Multisystemic alterations in humans induced by bisphenol A and phthalates: Experimental, epidemiological and clinical studies reveal the need to change health policies.

A vast amount of evidence indicates that bisphenol A (BPA) and phthalates are widely distributed in the environment since these compounds are mass-produced for the manufacture of plastics and plasticizers. These compounds belong to a large group of substances termed endocrine-disrupting chemicals (EDC). It is well known that humans and living organisms are unavoidably and unintentionally exposed to BPA and phthalates from food packaging materials and many other everyday products. BPA and phthalates exert their effect by interfering with hormone synthesis, bioavailability, and action, thereby altering cellular proliferation and differentiation, tissue development, and the regulation of several physiological processes. In fact, these EDC can alter fetal programming at an epigenetic level, which can be transgenerational transmitted and may be involved in the development of various chronic pathologies later in the adulthood, including metabolic, reproductive and degenerative diseases, and certain types of cancer. In this review, we describe the most recent proposed mechanisms of action of these EDC and offer a compelling selection of experimental, epidemiological and clinical studies, which show evidence of how exposure to these pollutants affects our health during development, and their association with a wide range of reproductive, metabolic and neurological diseases, as well as hormone-related cancers. We stress the importance of concern in the general population and the urgent need for the medical health care system to closely monitor EDC levels in the population due to unavoidable and involuntary exposure to these pollutants and their impact on human health.

Hormone-Related Cancer and Autoimmune Diseases: A Complex Interplay to be Discovered.

Neoplasic transformation is a continuous process that occurs in the body. Even before clinical signs, the immune system is capable of recognizing these aberrant cells and reacting to suppress them. However, transformed cells acquire the ability to evade innate and adaptive immune defenses through the secretion of molecules that inhibit immune effector functions, resulting in tumor progression. Hormones have the ability to modulate the immune system and are involved in the pathogenesis of autoimmune diseases, and cancer. Hormones can control both the innate and adaptive immune systems in men and women. For example androgens reduce immunity through modulating the production of pro-inflammatory and anti-inflammatory mediators. Women are more prone than men to suffer from autoimmune diseases such as systemic lupus erythematosus, psoriasis and others. This is linked to female hormones modulating the immune system. Patients with autoimmune diseases consistently have an increased risk of cancer, either as a result of underlying immune system dysregulation or as a side effect of pharmaceutical treatments. Epidemiological data on cancer incidence emphasize the link between the immune system and cancer. We outline and illustrate the occurrence of hormone-related cancer and its relationship to the immune system or autoimmune diseases in this review. It is obvious that some observations are contentious and require explanation of molecular mechanisms and validation. As a result, future research should clarify the molecular pathways involved, including any causal relationships, in order to eventually allocate information that will aid in the treatment of hormone-sensitive cancer and autoimmune illness.

Strong Purcell Effect on a Neutral Atom Trapped in an Open Fiber Cavity.

We observe a sixfold Purcell broadening of the D_{2} line of an optically trapped ^{87}Rb atom strongly coupled to a fiber cavity. Under external illumination by a near-resonant laser, up to 90% of the atom's fluorescence is emitted into the resonant cavity mode. The sub-Poissonian statistics of the cavity output and the Purcell enhancement of the atomic decay rate are confirmed by the observation of a strongly narrowed antibunching dip in the photon autocorrelation function. The photon leakage through the higher-transmission mirror of the single-sided resonator is the dominant contribution to the field decay (κ≈2π×50 MHz), thus offering a high-bandwidth, fiber-coupled channel for photonic interfaces such as quantum memories and single-photon sources.

Fast Nondestructive Parallel Readout of Neutral Atom Registers in Optical Potentials.

We demonstrate the parallel and nondestructive readout of the hyperfine state for optically trapped ^{87}Rb atoms. The scheme is based on state-selective fluorescence imaging and achieves detection fidelities >98% within 10 ms, while keeping 99% of the atoms trapped. For the readout of dense arrays of neutral atoms in optical lattices, where the fluorescence images of neighboring atoms overlap, we apply a novel image analysis technique using Bayesian inference to determine the internal state of multiple atoms. Our method is scalable to large neutral atom registers relevant for future quantum information processing tasks requiring fast and nondestructive readout and can also be used for the simultaneous readout of quantum information stored in internal qubit states and in the atoms' positions.

[Effectiveness of a program of early instillation single chemotherapy in patients with bladder cancer]. / Efectividad de un programa de instilación de quimioterapia precoz en pacientes con cáncer de vejiga.

