun-protection policies., Design: Randomized trial of 14 outdoor recreation sites on the island of Oahu, Hawaii. The trial had three arms: control, education only, and education/environment., Intervention: The education arm included staff training, on-site activities, take-home booklets, behavior-monitoring boards, and incentives. The education/environment arm included all education components plus provision of sunscreen and promotion of sun-safe environments., Participants: Children 6 to 8 years of age and their parents., Outcome Measures: Reports from parents of children's sun-protection behaviors and the sun-protection policies of recreation sites. The cohort for analysis from baseline to 6 weeks after testing had 383 participants; the cohort from 6 weeks after testing to 3 months of follow-up had 285 participants., Results: Program implementation was high in the education only and the education/environment sites. Compared with control sites, children's sun-protection behaviors and, in particular, the use of sunscreen improved significantly at sites where the two interventions were implemented. In addition, sun-protection policies of recreation sites were markedly higher at intervention arm sites. The education/environment intervention was not superior to education alone. Changes were partly maintained at 3 months of follow-up., Conclusion: A creative, engaging, multicomponent skin cancer prevention program in outdoor recreation settings can lead to modest improvements in children's sun-protection behaviors.

Objective: To determine the prevalence and socioeconomic and clinical predictors of early organ damage in a cohort of patients with systemic lupus erythematosus (SLE) of 2-7 years' duration randomly sampled at 5 centers and balanced by socioeconomic status and race., Methods: The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index was measured in 200 patients who met the ACR criteria for SLE with a mean disease duration of 3.8 years. The SLICC/ACR scores for each organ system and the prevalence of damage within organ systems were assessed. Logistic regression analyses evaluated the simultaneous effects of age at diagnosis, disease duration, disease activity, and sociodemographic factors., Results: Sixty-one percent of the patients had damage within 7 years of onset (mean 3.8 yrs). Neuropsychiatric (20.5%) and musculoskeletal (18.5%) systems were the most frequently involved, followed by renal (15.5%) and skin (12.5%) systems, all with median SLICC/ACR organ system scores of 1. In multivariate models, African-American race was associated with skin damage but not with damage in other specific organ systems. Socioeconomic status was not associated with organ system damage. Older age at diagnosis correlated with cardiovascular, musculoskeletal, gastrointestinal, ocular, and pulmonary damage. Clinical factors such as longer disease duration correlated with higher renal and cardiovascular damage, and greater disease activity at diagnosis of SLE correlated with greater renal, musculoskeletal, and pulmonary damage., Conclusion: There is evidence of organ system damage in SLE within a mean of 3.8 years after onset. We found little evidence for differences in early organ damage according to race or socioeconomic status. Damage to most organ systems was related to age at diagnosis of SLE and clinical factors such as disease duration.

We have developed a novel inhibitor of the metalloendopeptidases EC 3.4.24.15 (EP24.15) and EC 3.4.24.16 (EP24.16), N-[1-(R, S)-carboxy-3-phenylpropyl]-Ala-Aib-Tyr-p-aminobenzoate (JA2), in which alpha-aminoisobutyric acid (Aib) is substituted for an alanine in a well-described but unstable inhibitor, cFP-AAY-pAB. This substitution increases the resistance of the inhibitor to degradation without altering potency. In the present study, we investigated the effects of JA2 (5 mg/kg) on the responses of mean arterial pressure to bradykinin, angiotensin I, and angiotensin II in conscious rabbits. The depressor responses to both low (10 ng/kg) and high (100 ng/kg) doses of bradykinin were increased 7.0+/-2. 7-fold and 1.5+/-0.3-fold, respectively, during the 30 minutes after JA2 administration (mean+/-SEM, n=8). Bradykinin potentiation was undiminished 4 hours after JA2 injection. In contrast, the hypertensive effects of angiotensins I and II were unaltered, indicating that the bradykinin-potentiating effects were not due to angiotensin-converting enzyme inhibition. These data suggest that JA2 is not only a potent and specific inhibitor of EP24.15 and EP24. 16 but is also stable in vivo. Furthermore, the potentiation of bradykinin-induced hypotension by JA2 suggests for the first time a role for one or both of these peptidases in the metabolism of bradykinin in the circulation.

Solid-phase synthesis was used to prepare a series of modifications to the selective and potent inhibitor of endopeptidase EC 3.4.24.15 (EP24.15), N-[1(R, S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP), which is degraded at the Ala-Tyr bond, thus severely limiting its utility in vivo. Reducing the amide bond between the Ala and Tyr decreased the potency of the inhibitor to 1/1000. However, the replacement of the second alanine residue immediately adjacent to the tyrosine with alpha-aminoisobutyric acid gave a compound (JA-2) that was equipotent with cFP, with a K(i) of 23 nM. Like cFP, JA-2 inhibited the closely related endopeptidase EC 3.4.24.16 1/20 to 1/30 as potently as it did EP24.15, and did not inhibit the other thermolysin-like endopeptidases angiotensin-converting enzyme, endothelin-converting enzyme and neutral endopeptidase. The biological stability of JA-2 was investigated by incubation with a number of membrane and soluble sheep tissue extracts. In contrast with cFP, JA-2 remained intact after 48 h of incubation with all tissues examined. Further modifications to the JA-2 compound failed to improve the potency of this inhibitor. Hence JA-2 is a potent, EP24.15-preferential and biologically stable inhibitor, therefore providing a valuable tool for further assessing the biological functions of EP24.15.

The generation and metabolism of bioactive peptides involves a series of highly ordered proteolytic events. This post-translational processing can occur either within the cell, at the cell surface or after secretion. In the central nervous system a number of extracellular peptidases have been implicated in the regulated processing of peptides, particularly in the regulation of neuroendocrine function. The aim of this study has been to identify the peptidases involved in the metabolism of gonadotropin-releasing hormone (GnRH) and to characterize the factors and the mechanisms by which the activity of these peptidases are regulated. We have shown that both prolylendopeptidase and the thimet oligopeptidase EC 3.4. 24.15 are involved in GnRH metabolism and that both oestrogen and thiol-based reductants could be involved in the physiological regulation of their activities.

