Lithium use and risk of fracture: a systematic review and meta-analysis of observational studies.

This systematic review and meta-analysis summarized the results from nine eligible observational studies. Lithium use was significantly associated with a decrease risk of fractures. INTRODUCTION: The association between lithium use and risk of fracture is uncertain. To date, there have been no meta-analyses that have studied the association between the two. We conducted a systematic review and meta-analysis to examine the effect of lithium medication on the risk of fracture. METHODS: A comprehensive literature search was performed in PubMed, Embase, and MEDLINE to include eligible observational studies. Three reviewers conducted the literature search, study selection, study appraisal, and data abstraction independently. Random effects models were used to obtain the overall estimate for meta-analysis. Cochran's Q and Higgins' I2 were used to assess heterogeneity. A funnel plot and Egger's regression test were employed to assess publication bias. RESULTS: Of the 3819 studies that were identified by our search strategy, eight were eligible for the systematic review, while seven of them qualified for the meta-analysis. In studies that reported risk ratio (RR) of fracture as an outcome (five studies [n = 1,134,722]), lithium use was associated with a 20% decrease in risk of fracture (RR = 0.80; 95% CI, 0.73-0.87; p < 0.01). A decreased risk of fracture associated with lithium was also observed in studies that adjusted for previous fractures (RR = 0.81; 95% CI, 0.73-0.89; p < 0.01). The decreased risk of fracture associated with lithium use remained consistent in all the analyses with different inclusion criteria. Neither significant heterogeneity nor significant publication bias was observed. CONCLUSION: The present systematic review and meta-analysis demonstrated that lithium use was associated with a significant decreased risk of fracture.

Úlcera dolorosa en paciente de raza negra / Painful Ulcer in a Black Man

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Genetic diversity of the human serotonin receptor 1B (HTR1B) gene.

We systematically and comprehensively investigated polymorphisms of the HTR1B gene as well as their linkage disequilibrium and ancestral relationships. We have detected the following polymorphisms in our sample via denaturing gradient gel electrophoresis, database comparisons, and/or previously published assays: G-511T, T-261G, -182INS/DEL-181, A-161T, C129T, T371G, T655C, C705T, G861C, A1099G, G1120A, and A1180G. The results of the intermarker analyses showed strong linkage disequilibrium between the C129T and the G861C polymorphisms and revealed four common haplotypes: ancestral (via chimpanzee comparisons), 129T/861C, -161T, and -182DEL-181. The results of association tests with schizophrenia were negative, although A-161T had a nominal P = 0.04 via ASPEX/sib_tdt. The expressed missense substitutions, Phe124Cys, Phe219Leu, Ile367Val, and Glu374Lys, could potentially affect ligand binding or interaction with G proteins and thus modify drug response in carriers of these variants. On average, the human cSNPs and differences among other primates clustered in the more thermodynamically unstable regions of the mRNA, which suggests that the evolutionary survival of nucleotide sequence variation may be influenced by the mRNA structure of this gene.

Sarcoidal foreign-body granulomatous dermatitis associated with ophthalmic drops.

Sarcoidal granulomas are found in sarcoidosis and in reactions to foreign materials. We report the case of an 81-year-old woman with glaucoma who presented with multiple brown-black asymptomatic papules over the chin and involving nasal mucosa and columella of 1-year duration. Biopsy of the nasal mucosa and cutaneous papules showed sarcoidal granulomas associated with brown-black intracellular pigment within multinucleated giant cells. Electron-probe x-ray microanalysis demonstrated high sulfur content. Clinical studies showed no evidence of systemic sarcoidosis. Two of three ophthalmologic drops contained sodium bisulfite; bisulfite is known to cause allergic reactions. Although the exact substance causing the granulomatous reaction is unknown, the distribution of the lesions--nasal mucosa and columella (via the nasal lacrimal duct) and the underlying chin--implicate the eyedrops in the production of the pigmented granulomatous nodules.

Expression of the CD44 cell adhesion molecule in urinary bladder transitional cell carcinoma.

