Human GnRH deficiency: a unique disease model to unravel the ontogeny of GnRH neurons.

Evolutionary survival of a species is largely a function of its reproductive fitness. In mammals, a sparsely populated and widely dispersed network of hypothalamic neurons, the gonadotropin-releasing hormone (GnRH) neurons, serve as the pilot light of reproduction via coordinated secretion of GnRH. Since it first description, human GnRH deficiency has been recognized both clinically and genetically as a heterogeneous disease. A spectrum of different reproductive phenotypes comprised of congenital GnRH deficiency with anosmia (Kallmann syndrome), congenital GnRH deficiency with normal olfaction (normosmic idiopathic hypogonadotropic hypogonadism), and adult-onset hypogonadotropic hypogonadism has been described. In the last two decades, several genes and pathways which govern GnRH ontogeny have been discovered by studying humans with GnRH deficiency. More importantly, detailed study of these patients has highlighted the emerging theme of oligogenicity and genotypic synergism, and also expanded the phenotypic diversity with the documentation of reversal of GnRH deficiency later in adulthood in some patients. The underlying genetic defect has also helped understand the associated nonreproductive phenotypes seen in some of these patients. These insights now provide practicing clinicians with targeted genetic diagnostic strategies and also impact on clinical management.

The epidemiological significance of Chagas' disease in womem

Little is known about the risks associated with Trypanosoma cruzi infection in non-pregnant and pregnant women. From a limited number of studies it appears that in rural areas, parasite rates and rates of serological positivity are similar in both sexes. Abnormal ECG tracings are consistently more frequent in men suggesting that immunity to T. cruzi may be different in females. Complications arising from Chagas' disease in pregnancy are only infrequently reported. Evidence for increased risk of abortion or prematurity is inconclusive except in cases of congenital infection. Most cases of congenital Chagas' disease have been reported from non-endemic areas and there is a suggestion that parasitemic episodes during pregnancy may influence pregnancy outcome. Preliminary evidence indicates that chronic infection can result in in-utero sensitization via passively acquired maternal antibodies. The review concludes that maternal T. cruzi infection carries risks for the child and these warrant systematic research because of their public health significance.

Congenital giant aneurysm of the left coronary artery.

We report an unusual case of congenital giant coronary aneurysm. A 23 year-old male with a history of acute myocardial infarction presented an abnormal shadow in the left cardiac border on routine X-ray. Electrocardiogram and physical examination were normal without any clinical signs of inflammation, but computed tomography (CT) scan and cardiac magnetic resonance imaging (MRI) revealed a giant (>50mm) coronary aneurysm. Coronary artery bypass grafting (CABG) with coronary artery aneurysm (CAA) resection resolved the CAA. Coronary artery aneurysms are entities of localised dilation and can be common events in chronic infectious disease as a result of the systemic inflammatory state; however, giant coronary aneurysms (measuring more than 50mm) are rare. This is especially true where the pathological aetiology was not clearly defined or was believed to be of congenital origin. To date only a few published case reports exist for this type of pathological entity.

IRM cardiaque dans le suivi des cardiopathies congénitales à l'âge adulte [Cardiac MRI in the follow-up of adult congenital cardiomyopathy patients].

Magnetic resonance imaging is a rapidly developing modality in cardiology. It offers an excellent image definition and a large field of view, allowing a more accurate morphological assessment of cardiac malformations. Due to its unique versatility and its ability to provide myocardial tissue characterization, cardiac magnetic resonance (CMR) is now recognized as a central imaging modality for a wide range of congenital heart diseases, including assessment of post-surgical cardiac anatomy, quantification of valvular disease and detection of myocardial ischemia. CMR provides useful diagnostic information without any radiation exposure, and improves the global management of patients with congenital heart disease.

Myocarditis and coronary dilatation in the 1st week of life: neonatal incomplete Kawasaki disease?

Acute heart failure in the early neonatal period is rare. Normally it is due to asphyxia, severe septicaemia, a congenital heart malformation or a viral myocarditis. Kawasaki disease (KD) as a cause of an neonatal myocarditis is not an established diagnosis. KD is a vasculitis of still unknown origin occurring predominantly in infants and preschool children. KD before the age of 3 months is rare. There are only few reports about KD in the 1st month. We present a newborn who showed the cardiac symptoms of KD in the 1st week of life with coronary dilatation and myocarditis. CONCLUSION: The diagnosis of incomplete KD should be considered not only in infants but also in newborns with signs of myocarditis and coronary abnormalities. Therapy with gammaglobulins may prevent the sequelae of coronary involvement.

