Serenoa repens as an Endocrine Disruptor in a 10-Year-Old Young Girl: A New Case Report.

Serenoa repens, commonly known as saw palmetto, is the sole species currently classified in the genus Serenoa. The plant is a low shrubby palm that is native of West Indies, and it grows in the coastal lands of North America and other European mediterranean countries. Its fruits contain high concentrations of fatty acids and phytosterols. S. repens extracts have been studied for the symptomatic treatment of benign prostatic hyperplasia. Recently, they have been proposed to treat androgenic alopecia and other hair disorders. We report a new case of hot flashes in a 10-year-old girl using a food supplement containing the extract of S. repens for the treatment of hirsutism. When the girl discontinued the treatment, the hot flashes stopped. A 'rechallenge' of the supplement was tried and symptoms reappeared. About 4 months after starting therapy, the girl experienced menarche. Exposure to the plant-derived product could be responsible for the appearance of menarche. In our opinion, use of phytotherapeutic agents in pediatric patients should be associated to a better evaluation of benefit/risk profile taking in account the physiological changes that occurs at different ages in this subgroup of population.

Epidemiology of gout and hyperuricaemia in Italy during the years 2005-2009: a nationwide population-based study.

OBJECTIVE: To assess the epidemiology of gout and hyperuricaemia in the Italian general population during the years 2005-2009. METHODS: Using the Italian primary care database (Health Search/CSD Longitudinal Patient Database), the prevalence, incidence and recurrence rates of gout and/or hyperuricaemia (serum urate level >360 mmol/l (6 mg/dl)) in outpatients aged ≥18 years during the years 2005-2009 were estimated. Rates together with 95% CI were measured overall and stratified by age, gender and calendar year. The characteristics of patients with newly diagnosed gout and hyperuricaemia were investigated and compared with the general population. RESULTS: The prevalence of gout increased from 6.7 per 1000 inhabitants in 2005 to 9.1 per 1000 inhabitants in 2009. It increased with advancing age and was fourfold higher in men. A similar trend was observed for asymptomatic hyperuricaemia (85.4 per 1000 inhabitants in 2005 vs 119.3 per 1000 inhabitants in 2009). The incidence of gout remained stable during the observation years (0.93 per 1000 person years in 2005 vs 0.95 in 2009). Recurrent episode rate was 19.1% during the first year following the first gout attack and 31.6% during the following 5 years. Advanced age, increased levels of uric acid, nephrolithiasis and concomitant use of ciclosporin were the main predictors of recurrence of gout attacks. CONCLUSION: The prevalence of gout and hyperuricaemia increased in Italy from 2005 to 2009. A high recurrence rate for gout attack was observed during the first year following the first episode. Early management of hyperuricaemia in patients at higher risk of recurrent gout attack should be considered in primary care.

Phenotypic and Functional Heterogeneity of Low-Density and High-Density Human Lung Macrophages.

BACKGROUND: Pulmonary macrophages are a highly heterogeneous cell population distributed in different lung compartments. METHODS: We separated two subpopulations of macrophages from human lung parenchyma according to flotation over density gradients. RESULTS: Two-thirds 65.4% of the lung macrophages have a density between 1.065 and 1.078 (high-density macrophages: HDMs), and the remaining one-third (34.6) had a density between 1.039 and 1.052 (low-density macrophages: LDMs). LDMs had a larger area (691 vs. 462 µm2) and cell perimeter (94 vs. 77 µm) compared to HDMs. A significantly higher percentage of HDMs expressed CD40, CD45, and CD86 compared to LDMs. In contrast, a higher percentage of LDMs expressed the activation markers CD63 and CD64. The release of TNF-α, IL-6, IL-10 and IL-12 induced by lipopolysaccharide (LPS) was significantly higher in HDMs than in LDMs. CONCLUSION: The human lung contains two subpopulations of macrophages that differ in buoyancy, morphometric parameters, surface marker expression and response to LPS. These subpopulations of macrophages probably play distinct roles in lung inflammation and immune responses.

Extended flow cytometry characterization of normal bone marrow progenitor cells by simultaneous detection of aldehyde dehydrogenase and early hematopoietic antigens: implication for erythroid differentiation studies.

