Immunology of cutaneous vasculitis associated with both etanercept and infliximab.

Targeted inhibition of tumour necrosis factor-alpha (TNF-alpha) is an effective therapy in rheumatoid arthritis and Crohn's disease (CD). Infliximab, a monoclonal murine-human chimeric antibody to TNF-alpha, and etanercept, a fusion protein of two p75 chains of the TNF receptor II and the Fc portion of IgG1, are generally well tolerated. Rarely does clinically significant autoimmunity, including drug-induced lupus and vasculitis occur. Immunologic mechanisms underlying the development of autoimmunity in the presence of such powerful immunosuppressants are unknown. We describe a patient with CD, who developed cutaneous vasculitis on etanercept, which worsened significantly with switch to infliximab. Investigation of the associated systemic and local immune response demonstrated the absence of human antichimera antibodies, but mRNA for T-helper 1 cytokines, chemokines and defensins in the skin and elevated angiogenesis factors in the serum, as determined by reverse-transcriptase polymerase chain reaction and enzyme-linked immunosorbent assay. Histopathology revealed a lymphocytic vasculitis composed of T cells. A permanent B-cell line (MD-B) producing extremely high amounts of chemokines and interleukin-6 was established from this patient's peripheral blood. Lesions progressed despite discontinuation of the drugs and (40 mg/day) prednisone but almost completely resolved with single dose of (0.1 mg/kg) intravenous dexamethasone, which may be therapy of choice for this reaction. A few lesions (<10) have recurred intermittently over 4 years of follow-up, suggesting possible persistence of this TNF-inhibitor-triggered autoimmune disease.

Completing tuberculosis prophylaxis in jail: targeting treatment and comparison of rifampin/pyrazinamide with isoniazid regimens.

SETTING: A county jail. OBJECTIVE: To characterize the treatment of latent tuberculosis infection and the impact on treatment completion of the 2-month rifampin and pyrazinamide regimen as compared to the traditional 6- to 12-month isoniazid regimen among persons incarcerated at a county correctional facility. DESIGN: Retrospective review of tuberculosis records from January 1998 to December 2000. RESULTS: Of 2127 inmates who were tuberculin skin test positive, 146 were started on treatment. This was generally limited to those expected to remain incarcerated long enough to complete the course of treatment. Completion rates were 88% (67/76) for the 2-month and 74% (51/69) for the 6- to 12-month courses (P = 0.03), and 82% overall. The two regimens were similarly tolerated, but inmates on isoniazid were more likely to be released (despite longer projected incarceration) and not complete treatment once in the community. Thirty-seven per cent of persons for whom treatment was not indicated by the previous guidelines should have had treatment by the new guidelines. CONCLUSION: The 2-month rifampin/pyrazinamide regimen had a higher completion rate than the longer isoniazid regimen, without additional toxicity, and allowed more patients to be treated. Latent tuberculosis treatment targeted to those able to complete the regimen in jail yields high completion rates.

Alterations of mismatch repair protein expression in benign melanocytic nevi, melanocytic dysplastic nevi, and cutaneous malignant melanomas.

Immunoperoxidase-staining methods were used to examine the expression of hMLH1, hMSH2, and hMSH6 mismatch repair (MMR) proteins in 50 melanocytic lesions. Microsatellite instability (MSI), screened previously in these lesions by polymerase chain reaction-based microsatellite assay, showed low-level microsatellite instability (MSI-L) in 11 of 22 melanocytic dysplastic nevi (MDN) and two of nine primary cutaneous malignant melanomas (CMMs) but not in the benign melanocytic nevi (BN). Mismatch repair proteins were widely expressed in the epidermis and adnexal structures. All lesions showed positive immunoreactivity with a gradual decrease in the MMR staining values during the progression from BN to MDN to CMMs. The average percentage of positively (PP) stained cells for hMLH1, hMSH2, and hMSH6 in BN was 85.50 +/- 1.95, 77.90 +/- 4.50, and 87.11 +/- 1.85, respectively. The PP cell values in CMMs were significantly reduced as compared with BN (75.22 +/- 3.57, p= 0.01; 56.11 +/- 8.73, p= 0.02; 65.22 +/- 6.47, p = 0.0002 for hMLH1, hMSH2, and hMSH6, respectively). No comparable significant difference was found between microsatellite stable and MSI-L lesions (p = 0.173, p = 0.458, and p = 0.385), suggesting a lack of correlation between MMR expression and MMR function. There was a direct correlation between PP cell values of hMSH2 and hMSH6 (R = 0.39, p = 0.008), implying that their expression could be regulated by a common mechanism. Thus, an important finding of these studies was the reduction of MMR protein levels in CMMs; whether this reflects underlying genetic or epigenetic mechanisms is still to be determined.