CD44 cell adhesion molecule (PgP-1, ECM III, Hermes antigen) is a polymorphic integral membrane glycoprotein associated with cell matrix adhesion, lymphocyte activation, recirculation, and homing. CD44 expression has been reported in in malignant lymphoma and in a variety of epithelial human cancers but has not been studied as a prognostic marker in urinary bladder transitional cell carcinoma. CD44s (standard 85- to 95-kDa macromolecule) expression was measured by qualitative and image analysis-quantitated immunohistochemical techniques using the A3D8 monoclonal antibody. CD44v6 (a splice variant exon of CD44s) expression was measured by qualitative immunohistochemical techniques using the 2F10 monoclonal antibody. The results of CD44s and CD44v6 expression were compared with tumor grade, pathologic stage, and DNA content analysis on Feulgen-stained tissue sections in 44 cases of urinary bladder transitional cell carcinoma. The mean percentage-positive area of staining intensity for CD44s expression in Grade 1 tumors was 61%, compared with 30% for the Grade 3 tumors (P < 0.001). Non-invasive tumors featured a 59%-positive area of staining intensity, compared with the 30% staining percentage for the deeply invasive tumors (P < 0.001). There was significant correlation of aneuploid DNA content with loss of CD44s staining (P < 0.05). The staining results for CD44v6 paralleled those for the CD44s, with a significant loss of staining in high-grade and high-stage aggressive tumors in comparison with the low-grade nonaggressive tumors (P < 0.01). In urinary bladder transitional cell carcinoma, CD44s and CD44v6 expression parallels that for other cell adhesion molecules, such as E-cadherin, that feature a significant progressive loss of immunoreactivity in association with tumor dedifferentiation, advancing pathologic stage, and abnormal DNA content.

Selective expression of CD44 cell-adhesion molecule in thyroid papillary carcinoma fine-needle aspirates.

Recent descriptions of numerous pitfalls in the cytologic diagnosis of thyroid papillary carcinoma on fine-needle aspiration biopsy specimens have prompted studies of new ancillary diagnostic methods. We evaluated the potential use of immunocytochemical staining of thyroid fine-needle aspiration biopsy specimens for CD44, a glycosylated cartilage link protein associated with extracellular matrix adhesion and lymphocyte homing. Fourteen of 16 (88%) classic, surgically confirmed, thyroid aspiration biopsies stained intensely positive for this marker, whereas 0 of 30 (0%) similarly-processed benign aspirates from colloid nodules showed immunoreactivity for CD44 antigen. From this study, we conclude that most papillary carcinomas of the thyroid express the celladhesion molecule CD44, which may be of clinical value in confirming the diagnosis on borderline fine-needle aspiration specimens. Further study of CD44 expression may prove of significant interest in explaining the unusual mode of spread and clinical course of this disease.

E-cadherin cell-adhesion molecule expression as a diagnostic adjunct in urothelial cytology.

E-cadherin (E-CD) is a cell-adhesion molecule that has been associated with invasion and metastasis in a wide variety of human neoplasms. We have recently shown that, although decreased E-CD expression is associated with increased bladder-wall invasion and higher tumor grade of infiltrating transitional cell carcinomas (TCC), E-CD expression in the exophytic portion of pure papillary and papillary-infiltrating TCC is increased over that of normal transitional cells. To evaluate whether E-CD levels could serve as a diagnostic adjunct in urinary cytology specimens, we stained 40 alcohol-fixed bladder-washing cytospin preparations with an avidin-biotin-peroxidase method using a monoclonal antibody to E-CD (Sigma Chemical Co., St. Louis, MO). E-CD expression level was defined as a high-intensity or low-intensity staining increase over background squamous cell staining for the transitional cells in 21 biopsy-proven transitional cell carcinomas with papillary components, and in 19 benign or reactive control specimens. Twenty-one of 21 TCC (100%) showed an increased E-CD level over background, with 13 low-intensity and 8 highintensity cases. Ten of 19 benign cases (53%) showed increased E-CD staining over background, with 8 low-intensity and 2 highintensity cases. This difference between malignant and benign specimens was statistically significant (chi-square test. P approximately 0.001). We conclude that increased E-CD expression in the papillary components of TCC can be identified in urinary cytology specimens, may reflect the physical and chemical structural makeup of papillary architecture, and warrants further study as a diagnostic adjunct in the interpretation of urine cytology specimens.

