Development of a prognostic model for survival time prediction in castration-resistant prostate cancer patients.

BACKGROUND: To identify predictors of survival in patients treated with docetaxel chemotherapy for castration-resistant prostate cancer (CRPC). METHODS: We retrospectively analyzed clinical data from 186 patients who underwent docetaxel chemotherapy for CRPC from 2005 to 2016 at a single center. Pretreatment baseline variables including demographic and clinicopathological data were reviewed. Disease progression was defined by imaging and/or consecutive prostate-specific antigen (PSA) elevation. The systemic immune-inflammation index (SII), the modified Glasgow Prognostic Score (mGPS), and the neutrophil-lymphocyte ratio (NLR) were calculated. Univariable and multivariable Cox proportional hazards regression analyses reporting hazard ratios assessed the risk for disease progression and overall survival (OS). A survival nomogram was constructed. RESULTS: Most patients (n = 139, 74.7%) completed at least 6 cycles of docetaxel chemotherapy. 156 patients (82.9%) experienced disease progression during the studied period. Only mGPS was independently associated with disease progression in a multivariable model (P < 0.01). During the studied period, 98 patients (52.1%) died. The built survival nomogram included statistically significant variables for OS in univariable analysis: hemoglobin, PSA, alkaline phosphatase (AP), lactate dehydrogenase, SII, neutrophil-lymphocyte ratio, mGPS, and site of metastases; and had a concordance index of 0.703. At decision curve analysis, the nomogram led to superior outcomes for any decision associated with a threshold probability of above 40%. In multivariable analysis, only AP (P = 0.02), hemoglobin and PSA (P < 0.01, respectively) remained associated with OS. CONCLUSIONS: PSA, AP, and hemoglobin are independent prognosticators for OS. Although mGPS is a promising marker for tumor progression and SII is a plausible prognostic marker for OS, valid integration of inflammatory indices into a prognostic model requires validation studies. Predictive and prognostic biomarkers are desperately needed to guide physicians in treatment counseling given the heterogeneous nature of CRPC and the plethora of effective therapies.

Minoxidil for patchy alopecia areata: systematic review and meta-analysis.

BACKGROUND: Alopecia areata (AA) is a complex immune and polygenic inflammatory disease that causes hair loss on some or all areas of the body; extent, severity and progression vary widely among individuals. Alopecia areata, considered one of the most frequently occurring immune diseases, affects 0.2% of the world population at any given time. Uncertainty prevails about the most appropriate intervention for AA. The aim is to evaluate the effectiveness and safety of over 80 interventions for AA, including minoxidil - one of the most promising interventions for patchy AA in children and adults of both sexes. MATERIAL AND METHODS: An extensive search was conducted of international medical literature involving randomized clinical trials (RCTs) of AA interventions. RCTs were evaluated qualitatively and quantitatively according to the previously published protocol and for seven specific outcomes. RESULTS: The meta-analysis involving 5% minoxidil vs. placebo presented a significant difference in favor of 5% minoxidil with the moderate quality of evidence in children and adults with patchy AA (RR 8.37 [3.16-22.14], 95% CI). No severe adverse event was reported. CONCLUSIONS: Treatment of patchy AA with 5% minoxidil proved effective, and clinically and statistically safe in studies with limited sample size; quality of evidence was moderate. Further studies with sound methodological quality, more participants and outcome observations lasting longer than 6 months are needed to address remaining uncertainties.

Multifactor effects and evidence of potential interaction between complement factor H Y402H and LOC387715 A69S in age-related macular degeneration.