Sex of first child and breast cancer survival in young women.

Two studies have reported that young women with breast cancer face increased risk of early mortality if their first child was male rather than female. An immunological mechanism has been suggested. We sought to confirm these results in a larger, historical cohort study of 223 parous women who were aged <45 years at breast cancer diagnosis during 1983-1987. Subjects were identified through the Maine Cancer Registry. Follow-up data were obtained from hospitals, physicians, and death certificates. Reproductive history data were obtained from the next of kin of the deceased women, birth certificates, physicians, hospitals, and lastly, subjects. With a 7-year follow-up, multivariate modeling found a lower mortality risk in women with a male first child (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.32-0.81, log-rank comparison). The survival advantage remained for at least 13 years in women with a male firstborn. Thus, previous studies were not confirmed. Mortality risk in young women with breast cancer is not increased by having borne a male first child rather than a female first child.

Comprehensive analysis of 112 melanocytic skin lesions demonstrates microsatellite instability in melanomas and dysplastic nevi, but not in benign nevi.

INTRODUCTION: the length of DNA repetitive sequences (microsatellite instability (MSI)) represent distinct tumorigenic pathways associated with several familial and sporadic tumors. MATERIAL AND METHODS: To investigate the prevalence and frequency of MSI in melanocytic lesions, the polymerase chain reaction (PCR)-based microsatellite assay was used to examine formalin-fixed, paraffin-embedded tissues of 30 benign melanocytic nevi, 60 melanocytic dysplastic nevi (MDN), and 22 primary vertical growth phase cutaneous malignant melanomas (CMM). Twenty-four microsatellite markers at the 1p, 2p, 3p, 4q and 9p chromosomal regions were used. RESULTS: MSI was found at 1p and 9p in MDN and CMM but not in benign melanocytic nevi. The overall prevalence of MSI was 17/60 (28%) in MDN and 7/22 (31%) in CMM. The frequency of MSI ranged from 2/24 (9%) to 4/24 (17%) and was most commonly found at D9S162. There was a statistically significant correlation between degree of atypia and frequency of MSI (p<0.001) in MDN. There were two MSI banding patterns: band shifts and additional bands. CONCLUSIONS: The data presented revealed the presence of low-frequency MSI (MSI-L) at the 1p and 9p regions in both MDN and CMM. Whether the MSI-L pattern reflects a defect in mismatch repair genes is still to be determined.

An early lesion in hepatic carcinogenesis: loss of heterozygosity in human cirrhotic livers and dysplastic nodules at the 1p36-p34 region.

Loss of heterozygosity (LOH) of chromosome 1 has been suggested, by karyotyping, to be an initial episode in human hepatocarcinogenesis. However, this alteration has not yet been investigated in cirrhotic nodules (CNs) or dysplastic nodules (DNs). In an initial study from explanted or resected cirrhotic livers, LOH in 1p36-p32 was examined in 31 hepatocellular carcinomas (HCCs), 25 low-grade dysplastic nodules (LGDNs), and 24 high-grade dysplastic nodules (HGDNs). In HCCs, LOH was detected most frequently at loci D1S2843 (1p36.1) (28.6%), D1S513 (1p34.3) (29.2%), and MYCL1 (1p34.1) (28.6%). In HGDN and LGDN, LOH incidences at D1S513 were 11.1% and 13.6%, respectively. To further refine those results and to determine sequential relationships among CN, DN, and HCC, LOH was next studied in an additional 53 HCCs, 56 HGDNs, 30 LGDNs, and 215 CNs from 11 explanted human cirrhotic livers, including 30 "nodule-in-nodule" lesions. Seven markers between D1S2843 (1p36.12) and MYCL1 (1p34.1), and 1 each at D1S484 (1q24.1), IGF2R-3 (6q26), and TP53 (17p13.1) were used. LOH at D1S2843 and D1S513 was detected in HCCs (20.4% and 23.5%, respectively), HGDNs (7.7% and 18.5%), LGDNs (13.6% and 6.9%), and CNs surrounding either HCCs or DNs (7.4% and 8.3%). These results demonstrate that LOH at D1S2843 and D1S513 are early events in human liver carcinogenesis. Data from CN surrounding either HCCs or DN, and also nodule-in-nodule lesions, provide evidence supporting a CN-->DN-->HCC progression. Different deletion patterns from multiple HCCs and DNs suggest independent origins for carcinogenesis in the same individual.