Background: Previous follow-up studies of patients with Lyme disease suggest that disseminated infection may be associated with long-term neurologic and musculoskeletal morbidity., Objective: To determine clinical and functional outcomes in persons who were treated for Lyme disease in the late 1980s., Design: Population-based, retrospective cohort study., Setting: Nantucket Island, Massachusetts., Participants: 186 persons who had a history of Lyme disease (case-patients) and 167 persons who did not (controls)., Measurements: Standardized medical history, physical examination, functional status measure (Medical Outcomes Study 36-item Short Form Health Survey [SF-36]), mood state assessment (Profile of Mood States), neurocognitive tests, and serologic examination., Results: The prevalence of Lyme disease among adults on Nantucket Island was estimated to be 14.3% (95% CI, 9.3% to 19.1%). In multivariate analyses, persons with previous Lyme disease (mean time from infection to study evaluation, 6.0 years) had more joint pain (odds ratio for having joint pain in any joint, 2.1 [CI, 1.2 to 3.5]; P = 0.007), more symptoms of memory impairment (odds ratio for having any memory problem, 1.9 [CI, 1.1 to 3.5]; P = 0.003), and poorer functional status due to pain (odds ratio for 1 point on the SF-36 scale, 1.02 [CI, 1.01 to 1.03]; P < 0.001) than persons without previous Lyme disease. However, on physical examination, case-patients and controls did not differ in musculoskeletal abnormalities, neurologic abnormalities, or neurocognitive performance. Persons with previous Lyme disease who had persistent symptoms after receiving treatment (n = 67) were more likely than those who had completely recovered to have had fever, headache, photosensitivity, or neck stiffness during their acute illness (87% compared with 13%; odds ratio, 2.4 [CI, 1.0 to 5.5]; P = 0.045); however, the performance of the two groups on neurocognitive tests did not significantly differ., Conclusions: Because persons with previous Lyme disease exhibited no sequelae on physical examination and neurocognitive tests a mean of 6.0 years after infection, musculoskeletal and neurocognitive outcomes seem to be favorable. However, long-term impairment of functional status can occur.

Calcium and proton ion fluxes were mapped at the growing apices of two hyphal organisms, the oomycete Saprolegnia ferax and the ascomycete Neurospora crassa and pseudohyphal Saccharomyces cerevisiae using self-referencing ion-selective probes. S. ferax exhibited well-defined transport zones absent in N. crassa. Ca2+ fluxes were located within 8 microm of the growing hyphal tip; the net Ca2+ flux was either inward (75% of all experiments) or outward. The inward component of the net flux was inhibited by Gd3+, known to inhibit Ca2+ permeable stretch-activated channels. Because the Ca2+ flux is located at the region of maximal hyphal expansion, exocytosis may contribute to Ca2+ efflux, in addition to the stretch-activated channel mediated influx. Maximal inward H+ flux was observed 10-30 microm behind the hyphal tip where peak mitochondria densities taper off at the onset of a vacuolation zone, presumably due to highly localized H+ cotransporter activity. By contrast, N. crassa exhibited no net Ca2+ flux and a consistently inward H+ flux (93% of all experiments) that was homogeneously distributed up to 60 microm behind the hyphal apex. Both hyphal organisms have similar tip morphology and growth rates, and are reported to have tip-high cytosolic Ca2+ gradients associated with growth. Only S. ferax exhibited tip-localized Ca2+ fluxes and a well defined H+ influx zone just behind the tip. Differences in ecological habitats and cytology--S. ferax is an aquatic organism that grows as a migrating plug of cytoplasm while N. crassa is normally terrestrial with a cytoplasm-rich mycelium and highly active cytoplasmic streaming behind the growing margin--may account for the differences in the 'architecture' of ion transport occurring during the process of tip growth. Net Ca2+ efflux and H+ influx of growing S. cerevisiae pseudohyphae were also measured but localization was not possible due to small cell size.

Objective: Laboratory testing is important in the evaluation of patients with possible systemic rheumatic disease, but uncritical use of any test may result in misleading information and unnecessary costs. We attempted to reduce the number of unnecessary antinuclear antibody, rheumatoid factor, and complement level tests ordered by house officers at a large teaching hospital, where inpatient orders are written through a computer based order entry system., Methods: We conducted a prospective cohort study of an interactive test ordering program. The intervention consisted of displaying post-test probability estimates during the usual physician order entry session. These estimates were based on pretest probabilities entered by the ordering physician and sensitivities and specificities derived from a literature review. Another group of test orders did not prompt the intervention and were considered controls. The outcome of interest was the percentage of tests canceled in the intervention group versus the control group., Results: Eleven percent (11/99) of intervention orders were canceled, versus only one order among 236 controls (p = 0.001). However, there was no association between the physicians' pretest probability estimates and whether test orders were canceled (p = 0.59). Additionally, 43 of the 335 orders (13%) yielded positive tests, but only 4 patients (1%) were given new diagnoses of rheumatic disease., Conclusion: The computer based intervention significantly reduced orders for antinuclear antibody and rheumatoid factor levels by 10%. Further reductions without clinical harm are probably possible, since the yield of testing for new rheumatic diseases was low.

Background: Skin cancer is the most common cancer in the United States. Increasing evidence suggests that screening for malignant melanoma is effective, but its cost-effectiveness has not been determined., Objective: We attempted to determine the effectiveness and costs of a visual screen to diagnose malignant melanoma in high-risk persons., Methods: We developed a decision analysis comparing no skin cancer screen with a single screen by a dermatologist. Clinical outcomes included malignant melanoma, nonmelanoma skin cancer, or no skin cancer. Life expectancy and costs of care were projected on the basis of clinical findings., Results: Skin cancer screening increased average discounted life expectancy from 15.0963 years to 15.0975 years. Based on the prevalence of malignant melanoma, however, this translates into an increased discounted life expectancy of 0.9231 years for each person with diagnosed melanoma. Using a cost of $30 per screen, total skin cancer-related costs for a cohort of 1 million people increased from $826 million with no screen to $861 million with screening, with an increase of 1200 years of life. This results in an incremental cost-effectiveness ratio of $29,170 per year of life saved (YLS) with screening. Sensitivity analysis showed that the cost-effectiveness ratio for screening remained below $50,000/YLS if the prevalence of melanoma in the screened population was at least 0. 0009, the probability that a melanoma detected in screening was localized was at least 94.8%, or the cost of each screen was below $57., Conclusion: Skin cancer screening in high-risk patients is likely to be associated with a small increase in discounted life expectancy and is reasonably cost-effective compared with other cancer screening strategies.