Experimental toxoplasmosis in Balb/c mice. Prevention of vertical disease transmission by treatment and reproductive failure in chronic infection

In a study of congenital transmission during acute infection of Toxoplasma gondii, 23 pregnant Balb/c mice were inoculated orally with two cysts each of the P strain. Eight mice were inoculated 6-11 days after becoming pregnant (Group 1). Eight mice inoculated on the 10th-15th day of pregnancy (Group 2) were treated with 100 mg/kg/day of minocycline 48 h after inoculation. Seven mice inoculated on the 10th-15th day of pregnancy were not treated and served as a control (Group 3). Congenital transmission was evaluated through direct examination of the brains of the pups or by bioassay and serologic tests. Congenital transmission was observed in 20 (60.6%) of the 33 pups of Group 1, in one (3.6%) of the 28 pups of Group 2, and in 13 (54.2%) of the 24 pups of Group 3. Forty-nine Balb/c mice were examined in the study of congenital transmission of T. gondii during chronic infection. The females showed reproductive problems during this phase of infection. It was observed accentuated hypertrophy of the endometrium and myometrium. Only two of the females gave birth. Our results demonstrate that Balb/c mice with acute toxoplasmosis can be used as a model for studies of congenital T. gondii infection. Our observations indicate the potential of this model for testing new chemotherapeutic agents against congenital toxoplasmosis.

The C57BL/6J Mouse Exhibits Sporadic Congenital Portosystemic Shunts.

C57BL/6 mice are the most widely used strain of laboratory mice. Using in vivo proton Magnetic Resonance Spectroscopy ((1)H MRS), we have repeatedly observed an abnormal neurochemical profile in the brains of both wild-type and genetically modified mice derived from the C57BL/6J strain, consisting of a several fold increase in cerebral glutamine and two fold decrease in myo-inositol. This strikingly abnormal neurochemical "phenotype" resembles that observed in chronic liver disease or portosystemic shunting and appeared to be independent of transgene, origin or chow and was not associated with liver failure. As many as 25% of animals displayed the abnormal neurochemical profile, questioning the reliability of this model for neurobiology. We conducted an independent study to determine if this neurochemical profile was associated with portosystemic shunting. Our results showed that 100% of the mice with high brain glutamine displayed portosystemic shunting by concomitant portal angiography while all mice with normal brain glutamine did not. Since portosystemic shunting is known to cause alterations in gene expression in many organs including the brain, we conclude that portosystemic shunting may be the most significant problem associated with C57BL/6J inbreeding both for its effect on the central nervous system and for its systemic repercussions.

Infectious disease among enslaved African Americans at Eaton's Estate, Warren County, North Carolina, ca. 1830-1850

The skeletal remains of 17 people buried in the Eaton Ferry Cemetery in northern North Carolina provide a means of examining health and infectious disease experience in the XIX century South. The cemetery appears to contain the remains of African Americans enslaved on the Eaton family estate from approximately 1830-1850, and thus offers a window into the biological impacts of North American slavery in the years preceding the Civil War. The sample includes the remains of six infants, one child, and one young and nine mature adults (five men, four women, and one unknown). Skeletal indices used to characterize health and disease in the Eaton Ferry sample include dental caries, antemortem tooth loss, enamel hypoplasia, porotic hyperostosis, periosteal lesions, lytic lesions, and stature. These indicators reveal a cumulative picture of compromised health, including high rates of dental disease, childhood growth disruption, and infectious disease. Specific diseases identified in the sample include tuberculosis and congenital syphilis. Findings support previous research on the health impacts of slavery, which has shown that infants and children were the most negatively impacted segment of the enslaved African American population.