BACKGROUND: Variants in the complement cascade genes and the LOC387715/HTRA1, have been widely reported to associate with age-related macular degeneration (AMD), the most common cause of visual impairment in industrialized countries. METHODS/PRINCIPAL FINDINGS: We investigated the association between the LOC387715 A69S and complement component C3 R102G risk alleles in the Finnish case-control material and found a significant association with both variants (OR 2.98, p = 3.75 x 10(-9); non-AMD controls and OR 2.79, p = 2.78 x 10(-19), blood donor controls and OR 1.83, p = 0.008; non-AMD controls and OR 1.39, p = 0.039; blood donor controls), respectively. Previously, we have shown a strong association between complement factor H (CFH) Y402H and AMD in the Finnish population. A carrier of at least one risk allele in each of the three susceptibility loci (LOC387715, C3, CFH) had an 18-fold risk of AMD when compared to a non-carrier homozygote in all three loci. A tentative gene-gene interaction between the two major AMD-associated loci, LOC387715 and CFH, was found in this study using a multiplicative (logistic regression) model, a synergy index (departure-from-additivity model) and the mutual information method (MI), suggesting that a common causative pathway may exist for these genes. Smoking (ever vs. never) exerted an extra risk for AMD, but somewhat surprisingly, only in connection with other factors such as sex and the C3 genotype. Population attributable risks (PAR) for the CFH, LOC387715 and C3 variants were 58.2%, 51.4% and 5.8%, respectively, the summary PAR for the three variants being 65.4%. CONCLUSIONS/SIGNIFICANCE: Evidence for gene-gene interaction between two major AMD associated loci CFH and LOC387715 was obtained using three methods, logistic regression, a synergy index and the mutual information (MI) index.

Primary intraocular lymphoma: improving the diagnostic procedure.

OBJECTIVE: To analyze the clinical features of primary intraocular lymphoma (PIOL) and to describe cytochemical and immunocytochemical findings of the vitreous specimens as well as the reasons for delayed diagnosis of PIOL. DESIGN: Prospective noncomparative study. PARTICIPANTS: Eleven patients referred to the uveitis or medical retina units, Department of Ophthalmology, University of Helsinki, were diagnosed as having PIOL between 2000 and 2005. The median follow-up of the patients was 32 months. METHODS: Clinical features and diagnostic workup of uveitis were described. Twelve vitrectomies were performed on 9 patients. The first 5 biopsies were fixed in an equal volume of 50% alcohol. The specimens of the next 7 vitrectomies were handled without alcohol, and tissue culture medium was added to the samples. MAIN OUTCOME MEASURES: Clinical features of PIOL, intervals from ocular symptoms and from first ophthalmological examination to diagnosis, and the role of a proper handling of the vitreous sample in the diagnosis of PIOL. RESULTS: Six females (54%) and 5 males (46%) (median age, 61 years) were included. Ten patients had ocular symptoms for 1 to 30 months (median, 8) before the first contact with an ophthalmologist. Uveitis was bilateral in 9 patients. Vitreitis was seen in all patients, and it was severe in 8. Fundus lesions dominated in 3 patients. Six patients lost useful vision in one eye before the diagnosis of PIOL. Cytologic and immunohistochemical stainings prepared of the unfixed vitreous specimens showed PIOL in 6 patients. The samples fixed in alcohol were nondiagnostic in 4 patients, and in them, verification of diagnosis was based on brain biopsy (3) or cerebrospinal fluid (1) findings. Seven patients died due to primary nervous system lymphoma. CONCLUSIONS: Diagnosis of PIOL is difficult but can be improved. Severe bilateral vitreitis in an elderly patient is a characteristic finding of PIOL. Alcohol fixation may jeopardize the identification of PIOL cells in the vitreous sample. Optimal handling of the vitreous specimens and examination of the slides by an experienced cytopathologist are critical in the diagnostic workup of PIOL.

Cutaneous T-cell lymphoma with HTLV-I infection: clinical overlap with adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a malignant proliferation of mature helper T lymphocytes,(1) and is caused by human T-lymphotropic virus type I (HTLV-I);(2) an HTLV-I infection endemic in the Caribbean, south-western Japan, South America and Africa.(3,4) Seroepidemiological studies suggest that it is also endemic in Brazil.(5) Although carriers of HTLV-I show polyclonal integration of virus in T lymphocytes, only patients with ATLL of various subtypes show monoclonal integration of HTLV-I in tumor cells.(6,7) Cutaneous T-cell lymphomas (CTCL) are a group of primary cutaneous lymphoproliferative diseases(8) with unknown etiology.(9) The two most common presentations of CTCL are mycosis fungoides (MF) and Sézary syndrome (SS).(10-13) However, both CTCL categories can easily resemble ATLL. Therefore, in HTLV-I endemic areas, differentiation between ATLL and CTCL must be performed, as they have different prognoses and treatment approaches.(14).