Self-reported health and prior health behaviors of newly admitted correctional inmates.

OBJECTIVES: This study obtained comprehensive health information from newly admitted correctional inmates. METHODS: Interviews were conducted with 1198 inmates on day 3 of their incarceration. RESULTS: Interviewers found a high prevalence of chronic medical and mental health issues, limited access to health care, high rates of infections and sexually transmitted diseases, substantial substance abuse, other unhealthy behaviors and violence, and a strong desire for help with health-related problems. CONCLUSIONS: The data document the need to apply the public health approach to correctional health care, including detection and early treatment of disease, education and prevention to facilitate health and behavior change, and continuity of care into the community.

Uterine rhabdomyosarcoma metastatic to mediastinal lymph nodes: diagnosis by transbronchial needle aspiration.

Uterine rhabdomyosarcoma is rare, with only 60 reported cases. We describe an asymptomatic patient with metastatic uterine rhabdomyosarcoma manifested as extensive mediastinal lymphadenopathy. This 73-year-old woman had been previously treated for endometrial rhabdomyosarcoma and was referred to us when a right hilar density was seen on a chest radiograph; computed tomography showed a nodule in the right upper lobe and extensive right hilar and subcarinal lymphadenopathy. The diagnosis of metastatic rhabdomyosarcoma was made by fiberoptic bronchoscopy using transbronchial needle aspiration (TBNA). The patient is well 11 months after completing five cycles of chemotherapy. This is the first reported case of uterine rhabdomyosarcoma with metastasis to the mediastinum and the first case diagnosed with TBNA, which avoided the need for an invasive diagnostic procedure.

Factors associated with repeat mammography in a New York State public health screening program.

Screening mammography is the most effective method for early detection of breast cancer, but repeat mammography rates are not optimal in most populations. Since 1988, New York State has supported a program of breast cancer screening for underserved, uninsured, or underinsured women. The present study was designed to identify sociodemographic and clinical factors associated with failure to return for repeat mammography screening after a negative initial mammogram. Of women initially screened between 1988 and 1991 (N = 9,485), 27 percent obtained repeat mammograms by 1993. The final logistic regression model contained program site, race and ethnicity, family income, and time since last mammogram.

Disseminated intravascular coagulation associated with acute ischemic hepatitis after elective aortic aneurysm repair: comparative analysis of 10 cases.

OBJECTIVE: To assess the characteristics of patients with perioperative disseminated intravascular coagulation (DIC) and acute ischemic hepatitis after elective aortic aneurysm repair (AAR). DESIGN: A retrospective case-control study. SETTING: A single tertiary referral center. PARTICIPANTS: Between 1982 and 1993, 1966 patients underwent elective AAR. Of these, 10 patients (eight with abdominal and two with thoracoabdominal aneurysms) developed DIC and acute elevation of serum transaminases consistent with acute ischemic hepatitis during or shortly after surgery. The control group included 30 patients matched by age, sex, year of surgery, and aneurysm type and size. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: None of the patients in either group had preoperative hemostatic abnormalities or other causes for DIC. There was no difference between the two groups in the duration of aortic cross-clamping. In all study patients, severe coagulopathy or systemic hypotension developed after the aortic cross-clamp was released. This resulted in significantly increased surgery time after unclamping (p < 0.001), and increased estimated blood loss (p < 0.001). DIC developed within 24 hours, and mean concentrations of aspartate transaminase (4,021 +/- 3,579 IU/L) and lactate dehydrogenase (4,332 +/- 2,903 IU/L) peaked on the second postoperative day. Nine (90%) of the study patients required repeat operations (seven for bleeding), and all of them died; the median survival time was 6 days (mean, 8.3 +/- 8.2 days). Only one patient in the control group needed a repeat operation. Liver infarction or necrosis was seen in all seven patients who underwent autopsy or biopsy. CONCLUSIONS: The combination of DIC and acute ischemic hepatitis ("hepatohemorrhagic syndrome") rarely occurs after elective AAR and is associated with a very high mortality rate. DIC was temporally related to the release of the aortic cross-clamp. The cause-effect relationship of this rare syndrome cannot be explained by operative course before the release of the aortic cross-clamp.