BACKGROUND: Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme highly expressed in hematopoietic precursors from cord blood and granulocyte-colony stimulating factor mobilized peripheral blood, as well as in bone marrow from patients with acute myeloblastic leukemia. As regards human normal bone marrow, detailed characterization of ALDH+ cells has been addressed by one single study (Gentry et al, 2007). The goal of our work was to provide new information about the dissection of normal bone marrow progenitor cells based upon the simultaneous detection by flow cytometry of ALDH and early hematopoietic antigens, with particular attention to the expression of ALDH on erythroid precursors. To this aim, we used three kinds of approach: i) multidimensional analytical flow cytometry, detecting ALDH and early hematopoietic antigens in normal bone marrow; ii) fluorescence activated cell sorting of distinct subpopulations of progenitor cells, followed by in vitro induction of erythroid differentiation; iii) detection of ALDH+ cellular subsets in bone marrow from pure red cell aplasia patients. RESULTS: In normal bone marrow, we identified three populations of cells, namely ALDH+CD34+, ALDH-CD34+ and ALDH+CD34- (median percentages were 0.52, 0.53 and 0.57, respectively). As compared to ALDH-CD34+ cells, ALDH+CD34+ cells expressed the phenotypic profile of primitive hematopoietic progenitor cells, with brighter expression of CD117 and CD133, accompanied by lower display of CD38 and CD45RA. Of interest, ALDH+CD34- population disclosed a straightforward erythroid commitment, on the basis of three orders of evidences. First of all, ALDH+CD34- cells showed a CD71bright, CD105+, CD45- phenotype. Secondly, induction of differentiation experiments evidenced a clear-cut expression of glycophorin A (CD235a). Finally, ALDH+CD34- precursors were not detectable in patients with pure red cell aplasia (PRCA). CONCLUSION: Our study, comparing surface antigen expression of ALDH+/CD34+, ALDH-/CD34+ and ALDH+/CD34- progenitor cell subsets in human bone marrow, clearly indicated that ALDH+CD34- cells are mainly committed towards erythropoiesis. To the best of our knowledge this finding is new and could be useful for basic studies about normal erythropoietic differentiation as well as for enabling the employment of ALDH as a red cell marker in polychromatic flow cytometry characterization of bone marrow from patients with aplastic anemia and myelodysplasia.

A beta3 Asp217-->Val substitution in a patient with variant Glanzmann Thrombasthenia severely affects integrin alphaIIBbeta3 functions.

A dysfunctional Glanzmann Thrombasthenia (variant) is a rare bleeding disorder due to qualitative abnormalities of platelets alphaIIBbeta3 heterodimers. Dynamically conformational change of alphaIIBbeta3 is a complex mechanism that is not fully understood. For these reasons, genotyping and functional analysis of variant Glanzmann Thrombasthenia is important to elucidate the molecular basis of alphaIIBbeta3 receptor functions. In this report, we have analyzed the molecular effects of an A>T substitution leading to an amino acid change, D217>V, in the beta3 integrin gene identified in patients with variant Glanzmann Thrombasthenia. As the D217 residue is highly conserved among all seven beta integrin subunits and among beta3 integrins of different species, we tested the effect on the phenotype of the D217V mutation by cotransfecting the beta3 mutant (V217) or wild-type beta3 (D217) construct with the wild-type alphaIIb into eukaryotic Chinese hamster ovary cells. Levels of mutant alphaIIBbeta3 heterodimers on Chinese hamster ovary cell surface were lightly reduced as compared with the wild type. Functional investigation of alphaIIBbeta3 V217 on Chinese hamster ovary cell surface was carried out, as fibrinogen binding, adhesion and aggregation tests showed a substantial reduction in respect to the control sample. Our results confirm ex-vivo data and suggest that the D217 amino acid is required for alphaIIBbeta3 receptor interactions with fibrinogen.

The Role of Levomilnacipran in the Management of Major Depressive Disorder: A Comprehensive Review.