The girl from the Church of the Sacrament: a case of congenital syphilis in XVIII century Lisbon

Syphilis is a sexually or congenitally transmitted infectious disease with an impact on the health of human populations that has undergone important cycles in different countries and periods of history. Its presence was first diagnosed in Europe in the late XIV century. In Portugal, although there are various written records of the infection in the last centuries, there are rare references to it in archeological findings (mummified bodies are also rare in Portugal). The current study describes a probable case of congenital syphilis in an 18-month-old girl buried in the Church of the Sacrament in Lisbon. Her body, dating to the XVIII century, was found mummified together with dozens of others, still not studied. Symmetrical periostitis of the long bones, osteitis, metaphyseal lesions, left knee articular, and epiphyseal destruction, and a rarefied lesion with a radiological appearance compatible with Wimberger's sign all point to a diagnosis of congenital syphilis. The diagnosis of this severe form of the infection, possibly related to the cause of death in this upper-class girl, calls attention to the disease's presence in XVIII century Lisbon and is consistent with the intense mobilization at the time in relation to the risks posed by so-called heredosyphilis. It is the first case of congenital syphilis in a child reported in archeological findings in Portugal, and can be correlated with other cases in skeletons of adults buried in cemeteries in Lisbon (in the XVI to XVIII centuries) and Coimbra (XIX century). Finally, this finding highlights the need to study the entire series of mummified bodies in the Church of the Sacrament in order to compare the paleopathological findings and existing historical documents on syphilis, so as to expand the paleoepidemiological knowledge of this infection in XVIII century Lisbon.

Chagas disease in Andean countries

The Andean Countries' Initiative (ACI) for controlling Chagas disease was officially created in 1997 within the framework of the Hipolito Unanue Agreement (UNANUE) between the Ministries of Health of Colombia, Ecuador, Peru, and Venezuela. Its objective was to interrupt transmission via vector and transfusion in the region, taking into account that there are 12.5 million people at risk in the four Andean countries forming the initiative in the area and around 3 million people are infected by Trypanosoma cruzi. The progress of control activities for the vector species present in the Andean sub-region, for different reasons, has been slow and control interventions have still not been installed in all geographical areas occupied by the target species. This has been partly due to lack of knowledge about these vector populations' biological characteristics, and consequent uncertainty about which are the appropriate control measures and strategies to be implemented in the region. The main vector species present important similarities in Venezuela and Colombia and in Ecuador and Northern Peru and they can be approached in a similar way throughout the whole regions, basing approaches on and adapting them to the current strategies being developed in Venezuela during the 1960s which have been progressively adopted in the Southern Cone and Central-American region. Additional measures are needed for keeping endemic areas free from Rhodnius prolixus silvatic populations, widely spread in the Orinoco region in Colombia and Venezuela. Regarding aetiological treatment, it is worth mentioning that (with the exception of Colombia) none of the other countries forming the ACI have registered medicaments available for treating infected young people. There are no suitable follow-up programmes in the sub-region or for treating cases of congenital Chagas disease. An integral and integrated programme encompassing all the aspects including transmission by transfusion which seems to have achieved extremely encouraging results in all countries, are urgently needed.

Epidemiology of Chagas disease in non endemic countries: the role of international migration

Human infection with the protozoa Trypanosoma cruzi extends through North, Central, and South America, affecting 21 countries. Most human infections in the Western Hemisphere occur through contact with infected bloodsucking insects of the triatomine species. As T. cruzi can be detected in the blood of untreated infected individuals, decades after infection took place; the infection can be also transmitted through blood transfusion and organ transplant, which is considered the second most common mode of transmission for T. cruzi. The third mode of transmission is congenital infection. Economic hardship, political problems, or both, have spurred migration from Chagas endemic countries to developed countries. The main destination of this immigration is Australia, Canada, Spain, and the United States. In fact, human infection through blood or organ transplantation, as well as confirmed or potential cases of congenital infections has been described in Spain and in the United States. Estimates reported here indicates that in Australia in 2005-2006, 1067 of the 65,255 Latin American immigrants (16 per 1000) may be infected with T. cruzi, and in Canada, in 2001, 1218 of the 131,135 immigrants (9 per 1000) whose country of origin was identified may have been also infected. In Spain, a magnet for Latin American immigrants since the 2000, 5125 of 241,866 legal immigrants in 2003 (25 per 1000), could be infected. In the United States, 56,028 to 357,205 of the 7,20 million, legal immigrants (8 to 50 per 1000), depending on the scenario, from the period 1981-2005 may be infected with T. cruzi. On the other hand, 33,193 to 336,097 of the estimated 5,6 million undocumented immigrants in 2000 (6 to 59 per 1000) could be infected. Non endemic countries receiving immigrants from the endemic ones should develop policies to protect organ recipients from T. cruzi infection, prevent tainting the blood supply with T. cruzi, and implement secondary prevention of congenital Chagas disease.