CD34 and factor-XIIIa immunoreactivity in dermatofibrosarcoma protuberans and dermatofibroma.

The histologic distinction between dermatofibrosarcoma protuberans (DFSP) and the fibrous type of benign fibrous histiocytoma (dermatofibroma, DF) may be extremely difficult. In this study, we evaluated the extent and pattern of immunoreactivity of both CD34 and factor XIIIa in a large number of DFSPs and DFs in order to determine the utility of these markers in their distinction. Using histologic criteria alone, the authors independently evaluated and agreed upon 30 cases of DF and 24 cases of DFSP, and a representative section was stained with antibodies to both factor XIIIa and CD34. Immunopositivity was evaluated semiquantitatively and assigned a score from 0 to 5. CD34 immunoreactivity was seen in 22 (92%) of 24 DFSPs (mean CD34 score, 4.60 +/- 0.3). Only 12 (40%) of 30 DFs showed CD34 immunopositivity (mean CD34 score, 0.6 +/- 0.1). Factor XIIIa was seen in 29 (97%) of 30 DFs (mean factor-XIIIa score, 4.1 +/- 0.3). In contrast, 18 (75%) of 24 DFSPs stained for factor XIIIa (mean factor-XIIIa score, 1.3 +/- 0.2), but in most of these cases the factor-XIIIa-positive cells were felt to be entrapped nonneoplastic dermal dendrocytes. Thus, an immunoprofile using antibodies to CD34 and factor XIIIa is capable of distinguishing between DFSP and the fibrous type of DF in the vast majority of cases, as long as there is recognition that there may be some CD34-positive cells in DFs, as well as some factor-XIIIa-positive cells in DFSPs.

A multi-city community based smoking research intervention project in the african-american populatio.

OBJECTIVE: To carry out a community-based research approach to determine the most effective educational interventions to reduce smoking among African-American smokers. The intervention included preparation of the community, planning and developing a model of change, and developing a community-based intervention. The study population consisted of 2,544 randomly selected adult African-American smokers residing in four sites in the northeastern and southeastern parts of the United States. The research design provided a comparison of active intervention sites with passive control sites as well as low income and moderate income areas. MAJOR OUTCOME MEASURES: Point prevalence of non-smoking at the time of interview; Period prevalence of non-smoking at the time of interview; Period prevalence of quit attempts in the prior six months; Number of smoke-free days in the prior six months; Number of cigarettes smoked daily at the time of interview. RESULTS: Based upon a survey eighteen months after baseline data was collected, all four measures of cigarette smoking behavior showed a strong statistically significant reduction of personal smoking behavior among those receiving active interventions versus the passive group. On the basis of process variable analysis, direct contact with the project staff in the prior six months was significantly higher in the active intervention areas. There was only a small non-significant increase in personal smoking behavior in moderate income groups as opposed to low income groups. CONCLUSION: An analysis of process variables strongly suggests that, within this African-American Community, "hands on" or "face to face" approaches along with mass media, mailings, and other less personal approaches were more effective in reducing personal smoking behavior than media, mailings, and other impersonal approaches alone addressed to large audiences.

Quinidine-induced pigmentation.

Antimalarial agents have long been known to cause a variety of pigmentary disturbances. Quinidine, a cincha alkaloid and D-isomer of quinine, is widely used for the treatment of ventricular arrhythmias. A paucity of literature, however, exists concerning quinidine-associated hyperpigmentation. We describe a case of focal ceruloderma we believe to be secondary to quinidine therapy.

Hair lead levels related to children's classroom attention-deficit behavior.