Copper stabilizes a heterodimer of the yCCS metallochaperone and its target superoxide dismutase.

The copper chaperone for superoxide dismutase (CCS) activates the antioxidant enzyme Cu,Zn-SOD (SOD1) by directly inserting the copper cofactor into the apo form of SOD1. Neither the mechanism of protein-protein recognition nor of metal transfer is clear. The metal transfer step has been proposed to occur within a transient copper donor/acceptor complex that is either a heterodimer or heterotetramer (i.e. a dimer of dimers). To determine the nature of this intermediate, we generated a mutant form of SOD1 by replacing a copper binding residue His-48 with phenylalanine. This protein cannot accept copper from CCS but does form a stable complex with apo- and Cu-CCS, as observed by immunoprecipitation and native gel electrophoresis. Fluorescence anisotropy measurements corroborate the formation of this species and further indicate that copper enhances the stability of the dimer by an order of magnitude. The copper form of the heterodimer was isolated by gel filtration chromatography and contains one copper and one zinc atom per heterodimer. These results support a mechanism for copper transfer in which CCS and SOD1 dock via their highly conserved dimer interfaces in a manner that precisely orients the Cys-rich copper donor sites of CCS and the His-rich acceptor sites of SOD1 to form a copper-bridged intermediate.

Oral treatment of crusted scabies with ivermectin: report of two cases.

Oral treatment with ivermectin of crusted (Norwegian) scabies in two immunosuppressed patients is reported. There was resolution of symptoms and signs of the cutaneous parasitosis on administration of 18-36 mg ivermectin (total doses) in 2- and 3-week periods of treatment, with remission periods of 3 and 4 months, respectively.

DNA sequence-specific recognition by the Saccharomyces cerevisiae "TATA" binding protein: promoter-dependent differences in the thermodynamics and kinetics of binding.

The equilibrium binding and association kinetics of the Saccharomyces cerevisiae TATA Binding Protein (TBP) to the E4 and Major Late promoters of adenovirus (TATATATA and TATAAAAG, respectively), have been directly compared by quantitative DNase I titration and quench-flow "footprinting". The equilibrium binding of TBP to both promoters is described by the equilibrium TBP + DNA"TATA" left and right arrow TBP-DNA"TATA". The salt dependence of TBP binding to both promoters is identical within experimental error while the temperature dependence differs significantly. The observed rate of association follows simple second-order kinetics over the TBP concentration ranges investigated. The salt and temperature dependencies of the second-order association rate constants for TBP binding the two promoters reflect the dependencies determined by equilibrium binding. The TBP-E4 promoter interaction is entropically driven at low temperature and enthalpically driven at high temperature while the TBP-Major Late promoter reaction is entropically driven over virtually the entire temperature range investigated. These data suggest that the reaction mechanisms of TBP-promoter interactions are TATA sequence-specific and provide for differential regulation of promoters as a function of environmental variables.

Quantitative nucleic acids footprinting: thermodynamic and kinetic approaches.

Quantitative footprinting techniques allow a detailed analysis of the thermodynamic forces that characterize nucleic acid-ligand interactions and ligand-induced changes in nucleic acid structure by separately resolving the intrinsic and cooperative Gibbs free energy changes describing the reactions being investigated. A new implementation of the quantitative footprinting technique is the application of stopped-flow techniques to the study of kinetic reactions.

Thermodynamic and kinetic characterization of the binding of the TATA binding protein to the adenovirus E4 promoter.

