Response properties of the brainstem neurons of the cat following intra-esophageal acid-pepsin infusion

Studies in humans have documented that acute acid infusion into the esophagus leads to decrease in threshold for sensations to mechanical distension of the esophagus. It is not known whether acid infusion leads to sensitization of brainstem neurons receiving synaptic input from vagal afferent fibers innervating the esophagus. The aim of this study was to investigate the correlation of responses of vagal afferents and brainstem neurons after acute infusion of acid (0.1 N HCl)+pepsin (1 mg/ml) into the esophagus of cats. The vagal afferent fibers (n=20) exhibited pressure-dependent increase in firing to graded esophageal distension (5-80 mm Hg). Infusion of acid+pepsin into the esophagus produced a significant increase in ongoing resting firing of five of 16 fibers (31%) tested. However, their responses to graded esophageal distension did not change when tested 30 min after infusion. Pepsin infusion did not change the resting firing and response to esophageal distension (n=4). Twenty-one brainstem neurons were recorded that responded in an intensity-dependent manner to graded esophageal distension. Responses of 12 excited neurons were tested after intra-esophageal acid+pepsin infusion. Neurons exhibited a decrease in threshold for response to esophageal distension and increase in firing after acid+pepsin infusion. The sensitization of response after intra-esophageal acid remained unaffected after cervical (C1-C2) spinal transection (n=3). Results indicate that the esophageal distension-sensitive neurons in the brainstem exhibit sensitization of response to esophageal distension after acute acid+pepsin exposure. The sensitization of brainstem neurons is possibly initiated by increased spontaneous firing of the vagal afferent fibers to acid+pepsin, but not to sensitized response of vagal distension-sensitive afferent fibers to esophageal distension. Results also indicate that spinal pathway does not contribute to sensitization of brainstem neurons.     

Identification and characterization of aquaporin-2 water channel mutations causing nephrogenic diabetes insipidus with partial vasopressin response

Congenital nephrogenic diabetes insipidus (NDI) is a rare disease caused most often by mutations in the vasopressin V2 receptor (AVPR2). We studied a family which included a female patient with NDI with symptoms dating from infancy. The patient responded to large doses of desmopressin (dDAVP) which decreased urine volume from 10 to 4 I/day. Neither the parents nor the three sisters were polyuric. The patient was found to be a compound heterozygote for two novel recessive point mutations in the aquaporin-2 (AQP2) gene: L22V in exon 1 and C181W in exon 3. Residue Cys181 in AQP2 is the site for inhibition of water permeation by mercurial compounds and is located near to the NPA motif conserved in all aquaporins. Osmotic water permeability (Pf) in Xenopus oocytes injected with cRNA encoding C181W-AQP2 was not increased over water control, while expression of L22V cRNA increased the Pf to approximately 60% of that for wild-type AQP2. Co-injection of the mutant cRNAs with the wild-type cRNA did not affect the function of the wild-type AQP2. Immunolocalization of AQP2-transfected CHO cells showed that the C181W mutant had an endoplasmic reticulum-like intracellular distribution, whereas L22V and wild-type AQP2 showed endosome and plasma membrane staining. Water permeability assays showed a high Pf in cells expressing wild-type and L22V AQP2. This study indicates that AQP2 mutations can confer partially responsive NDI.      