OBJECTIVE: To determine the effectiveness of early intravesical chemotherapy intervention for patients with non-muscle invasive bladder cancer, before and after a training and inter-professional communication plan. METHOD: Non-experimental prospective longitudinal study of a cohort of 349 patients with endoscopic diagnosis of a non-muscle invasive bladder tumour in Northern Area Health Management of Cadiz between 2010 and 2013 and amenable to postoperative treatment with mitomycin C. RESULTS: The mean rate of patients included in the program was 53.9%. The inclusion rate rose by 79.3% at 3 years. The absolute risk reduction of recurrence for patients receiving treatment is 18.1% (95% CI; 8.81% - 27.48%, p<.001), and the number of patients needed to treat was 5.5 (95% CI; 3.6 - 11.3, p<.001). CONCLUSIONS: A program of early postoperative chemotherapy that includes a plan for evaluation and dissemination of results has achieved a good level of adherence among professionals, obtaining the expected impact on the reduction of early recurrence of non-muscle invasive bladder cancer.

[Oropharyngeal dysphagia as a first manifestation of dermatomyositis associated with colon cancer]. / Disfagia orofaríngea como primera manifestación de dermatopolimiositis asociada a cáncer de colon.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy associated with characteristic skin manifestations. In 15-20% of patients present with dysphagia, it is associated with nutritional deficiency, predisposition to aspiration pneumonia, decreased quality of life and a poor prognosis. There is a well-recognized association between DM and malignancies, including ovarian, breast, lung, and colon cancer. We report a case of a male patient aged 85 with DM associated with colon adenocarcinoma; progressive dysphagia was the first manifestation, and subsequently proximal muscle weakness and typical skin lesions were present. Given the clinical suspicion of DM as a paraneoplastic syndrome, tumor markers were order and a high carcinoembryonic antigen was found. A colonoscopy study and histopathologic examination revealed the presence of adenocarcinoma of the colon.

Altered expression of cytokines and sex steroid receptors in the reproductive tract of cysticercotic male mice.

Infection with Taenia crassiceps cysticerci in male mice produces an increase in serum oestradiol levels, whereas serum testosterone is abolished. Concomitantly, complete atrophy of the reproductive tract of infected male mice is observed. The present study was undertaken to determine the expression pattern of cytokines involved in steroidogenesis and sex steroid receptors in the reproductive tissues of normal and infected male mice, and relating this expression pattern to whole parasite counts, serum sex steroid levels and pathology of the reproductive tract in infected male mice. The expression of IL-4, IFN-gamma and TNF-alpha in testes and seminal vesicles was markedly increased in infected mice; however, IL-10 and IL-1beta expression was importantly decreased in the same organs. IL-2 expression in reproductive tissues was not affected by infection. The infection markedly induced the expression of androgen receptor, in both reproductive organs tested, while subtypes of oestrogen receptors were decreased in both tissues.

The FTO gene is associated with adulthood obesity in the Mexican population.

Common polymorphisms in the fat mass and obesity-associated gene (FTO) have shown strong association with obesity in several populations. In the present study, we explored the association of FTO gene polymorphisms with obesity and other biochemical parameters in the Mexican population. We also assessed FTO gene expression levels in adipose tissue of obese and nonobese individuals. The study comprised 788 unrelated Mexican-Mestizo individuals and 31 subcutaneous fat tissue biopsies from lean and obese women. FTO single-nucleotide polymorphisms (SNPs) rs9939609, rs1421085, and rs17817449 were associated with obesity, particularly with class III obesity, under both additive and dominant models (P = 0.0000004 and 0.000008, respectively). These associations remained significant after adjusting for admixture (P = 0.000003 and 0.00009, respectively). Moreover, risk alleles showed a nominal association with lower insulin levels and homeostasis model assessment of B-cell function (HOMA-B), and with higher homeostasis model assessment of insulin sensitivity (HOMA-S) only in nonobese individuals (P (dom) = 0.031, 0.023, and 0.049, respectively). FTO mRNA levels were significantly higher in subcutaneous fat tissue of class III obese individuals than in lean individuals (P = 0.043). Risk alleles were significantly associated with higher FTO expression in the class III obesity group (P = 0.047). In conclusion, FTO is a major risk factor for obesity (particularly class III) in the Mexican-Mestizo population, and is upregulated in subcutaneous fat tissue of obese individuals.

Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population.