A thermodynamic analysis of the binding of the TATA binding protein (TBP) from Saccharomyces cerevisiae to the adenovirus E4 promoter was conducted using quantitative DNase I "footprint" titration techniques. These studies were conducted to provide a foundation for studies of TBP structure-function relations and its assembly into transcription preinitiation complexes. The binding of TBP to the E4 promoter is well described by the Langmuir binding polynomial, suggesting that no linked equilibria contribute to the binding reaction under the conditions examined. Van't Hoff analysis yielded a nonlinear dependence on temperature with the TBP-E4 promoter interaction displaying maximal affinity at 30 degrees C. An unusually negative value of the apparent standard heat capacity change, delta Cp degrees = -3.5 +/- 0.5 kcal/mol.K, was determined from these data. The dependence of the TBP-E4 promoter interaction on [KCl] indicates that 3.6 +/- 0.3 K+ ions are displaced upon complex formation. Within experimental error, no linkage of proton binding with the TBP-E4 promoter interaction is detectable between pH 5.9 and 8.7. Rates of association of TBP for the E4 promoter were obtained using a novel implementation of a quench-flow device and DNase I "footprinting" techniques. The value determined for the second-order rate constant at pH 7.4, 100 mM KCl, 5 mM MgCl2, 1 mM CaCl2, 30 degrees C (ka = 5.2 +/- 0.5) x 10(5) M-1 s-1) confirms the results obtained by Hawley and co-workers [Hoopes, B.C., LeBlanc, J.F., & Hawley, D.K. (1992) J. Biol. Chem. 267, 11539-11547] and extends them through TBP concentrations of 636 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Lindefemas dos membros inferiores: estudo linfocintilográfico / Lymphedema of the lower limbs: a lymphoscintigraphic approach

Pacientes con linfedema dos membros inferiores säo, geralmente, acometidos de erisipela recorrente. Essa infecçäo bacteriana costuma ser admitida como fator causal, mas poede ser consequüência de anomalia linfática prévia inaparente. Classicamente, admitem-se como causas mais comuns de linfedema dos membros inferiores as infecçöes bacterianas, úlceras de estase, trauma (que levam ao linfedema secundário) e as anomalias congênitas do sistema linfático (linfedemas primários - precoces ou tardios). OBJETIVO - Identificar anomalias linfáticas právias em pacientes com linfedemas supostamente secundários dos membros inferiores - conseqüentes a infecçöes, trauma ou outros fatores -, com o emprego da linfocitilografia. Observar as vantagens desse procedimento da prática assistencial e avaliar os casos de linfedemas do membros inferiores. MÉTODOS - Doze pacientes com diagnósticos clínicos preliminares de linfedema dos membros inferiores primário (congênito) ou secundário, atingindo um ou ambos os membros, foram submetidos à linfocintilografia, na Escola Paulista de Medicina, Säo Paulo. Cada paciente recebeu injeçäo intradérmica de dextran marcado (Dx99mTc) no primeiro espaço interdigital de cada um dos pés e, passadas uma a três horas, foram obtidas por gama-câmara (Gammatone CGR) imagem de extremidades inferiores, área pélvica e abdome. RESULTADOS - O exame clínico-dermatológico dos 24 membros inferiores permitiu diagnosticar linfedema em, 17 (70,8 por cento) deles, sendo cinco (41,6 por cento) com sinais de linfedema de ambas as extremidades e sete (58,3 por cento) com linfedema de um só membro inferior. O exame linfocintigráfico revelou anormalidades linfáticas em 22 dos 24 membros estudados (91,7 por cento). Anomalias linfocintigráficas foram dcetectadas em cinco casos de extremidades inferiores aparentemente normais, ao primeiro exame ambulatorial (41,3 por cento). CONCLUSAO - A linfocintilografia é método näo-invasivo útil para o estudo dos linfedemas dos membros inferiores cpm envolvimento uni ou bilateral. Näo permite diferenciar entre linfede-ma primário e secundário, mas torna possível a detecçäo de ca-sos de aparência normal do membro com defeito linfático prévio, modificando o diagnóstico etiológico do linfedema. Alguns casos que a princípio pareceram ser linfedemas secundários po-deriam ser, de fato, associados a anomalias linfáticas congênitas e desencadeados por fatores como trauma ou úlceras de estase venosa

[Lymphedemas of the lower limbs: a lymphoscintigraphic study]. / Linfedemas dos membros inferiores: estudo linfocintilográfico.