E-cadherin expression in papillary transitional cell carcinoma of the urinary bladder.

E-cadherin (E-CD), a cell adhesion molecule that plays a diverse role in cell-cell and cell-matrix interaction, has recently been associated with tumor invasion and metastasis. We evaluated the E-CD expression in 55 cases of urinary bladder papillary transitional cell carcinoma using a double-linked immunoalkaline phosphatase procedure on formalin-fixed, paraffin-embedded specimens quantified as percentage positive staining area with the Roche RPW image analyzer (Roche Image Analysis Systems, Elon College, NC). The 10 grade I tumors stained intensely for E-CD (66%) and showed enhanced staining compared with normal transitional epithelium. The 20 grade II lesions stained moderately at 45%, and the 25 grade III lesions showed weak expression of E-CD with a 33% positive stain. This loss of expression for high-grade versus low-grade tumors was statistically significant (P < .02). There was a similar decrease in E-CD expression for high-stage versus low-stage specimens with 30 stage 0 and stage A cases having an average of 51% positive stain and 25 stage B, C, and D cases having an average stain of 33%. This difference was also statistically significant (P < .001). We conclude that loss of expression of E-CD in high-grade, high-stage urinary bladder transitional cell carcinoma is associated with significant bladder wall invasion, indicates potential for metastasis, and may be of clinical value in the assessment of prognosis and planning of therapy for patients with bladder tumors.

True synovial metaplasia of breast implant capsules: a light and electron microscopic study.

The formation of true synovial-lined membranes at tissue sites not intimately related to an articulation or a tendon sheath has been described in a variety of pathologic and postsurgical conditions, but until recently has not been well recognized to occur in association with tissue surrounding silicone breast implants. Of 15 cases with resected periprosthetic breast capsules, 7 (47%) demonstrated true synovial metaplasia with capsule-implant interfaces lined by typical synovial cells. Histochemical and immunohistochemical staining reactions were essentially identical to those observed in synovial control cases and featured positive reactions to Alcian blue-periodic acid-Schiff, reticulin, and vimentin. Focal positive immunoreactivity was observed with alpha 1-antitrypsin, alpha 1-antichromotrypsin, lysozyme, and CD68. No immunoreactivity was observed with cytokeratin AE1/AE3, S-100 protein, carcinoembryonic antigen, or basement membrane antigens. Transmission electron microscopy of the lining cells confirmed their true synovial nature with the type A (macrophage-like) cells, type B (fibroblast-like) cells, and intermediate forms or type AB cells identified. We conclude that the cellular lining surrounding silicone breast implants is a true synovial membrane, that synovial metaplasia may occur in nearly one half of all resected periprosthetic capsules, and that awareness of this entity will enable the surgical pathologist to render an accurate histopathologic diagnosis.

Preferential expression of the cell adhesion molecule CD44 in papillary thyroid carcinoma.