Family planning in Italy

In the past 5 years, four knowledge, attitude and practice (KAP) surveys on family planning have been organized by the Unit of Population Survey Methodology of the Istituto Superiore di Sanita' (National Institute of Health). These surveys show that during the past 20 years, use of reliable contraceptives in Italy has increased, particularly in the North, encouraged by the more open attitude toward sexual behavior, following legalization of the provision of information on contraception and abortion upon request, and other social and cultural changes.In 1989 and 1991, 25% of women in Central and Southern Italy were using the pill or an IUD. However, the percentage of women not using contraceptives was still high (26% in 1989, and 19% in 1991) and withdrawal was the most widley used method (31% and 33%). The data show large regional differences.The main reasons for not using contraception, in the 1989 study, were fear of side-effects and ignorance, especially in the youngest and oldest women. Those least likely to use modern contraception were the young, the ill-educated and the nulliparous women.Lack of information seems to be the main problem in Italy. In fact, the 5044 women interviewed showed a medium level of knowledge of contraception, with only 63% who could identify correctly the fecund period in the menstrual cycle. However, their attitude toward the use of modern contraception was positive; 65% of the women interviewed said they would recommend the Pill or an IUD to a friend, and 10% of them would recommend condoms.Induced abortion is still common in Italy (13 reported abortions per 1000 women aged 15–44), although the incidence has steadily decreased since 1982. In the vast majority of cases, abortion was an emergency measure after the failure of contraceptive methods. It has been calculated that from 10% to 50% of induced abortions might be prevented in a short period through appropriate programs of health education and family planning involving the 2474 governmental maternal and child healt clinics in Italy.

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Resumen En los 5 últimos años, la Sección de Metodología de Encuestas Demográficas del Istituto Superiore di Sanità realizó cuatro estudios de conocimiento, actitud y práctica (KAP) respecto a la planificación familiar. Estos estudios indican que, en los 20 últimos años, el uso de anticonceptivos fiables en Italia ha aumentado, especialmente en el norte, fomentado por una actitud más abierta en cuanto a la conducta sexual, tras la legalización y otros cambios sociales y culturales.En 1989 y 1991, el 25% de las mujeres de la región central y meridional de Italia utilizaban la pídora o el DIU. Sin embargo, el porcentaje de mujeres que no utilizaban anticonceptivos continuaba siedo alto (26% en 1989 y 19% en 1991) y elcoitus interruptus era el método más utilizado (31% y 33%). Los datos indican grandes differencias regionales.Los motivos principales de la no utilización de anticonceptivos, en el estudio de 1989, eran el temor a los efectos secundarios y la ignorancia, especialmente entre las mujeres de menor y de mayor edad. Las que probablemente menos utilizaran anticonceptivos modernos eran las mujeres jóvenes, las de bajo nivel de educación y las nulíparas.La falta de información parece ser el problema principal en Italia. En realidad, las 5044 mujeres entrevistadas tenían un nivel medio de conocimiento y sólo el 63% pudo identificar correctamente el período de fecundidad del ciclo menstrual. Sin embargo, su actitud respecto al uso de anticonceptivos modernos era positiva; el 65% de las mujeres entrevistadas manifestaron que recomendarían la píldora o el DIU a una amiga y el 10% de ellas recomendarían preservativos.El aborto provocado continúa siendo común en Italia (13 abortos notificados por cada 1000 mujeres de 15–44 años de edad) si bien su incidencia ha disminuido constantemente desde 1982. En la gran mayoría de los casos, el aborto era una medida de emergencia después del fracaso de un método anticonceptivo. Se ha calculado que del 10 al 50% de los abortos provocados podría impedirse en un plazo breve mediante programas apropiados de educación sanitaria y planificación familiar con la participación de las 2474 clínicas maternoinfantiles estatales de Italia.