The Arabidopsis thaliana ARAKIN (ATMEKK1) gene shows strong homology to members of the (MAP) mitogen-activated protein kinase family, and was previously shown to functionally complement a mating defect in Saccharomyces cerevisiae at the level of the MEKK kinase ste11. The yeast STE11 is an integral component of two MAP kinase cascades: the mating pheromone pathway and the HOG (high osmolarity glycerol response) pathway. The HOG signal transduction pathway is activated by osmotic stress and causes increased glycerol synthesis. Here, we first demonstrate that ATMEKK1 encodes a protein with kinase activity, examine its properties in yeast MAP kinase cascades, then examine its expression under stress in A. thaliana. Yeast cells expressing the A. thaliana ATMEKK1 survive and grow under high salt (NaCl) stress, conditions that kill wild-type cells. Enhanced glycerol production, observed in non-stressed cells expressing ATMEKK1 is the probable cause of yeast survival. Downstream components of the HOG response pathway, HOG1 and PBS2, are required for ATMEKK1-mediated yeast survival. Because ATMEKK1 functionally complements the sho1/ssk2/ssk22 triple mutant, it appears to function at the level of the MEKK kinase step of the HOG response pathway. In A. thaliana, ATMEKK1 expression is rapidly (within 5 min) induced by osmotic (NaCl) stress. This is the same time frame for osmoticum-induced effects on the electrical properties of A. thaliana cells, both an immediate response and adaptation. Therefore, we propose that the A. thaliana ATMEKK1 may be a part of the signal transduction pathway involved in osmotic stress.

The AT4 receptor was characterized initially as a specific binding site for angiotensin IV, a C-terminal fragment of the vasoactive peptide angiotensin II. Recently, we found that LVV-hemorphin-7, a fragment of beta globin, is an abundant peptide in the brain and binds to the AT4 receptor with high affinity and specificity. In the neuroblastoma/glioma hybrid cell line, NG108-15, LVV-hemorphin-7 and angiotensin IV competed for 125I-angiotensin IV binding in a biphasic fashion with IC50 values of 1.2 x 10(-10) and 1.1 x 10(-9) M for the high-affinity site, respectively, and 6.7 x 10(-8) and 1.5 x 10(-8) M for the low-affinity site, respectively. Both peptides were internalized rapidly by the cells. However, LVV-hemorphin-7, but not angiotensin IV, elicited a 1.8-fold increase in DNA synthesis in a dose-dependent manner. Furthermore, co-incubation of the cells with an excess of angiotensin IV (10(-6) M) inhibited LVV-hemorphin-7-stimulated DNA synthesis. Therefore, whereas LVV-hemorphin-7 and angiotensin IV were capable of binding to the AT4 receptor, only LVV-hemorphin-7 elicited [3H]thymidine incorporation in NG108-15 cells. In contrast, angiotensin IV behaved as an antagonist. The current finding suggests that LVV-hemorphin-7 is a functional peptide in the central nervous system and in view of its abundance in neural tissue, compared with angiotensin IV, may be of significant physiological importance.

We have identified the value of 18F-fallypride [(S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]fluoropropyl)-2, 3-dimethoxybenzamide], as a dopamine D-2 receptor radiotracer for the study of striatal and extrastriatal receptors. Fallypride exhibits high affinities for D-2 and D-3 subtypes and low affinity for D-4 (3H-spiperone IC50s: D-2 = 0.05 nM [rat striata], D-3 = 0.30 nM [SF9 cell lines, rat recombinant], and D-4 = 240 nM [CHO cell lines, human recombinant]). Biodistribution in the rat brain showed localization of 18F-fallypride in striata and extrastriatal regions such as the frontal cortex, parietal cortex, amygdala, hippocampus, thalamus, and hypothalamus. In vitro autoradiographic studies in sagittal slices of the rat brain showed localization of 18F-fallypride in striatal and several extrastriatal regions, including the medulla. Positron emission tomography (PET) experiments with 18F-fallypride in male rhesus monkeys were carried out in a PET VI scanner. In several PET experiments, apart from the specific binding seen in the striatum, specific binding of 18F-fallypride was also identified in extracellular regions (in a lower brain slice, possibly the thalamus). Specific binding in the extrastriata was, however, significantly lower compared with that observed in the striata of the monkeys (extrastriata/cerebellum = 2, striata/cerebellum = 10). Postmortem analysis of the monkey brain revealed significant 18F-fallypride binding in the striata, whereas binding was also observed in extrastriatal regions such as the thalamus, cortical areas, and brain stem.

A better understanding of factors influencing sun protection practices can improve the design and evaluation of skin cancer prevention programs. These data are from a cross-sectional survey of 756 parents with children in Grades 1 through 3, and 176 recreation program staff members in a multiethnic population in Hawaii. Questionnaires asked about skin cancer prevention practices (sunscreen use, covering up, shade seeking), knowledge, benefits and barriers, policies, and staff norms for prevention. The most important correlates of children's prevention practices were their parents' sun protection habits. Multiple regression models--which included knowledge, beliefs, program policies, and covariates related to sun protection--explained a total of between 38% and 41% of the variance in children's sun safety habits, 22% to 25% of parents' habits, and 24% of recreation staff members' sun safety habits. The models were less successful at predicting the use of hats, shirts, and shade seeking and a composite sun protection habits index. Parents and caregivers' knowledge, beliefs, and behaviors, as well as recreation program policies, are strong predictors of sun protection practices among children in Grades 1 to 3 in a multiethnic sample.

Background: Surveys of U.S. physicians show deficiencies in cancer detection and counseling skills. Thus, there is a compelling need to provide skills teaching during medical school for cancers with preventable mortality and for counseling techniques for smoking prevention and cessation., Methods: In advance of the integration of initiatives for cancer education into the medical school curriculum, the authors conducted a baseline survey of students' knowledge, attitudes, skills, practices, observation, and training (KASPOT) related to cancer education. Eighty-one percent of Boston University School of Medicine students (n = 499) completed surveys., Results: The students reported higher levels of KASPOT for breast and cervical cancers, compared with skin cancer examination or tobacco use cessation or prevention counseling. More than half of third- and fourth-year students reported that too little emphasis was given to cancer control education., Conclusions: It appears that students' practice and skills for detection of the most common cancer (skin cancer), and for cancers with the greatest mortality (tobacco-related cancers) are deficient. Revisions in medical students' curricula should seek to address these shortcomings.