Levomilnacipran, the more active enantiomer of the serotonin and norepinephrine reuptake inhibitor (SNRI) milnacipran, was recently approved in the US for the treatment of major depressive disorder (MDD). The drug was developed as an extended release (ER) capsule formulation to allow for once-daily administration, thereby improving patient adherence. This agent differs from other available SNRIs in having a greater potency for inhibition of norepinephrine relative to serotonin reuptake. The efficacy of levomilnacipran ER has been evaluated in seven randomised, double-blind clinical trials (one Phase II and four Phase III trials, and two long-term efficacy studies). These studies documented that levomilnacipran is generally more effective than placebo for the treatment of MDD in the short-term, whereas no firm evidence exists on long-term efficacy for relapse prevention. Preliminary evidence suggests that levomilnacipran ER may be effective in improving not only depressive symptoms but also symptoms related to functioning (social life, work, and family life). Short-and longer-term studies found that the rate of withdrawal from levomilnacipran therapy due to adverse events was rather low. Moreover the drug appeared to be generally well tolerated. The most common adverse effects included nausea, hyperhidrosis, constipation, tachycardia, palpitations, erectile dysfunction and ejaculation disorder. As hypertension or orthostatic hypotension may occur in a few patients, the cardiovascular safety of levomilnacipran needs to be more extensively investigated especially on long-term treatment. Additional active comparator trials evaluating efficacy, tolerability and cost-effectiveness are required to better define the role of levomilnacipran ER in the treatment of MDD in relation to currently available antidepressants including other SNRIs.

Complete remission induced by G-CSF in a patient with acute myeloid leukemia with t(8;21)(q22;q22).

We describe a case of acute myeloid leukemia (AML) with t(8;21) in which complete remission (CR) was obtained with G-CSF given at 10 microg/kg in the absence of concomitant cytotoxic chemotherapy. CR was achieved following 2 weeks of therapy and confirmed by investigating minimal residual disease by four-color flow cytometry analysis. During treatment with G-CSF, maturing cells with cytoplasmic Auer Rods were observed in the peripheral blood, suggesting a differentiation effect. This case adds further evidence for a specific role of G-CSF in the treatment of AML with t(8;21), namely in patients who are not eligible for aggressive chemotherapy.

Adrenal disorders and the paediatric brain: pathophysiological considerations and clinical implications.

Various neurological and psychiatric manifestations have been recorded in children with adrenal disorders. Based on literature review and on personal case-studies and case-series we focused on the pathophysiological and clinical implications of glucocorticoid-related, mineralcorticoid-related, and catecholamine-related paediatric nervous system involvement. Childhood Cushing syndrome can be associated with long-lasting cognitive deficits and abnormal behaviour, even after resolution of the hypercortisolism. Exposure to excessive replacement of exogenous glucocorticoids in the paediatric age group (e.g., during treatments for adrenal insufficiency) has been reported with neurological and magnetic resonance imaging (MRI) abnormalities (e.g., delayed myelination and brain atrophy) due to potential corticosteroid-related myelin damage in the developing brain and the possible impairment of limbic system ontogenesis. Idiopathic intracranial hypertension (IIH), a disorder of unclear pathophysiology characterised by increased cerebrospinal fluid (CSF) pressure, has been described in children with hypercortisolism, adrenal insufficiency, and hyperaldosteronism, reflecting the potential underlying involvement of the adrenal-brain axis in the regulation of CSF pressure homeostasis. Arterial hypertension caused by paediatric adenomas or tumours of the adrenal cortex or medulla has been associated with various hypertension-related neurological manifestations. The development and maturation of the central nervous system (CNS) through childhood is tightly regulated by intrinsic, paracrine, endocrine, and external modulators, and perturbations in any of these factors, including those related to adrenal hormone imbalance, could result in consequences that affect the structure and function of the paediatric brain. Animal experiments and clinical studies demonstrated that the developing (i.e., paediatric) CNS seems to be particularly vulnerable to alterations induced by adrenal disorders and/or supraphysiological doses of corticosteroids. Physicians should be aware of potential neurological manifestations in children with adrenal dysfunction to achieve better prevention and timely diagnosis and treatment of these disorders. Further studies are needed to explore the potential neurological, cognitive, and psychiatric long-term consequences of high doses of prolonged corticosteroid administration in childhood.