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Resumé Au cours de cinq dernières années, le service chargé de la méthodologie pour les enquêtes sur la population à l'Istituto Superiore di Sanità a organisé quatre enquêtes sur les connaissances, les attitudes et les pratiques en matière de planning familial. Ces enquêtes ont révélé qu'au cours de vingt dernières années en Italie, l'utilisation de contraceptifs fiables s'est répandue, notamment dans le nord du pays, encouragée par une attitude plus ouverte à l'égard du comportement sexuel à la suite de changements législatifs et autres dans le domaine social et culturel.En 1989 et 1991, 25% des femmes en Italie centrale et méridionale utilisaient la pilule ou un DIU. Le pourcentage de femmes ne faisant appel à aucune méthode de contraception était cependant encore élvé (26% en 1989 et 19% en 1991) et le retrait était la méthode la plus fréquemment adoptée (31% et 33%). Les données font apparaître d'importantes différences régionales. D'après l'étude de 1989, les raisons essentielles du non emploi des contraceptifs provenaient de la crainte d'éventuels effects secondaires et de l'ignorance, surtout chez les juenes et les femmes plus âgées. Les femmes les moins susceptibles de faire appel à la contraception moderne étaient les jeunes, les femmes peu éduquées et les nullipares.Le manque d'information semble être le problème principal en Italie. En fait, les 5044 femmes interrogées ont fait preuve de connaissances moyennes sur la contraception, 63% à peine étant capables d'identifier correctement la période de fécondité du cycle menstruel. Leur attitude à l'égard de la contraception moderne était cependant positive; 65% des femmes interrogées ont répondu qu'elles recommanderaient la pilule on un DIU à une amine, et 10% qu'elles recommanderaient le préservatif.Les avortements provoqués sont encore fréquents en Italie (13 avortements signalés pour 1000 femmes de 15 à 44 ans), mais leur incidence a progressivement diminué dequis 1982. Dans la grande majorité des cas, l'avortement est une mesure d'urgence après l'échec des méthodes de contraception. On a calculé que 10 à 50% des avortements provoqués pourraient être évités en peu de temps si l'on prévoyait des programmes appropriés d'éducation sanitaire et de planning familial dans les 2474 cliniques maternelles et infantiles qui existent en Italie.

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This paper is a revised version of one presented at the Workshop Acceptance and Effectiveness of Modern Contraception, organized by the International Health Foundation at the SAC Meeting, Barcelona, Spain, October 1992.     

Pilot study on compulsory vaccination coverage

The disappearance of diphtheria and poliomyelitis is the best evidence of the efficacy of the vaccination strategies adopted in Italy. The active offer of the prophylaxis, reinforced by law, has characterised the operational aspects of the strategy. The active surveillance system is the main tool to take under control the effectiveness of health services responsible for vaccination. This system could be more easily implemented if the health services will be given a specific software aiming to handle and evaluate vaccination registers. The present pilot study, performed in the regions Marche and Sardegna, is an example of active surveillance and it is based on the ARVA software produced by the Istituto Superiore di Sanità. The results show a good level of coverage (> 95%) within the second year of life. Unsatisfactory results were obtained on the timing of vaccinations, as recommended by the vaccination schedule, mostly for the third doses.     

Congenital forms of hypothyroidism: study of risk factors and preventive interventions

Maternal and child health represents one of the most relevant fields of interest in public health and particular attention is given to congenital pathologies. In Italy, the incidence of congenital hypothyroidism (CH) is 1:3200 live birth. CH is diagnosed at birth by neonatal thyroid screening. This allows a precocious onset of substitutive therapy which avoids severe psychomotor deficits in infants with CH. Moreover, the newborn screening program have permitted to identify transient disorders of thyroid function in newborns. These are essentially due to neonatal, maternal and environmental risk factors, especially iodine deficiency. The National Register (NR) of infants with CH was established in 1987. The aim of the NR is to provide disease surveillance and to monitor efficiency and effectiveness of neonatal screening. Furthermore, the NR represents an useful tool for developing epidemiological studies to identify possible environmental and/or familial risk factors of CH.     

Telomerase activity,telomere length and hTERT DNA methylation in peripheral blood mononuclear cells from monozygotic twins with discordant smoking habits