A multidimensional community-based skin cancer prevention program was conducted in Falmouth, Massachusetts, combining community activism with publicity campaigns and behavioral interventions to improve sun protection knowledge; attitudes; and practices in parents, caregivers, and children. The program was associated with improvements in target outcomes, based on two telephone surveys of random samples of parents (n = 401, 404). After program implementation, fewer parents reported sunburning of their children, particularly among children 6 years old or younger (18.6% in 1994 vs. 3.2% in 1997), and more parents reported children using sunscreen, particularly continuous use at the beach (from 47.4% to 69.9% in younger children). Hat and shirt use did not increase. Improvements also were seen in parent role modeling of sun protection practices, parents' self-efficacy in protecting children from the sun, and sun protection knowledge. While these findings must be interpreted cautiously, they do suggest that this project was effective in promoting sun protection.

T lymphocyte activation and increased cytokine levels have been described in retrospective studies of children presenting with dengue hemorrhagic fever (DHF). Serial plasma samples obtained in a prospective study of Thai children presenting with <72 h of fever were studied. Plasma levels of 80-kDa soluble tumor necrosis factor receptors (sTNFRs) were higher in children who developed DHF than in those with dengue fever (DF) or other nondengue febrile illnesses (OFIs) and were correlated with the degree of subsequent plasma leakage. Soluble CD8 and soluble interleukin-2 receptor levels were also elevated in children with DHF compared with those with DF. Interferon-gamma and sTNFR 60-kDa levels were higher in children with dengue than in those with OFIs. TNF-alpha was detectable more often in DHF than in DF or OFIs (P<.05). These results support the hypothesis that immune activation contributes to the pathogenesis of DHF. Further studies evaluating the predictive value of sTNFR80 for DHF are warranted.

Background: More than 1 million Americans have attended the American Academy of Dermatology's Melanoma/Skin Cancer Screening Programs since 1985. However, there have been no reports of the participants' perceived value, satisfaction, and benefits of skin cancer screening., Objective: We attempted to measure the benefits and subsequent screening practices of persons with presumptive positive screening diagnoses., Methods: A self-administered questionnaire was sent to participants with positive screening diagnoses in Massachusetts., Results: Of the 643 respondents, 81% rated their satisfaction as high and 84% had similar ratings for the value of the screening. Screenings apparently led to an increase in self-screening (60% before screening compared with 84% after screening)., Conclusion: Although screening appears to have relatively strong benefits, further studies should be conducted nationally.

There is little information on the effect of nonsurgical factors or postoperative anemia on achieving spinal fusion. In a prospective cohort study of 184 consecutive lumbar spinal fusions, we obtained data on socioeconomic, clinical, radiologic, and traditional surgical factors and analyzed associations between these factors and fusion status at 6 months post surgery. The overall fusion rate was 74%. Among the surgical factors, use of pedicle screw fixation (p = 0.005) predicted fusion success; postoperative anemia (hematocrit < 30%; p = 0.003) and a history of smoking (p = 0.050) predicted fusion failure. However, when the surgical factors were analyzed together with clinical and socioeconomic factors, back pain greater than or equal to leg pain (p < 0.001) and patients working at the initial visit (p = 0.001) predicted fusion success; shoulder pain at the initial visit (p < 0.001) and a family history of back surgery (p = 0.006) predicted fusion failure. These factors were stronger predictors of fusion status than were traditional surgical factors.

We have synthesized N-(6-18F-fluorohexyl)-N-methylpropargylamine (18F-FHMP) as a positron emission tomography (PET) radiotracer for monoamine oxidase B (MAO-B). The radiosynthesis was carried out by a fluorine-for-bromine substitution in 30-40% radiochemical yield in specific activities of 1-2 Ci/micromol. Selectivity for MAO-B was demonstrated by the high affinity of (R)-deprenyl (IC50 = 6.8 nM) and lower affinity of clorgyline (IC50 = 1.2 microM) for the inhibition of 18F-FHMP binding in vitro in rat brain homogenates. In vitro autoradiographic studies in rat brain slices showed localization of 18F-FHMP in regions such as the ependyma of the lateral ventricle, dorsal raphe, area postrema, and other regions such as the cerebellum. The specific binding observed in the autoradiograms was displaced by preincubation with (R)-deprenyl. In in vivo experiments, the uptake of 18F-FHMP in the rat brains was high (0.10-0.20% injected dose/g). The binding of 18F-FHMP in the rat brain correlated with the general distribution of MAO-B and was displaced completely by preadministration of 10 microM (R)-deprenyl. These results suggest that 18F-FHMP is a potential PET radiotracer for MAO-B for use in in vitro and in vivo experiments.

Relatively little attention has been directed towards the study of the ability of health status measures to demonstrate clinically meaningful change. We examined the use of Tukey's stem and leaf plots and time-path diagrams to assess the sensitivity of a health status measure in showing change. We compared the evaluative characteristics of the physical ability scales of the Sickness Impact Profile (PSIP), and the SF-36 (PSF-36), in 54 consecutive patients undergoing elective primary or revision total hip replacement. To validate time-path diagrams, we used patients' perception of change in physical function (transition question) as an external standard. At baseline there was no clustering at the end of the scales. At 3 months, the distribution of the PSIP showed a clustering at the upper end of the scale and a strong skewness towards lower scores, whereas the PSF-36 showed a wide distribution of the scores. Seven out of 54 patients had perfectly normal scores on the PSIP at 3 months, whereas one patient had a perfect score on the PSF-36 at 3 months. In time-path diagrams the response pattern of the PSIP was similar to that of the PSF-36, with the exception of the patient-fifth with the best initial health status. The overall impression of the time-path diagram for these patients was that of no change. A closer examination revealed that half of these patients had horizontal or downwards sloping lines, indicating a worsening in physical function. However, all these patients perceived themselves as improved. The PSIP has a ceiling effect for patients with relatively good physical health. It was concluded that stem and leaf plots are useful in the assessment of health status measures, for discriminative purposes, to differentiate patients' health cross-sectionally. Time-path diagrams stratified by baseline health status with information on patients' perception or valuation of change provide useful information about the ability of an instrument to detect change over time.