Sox10 promotes the formation and maintenance of giant congenital naevi and melanoma.

Giant congenital naevi are pigmented childhood lesions that frequently lead to melanoma, the most aggressive skin cancer. The mechanisms underlying this malignancy are largely unknown, and there are no effective therapies. Here we describe a mouse model for giant congenital naevi and show that naevi and melanoma prominently express Sox10, a transcription factor crucial for the formation of melanocytes from the neural crest. Strikingly, Sox10 haploinsufficiency counteracts Nras(Q61K)-driven congenital naevus and melanoma formation without affecting the physiological functions of neural crest derivatives in the skin. Moreover, Sox10 is also crucial for the maintenance of neoplastic cells in vivo. In human patients, virtually all congenital naevi and melanomas are SOX10 positive. Furthermore, SOX10 silencing in human melanoma cells suppresses neural crest stem cell properties, counteracts proliferation and cell survival, and completely abolishes in vivo tumour formation. Thus, SOX10 represents a promising target for the treatment of congenital naevi and melanoma in human patients.

Congenital toxoplasmosis and DALYs in the Netherlands

The calculation of disability-adjusted life years (DALYs) enables public health policy makers to compare the burden of disease of a specific disease with that of other (infectious) diseases. The incidence of a disease is important for the calculation of DALYs. To estimate the incidence of congenital toxoplasmosis (CT), a random sample of 10,008 dried blood spot filter paper cards from babies born in 2006 in the Netherlands were tested for Toxoplasma gondii-specific IgM antibodies. Eighteen samples were confirmed as positive for IgM, resulting in an observed birth incidence of CT of 1.8 cases per 1,000 live-born children in 2006 and an adjusted incidence of 2.0 cases per 1,000. This means that 388 infected children were born in 2006. The most likely burden of disease is estimated to be 2,300 DALYs (range 820-6,710 DALYs). In the previous calculations, using data from a regional study from 1987, this estimate was 620 DALYs (range 220-1,900 DALYs). The incidence of CT in the Netherlands is much higher than previously reported; it is 10 times higher than in Denmark and 20 times higher than in Ireland, based on estimates obtained using the same methods. There is no screening program in the Netherlands; most children will be born asymptomatic and therefore will not be detected or treated.

Novel MLPA procedure using self-designed probes allows comprehensive analysis for CNVs of the genes involved in Hirschsprung disease.

Background: Hirschsprung disease is characterized by the absence of intramural ganglion cells in the enteric plexuses, due to a fail during enteric nervous system formation. Hirschsprung has a complex genetic aetiology and mutations in several genes have been related to the disease. There is a clear predominance of missense/nonsense mutations in these genes whereas copy number variations (CNVs) have been seldom described, probably due to the limitations of conventional techniques usually employed for mutational analysis. In this study, we have looked for CNVs in some of the genes related to Hirschsprung (EDNRB, GFRA1, NRTN and PHOX2B) using the Multiple Ligation-dependent Probe Amplification (MLPA) approach. Methods: CNVs screening was performed in 208 HSCR patients using a self-designed set of MLPA probes, covering the coding region of those genes. Results: A deletion comprising the first 4 exons in GFRA1 gene was detected in 2 sporadic HSCR patients and in silico approaches have shown that the critical translation initiation signal in the mutant gene was abolished. In this study, we have been able to validate the reliability of this technique for CNVs screening in HSCR. Conclusions: The implemented MLPA based technique presented here allows CNV analysis of genes involved in HSCR that have not been not previously evaluated. Our results indicate that CNVs could be implicated in the pathogenesis of HSCR, although they seem to be an uncommon molecular cause of HSCR.

Elimination of Chagas disease transmission: perspectives

One hundred years after its discovery by Carlos Chagas, American trypanosomiasis, or Chagas disease, remains an epidemiologic challenge. Neither a vaccine nor an ideal specific treatment is available for most chronic cases. Therefore, the current strategy for countering Chagas disease consists of preventive actions against the vector and transfusion-transmitted disease. Here, the present challenges, including congenital and oral transmission of Trypanosoma cruzi infections, as well as the future potential for Chagas disease elimination are discussed in light of the current epidemiological picture. Finally, a list of challenging open questions is presented about Chagas disease control, patient management, programme planning and priority definitions faced by researchers and politicians.