Isavuconazole-tacrolimus drug-drug interactions in HSCT patients.

OBJECTIVES: Because tacrolimus has a narrow therapeutic window and exhibits both intraindividual and interindividual variability, we attempted to establish the percentage of calcineurin inhibitor (CNI) dose reduction to prevent toxicity and ensure stem cell engraftment when using this immunosuppressant with the antifungal isavuconazole (ISA). By calculating the tacrolimus concentration/dose (C/D) ratio, we expected to demonstrate the magnitude of change in the C/D ratio from baseline after ISA administration. METHODS: We evaluated the interaction between ISA, a new triazole antifungal used in prophylaxis for invasive fungal infections, and the CNI class of immunosuppressive drugs, specifically tacrolimus, in 11 blood samples from HSCT recipients. RESULTS: The mean tacrolimus C/D ratio increased 1.44-fold from baseline 48 h after ISA administration (P = 0.001). CONCLUSIONS: Although further investigation is needed, the results of this study suggest that a reduction of 18% in tacrolimus may be recommended.

Sex-specific association of the Reelin gene with bipolar disorder.

The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female) = 1.79, P = 8.9 x 10(-5) vs. OR(Male) = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support.

Genome-wide association study of bipolar disorder in European American and African American individuals.

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n=1001 cases; n=1033 controls), and one involving a sample of individuals of African ancestry (AA; n=345 cases; n=670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 (P=1.6 x 10(-6)) and rs10193871 in NAP5 at 2q21.2 (P=9.8 x 10(-6)). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 (P=1.5 x 10(-6)) and rs2769605 in NTRK2 at 9q21.33 (P=4.5 x 10(-5)). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53; other evidence implicates BD candidate genes such as SLITRK2. We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 (P=1.4 x 10(-6)), rs4657247 in RGS5 at 1q23.3 (P=4.1 x 10(-6)), and rs7078071 in BTBD16 at 10q26.13 (P=4.5 x 10(-6)). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Family-based association of FKBP5 in bipolar disorder.

The FKBP5 gene product forms part of a complex with the glucocorticoid receptor and can modulate cortisol-binding affinity. Variations in the gene have been associated with increased recurrence of depression and with rapid response to antidepressant treatment. We sought to determine whether common FKBP5 variants confer risk for bipolar disorder. We genotyped seven tag single-nucleotide polymorphisms (SNPs) in FKBP5, plus two SNPs previously associated with illness, in 317 families with 554 bipolar offspring, derived primarily from two studies. Single marker and haplotypic analyses were carried out with FBAT and EATDT employing the standard bipolar phenotype. Association analyses were also conducted using 11 disease-related variables as covariates. Under an additive genetic model, rs4713902 showed significant overtransmission of the major allele (P=0.0001), which was consistent across the two sample sets (P=0.004 and 0.006). rs7757037 showed evidence of association that was strongest under the dominant model (P=0.001). This result was consistent across the two datasets (P=0.017 and 0.019). The dominant model yielded modest evidence for association (P<0.05) for three additional markers. Covariate-based analyses suggested that genetic variation within FKBP5 may influence attempted suicide and number of depressive episodes in bipolar subjects. Our results are consistent with the well-established relationship between the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response through regulation of cortisol, and mood disorders. Ongoing whole-genome association studies in bipolar disorder and major depression should further clarify the role of FKBP5 and other HPA genes in these illnesses.

Singleton deletions throughout the genome increase risk of bipolar disorder.

An overall burden of rare structural genomic variants has not been reported in bipolar disorder (BD), although there have been reports of cases with microduplication and microdeletion. Here, we present a genome-wide copy number variant (CNV) survey of 1001 cases and 1034 controls using the Affymetrix single nucleotide polymorphism (SNP) 6.0 SNP and CNV platform. Singleton deletions (deletions that appear only once in the dataset) more than 100 kb in length are present in 16.2% of BD cases in contrast to 12.3% of controls (permutation P=0.007). This effect was more pronounced for age at onset of mania

[Stromal tumor of the ileum (GIST) at the same time as a renal carcinoma. Description of a case and review of the literature]. / Tumore stromale dell'ileo (GIST) sincrono a carcinoma renale. Descrizione di un caso e revisione della letteratura.

The gastrointestinal mesenchymal tumors from a heterogenous group that include several entities: leiomyomas, schwanomas and less differentiated tumors often referred as GIST. These neoplasm are uncommon and their clinical behaviour is most difficult to predict. We describe a malignant gastrointestinal stromal tumor of the ileum coexisting with renal cell carcinoma. The neoplasms were fixed in formaldehyde, embedded in paraffin and stained with hematoxylin-eosin. For immunohistochemical studies deparaffinized tissue sections were incubated with antibodies against vimentin, desmin, muscle specific actin, S100, CD34, GFAP, NSE and keratin. The epithelioid and spindle cells of ileal neoplasm were arranged in interlacing fascicle with occasional palisading and were positive for vimentin and CD34. Positivity for muscle specific actin was focally found. The renal neoplasm required differential diagnosis from metastatic GIST. The morphological and immunohistochemical investigations in our case were consistent with GIST coexisting with primitive renal cell carcinoma. One of the problems connected to the anatomo-clinical evaluation of GIST consist in the difficulty of making a prognosis. An almost complete review of the literature and view point on the topic has been performed. As a conclusion judging from papers regarding this argument, no clear parameters of biological behaviour exist excluding mitotic index.