Objective: To study the outcome of Lyme disease (LD) in children identified in a total population survey of an endemic island., Methods: We conducted a population-based retrospective cohort study off the coast of Massachusetts. Twenty-five children who met the Centers for Disease Control case definition for prior LD were compared with 26 children without LD from the same community. All children with LD received antibiotics during the acute phase of their disease. All 51 children were invited for a clinical evaluation, including 12-lead electrocardiogram (EKG), and measurement of antibodies to Borrelia burgdorferi by antibody-capture ELISA and Western blot., Results: At a mean of 3.2 years from the initial manifestation of LD, children with prior LD did not have a higher prevalence of musculoskeletal or neurological symptoms, examination abnormalities, abnormal EKG, or behavioral difficulties, compared to children with no history of LD., Conclusion: Children who receive appropriate antimicrobial therapy for LD appear to have no demonstrable longterm morbidity.

1. Angiotensin IV (AngIV), the (3-8) fragment of AngII, was previously believed to be an inactive metabolite. However, specific binding sites, termed AT4 receptors, have been identified in the brain and peripheral organs and the peptide has been reported to enhance memory recall in passive avoidance studies and to dilate pial and renal cortical vessels. 2. AT4 receptors are distinct from AngII AT1 and AT2 receptors with respect to function, ligand specificity and distribution. 3. In the brain, AT4 receptors are abundant in cerebral and cerebellar cortex, hippocampal formation and cholinergic systems, as well as sensory and motor systems. However, the peptide AngIV is low or undetectable in the central nervous system. This led us to search for an alternative peptide ligand of the AT4 receptor. 4. The decapeptide LVVYPWTQRF was isolated from cerebral cortex and binds with high affinity to brain AT4 receptors. This peptide sequence corresponds to an internal sequence of beta-globin and has previously been named LVV-haemorphin 7. 5. Haemorphin may represent a new class of endogenous neuropeptides, some of which interact potently with the brain AT4 receptor to elicit a range of actions.

We have developed 18F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of 18F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of 18F-fluoxetine was not obtained. Even when fluoxetine (10 microM) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of 18F-fluoxetine. Ex vivo autoradiographic experiments with 18F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of 18F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of 18F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with 18F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of 18F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

The objective of this study was to describe patterns and predictors of work absence in the prospective, community-based Maine Carpal Tunnel Study. Three hundred fifteen patients with carpal tunnel syndrome (CTS) were recruited from physicians' offices throughout Maine. The patients completed questionnaires at entry and after 6, 18, and 30 months. The questionnaires included scales measuring symptom severity, functional status, general and mental health status, exposure to physical stressors, work status, and other indicators. The analyses examined univariate and multivariate correlates of work absence. The mean age was 43, 72% of subjects were female, 71% underwent carpal tunnel release, and 45% were receiving Workers' Compensation. Fifty-two percent worked in managerial or technical occupations, 15% in service occupations, and 13% in heavy labor or machine operation. Forty-five percent of patients changed jobs or were absent from work (aside from postoperative recovery) during the 30-month follow-up. In multivariate logistic regression models, correlates of work absence at 18 months included worse functional status of the hand at study entry and at 6-month follow-up, involvement of an attorney at the time of enrollment (P < 0.002 for each), and work absence at 6 months (P = 0.03). Worse upper extremity functional status and having a contested Workers' Compensation claim are critical predictors of work absence and should be principal targets of interventions to reduce work disability in CTS.

The possibility that there is an increased risk of melanoma in patients with psoriasis treated with psoralen-UV-A (PUVA) therapy has raised concern on the part of physicians and patients about the long-term safety of this treatment. In response to this concern, the National Psoriasis Foundation sponsored a workshop at which invited participants with expertise in PUVA therapy, psoriasis treatment, melanoma and nonmelanoma skin cancer, and epidemiological and clinical trials were asked to develop a consensus on the following 3 issues: the risk of long-term adverse effects of PUVA therapy with emphasis on nonmelanoma and melanoma skin cancer; the guidelines for physicians and patients for selection and use of PUVA therapy with consideration of the risk-benefit ratio of this treatment compared with the risk-benefit ratios of alternative treatments; and the directions for further evaluation of the long-term effects Of PUVA therapy.

Objectives: This study reports population estimates of Pap smear testing among Korean-American women and evaluates correlates of testing., Methods: Korean Americans in 2 California counties were surveyed by telephone. Frequencies were age-adjusted to the 1990 census to produce population estimates of testing. Logistic regression models were used to evaluate independent correlates of testing, Results: Only 50% of the Korean-American women surveyed had a Pap test in the previous 2 years. The strongest independent correlate was having had a regular check-up in the previous 2 years (odds ratio 7.2, 95% confidence interval 4.2, 12.1)., Conclusions: Rates of Pap testing among Korean-American women are well below national objectives. Collaboration and community-sensitive research are essential to collect data and design programs to improve the health of ethnic minority communities.

Background: Mammography and clinical breast examination (CBE) are underutilized, especially by women from some racial/ethnic minorities. Few published studies of screening practices or correlates for these subgroups exist., Methods: A population-based telephone survey of 1,090 Korean Americans living in two California counties was conducted. To produce population estimates of mammography and CBE testing, we adjusted frequencies to account for different selection probabilities. Multivariable logistic regression was performed to determine independent correlates of testing., Results: Only 34% [95% confidence intervals (CI) 30%, 39%] of Korean American women age 50 and older were estimated to have had a mammogram in the past 2 years. Only 32% (95% CI 28%, 37%) had had a CBE in the past 2 years. The strongest independent correlate of testing was having a regular medical checkup [odds ratio (OR) for mammogram = 9.21, 95% CI 3.98, 21.35; OR for CBE = 11.58, 95% CI 4.71, 28.46]., Conclusions: These estimates are lower than the Healthy People 2000 objectives as well as published estimates for other populations in the United States. Planning and implementing tailored programs to improve screening are best done using a community-sensitive approach, which, because racial/ethnic subgroups are growing, will assume increasing public health importance.

Background: In response to the increasing rate of skin cancer, particularly melanoma in the United States, the Environmental Protection Agency, the National Weather Service, the Centers for Disease Control and Prevention, National Association of Physicians for the Environment, and the American Academy of Dermatology, developed the Ultraviolet Index (UVI) to inform the public of the strength of the sun's rays and advise on methods for sun protection., Objective: Our purpose was to evaluate the extent to which television stations and newspapers reported the UVI and assess the public's response to it., Methods: To evaluate the effect of this effort, we surveyed television weather forecasters at 185 stations and examined weather pages in 54 newspapers in 58 cities that received the UVI reports. We also conducted a population probability telephone survey of 700 white adults (18 years of age and older) in these 58 cities., Results: Seventy-one percent of the 169 stations that provided survey data for both 1994 and 1995 broadcast the UVI; 61% of newspapers reported the UVI. Nearly 64% of the 700 respondents (n = 445) had heard of the UVI. Of these respondents, 38% (n = 170) stated that they or their family changed their sun protection practices as a result of the UVI., Conclusion: The majority of television weather forecasters and newspapers reported the UVI. Most of the public was aware of the UVI, causing some to change sun protection practices. Further evaluation is required to maximize the effect of the UVI on sun protection practices.