OBJECTIVE: The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic beta-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS: The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20-69 years (121 with onset 50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS: R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis

Differential expression of AP-1 transcription factor genes c-fos and c-jun in the helminth parasites Taenia crassiceps and Taenia solium.

Homologues of c-fos and c-jun from total DNA of Taenia crassiceps and Taenia solium were cloned and sequenced. The amino acid alignment analysis revealed that c-fos DNAs from T. crassiceps and T. solium were highly homologous (96%), and both have high homology compared to several mammalian c-fos proteins (93% to mouse, 96% to rat and 86% to human). The c-jun protein alignment showed higher homology (T. crassiceps and T. solium have 98%), when compared with mouse, rat and human, being 92%, 98% and 93% respectively. RT-PCR amplification of the parasite's total RNA, showed that T. crassiceps expressed both AP-1 complex genes, while T. solium only expressed c-fos. Southern blot hybridization analysis confirmed the true origin of each amplified gene. AP-1 transcription gene expression is regulated by oestradiol in the same fashion as their mammalian counterparts only in T. crassiceps. To study if AP-1 genes are involved in a physiological function of the cyst, reproduction was studied in vitro. Oestradiol treatment stimulated reproduction in T. crassiceps but not in T. solium cysticerci. This is the first report of the detection and functionality of AP-1 transcription factor genes in any species of helminth parasite.

Remote sensing of intraperitoneal parasitism by the host's brain: regional changes of c-fos gene expression in the brain of feminized cysticercotic male mice.

Experimental intraperitoneal Taenia crassiceps cysticercosis in mice exhibits distinct genetical, immunological and endocrinological features possibly resulting from the complex interactive network of their physiological systems. Very notable is the tendency of parasites to grow faster in hosts of the female sex. It is also remarkable in the feminization process that the infection induces in chronically infected male mice, characterized by their estrogenization, deandrogenization and loss of sexual and aggressive patterns of behaviour. The proto-oncogene c-fos is a sex steroid-regulated transcription factor gene, expressed basally and upon stimulation by many organisms. In the CNS of rodents, c-fos is found expressed in association to sexual stimulation and to various immunological and stressful events. Hence, we suspected that changes in c-fos expression in the brain could be involved in the feminization of the infected male mice. Indeed, it was found that c-fos expression increased at different times during infection in the hypothalamus, hippocampus, less so in the preoptic area and cortex, and not in several other organs. The significant and distinctive regional changes of c-fos in the CNS of infected mice indicate that the brain of the host senses intraperitoneal cysticercosis and may also announce its active participation in the regulation of the host-parasite relationship. Possibly, the host's CNS activity is involved in the network that regulates the estrogenization and deandrogenization observed in the chronically infected male mice, as well as in the behavioural and immunological peculiarities observed in this parasitic infection.

Evidence that steroid 5alpha-reductase isozyme genes are differentially methylated in human lymphocytes.

The synthesis of dihydrotestosterone (DHT) is catalyzed by steroid 5alpha-reductase isozymes 1 and 2, and this function determines the development of the male phenotype during embriogenesis and the growth of androgen sensitive tissues during puberty. The aim of this study was to determine the cytosine methylation status of 5alpha-reductase isozymes types 1 and 2 genes in normal and in 5alpha-reductase deficient men. Genomic DNA was obtained from lymphocytes of both normal subjects and patients with primary 5alpha-reductase deficiency due to point mutations in 5alpha-reductase 2 gene. Southern blot analysis of 5alpha-reductase types 1 and 2 genes from DNA samples digested with HpaII presented a different cytosine methylation pattern compared to that observed with its isoschizomer MspI, indicating that both genes are methylated in CCGG sequences. The analysis of 5alpha-reductase 1 gene from DNA samples digested with Sau3AI and its isoschizomer MboI which recognize methylation in GATC sequences showed an identical methylation pattern. In contrast, 5alpha-reductase 2 gene digested with Sau3AI presented a different methylation pattern to that of the samples digested with MboI, indicating that steroid 5alpha-reductase 2 gene possess methylated cytosines in GATC sequences. Analysis of exon 4 of 5alpha-reductase 2 gene after metabisulfite PCR showed that normal and deficient subjects present a different methylation pattern, being more methylated in patients with 5alpha-reductase 2 mutated gene. The overall results suggest that 5alpha-reductase genes 1 and 2 are differentially methylated in lymphocytes from normal and 5alpha-reductase deficient patients. Moreover, the extensive cytosine methylation pattern observed in exon 4 of 5alpha-reductase 2 gene in deficient patients, points out to an increased rate of mutations in this gene.

