Recurrent endometrial carcinoma regression with the use of the aromatase inhibitor anastrozole

Recurrent/metastatic endometrial adenocarcinoma that is not amenable to cure with local or regional therapy and/or chemotherapy represents a discouraging clinical entity for the clinician. We report the case of 58-year-old woman with recurrent endometrial carcinoma that was resistant to chemotherapy that was treated successfully with the aromatase inhibitor anastrozole.     

Takayasu's arteritis: therapeutic strategies.

Takayasu's arteritis (TA) is a chronic inflammatory disease of unknown origin, primarily affecting the walls of large vessels. TA can be a severe and life-threatening disease, and has relevant consequences for the patient's life-style. Mortality and morbidity depend on both the direct effect of the vascular lesions and the following complications. The mainstay of TA therapy is based on the use of glucocorticoids alone or in association with cytotoxic drugs. Unfortunately, in the majority of cases, only a partial control of the disease is obtained. The therapeutic strategy may vary in different countries, and in Japan, where the disease was first described, high dose glucocorticoids are preferred to glucocorticoids in association with cytotoxic agents. We present here a review of the pharmacologic strategies most commonly adopted for the treatment of TA in America, Italy and Japan, together with our experience on 31 TA patients, who have been followed in the last two decades. The discussion is also open on which criteria are more accurate in measuring disease activity.     

Longitudinal evaluation of mycophenolic acid pharmacokinetics in pediatric kidney transplant recipients. The role of post-transplant clinical and therapeutic variables

Abstract:  This longitudinal study assessed the influence of post-transplant clinical and therapeutic variables in 50 kidney transplant recipients aged 2–19 yr receiving a triple immunosuppressive regimen consisting of cyclosporine microemulsion (CsA), steroids and MMF (300–400 mg/m² body surface area twice daily), the full pharmacokinetic profile (10 points) of which was investigated on post-transplant days 6, 30, 180 and 360. Total plasma MPA was measured by Enzyme Multiplied Immunoassay Technique. CsA therapeutic drug monitoring (TDM) was performed via C2 blood monitoring, while MPA TDM via C0. MPA Cmax, tmax, AUC0-12 and AUC0-4 pharmacokinetic profile changed significantly during the first post-transplant year. C0 was a poor predictor of the total MPA exposure [as measured by the area under the concentration-time curve AUC)], while a truncated AUC was a good surrogate of the 12-h profile (r = 0.91; p < 0.001) Graft function and cyclosporine therapy influenced MPA pharmacokinetics, as shown by the univariate and multivariate analyses. We conclude that because after transplantation MPA exposure varied over time, a strict TDM is advisable in the pediatric population.     

5-HTTLPR,anxiety and gender interaction moderates right amygdala volume in healthy subjects

Genetic variants within the serotonin transporter gene (5-HTTLPR) impact the neurobiology and risk for anxiety-related behaviours. There are also gender differences in the prevalence of anxiety-related behaviours. Although numerous studies have investigated the influence of 5-HTTLPR genotype on the neural systems involved in emotional regulation, none have investigated how these effects are modulated by gender and anxiety. We investigated this issue using two complementary region of interest-based structural neuroimaging approaches (voxel-based morphometry and Freesurfer) in 138 healthy individuals categorized into ‘no anxiety’ and ‘subclinical anxiety’ groups based on the Hamilton Rating Scale for Anxiety (HAM-A). Preliminarily, using anxiety as a continuous variable, we found a significant interaction effect of genotype by gender on anxiety. Females homozygous for the Short allele showed the highest HAM-A scores and males the lowest. In addition, a three-way significant interaction among genotype, gender and anxiety category was found for the right amygdala volume. Post hoc tests revealed that homozygous females carrying the Short variant with a subclinical anxiety condition had larger volume. The reported interaction effects demonstrate that gender strongly modulates the relationship between 5-HTTLPR genotype and subclinical expression of anxiety acting on amygdala, one region of the emotional neural network specifically involved in the anxiety-like behaviours.     