[Endopyelotomy: mid- and long-term follow up]. / Endopielotomia: follow-up a medio e lungo termine.

We report our experience on 24 UPJ obstruction, that underwent endopyelotomy. The follow-up on these patients range from 12 to 72 months. The success rate, based on patient symptomatology as well as urographical and scintigraphical parameters, was 83.3%. An adequate selection of cases, with grade of hydronephrosis and crossing vessels pre-operatorial detection, would possibly show a further improvement of success rate. The antegrade transpelvic endopyelotomy adopted in the most recent cases, allows the identification of crossing vessels and the performance of a safer endopyelotomy. The average operating time was very short, while morbidity was limited to 3 cases (2 of gross haematuria and 1 urosepsis). All this shows that endopyelotomy is the first choice treatment of UPJ obstruction.

[Post-voiding contraction: evidence and characterization in other 250 urodynamic studies]. / Post-voiding contraction (PVC): evidenza e caratterizzazione in oltre 250 indagini urodinamiche.

We report our experience on PVC detection in 250 consecutive urodynamic evaluations in female patients. We emphasize the absence of evident correlations between the post-voiding contractions (PVCs) and their amplitude and the urodynamic features. We suggest a possible relation between the PVCs and two clinical features: enuresis (80% of cases associated with PVC) and mixed urinary incontinence (61.5%). Defining PVC as an improper form of detrusor instability, probably generated by a reduction of pelvic muscle tone, we underline the role performed by an urodynamic investigation defining urethral sphincter as well pelvic floor activity, this procedure being justified by the notorious interdependence between perineal and detrusorial activity.

Uptake and intracellular distribution of idarubicin in secondary cultures of normal and neoplastic urothelium.

This study analyzes the uptake and endocellular distribution of idarubicin (IDA) in normal and neoplastic urothelial secondary cultures in relation to the changes in concentration and time of exposure. The urothelial lines were isolated by Freshney's method from biopsy fragments taken from five patients with superficial bladder cancer. Pharmacological experiments were carried out on subcultures previously immunophenotypically characterized and did not exceed ten passages. The uptake and endocellular distribution of IDA was analyzed by densitometric image analysis on cells treated for 10, 20, 30 and 60 min and 2 h with scalar dosages from 10 ng/ml to 2430 ng/ml. Microscopic observations and densitometric analyzes revealed that in the cells treated with IDA, fluorescence was higher in the cytoplasm compared to the nucleus and increased with the change in dosage. Moreover, densitometric data showed that IDA uptake in the first 20 min was higher in the neoplastic cells, but after that period its behavior became heterogeneous at 30 and 60 min, while at 2 h there was an inversion of the trend. These results suggest that the in vitro cytotoxicity should be evaluated in order to verify whether the elevated uptake of IDA in the first 20 min of treatment is really correlated to a more elevated toxicity in the neoplastic cells with respect to the normal cells. This is presently under investigation.

Carcinosarcoma of penis. Case report and review of the literature.

AIMS OF THE STUDY: Carcinosarcomas (sarcomatoid carcinomas) are controversial, biphasic tumors composed of both carcinomatous and sarcomatous elements. They are uncommon and occur in numerous locations. At the time of this report only 3 cases of carcinosarcoma of penis have been reported in the literature. The aim of this article is to provide a discussion of these lesions, using informations gleaned from the pertinent literature as well as the personal experience of the authors. METHODS: The formalin-fixed paraffin-embedded tissue was stained with hematoxylin and eosin, reticulum, alcian blue and Mallory's trichrome stains. Section from selected paraffin-embedded blocks, were stained with antibodies to citokeratins, EMA, vimentin, desmin, and a actin. RESULTS: In our case the carcinomatous elements were admixed with areas of "divergent differentiation": spindle-cell and giant-cell sarcomatoid component with bone and cartilage differentiation were noted. In situ carcinoma was also detected. Immunohistochemistry showed reactivity for keratin and epithelial membrane antigen (EMA). In most of pleomorphic spindle elements. Immunoreactivity for vimentin, desmin and actin were focally found. CONCLUSIONS: The carcinosarcomas may demonstrate "divergent" differentiation into bone, cartilage or myogenous tissue, so it is possible that the cell of origin could be heterogeneous. In our case myogenous differentiation was focally found. Although the clinical data, available from the only three cases of the literature, demonstrate that the behaviour of this tumors was not different from those of squamous cell carcinoma, the authors recommended a constant careful follow-up of the patients.

Buserelin treatment of advanced prostatic carcinoma: prognostic factor analysis.