Increased telomerase expression has been implicated in the pathogenesis of lung cancer and, since the primary cause of lung cancer is smoking, an association between telomerase reactivation and tobacco smoke has been proposed. In this work an investigation has been performed to assess the relationship between tobacco smoke exposure and telomerase activity (TA) in peripheral blood mononuclear cells of healthy smokers. The methylation status of the catalytic subunit of telomerase hTERT was concurrently investigated to assess the possible association between epigenetic modifications of hTERT and TA. Besides, the association between smoke and telomere length (TL) has been evaluated. Healthy monozygotic twins with discordant smoking habits were selected as study population to minimize inter‐individual differences because of demographic characteristics and genetic heterogeneity. Statistically significant higher values of TA and TL were observed in smokers compared to nonsmoker co‐twins. The multivariate analysis of data showed, besides smoking habits (P = 0.02), an influence of gender (P = 0.006) and BMI (P = 0.001) on TA and a borderline effect of gender (P = 0.05) on TL. DNA methylation analysis, focused on 100 CpG sites mapping in hTERT, highlighted nine CpG sites differentially methylated in smokers. When co‐twins were contrasted, selecting as variables the intra‐twin difference in TA and hTERT DNA methylation, a statistically significant inverse correlation (P = 0.003) was observed between TA and DNA methylation at the cg05521538 site. In conclusion, these results indicate an association of tobacco smoke with TA and TL and suggest a possible association between smoke‐induced epigenetic effects and TA in healthy smokers. Environ. Mol. Mutagen. 58:551–559, 2017. © 2017 Wiley Periodicals, Inc.     

Familial autoimmunity as a risk factor for systemic lupus erythematosus and vice versa: a case-control study

The objective of this multicentric case-control study was to investigate if a history of autoimmune disease (AD) in first-degree relatives (FDR) is a risk factor for systemic lupus erythematosus (SLE) and to evaluate the risk of AD among FDR of SLE patients. Cases were Italian SLE patients consecutively enrolled. Controls were orthopaedic inpatients without any autoimmune diseases. The strength of the association between family history of AD and SLE was measured as an odds ratio (OR) calculated from the coefficient of an unconditional regression model. To calculate the risk of AD among FDR of SLE patients, the extended generalized estimating equation technique was used. In total, 154 SLE cases and 140 controls were enrolled. A family history of AD was reported by 22.7% of SLE patients and by 5.7% of the controls. The risk of SLE increased with the number of FDR with AD (one FDR affected, OR = 4.1; two or more, OR = 11.3). The probability of having AD was higher among FDR of SLE cases in comparison to FDR of controls (RR = 4.6; 95%CI 1.9-11.1). A female SLE patient conferred an increased risk of AD to her FDR; this risk is doubled in females (OR 10.3; 95% CI 3.1-34.4).     

ATG16L1 and NOD2 polymorphisms enhance phagocytosis in monocytes of Crohn’s disease patients

AIM:To investigate if the presence of relevant genetic polymorphisms has effect on the effectual clearance of bacteria by monocytes and granulocytes in patients with Crohn’s disease(CD).METHODS:In this study,we assessed the differential responses in phagocytosis by measuring the phagocytic activity and the percentage of active phagocytic monocytes and granulocytes in inflammatory bowel disease patients as well as healthy controls.As both autophagy related like 1(ATG16L1)and immunityrelated guanosine triphosphatase gene are autophagy genes associated with CD and more recently nucleo-tide-binding ligomerization domain-containing protein2(NOD2)has been identified as a potent inducer of autophagy we genotyped the patients for these variants and correlated this to the phagocytic reaction.The genotyping was done with restriction fragment length polymorphisms analysis and the phagocytosis was determined with the pHrodo?Escherichia coli Bioparticles Phagocytosis kit for flowcytometry.RESULTS:In this study,we demonstrate that analysis of the monocyte and granulocyte populations of patients with CD and ulcerative colitis showed a comparable phagocytic activity(ratio of mean fluorescence intensity)between the patient groups and the healthy controls.CD patients show a significantly higher phagocytic capacity(ratio mean percentage of phagocytic cells)compared to healthy controls(51.91%±2.85%vs 37.67%±7.06%,P=0.05).The extend of disease was not of influence.However,variants of ATG16L1(WT:2.03±0.19 vs homozygoot variant:4.38±0.37,P<0.009)as well as NOD2(C-ins)(heterozygous variant:42.08±2.94 vs homozygous variant:75.58±4.34(P=0.05)are associated with the phagocytic activity in patients with CD.CONCLUSION:Monocytes of CD patients show enhanced phagocytosis associated with the presence of ATG16L1 and NOD2 variants.This could be part of the pathophysiological mechanism resulting in the disease.