Objective: To study the risk factors for early work disability in systemic lupus erythematosus (SLE)., Methods: A sample of 159 SLE patients who had been employed at some time since diagnosis was drawn from a multicenter study of outcome in SLE. Disease activity, organ damage, education, income, source of health insurance, and work-related factors were measured in a standardized interview. Work disability was defined by patient self-report of not working because of SLE. The outcome measure was current work status. Seven patients were excluded from the analysis because their choice not to work was unrelated to SLE., Results: An average of 3.4 years after diagnosis, 40% had quit work completely, and job modification was substantial. Univariate analysis (chi-square and t-test) showed that significant predictors of early work disability included having a high school education or less, receiving Medicaid or having no health insurance, having a job which required more physical strength, having an income below poverty level, and having greater disease activity at diagnosis. In multivariate models, significant predictors were education level (P = 0.0004), higher physical demands of the job (P = 0.0028), and higher disease activity at diagnosis (P = 0.0078). Race, sex, cumulative organ damage at diagnosis, and disease duration were not significant., Conclusion: Early work disability in SLE is strongly associated with some sociodemographic factors that might be amenable to intervention.

Introduction: This is a preliminary report from a research collaboration between Asian Health Services (community health center); Koreans in Alameda County, California; and the University of California at Berkeley School of Public Health. This five-year Centers for Disease Control and Prevention project supports a collaborative community intervention to improve breast and cervical cancer screening behavior among Korean women., Methods: A Korean Community Advisory Board and Korean-American staff were recruited, and community sensitive research (CSR) and participatory action research (PAR) principles were applied: (1) building community infrastructure for sustainable action, (2) cultural appropriateness, (3) assuring responsiveness to community needs, and (4) a prevention focus that would assist health care providers. We conducted a population-based telephone survey on 676 Korean adults (272 men and 404 women)., Results: The collaborative process yielded (1) a high response rate (79%), (2) baseline health information on Korean Americans, (3) broadening of the original research topic, (4) survey responses that will guide intervention design, (5) culturally competent strategies, and (6) expanded Korean-American Community capacity for local action., Conclusions: Research collaboration between universities, community-based organizations, and ethnic communities can yield high-quality research. CSR and PAR approaches help break through cultural barriers in otherwise "hard to reach" API sub-populations. Determinants of success include sharing common goals; trust, honesty, and integrity; shared decision making; mutual respect of each partner's expertise; cultural sensitivity and cultural competence; flexibility, good communication, and mutual learning; and continuity of partners. Actively engaging members of the study population in the research process builds community capacity, thus laying the foundation for future projects that improve health status.

Bradykinin exerts important influences on renal hemodynamics and tubular function by acting on renal bradykinin B2 receptors. However, the precise sites and mechanisms of its actions on the kidney are not known. To help elucidate the mechanisms of renal actions of bradykinin in vivo, we have employed high resolution electron microscopic autoradiography to localize bradykinin B2 binding sites in the rat kidney following intravenous administration of a radiolabeled ligand, 125I-HPP-Hoe140 (3-4-Hydroxyphenyl-propionyl-DArg0-[Hyp3-Thi5-D-Tic 7-Oic8]-bradykinin), a derivative of the highly selective bradykinin B2 receptor antagonist, Hoe140. In non-treated rats, bradykinin B2 binding sites were localized to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex. In the medulla (except for the outer stripe of the outer medulla), binding occurred in the distal tubules, thin limbs of the loop of Henle, collecting ducts, peritubular capillary endothelium and renomedullary interstitial cells. To exclude the possibility that the radioligand may bind to angiotensin converting enzyme, rats were pretreated with the angiotensin converting enzyme inhibitor, perindopril. In these rats, binding to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex was completely abolished, while binding remained unaltered in the medulla. Further studies using high performance liquid chromatography revealed that while the radioligand was degraded following systemic administration in nontreated rats, the degradation was significantly reduced in the rats pretreated chronically with perindopril. These results indicate that binding detected in the proximal tubules in the normal rats is due primarily to the tubular uptake of the degraded radioligand, and that bradykinin B2 binding sites occur predominantly in the renal tubules, vascular endothelium, and renomedullary interstitial cells of the renal medulla.

Several peptidases have been postulated to degrade the hypothalamic peptide gonadotropin-releasing hormone (GnRH), but it is not known if such enzymes contribute significantly to the delivery of GnRH to the pituitary in vivo. Furthermore, the activity of GnRH-inactivating peptidases may vary in different reproductive states, such as across the estrous cycle. In the present study, specific fluorescent substrates were used to measure the activity of the two major GnRH-degrading enzymes, prolyl endopeptidase (PEP) and endopeptidase 3.4.24.15 (EP 24.15), in soluble extracts of the median eminentes (ME) of ewes during different phases of the estrous cycle. Levels of EP 24.15 and PEP activity in the ME did not vary significantly across the cycle, although PEP activity was lowest at the time of the preovulatory luteinizing hormone (LH) surge. However, a statistically significant decline in PEP activity (18%, P = 0.02) was observed in the ME of OVX ewes in which a surge was induced by estrogen when compared to oil-treated OVX controls, suggesting a possible negative regulation of PEP activity by this steroid. The effect of intracerebroventricular (i.c.v.) infusion of several peptidase inhibitors on the pulsatile release of LH in the conscious OVX ewe was also examined. No consistent changes in the pattern of LH release were observed with i.c.v. infusion of the EP 24.15 inhibitor N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB) or the angiotensin-converting enzyme (ACE) inhibitor captopril. Similarly, administration of the prolyl endopeptidase inhibitor bacitracin, or a more specific inhibitor of this enzyme, Z-Proprolinal (ZPP), did not alter LH release patterns. The results did not demonstrate a major role for changes in the activity of EP 24.15, PEP, or ACE in altering the pattern of GnRH secretion, but a minor reduction in PEP levels may occur at the time of the estrogen-induced LH surge.