The goal of this study was to evaluate the relationship between hair lead levels of children and their attention-deficit behaviors in the classroom. Scalp hair specimens were obtained from 277 first-grade pupils, teachers completed the abbreviated Boston Teacher's Rating Scale for rating classroom attention-deficit behavior, and parents completed a short questionnaire. The children's hair lead concentrations ranged from less than 1 to 11.3 ppm (microg/g). The striking dose-response relationship between levels of lead and negative teacher ratings remained significant after controlling for age, ethnicity, gender, and socioeconomic status. An even stronger relationship existed between physician-diagnosed attention-deficit hyperactivity disorder and hair lead in the same children. There was no apparent 'safe' threshold for lead. Scalp hair should be considered a useful clinical and epidemiologic approach for the measurement of chronic low-level lead exposure in children.

Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis.

Central nervous system (CNS) expression of two chemokine mRNAs, encoding monocyte chemoattractant protein-1 (MCP-1) and IFN-gamma-inducible protein (IP-10), was previously shown to be closely related to the onset of clinical signs of murine experimental autoimmune encephalomyelitis (EAE). Chemokine mRNAs accumulated in a striking, transient burst within astrocytes, near inflammatory leukocyte infiltrates. It remained unclear if chemokines functioned to initiate leukocyte entry into CNS tissues, or to amplify the intrathecal inflammatory reaction. To address this issue, we determined the expression of chemokine mRNAs at the earliest evidence of CNS immune-mediated inflammation. For these experiments, mice were sacrificed in pairs at varying times after immunization. Only one member of each pair was symptomatic for EAE at the time of sacrifice. Symptom presence correlated well with histological inflammation at the time of sacrifice. RNA was prepared from two CNS sites, brain and spinal cord, and expression of chemokine mRNAs was analyzed by a sensitive and quantitative reverse transcriptase/polymerase chain reaction dot-blot hybridization assay. CNS expressions of MCP-1 and IP-10 gene were correlated tightly with histological inflammation; indeed, chemokine expression was never detected in the absence of leukocyte infiltrates. In situ hybridizations showed that astrocytes expressed chemokine transcripts. These findings provide new information about mechanisms controlling chemokine mRNA expression during immune-mediated inflammation in EAE and are consistent with a role for chemokines as amplifiers of CNS inflammatory reactions.

Direct visualization of the clonal progression of primary cutaneous melanoma: application of tissue microdissection and comparative genomic hybridization.

Human cutaneous malignant melanoma progresses through a series of well defined clinical and histopathological stages. It has been assumed that the neoplastic progression of this disease advances from a common acquired nevus or dysplastic nevus through the primary radial growth phase (RGP), primary vertical growth phase (VGP), and finally to distant metastasis. However, it has never been directly shown that VGP is clonally derived from RGP. Furthermore, it has not been possible previously to conduct a detailed genetic analysis on pure tumor cells from archival material because the lesions are a heterogeneous mixture of normal and neoplastic cells, and the entire specimen must be excised and fixed for clinical diagnosis. This report describes a new approach designed to identify DNA copy number changes in tumor cells from a series of progressive primary stages of cutaneous melanoma archival biopsies. Under direct high-power visualization, cells are procured with a sterile needle from highly specific areas of the tissue section. DNA is extracted from microdissected cells (normal, RGP, and VGP), PCR amplified, fluorescently labeled, and examined by comparative genomic hybridization to determine DNA copy number changes. Data obtained from three representative cases suggest a clonal derivation of VGP cells from RGP. This approach could be useful in identifying the sequence of genetic changes in progressive cutaneous melanoma stages.

Desmoplastic malignant melanoma: a clinicohistopathologic review.

Desmoplastic malignant melanoma is an unusual variant of cutaneous melanoma. Arising from either an occult or recognized superficial melanotic lesion, it evolves into an aggressive, locally recurrent and frequently metastasizing, deep, hard, fibrous tumefaction. A highly confusing clinical and histologic picture makes accurate diagnosis especially difficult. Appropriate treatment is often delayed until time of recurrence. Prognosis is invariably poor if the tumor is not adequately treated primarily. Close follow-up is essential. Since its original description by Conley et al. in 1971, in which 7 cases were presented, fewer than 150 additional cases have been cited. We provide a detailed report of 11 cases of this distinct histopathologic entity. Clinical course, histopathology, surgical management, and prognosis are discussed. It is our hope that this comprehensive review will instill a high index of suspicion among surgeon and pathologist alike, enabling earlier diagnosis and definitive therapy.