UNLABELLED: Patients with lymphoedema of the lower limbs (LLL) are usually affected by recurrent erysipelas. This bacterial infection is usually admitted as an aetiological factor, but it can be a consequence of some previous lymphatic abnormality. Classically, the commonest causative factors of LLL are bacterial infection, venous ulcers, trauma (leading to secondary lymphoedema) and congenital disorders of the lymphatic system (primary lymphoedema--praecox or tarda). PURPOSE: To identify previous lymphatics abnormalities in patients with LLL, admitted as having secondary lymphatic lymphoedema--as consequences of infection, trauma or other factors--, by using lymphoscintigraphic method. To observe advantages of this approach in practical assistance and evaluation of LLL cases. METHODS: Twelve patients with LLL, supposed to have primary (congenital) or secondary disorder affecting one or both lower extremities were submitted to lymphoscintigraphy at the Escola Paulista de Medicina of Sao Paulo, Brazil. Each patient received an intradermal injection of labelled Dextran (Dx-99mTc) at the first interdigital space of each foot and, after one to three hours, images of lower extremities, pelvic and abdominal areas were obtained with Gammatome CGR. RESULTS: Examination of all 24 lower extremities disclosed clinical diagnosis of lymphoedema in 17 (70.8%), being five (41.6%) with clinical signs of lymphoedema of both lower limbs and seven (58.3%) of a single one. The lymphoscintigraphic images revealed lymphatic disorders in 22 of the 24 extremities (91.7%). Lymphoscintigraphic abnormalities in clinically normal lower extremities were observed in five cases (41.3%). CONCLUSION: Lymphoscintigraphy is a non-invasive useful method to study LLL, with involvement of one or both limbs. It does not differentiate between primary and secondary lymphoedema, but makes possible to detect cases of normal appearance of the limbs with previous lymphatic defect(s), changing aetiological diagnosis. Some cases that appear to be secondary lymphoedema could be, in fact, associated with congenital abnormality(ies) of lymphatics, triggered by factors like trauma or venous ulcers.

Piedra blanca genital: reporte de tres casos / Genital white piedra: report of 3 cases

Se informa de 2 casos de micosis superficiales causados por Trichosporon beigelii, observados en personal militar y uno en un homosexual, en Sao Paulo, Brasil

Histology of the Mitsuda reaction of healthy adults with no known contacts with leprosy patients.

Mitsuda tests were performed on 100 healthy adult Brazilian males unrelated consanguineously to leprosy patients and with no known contacts with this disease. Three lepromatous patients served as negative Mitsuda controls. The lepromin employed was from Mycobacterium leprae-infected armadillo tissue prepared according to WHO standards. Clinical response to the lepromin inoculation was graded according to the recommendations of the VI International Leprosy Congress held in Madrid (1953). The histological reaction was graded according to the authors' criteria based on the intensity of the granulomatous response. The clinically positive (77), the doubtful (19), and 1 out of 4 clinically negative Mitsuda reactors disclosed histologically positive reactions of different degrees of intensity. A significant association between the clinical and histological readings of the Mitsuda reaction was demonstrated when the results of both readings were grouped in two classes: negative and non-negative. However, the different degrees of the histologically positive lepromin reactions were distributed at random among the clinically positive Mitsuda reactors. The frequency of histologically negative Mitsuda reactors observed among the healthy subjects who had no known contacts with leprosy patients (3%) was significantly low when compared to the frequencies reported in the pertinent literature concerning healthy contacts of patients with Hansen's disease.

Sarcoma de Kaposi em homossexuais jovens do sexo masculino. Relato de dois casos. / Kaposi's sarcoma in young male homosexuals. Report of 2 cases

Sao apresentados dois casos de sarcoma de Kaposi (SK) em homossexuais jovens do sexo masculino previamente sadios. Os dados epidemiologicos e o deficit de resposta linfocitaria a estimulacao com fito-hemaglutinina sugerem, em ambos os casos, a possibilidade da ocorrencia do SK como forma de expressao da sindrome da imunodeficiencia adquirida (AIDS)