Cyclic adenosine 3',5'-monophosphate increases pancreatic glucokinase activity and gene expression.

Comparison of the pancreatic and hepatic glucokinase gene transcripts reveals tissue-specific control of expression and the existence of two distinct promoters in a single glucokinase gene. The existence of alternate promoters suggests that separate factors regulate glucokinase transcription in the two tissues. Hepatic glucokinase expression has been shown to be repressed by cAMP; however, in the pancreatic beta-cell it is unlikely that cAMP represses glucokinase activity, as cAMP is known to positively affect glucose-induced insulin secretion, a process that in mature islets requires pancreatic glucokinase activity. In this work we demonstrate that cAMP indeed has a stimulatory effect on pancreatic glucokinase. The cyclic nucleotide stimulates pancreatic glucokinase activity after 3-h incubation, and maximal effects are observed after 6 and 12 h of treatment. Using the bDNA assay, a sensitive signal amplification technique, we detected relative increases in glucokinase messenger RNA levels of 40.5 +/- 7.5% after 3-h incubation with cAMP. This stimulatory effect was increased to 106.3 +/- 22% after 6-h incubation and sustained up to 12 h of incubation. Inhibition of gene transcription by actinomycin D abolishes cAMP-induced glucokinase activity. In transfected fetal islets, cAMP increased the activity of the -1000 bp rat glucokinase promoter by 60 +/- 6%. These data demonstrate that cAMP has a stimulatory effect on pancreatic glucokinase gene expression and that the nucleotide has opposite effects on pancreatic and hepatic glucokinase, supporting the concept that glucokinase transcription in the liver and that in the beta-cell differ.

Tissue damage in the male murine reproductive system during experimental Taenia crassiceps cysticercosis.

Chronic infection with Taenia crassiceps cysticerci in male mice increases the level of estradiol in serum, whereas it reduces that of testosterone. In addition, male mice lose their typical male reproductive behavior. The effects of cysticerci infection on the histomorphology of male reproductive tissues are unknown. The present study was undertaken to determine the histological changes in testes, seminal vesicles, and prostate of male mice infected with T. crassiceps cysticerci. At 16 wk of infection, all tissues exhibited high inflammatory infiltrate. Tissue lesions included marked dilation and peripheral fibrosis. In the testes, a diminution of spermiogenesis was observed. The overall results indicated that the histological changes in chronically parasitized male mice occurred with changes in hormone levels, simultaneously with the high inflammatory immune response.

Modified expression of steroid 5 alpha-reductase as well as aromatase, but not cholesterol side-chain cleavage enzyme, in the reproductive system of male mice during (Taenia crassiceps) cysticercosis.

Infection with Taenia crassiceps cysticerci in male mice produces an increase in serum estradiol levels, whereas serum testosterone is abolished. Concomitantly, complete atrophy of the reproductive tract of infected male mice is observed. The present study was under-taken to determine the expression pattern of three key steroidogenic enzymes in the reproductive tissues of normal and infected male mice. In infected mice, serum estradiol levels were increased 97 times as compared with control mice of the same age. Testosterone and dihydrotestosterone levels were completely inhibited. The expression of 5 alpha-reductase in the reproductive tract was markedly reduced, whereas aromatase mRNA levels were highly elevated in the testes of parasitized mice. No change in the mRNA content for cholesterol side-chain cleavage enzyme was evident. The overall results suggest that the change in the normal production of sex steroids in infected male mice is produced concomitantly by the inhibition of expression of the 5 alpha-reductase enzyme and the activation of aromatase gene expression. This induces a preferential metabolism from testosterone toestradiol instead of the normal metabolism from testosterone to dihydrotestosterone.

Differential expression of the estrogen-regulated proto-oncogenes c-fos, c-jun, and bcl-2 and of the tumor-suppressor p53 gene in the male mouse chronically infected with Taenia crassiceps cysticerci.