CD44 is a polymorphic family of immunologically related integral membrane glycoproteins associated with cell matrix adhesion, lymphocyte activation and targeting, and tumor growth and metastasis. We studied CD44 expression in 114 formalin-fixed paraffin-embedded thyroid tumors using the A3D8 anti-human CD44 monoclonal antibody. Sixty-five of 67 papillary carcinomas (97%) strongly expressed CD44 with an intense plasma membrane pattern. Thirty-seven of these cases originated from Albany, New York, and 30 cases from Russia. Immunoreactivity was also observed in 9 of 16 follicular adenomas (56%); 4 of 8 Hurthle cell neoplasms (50%); 5 of 15 medullary carcinomas (33%); and 3 of 8 follicular carcinomas (38%). These results show that among thyroid neoplasms, papillary carcinomas preferentially display the CD44 antigen (P < or = 0.001). Nonneoplastic follicular epithelium exhibited a low to moderate level of staining. To further characterize the CD44 isoform, we tested a subset of cases with the 2F10 anti-human CD44 variant 6 monoclonal antibody, which recognizes a CD44 variant exon (CD44v6) implicated in tumor metastasis. Eleven of 11 papillary carcinomas tested were 2F10 positive, and 1 of the follicular carcinomas was positive. These results suggest the hypothesis that deregulated CD44v6 expression on the plasma membrane of papillary carcinoma cells contributes to the ability of those cells to metastasize to regional lymph nodes and then to remain dormant for years. Our results suggest that human papillary thyroid cancer will be an interesting model in which to further study the role of CD44 isoforms, particularly those containing CD44v6, in tumor metastasis and lymphatic invasion.

Intracytoplasmic eosinophilic hyaline globules in cartilaginous neoplasms: a surgical, pathological, ultrastructural, and electron probe x-ray microanalytic study.

Hyaline globules (HGs), spherical intracytoplasmic eosinophilic droplets, have been associated with a variety of conditions, including hepatocellular carcinoma, lung adenocarcinoma, and Kaposi's sarcoma, but they have not been described in cartilaginous tumors. In specimens of 60 cartilaginous neoplasms we found that 22 of 33 chondrosarcomas (67%), eight of 16 enchondromas (50%), and three of seven soft tissue chondromas (43%) exhibited HGs. HGs were seen more commonly in low grade chondrosarcoma (70%) and were relatively rare in high grade chondrosarcoma (25%). No HGs were identified in three osteochondromas, one synovial chondromatosis, or 15 normal cartilaginous tissues taken from various sites. Cartilage associated HGs ranged in size from 2 to 20 microns, were diastase resistant and periodic acid-Schiff (PAS) stain positive, demonstrated autofluorescence, and variably stained with Mallory's phosphotungstic acid-hematoxylin stain (PTAH). A panel of immunostains did not show any specific staining reactions with HGs. Ultrastructurally the HGs were spherical, non-membrane-bound bodies having complex architectural features associated with profiles of rough endoplasmic reticulum. Electron probe x-ray microanalytic (EPXMA) study showed significant peaks of sulphur and calcium. We conclude that HGs represent secretory products of probable glycoprotein nature, may accumulate in a variety of cartilaginous neoplasms, and may be seen more frequently in low grade chondrosarcomas.

Prediction of pathologic stage and postprostatectomy disease recurrence by DNA ploidy analysis of initial needle biopsy specimens of prostate cancer.