Anticholinergic drugs rescue synaptic plasticity in DYT1 dystonia: Role of M1 muscarinic receptors

Broad‐spectrum muscarinic receptor antagonists have represented the first available treatment for different movement disorders such as dystonia. However, the specificity of these drugs and their mechanism of action is not entirely clear. We performed a systematic analysis of the effects of anticholinergic drugs on short‐ and long‐term plasticity recorded from striatal medium spiny neurons from DYT1 dystonia knock‐in (Tor1a^+/Δgag) mice heterozygous for ΔE‐torsinA and their controls (Tor1a^+/+ mice). Antagonists were chosen that had previously been proposed to be selective for muscarinic receptor subtypes and included pirenzepine, trihexyphenydil, biperiden, orphenadrine, and a novel selective M₁ antagonist, VU0255035. Tor1a^+/Δgag mice exhibited a significant impairment of corticostriatal synaptic plasticity. Anticholinergics had no significant effects on intrinsic membrane properties and on short‐term plasticity of striatal neurons. However, they exhibited a differential ability to restore the corticostriatal plasticity deficits. A complete rescue of both long‐term depression (LTD) and synaptic depotentiation (SD) was obtained by applying the M₁‐preferring antagonists pirenzepine and trihexyphenidyl as well as VU0255035. Conversely, the nonselective antagonist orphenadrine produced only a partial rescue of synaptic plasticity, whereas biperiden and ethopropazine failed to restore plasticity. The selectivity for M₁ receptors was further demonstrated by their ability to counteract the M₁‐dependent potentiation of N‐methyl‐d ‐aspartate (NMDA) current recorded from striatal neurons. Our study demonstrates that selective M₁ muscarinic receptor antagonism offsets synaptic plasticity deficits in the striatum of mice with the DYT1 dystonia mutation, providing a potential mechanistic rationale for the development of improved antimuscarinic therapies for this movement disorder. © 2014 International Parkinson and Movement Disorder Society     

Myoclonus in mitochondrial disorders

Myoclonus is a possible manifestation of mitochondrial disorders, and its presence is considered, in association with epilepsy and the ragged red fibers, pivotal for the syndromic diagnosis of MERRF (myoclonic epilepsy with ragged red fibers). However, its prevalence in mitochondrial diseases is not known. The aims of this study are the evaluation of the prevalence of myoclonus in a big cohort of mitochondrial patients and the clinical characterization of these subjects. Based on the database of the “Nation‐wide Italian Collaborative Network of Mitochondrial Diseases,” we reviewed the clinical and molecular data of mitochondrial patients with myoclonus among their clinical features. Myoclonus is a rather uncommon clinical feature of mitochondrial diseases (3.6% of 1,086 patients registered in our database). It is not strictly linked to a specific genotype or phenotype, and only 1 of 3 patients with MERRF harbors the 8344A>G mutation (frequently labeled as “the MERRF mutation”). Finally, myoclonus is not inextricably linked to epilepsy in MERRF patients, but more to cerebellar ataxia. In a myoclonic patient, evidences of mitochondrial dysfunction must be investigated, even though myoclonus is not a common sign of mitochondriopathy. Clinical, histological, and biochemical data may predict the finding of a mitochondrial or nuclear DNA mutation. Finally, this study reinforces the notion that myoclonus is not inextricably linked to epilepsy in MERRF patients, and therefore the term “myoclonic epilepsy” seems inadequate and potentially misleading. © 2014 International Parkinson and Movement Disorder Society     

Modulatory effect of prolactin on the resting and mitogen-induced activity of T, B, and NK lymphocytes

Prolactin (PRL) has been shown to contribute to the development of lymphoid tissues and maintenance of physiological immune function. Here we show that the role of the hormone extends to the control of the effector phase of the immune response. In addition to triggering resting lymphocytes to cell division, the hormone can also control the magnitude of their response to polyclonal stimuli. Concentrations of PRL in the physiological range increased the [3H]thymidine, [3H]uridine, and [3H]leucine incorporation of unstimulated NK cells cultured in serum-free conditions. The same concentrations of the hormone increased the response of NK, T, and B cells to the mitogenic stimuli interleukin 2 (IL2), phytohemagglutinin (PHA), and staphylococcus aureus cowan, respectively, the effect being maximally evident in the presence of suboptimal concentrations of the mitogens. By contrast concentrations of PRL five- to tenfold the physiological levels inhibited the mitogenic response to IL2 and PHA. These data indicate a double-faceted regulatory role of this hormone in vivo.     

Elizabethkingia meningoseptica: Emergent bacteria causing pneumonia in a critically ill child

Elizabethkingia meningoseptica is an unusual, highly resistant, gram‐ negative bacillus. While E. meningoseptica–associated meningitis outbreaks have been well‐documented in hospital neonatal wards and among immunocompromised adults, reports describing this microorganism in critically ill children are scarce. The purpose of this report was to describe a case of a 3 year‐old girl who developed pneumonia caused by E. meningoseptica in the setting of previous use of broad‐spectrum antibiotics and to review the pediatric literature regarding this pathogen.     