Identification of acute myocardial infarction from electronic healthcare records using different disease coding systems: a validation study in three European countries.

OBJECTIVE: To evaluate positive predictive value (PPV) of different disease codes and free text in identifying acute myocardial infarction (AMI) from electronic healthcare records (EHRs). DESIGN: Validation study of cases of AMI identified from general practitioner records and hospital discharge diagnoses using free text and codes from the International Classification of Primary Care (ICPC), International Classification of Diseases 9th revision-clinical modification (ICD9-CM) and ICD-10th revision (ICD-10). SETTING: Population-based databases comprising routinely collected data from primary care in Italy and the Netherlands and from secondary care in Denmark from 1996 to 2009. PARTICIPANTS: A total of 4 034 232 individuals with 22 428 883 person-years of follow-up contributed to the data, from which 42 774 potential AMI cases were identified. A random sample of 800 cases was subsequently obtained for validation. MAIN OUTCOME MEASURES: PPVs were calculated overall and for each code/free text. 'Best-case scenario' and 'worst-case scenario' PPVs were calculated, the latter taking into account non-retrievable/non-assessable cases. We further assessed the effects of AMI misclassification on estimates of risk during drug exposure. RESULTS: Records of 748 cases (93.5% of sample) were retrieved. ICD-10 codes had a 'best-case scenario' PPV of 100% while ICD9-CM codes had a PPV of 96.6% (95% CI 93.2% to 99.9%). ICPC codes had a 'best-case scenario' PPV of 75% (95% CI 67.4% to 82.6%) and free text had PPV ranging from 20% to 60%. Corresponding PPVs in the 'worst-case scenario' all decreased. Use of codes with lower PPV generally resulted in small changes in AMI risk during drug exposure, but codes with higher PPV resulted in attenuation of risk for positive associations. CONCLUSIONS: ICD9-CM and ICD-10 codes have good PPV in identifying AMI from EHRs; strategies are necessary to further optimise utility of ICPC codes and free-text search. Use of specific AMI disease codes in estimation of risk during drug exposure may lead to small but significant changes and at the expense of decreased precision.

Differentiation of monocytes into macrophages induces the upregulation of histamine H1 receptor.

BACKGROUND: Histamine modulates several functions in human monocytes, macrophages, and dendritic cells. However, responses elicited by histamine differ depending on cell type, suggesting variable expression of histamine receptors in the monocyte/macrophage lineage. OBJECTIVE: We sought to examine whether the expression of H(1) receptors was regulated by cell differentiation of human monocytes into macrophages or dendritic cells. METHODS: Expression of H(1) receptor was evaluated by RT-PCR and western blot in monocytes, monocyte-derived macrophages (MDMs), monocyte-derived dendritic cells (DCs) and human lung macrophages (HLMs). RESULTS: Expression of H(1) receptor mRNA and protein was higher in HLMs and DCs than in monocytes. H(1) expression was approximately 15-fold and 4-fold higher in MDMs and HLMs, respectively, as compared with that seen in monocytes. H(1) receptor protein was undetectable in monocytes, whereas it was conspicuous in MDMs. Simultaneous analysis of H(2) and H(1) mRNA expression indicated that the H(2)/H(1) ratio decreased from 202.7 +/- 14.8 in monocytes to 2.2 +/- 0.4 in MDM and 39.5 +/- 5.0 in DCs. Incubation of monocytes with histamine neither affected intracellular Ca(2+) concentrations nor influenced IL-8 production. In contrast, histamine rapidly induced a Ca(2+) signal and stimulated IL-8 production in MDMs. Both effects were inhibited by H(1) blockade with levocetirizine, but not by H(2) blockade with ranitidine. CONCLUSIONS: Differentiation of monocytes into macrophages or dendritic cells is associated with profound changes of histamine receptor expression. Upregulation of H(1) receptors confers on macrophages the capacity of being activated by histamine. CLINICAL IMPLICATIONS: Regulation of H(1) and H(2) receptor expression in the monocyte/macrophage lineage can be relevant to the pathogenesis of allergic inflammation.