BACKGROUND: DNA ploidy determination of carcinomas in radical prostatectomy specimens has shown significant correlation with patient outcome, but the predictive value of ploidy status of cancers obtained by transrectal ultrasound-guided needle biopsies has not been studied extensively. METHODS: Eighty-nine paired needle biopsy specimens (NBX) and radical prostatectomy (RPX) specimens from patients with early clinical stage (A2-B2) prostate cancer were evaluated for DNA content by image analysis of Feulgen stained tissue sections. Findings were compared with Gleason grading on the same specimens by univariate and multivariate analyses for prediction of local tumor invasion, metastasis, disease recurrence, and serum prostate specific antigen concentration during a 0.9-6.0 year clinical follow-up period. RESULTS: There was excellent correlation of ploidy status between NBX and RPX specimens (P < 0.0001); NBX and RPX grades did not correlate. On RPX specimens, aneuploid status correlated with high tumor grade (P < 0.0005). Aneuploidy in NBX specimens was associated with a twofold higher rate of extracapsular spread (ECS) (P = 0.04). Aneuploid NBX tumors featured a tenfold greater frequency of metastasis than did diploid NBX tumors (P < 0.005). Radical prostatectomy grade correlated with ECS (P < 0.001) and presence of metastatic disease (P = 0.04). On multivariate logistic regression analysis, aneuploidy in both NBX and RPX specimens was the most significant variable and independently predicted the presence of metastasis (P = 0.006 for NBX; P = 0.028 for RPX). Tumor grade of NBX and RPX specimens did not independently predict metastatic disease or disease recurrence, but RPX grade was associated independently with ECS (P = 0.005). Aneuploid NBX tumors recurred after RPX three times more often than did diploid cases, which was significant on univariate (P < 0.001) and multivariate (P = 0.018) analyses using the Cox proportional hazards model. There was no correlation with NBX or RPX Gleason score and disease recurrence. Preoperative serum PSA concentration did not correlate with tumor grade or ploidy status, but on multivariate analysis, when paired with ploidy status, independently contributed to the propensity for ECS, metastasis, and disease recurrence. CONCLUSIONS: DNA content analysis of early clinical stage prostate carcinoma needle biopsy specimens by image analysis directly correlates with radical prostatectomy specimen ploidy status and is associated independently, with the presence of metastasis, postprostatectomy disease recurrence, and ECS. Needle biopsy tumor grading did not correlate with prostatectomy grade and did not predict disease outcome accurately.

E-cadherin expression in prostatic carcinoma biopsies: correlation with tumor grade, DNA content, pathologic stage, and clinical outcome.

We compared tumor grade and DNA content with expression of E-cadherin (E-CD), a cell adhesion molecule associated with cell-cell and cell-matrix interaction, leukocyte function, and tumor invasion and metastases, on 56 prostate carcinoma needle biopsies. The findings were correlated with final pathologic stage at subsequent prostatectomy, preoperative serum prostate-specific antigen level and further development of metastases during an initial 2.4-yr mean clinical follow-up period (range 0.5 to 5.5 yr). E-CD expression (uvomorulin, L-CAM, cell CAM 80/120, ARC-1, Sigma, St. Louis, MO) was measured by double-linked immunoalkaline phosphatase immunohistochemistry quantified with a the Roche RPW image analyzer (Roche Image Analysis Systems, Elon College, NC). DNA ploidy was determined on formalin-fixed, paraffin-embedded Feulgen-stained 5-microns tissue sections of the narrow-bore initial prostate carcinoma biopsies with the Roche RPW image analyzer. The 51% mean positive area E-CD expression in the group of 56 adenocarcinomas was significantly less than the 76% expression level for 15 normal control prostate tissues (P < 0.001). E-CD expression was also decreased in aneuploid (39%) versus diploid tumors (54%, P < 0.001); and in high-grade (44%) versus low-grade lesions (54%; P < 0.01). The 44% E-CD expression level in patients with metastases was lower than the 52% level in the nonmetastatic cases, but this finding was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal angiomyolipoma. DNA content and immunohistochemical study of classic and multicentric variants.

Angiomyolipomas (AMLs) are polymorphic renal tumors that are composed of mature tissues and frequently associated with tuberous sclerosis; AMLs have long been considered hamartomatous in nature. We report the routine histologic and immunohistochemical features and DNA content analysis of two fatal cases of renal giant multicentric AML with distant organ involvement, and we contrast the findings with those of four similarly studied cases of classic solitary AML. Severe nuclear pleomorphism, significant mitotic activity, and necrosis, which are all characteristics of multicentric AML, were not seen in the cases of classic AML. Quantitation of DNA by image analysis of Feulgen-stained slides from paraffin-embedded blocks revealed an aneuploid pattern in the two cases of multicentric AML and an aneuploid pattern in one of the four cases of classic AML. Tumors in the liver, spleen, and lungs in one of the cases of multicentric AML were diploid. Immunohistochemical analysis revealed positive staining reaction of vascular and adipose tissue components with HMB-45 antibody in three of the six cases of AML. We conclude that AMLs may occur in a sarcomatous, infiltrating multicentric form involving multiple organs, that aneuploidy may be seen in lesions of both the multicentric AML and classic AML variants, that AMLs may feature DNA ploidy heterogeneity in multiple-organ sites, that HMB-45 immunoreactivity may be encountered in AMLs without evidence of nevomelanocytic differentiation, and that continued study of AMLs is needed to clarify further the histogenesis, lineage, clonality, and malignant potential of these tumors.