Chronic infection with Taenia crassiceps cysticerci produces a 200-fold increase in serum estradiol levels in male mice. The aim of this study was to investigate the expression pattern of c-fos and c-jun, two estradiol-regulated genes, as well as that of p53 and bcl2 in the testes, spleen, and thymus of male mice infected with T. crassiceps cysticerci. In parasitized animals the c-fos mRNA content was significantly increased in all tissues studied, whereas the c-jun mRNA content was increased only in the thymus. The p53 mRNA content was markedly reduced in all tissues of the parasitized animals analyzed, whereas bcl-2 gene expression was abolished in the thymus. On the other hand, thymic cell analysis performed by flow cytometry showed a diminution in the content of CD3+, CD4+, and CD8+ subpopulations in the parasitized mice. Our results suggest that the increase in estradiol levels of the host should change the expression pattern of several genes that participate in apoptosis regulation in the thymus of male mice during chronic infection with T. crassiceps cysticerci.

[The use of endocavitary fulguration in the treatment of common auricular flutter]. / Uso de la fulguración endocavitaria en el tratamiento del flutter auricular común.

Between April 1990 and July 1991, 10 patients, were fulgurated after right atrial endocardial mapping with the purpose of destroying or modifying the site of origin of atrial flutter. Mean age, 47 years old (23-61), 9 males. All patients suffered "common" atrial flutter episodes with very rapid ventricular response (greater than or equal to 150 beats per minute) refractory to pharmacological therapy. All patients had pathologic potentials with prolonged duration between 90 and 160 ms (m = 109) which preceded other reference electrodes in the high right atrium and His position. Electrical stimulation from that zone provoked the capture entrainment and termination of the flutter; the same configuration of the arrhythmia was obtained with electrical stimulation from the suspected zone. With the catheter in that situation one or two direct current cathodic, unipolar shocks were given with energy of 60-150 Joules (m = 117). In the follow up (16-73 weeks), 8 patients are free of symptoms without drugs, one suffered a new episode after 7 weeks, His fulguration was performed and a permanent pacemaker implanted. The other patient has failed two session and is still on treatment.

[The treatment of intranodal tachycardias with intracavitary fulguration]. / Tratamiento de las taquicardias intranodales con fulguración intracavitaria.

The electrical ablation of the His bundle with proximal intracardiac shocks of low energy was performed through an electrical catheter, to 14 patients with AV nodal reentry tachycardias refractory to pharmacological therapy, to whom at least 3 antiarrhythmic drugs were previously administered. The electrical energy applied oscillated between 10 to 150 Joules (114 average). 11 patients (72%) recovered the normal atrioventricular conduction and in the electrophysiological evaluation was found: 1--Increase in the duration of the AH interval. 2--No existence of two AV nodal pathways. 3--Absence of retrograde conduction. 4--Impossibility to induce tachycardia. The PR interval was prolonged (60 ms average) after the electrical shocks. These criteria defined the total effectiveness of the procedure. In the 3 remaining patients (28%) a permanent atrioventricular complete block was induced and the implantation of the permanent pacemaker was required. It was concluded that the electrical fulguration of the atrioventricular junction with low energy is an effective technique as curative treatment for intranodal reentry tachycardias, which can be applied without induction of permanent cardiac block.

Adipsic, but not anorectic, effect of fluprazine hydrochloride in rats.

The present experiment explored the anorectic and adipsic effects of fluprazine hydrochloride, a phenylpiperazine compound. Thirty-eight albino rats were randomly assigned either to a control saline group (six rats) or to groups (eight subjects each) receiving an IP dose of fluprazine in saline (1.25, 2.5, 5 or 10 mg/kg). No anorectic effect of the drug doses was observed 30, 60, 90, 120, 180 and 240 min, and 24 h after drug injection. However, water drinking was significantly decreased 30 min after drug administration, with 5 and 10 mg/kg, compared to saline.

[Experience with the use of an implantable automatic cardioverter defibrillator]. / Experiencia en el uso del desfibrilador cardioverter automático implantable.

An automatic implantable cardioverter-defibrillator with pacemaker was implanted in Cuba, in ten patients with malignant ventricular arrhythmias, sudden cardiac collapse, and ventricular tachycardia with syncope, after a previous electrophysiological study for analysis of the arrhythmia and pharmacological evaluation. The patients were 9 males, ranging in age from 23 a 70 years, with a mean of 48 years, and an ejection fraction of 32% (18-62%). The etiologies were: an old myocardial infarction (7 cases) and dilated cardiomyopathy (3 cases). During the follow-up, mean from 2 to 25 months, four patients received effective shocks for rapid palpitations and presyncope. Two patients died, one due to incessant ventricular tachycardia and one of a cause unrelated to device. We concluded that the GUARDIAN 4201 and 4202 device are useful to prevent sudden cardiac death in high risk patients who experienced a life threatening arrhythmia.