We have investigated the ability of dopamine to compete with the binding of the high affinity dopamine D2 receptor positron emission tomography (PET) radioligand, 18F-fallypride. In vitro dissociation of 18F-fallypride with dopamine in rat striatal homogenates exhibited a dissociation rate, k(off), of 1.76 x 10(-2) min(-1) while the association rate constant, k(on), was found to be 5.30 x 10(8) M(-1) min(-1). This resulted in a dissociation constant, K(D) of 33 pM for 18F-fallypride. For in vivo studies, we investigated the effects of reserpine and d-amphetamine treatment on 18F-fallypride in an attempt to study competition of endogenous dopamine with the radioligand at the receptor sites in rats and monkeys. PET experiments with 18F-fallypride in two male rhesus monkeys were carried out in a PETT VI scanner. In control experiments, rapid specific uptake of 18F-fallypride in the striata was observed (0.05-0.06% injected dose (ID)/g) while nonspecifically bound tracer cleared from other parts of the brain. Striata/cerebellum ratios for 18F-fallypride were approximately 8 at 80 min postinjection, respectively. The monkeys received various doses (0.25 to 1.50 mg/kg) of d-amphetamine (AMPH) pre- and postinjection of the radioligand. There was a decrease of specifically bound 18F-fallypride as well as evidence of an enhanced clearance of specifically bound 18F-fallypride after administering AMPH in the two monkeys. The dissociation rates, k(off), of 18F-fallypride without AMPH was <10(-4) min(-1) but after 25 min preadministration of AMPH (1 mg/kg), it was 4.1 x 10(-3) min(-1) and after 17, 45 and 90 min postadministration of AMPH (1 mg/kg) it was 3.6 x 10(-3) to 4.0 x 10(-3) min(-1). Lower doses of AMPH (0.25 mg/kg) had a reduced effect on the binding of 18F-fallypride. No effect was seen until about 30 minutes after the injection of AMPH. Studies with various doses indicated that 18F-fallypride has a maximum response at doses of 0.75-1.50 mg/kg, with an approximately 16%/hour reduction in binding. These results indicate that AMPH stimulated release of endogenous dopamine reduces the specific binding of 18F-fallypride.

We have investigated Ca(2+)-involving cell signaling, plasma membrane potentials and conductances and callose formation during early stages of pollination of papillae of Brassica napus. Using fluorescence imaging of calcium green-1, we found that application of a range of pollen types and controls all rapidly produced small localized peaks in papillar cytoplasmic [Ca2+]. This response was more frequent in compatible than incompatible interactions and was correlated with subsequent hydration of the applied pollen grains, indicating that it may be a differential prerequisite of the compatible signaling pathway leading to successful pollinations. In contrast, a slight trend to increased plasma membrane conductance (but with no indications of action potential-like responses) and also callose deposition in papillae adjacent to pollen grains followed pollination in both SC and SI interactions, indicating that alterations in plasma membrane permeability and callose deposition during early phases of pollination are not primary determinants of the fate of attempted pollinations.

Objectives: This study assessed current levels of sunbathing and sunscreen use in the United States., Methods: From a general-population telephone survey of aquatic activities among adults in 3042 US households, we examined responses by the 2459 Whites., Results: Most adults (59%) reported sunbathing during the past year, and 25% reported frequent sunbathing. Of the subsample who reported sunbathing during the month before the interview, 47% routinely used sunscreen. Of these individuals, almost half did not use sunscreens with a solar protection factor of 15 or higher., Conclusions: About a quarter of US White adults report frequent sunbathing, and only about a quarter of sunbathers use sunscreens at recommended levels. These results should help focus future sun protection educational efforts.

Background: Sun protection behaviors are recommended to prevent skin cancer, which has increased in incidence. This study measured the prevalence of sun protection behaviors and determined personal characteristics associated with them., Methods: Data from 10,048 white respondents to the 1992 National Health Interview Survey Cancer Control Supplement were analyzed. Multiple logistic regression models were constructed to relate personal characteristics to specific behaviors., Results: Fifty-three percent of respondents reported they were "very likely" to use sunscreen, wear protective clothing, or seek shade if they were outside on a sunny day for more than 1 hr. Proportions for the individual behaviors were 32, 28, and 30%, respectively. Compared with people who do not burn, those reporting severe sunburn after 1 hr of sun exposure reported more use of sunscreens (odds ratio [OR] = 2.4, 95% confidence interval [CI] 2.0, 2.9), shade (OR = 1.8, 95% CI 1.5, 2.1), and protective clothing (OR = 2.2, 95% CI 1.9, 2.7). Other factors associated with practicing protection behaviors included a personal history of skin cancer, older age, and female sex., Conclusions: A large percentage of white U.S. adults did not protect themselves from sun exposure. Additional education of the general public and persons at higher risk for skin cancer is needed.

Angiotensin IV (Val-Tyr-Ile-His-Pro-Phe) has been reported to interact with specific high-affinity receptors to increase memory retrieval, enhance dopamine-induced stereotypy behavior, and induce c-fos expression in several brain nuclei. We have isolated a decapeptide (Leu-Val-Val-Tyr-Pro-Trp-Thr-Gln-Arg-Phe) from sheep brain that binds with high affinity to the angiotensin IV receptor. The peptide was isolated using 125I-angiotensin IV binding to bovine adrenal membranes to assay receptor binding activity. This peptide is identical to the amino acid sequence 30-39 of sheep betaA- and betaB-globins and has previously been named LVV-hemorphin-7. Pharmacological studies demonstrated that LVV-hemorphin-7 and angiotensin IV were equipotent in competing for 125I-angiotensin IV binding to sheep cerebellar membranes and displayed full cross-displacement. Using in vitro receptor autoradiography, 125I-LVV-hemorphin-7 binding to sheep brain sections was identical to 125I-angiotensin IV binding in its pattern of distribution and binding specificity. This study reveals the presence of a globin fragment in the sheep brain that exhibits a high affinity for, and displays an identical receptor distribution with, the angiotensin IV receptor. This globin fragment, LVV-hemorphin-7, may therefore represent an endogenous ligand for the angiotensin IV receptor in the CNS.