Effect of blood transfusion during radiotherapy on the immune function of patients with cancer of the uterine cervix: role of interleukin-10

: To analyze prospectively the effects of blood transfusion administered during radiotherapy (RT) on the immune function of patients with locally advanced cervical cancer.

: In a total of 15 patients, 7 transfused and 8 untransfused, lymphocyte populations, including CD3+, CD4+, and CD8+ T-cell subsets, B cells (CD19+), and natural killer (NK) cells (CD56+, CD16+, CD3−) were studied before (i.e., time 0), during (i.e., times 1 and 2), and after (i.e., time 3) therapy. Expression of the early (CD25) and late (HLA-DR) activation markers on CD3+ T cells, the intracellular levels of perforin in CD8+ and CD56+ cells, and interferon (IFN)-γ, interleukin (IL)-2, and IL-4 in CD4+ and CD8+ T cells were also measured. NK cell cytotoxicity against the NK-sensitive target K-562 cells and CD8+ T-cell-directed cytotoxicity against OKT3 hybridoma cells were also assessed. Finally, the plasma levels of the immunoregulatory cytokine IL-10 were analyzed by enzyme-linked immunosorbent assay.

: The mean absolute number of all lymphocyte subsets compared with pretreatment levels decreased significantly during RT of both transfused and untransfused patients (p >0.001), with no detectable differences between the two groups in terms of total lymphocytes or relative numbers of CD3+ and CD4+ T cells, CD56+ NK cells, or CD19+ B cells. In contrast, concomitant with an inversion of the CD4/CD8 ratio, a significant increase in the number of CD8+ T cells at time 2 and CD3+ T cells, CD8+ T cells, and NK cells at time 3 was found in the transfused patients compared with the untransfused group. The percentages of CD25+/CD3+ T cells and HLA-DR+/CD3+ T cells increased during RT of the untransfused patients, but CD3+ T cells showed decreased CD25 expression and increased HLA-DR expression in the transfused group. An increase of CD8+ IFN-γ+ T cells with a concomitant decrease in CD8+ IL-2+ T cells was found in the transfused vs. untransfused group, and no differences were noted in the percentage of CD4+ IFN-γ+ T cells and CD4+ IL-2+ T cells. The proportion of perforin-positive CD8+ and CD56+ cells was higher in the transfused group than in the untransfused group. However, CD56+ cells and CD8+ T cells from the transfused patients showed markedly diminished cytotoxic function. Finally, IL-10 was detected only in the plasma of the transfused patients.

: Blood transfusion during primary RT for cervical cancer profoundly alters the magnitude and characteristics of radiation-induced immunosuppression. Elevated serum IL-10 in transfused patients may play a role in the disregulation of lymphocyte function, in particular, the depression of NK- and T-cell cytotoxicity. Investigation of alternatives to blood transfusion during RT that do not diminish host immunity is warranted.     

Oral distribution of Candida species and presence of oral lesions in Brazilian leprosy patients under multidrug therapy

Objective:  The aim of this study was to evaluate the prevalence of Candida spp. and presence of oral lesions in Brazilian leprosy patients under multidrug therapy (MDT).
Methods:  Thirty-eight individuals (18 males and 20 females, median age 53 years) clinically and microbiologically diagnosed as leprosy (lepromatous variant), and under MDT for at least 45 days were studied. The control group constituted by 38 healthy individuals (median age 53.5), matched to the test group in relation to age, gender and oral conditions. Oral rinses were collected and the Candida identification was performed by phenotypic tests. The existence of Candida dubliniensis among the isolates was analyzed using a validated multiplex PCR assay. Twenty-nine leprosy patients were examined intra-orally for the presence of lesions. Data were analyzed by z- and Mann–Whitney tests (α = 5%).
Results:  Yeast carriage rate between leprosy patients (65.8%) and controls (47.4%) was similar ( P  = 0.099), and no significant difference between yeast counts was observed ( P  = 0.1004). Candida albicans was the most frequently isolated species in both groups. In the leprosy group, Candida tropicalis and Candida parapsilosis were also identified. In the control group, we additionally identified Candida tropicalis , Candida glabrata and Candida kefyr. Candida dubliniensis was not detected. No leprosy-related oral lesion was registered.
Conclusion:  Within the limits of the study, we concluded that Brazilian leprosy patients under MDT showed similar levels of carriage and Candida species distribution in relation to the controls.