From August 1986 to August 1990, 116 patients with prostatic carcinoma, advanced disease (stage C-D1 only in patients older than 75 years, or D2) were treated with Buserelin (0.5 mg 3 times/day subcutaneously for 7 days, followed by 0.4 mg 3 times/day intranasally) until progression. No concomitant antiandrogens were administered. Of the 108 evaluable patients, 10 had complete remission (CR), 49 partial remission (PR), 46 remained stable while 3 progressed (response rate = 54.6%). Median duration of response was 31 months, median survival was 34 months. The toxicity of treatment was mild and mainly related to the hormonal effect of the drug. Castrate testosterone levels were obtained in all patients except 7. Slight, transient pain increase was noted at day 8 in 12 patients. Absence of symptoms at the start of treatment, well- or moderately differentiated tumor and serum testosterone negativization following Buserelin were associated with a significantly higher response rate as compared to presence of symptoms, poorly differentiated tumor and failure to obtain castrate testosterone levels, respectively. The following prognostic factors were found, at univariate analysis, to be associated with a prolonged survival: stage (C-D1 versus D2), PS (greater than 80 versus equal or less than 80), symptoms (absent versus present) and histological grade (G1 + G2 versus G3). Age and basal T levels did not influence survival. Those patients who obtained a CR or PR survived significantly longer than those with stable disease or progression.(ABSTRACT TRUNCATED AT 250 WORDS)

Partial response to lonidamine of advanced bladder carcinoma: a case report.

A 76 year old woman presented with locally advanced papillary transitional cell carcinoma. The patient had elsewhere had trans-urethral resection and radiotherapy and declined salvage cystectomy. She was treated with Lonidamine (150 mg X 3/day p.o. Repeat CT scan after 8 months showed partial remission. This response was unchanged after 28 months Lonidamine therapy.

Characteristics of antibodies adsorbed on the DNA immunoadsorbent, agarose poly-L-lysine-DNA.

Agarose-poly-L-lysine (Ag-(lys)n-DNA) has been used to bind DNA for assay of anti-DNA antibodies (ab). In this work, an algorithmic approach has been used to classify antinuclear ab (ANA) as being directed against native DNA (dsDNA), denatured DNA (ssDNA), DNA-protein complexes (deoxyribonucleoprotein; DNP), and against antigens which are independent of DNA (iDNA). These ab were subjected to Ag-(lys)n-DNA, and the selectivity of this adsorbent for the various specificities of ab was determined. The DNA on the columns was left untreated or treated with S1 nuclease, this being effected either by treating the DNA prior to introducing it onto the columns or by adding S1 nuclease to the columns after the DNA was bound. Ag-(lys)n-DNA adsorbs ab directed against ssDNA and DNP as well as ab to dsDNA; iDNA ab are not adsorbed. S1 nuclease treatment does not effectively remove ssDNA regions from the Ag-(lys)n-DNA, but it does result in the abolition of the adsorption of a population of ab which are in the anti-DNP sera and contribute to the total ANA load. While anti-iDNA ab are not adsorbed onto the columns, they do contribute to the ANA titer, unlike anti-ssDNA ab which are adsorbed onto the Ag-(lys)n-DNA but do not contribute to the ANA titer. We conclude that Ag-(lys)n-DNA bears antigenic sites for dsDNA, ssDNA, and DNP ab and suggest that our understanding of the characteristic ab-binding profile of this versatile immunoadsorbent may have applications in the study of autoimmune diseases.

Dermatitis de contacto liquenoide por poliamida. / Lichenoid contact dermatitis by polyamides

Se presentan dos pacientes con dermatitis de contacto por poliamidas, con aspecto clinico liquenoide y pigmentario.Se actualizan conceptos sobre dermatitis de contacto y causas sensibilizantes en fibras sinteticas

Bleeding in cirrhotic patients: a precipitating factor due to intravascular coagulation or to hepatic failure?

In 24 cirrhotic patients at different stages of hepatic failure, factor VIII:C (F VIII:C), factor VIIIR:AG (F VIIIR:AG), factor VIII AG/C ratio (F VIII AG/C), and serum fibrin-fibrinogen degradation products (FDP) were investigated. In 11 of the 24 patients, several instances of gastrointestinal bleeding due to esophageal varices rupture were documented and 5 patients died of unarrestable bleeding. In our study, we evaluated whether the cause of bleeding was the development of intravascular coagulation or the severity of hepatic failure. A statistically significant difference between F VIII:C, F VIIIR:AG/C ratio, and serum FDP was found in bleeding in comparison with non-bleeding patients. An inverse correlation between the F VIII:C plasma level and serum FDP as well as a direct correlation between F VIII AG/C ratio and serum FDP in the group of bleeding patients were also found. These data seem to suggest a hypercoagulable state which was more significant in the 5 patients who died owing to bleeding. Furthermore, only 1 of these patients had severe hepatic failure. From this study it appears that, in cirrhotic patients, bleeding is related more to the appearance of disseminated intravascular coagulation, as a consequence of both hemodynamic and endothelial changes, than to the degree of hepatic failure itself.