Administration of phentermine (Phen) together with (+/-) fenfluramine (Fen) enhances the weight reduction that is observed with either drug alone; consequently, these anorectic agents are commonly prescribed together for weight reduction. Repeated administration of Fen is known to cause long-term depletion of axonal serotonin (5-HT) and loss of 5-HT transporters, and is therefore considered neurotoxic. We now report that combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg, and 20 mg/kg/3.125 mg/kg) can enhance the neurotoxic effect of Fen (3.125 mg/kg) and Phen (5 mg/kg and 20 mg/kg) on central 5-HT systems. Rats were repeatedly treated once each hour for a total of four injections with saline, Phen (5 mg/kg and 20 mg/kg), Fen (3.125 mg/kg and 12.5 mg/kg), or combined Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg), and sacrificed either 7 or 28 days after cessation of treatment. Combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused significantly greater reductions of 5-HT levels in the striatum, nucleus accumbens/olfactory tubercle, hypothalamus, amygdala, frontal parietal cortex, and hippocampus than either drug alone. Combined Phen/Fen at the higher drug-dose combination (20 mg/kg/3.125 mg/kg) was observed to reduce the density of 5-HT transporters in rat striatum at both 7 and 28 days after cessation of treatment. In addition, combined administration of Phen/Fen (5 mg/kg/3.125 mg/kg and 20 mg/kg/3.125 mg/kg) caused greater weight loss than that observed with either compound alone. Collectively, the present data demonstrate that combined Phen/Fen administration enhances the neurotoxicity of Phen or Fen on 5-HT neurons.

Objective: To evaluate symptom patterns on a hand diagram as predictors of surgical outcome in carpal tunnel syndrome (CTS)., Methods: 202 patients with CTS enrolled in a prospective, community based cohort study in Maine completed a hand symptom diagram before surgery and at 6 month followup. They were asked to mark on the hand diagram the location of 3 symptoms: pain, numbness/tingling (NT), and "other" symptoms. The diagram was first divided into 6 regions following a standardized procedure. For the 6 regions, symptom patterns were identified separately for each of the 3 symptoms. Outcomes 6 months after surgery were expressed as the percentage of change on the Symptom Severity Scale and Function Status Scale of the Carpal Tunnel Syndrome Assessment Questionnaire, and the satisfaction with the results of the surgery., Results: Several distinct symptom patterns were associated with the 3 principal outcomes in univariate and multivariate analysis. In linear regression models controlling for the baseline severity of symptoms and function, as well as other predictors, the hand symptom pattern variables accounted for 30, 14, and 24%, respectively, of the total explained variance in satisfaction, symptom severity, and functional status. Patients receiving Workers' Compensation (37% of the cohort) had more wrist pain and NT of the arm, and less pain involving the arm and upper palm. This group also had worse outcomes and were less satisfied with surgery. Drawing expansion was associated with a low score on the SF-36 mental health subscale. However, psychological impairment was not associated with a worse outcome., Conclusion: Symptom patterns identified preoperatively with a hand symptom diagram help to predict the outcome of carpal tunnel release.

Objective: To study the relationship of race, socioeconomic status (SES), clinical factors, and psychosocial factors to outcomes in patients with systemic lupus erythematosus (SLE)., Methods: A retrospective cohort was assembled, comprising 200 patients with SLE from 5 centers. This cohort was balanced in terms of race and SES. Patients provided information on socioeconomic factors, access to health care, nutrition, self-efficacy for disease management, health locus of control, social support, compliance, knowledge about SLE, and satisfaction with medical care. Outcome measures included disease activity (measured by the Systemic Lupus Activity Measure), damage (measured by the SLICC/ACR damage index), and health status (measured by the SF-36)., Results: In multivariate models that were controlled for race, SES, center, psychosocial factors, and clinical factors, lower self-efficacy for disease management (P < or = 0.0001), less social support (P < 0.005), and younger age at diagnosis (P < 0.007) were associated with greater disease activity. Older age at diagnosis (P < or = 0.0001), longer duration of SLE (P < or = 0.0001), poor nutrition (P < 0.002), and higher disease activity at diagnosis (P < 0.007) were associated with more damage. Lower self-efficacy for disease management was associated with worse physical function (P < or = 0.0001) and worse mental health status (P < or = 0.0001)., Conclusion: Disease activity and health status were most strongly associated with potentially modifiable psychosocial factors such as self-efficacy for disease management. Cumulative organ damage was most highly associated with clinical factors such as age and duration of disease. None of the outcomes measured were associated with race. These results suggest that education and counseling, coordinated with medical care, might improve outcomes in patients with SLE.

Objective: Clinical studies of systemic lupus erythematosus (SLE) often necessitate assessment of previous disease activity, which is sometimes only possible by retrospective evaluation of information from the medical record. Using the Systemic Lupus Activity Measure (SLAM), the present study compared an assessment of disease activity obtained by chart abstraction with a direct clinical assessment., Methods: A chart SLAM was obtained using information abstracted from the clinic notes of 46 patients with SLE who were being followed up at a referral center. Chart SLAM scores were compared with SLAM scores derived from an independent assessor's direct clinical evaluation., Results: Direct SLAM and chart SLAM scores were correlated (r = 0.67 by Spearman's rank correlation, P = 0.0001). Chart review scores for disease activity tended to be lower, but to an inconsistent degree, reflecting both under- and overestimation of disease activity. The overall misclassification rate on a 3-category scale (mild, moderate, or severe activity) was 59%., Conclusion: Although chart SLAM scores were highly correlated with direct SLAM scores, misclassification of disease activity by chart review cannot be rectified. Thus, in research, medical record review should not be used as a proxy for the direct SLAM, nor should it be considered comparable with clinical assessments in the analysis of disease activity.

The activity of endopeptidase EC 3.4.24.15 (thimet oligopeptidase, EP 24.15), as measured by cleavage of a quenched fluorescent substrate, 7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-Pro-D-Lys (2,4-dinitrophenyl), was increased 2-3 fold by the addition of 1 mM Mn2+ or of 10 mM Ca2+. The inhibitory capability of a specific EP. 24.15 inhibitor, N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate, was also increased at similar concentrations of these metal ions. However, the hydrolysis of naturally-occurring peptides, thought to be the physiological substrates for EP 24.15, was not affected by either Mn2+ or Ca2+. These results suggest that the binding of synthetic analogs to the enzyme may differ significantly from the binding, and thus hydrolysis, of natural peptide substrates and caution against drawing conclusions about substrate interactions with the active site from data obtained with modified peptide ligands.