Risk factors for vitamin A deficiency in rural areas of the Philippines.

A survey of vitamin A deficiency was conducted in January and February 1991 on the island of Mindanao in the Philippines. Demographic, serum retinol, conjunctival impression cytology (CIC), anthropometric, and dietary data were collected from 248 preschool children in five randomly selected rural communities on the outskirts of Davao City. Twenty-nine per cent [95 per cent confidence interval (CI) 23-35 per cent] of preschool children had serum retinol levels below 20 micrograms/dl. Nearly 6 per cent (95 per cent CI 3-9 per cent) had serum retinol levels below 10 micrograms/dl. Thirty-two per cent (95 per cent CI 25-38 per cent) had abnormal CIC findings. The correlation between serum retinol and CIC results was poor. Recent history of diarrheal disease, reported night blindness, maternal education less than 9 years, and infrequent consumption of eggs, mangoes, and liver were associated with increased risk of vitamin A deficiency.

Role of DNA content determination by image analysis in confirmation of dysplasia in Barrett's esophagus.

Progression to cancer in Barrett's esophageal columnar metaplasia is classically heralded by the presence of epithelial dysplasia. Differentiation of reactive epithelial atypia and mild dysplasia from severe dysplasia, however, may often be difficult especially with limited biopsy material. We performed DNA content analysis of 11 cases of Barrett's esophagus showing variable reactive atypia, 24 cases of Barrett's with low- and high-grade dysplasia, and 30 cases of Barrett's with invasive adenocarcinoma (BCA) using Feulgen-stained paraffin sections and the CAS 200 image analyzer. The mean DNA index of the uniformly diploid BE was 1.06. The 1.26 mean DNA index for the low-grade Barrett's esophagus with dysplasia, 1.62 for high grade, and 1.88 DI for BCA were significantly greater than for variable reactive atypia (P < 0.004) but not different from each other. Six BCA cases (20%) were diploid; 24 cases (80%) were aneuploid. Mean survival of diploid BCA at 20.4 mo was nearly double the survival of 10.6 mo for aneuploid BCA. However, this difference was not statistically significant (P < 0.21) and survival at 3 yr was identical for all BCA cases. Tumor grade, stage, and lymph node status did not significantly correlate with ploidy pattern. Thus, although DNA analysis does not seem to predict ultimate outcome in BCA, aneuploidy and high DNA index are associated with Barrett's esophagus with dysplasia and BCA and may be of significant value in the differentiation from variable reactive atypia in small biopsies.

Nuclear DNA content and clinical follow-up in resected pancreatic adenocarcinoma.

Nuclear DNA content was determined by image analysis of paraffin-embedded tissue sections in 20 cases of resected pancreatic ductal adenocarcinoma. Seven cases (35%) showed a diploid pattern; 13 (65%) were aneuploid. Mean survival time of patients with diploid tumors was significantly greater (17 months) than for patients with aneuploid carcinomas, 7.5 months (P < .03, Kaplan-Meier and Cox univariate analysis). Patient age, grade of differentiation, primary tumor size and lymph node status did not correlate significantly with ploidy pattern and survival. In four cases atypical hyperplasia/adenocarcinoma in situ was present in the main duct epithelium at the pancreatectomy resection line. These intraductal foci were uniformly diploid. We conclude that despite the uniform fatality of pancreatic cancer, adenocarcinomas with aneuploid patterns pursue a significantly more rapid and aggressive clinical course than do diploid tumors and that the atypical intraductal epithelial foci that may accompany resected specimens from invasive adenocarcinoma are DNA diploid, may represent noninvasive precursor lesions and are of uncertain clinical significance.