Child abuse in Malta : a review

Child abuse constitutes one of the most difficult areas of paediatric practice in Malta and, sadly, non accidental injury (NAI) is not only relatively common but is also increasing in incidence. The multi-factorial and socially complex aetiology of child abuse makes its eradication at source very difficult indeed. Nevertheless, the significant negative impact of this diagnosis on the affected child, both in the immediacy as well as in the long term, dictates damage-limitation through early identification and appropriate management. To this end, local awareness of the magnitude of the problem has galvanized the relevant authorities who have now established efficient tracking and processing protocols for cases of NAI, covering medical, social, legal and police aspects.peer-reviewe

The role of the A C395 IFNGR1 mutation in determining susceptibility to intracellular infection in Malta

Background: The first human mycobacterial susceptibility gene was identified amongst four children on the island of Malta in 1995. All affected children were homozygous for a nonsense mutation at position 395 of the interferon gamma receptor 1 (IFNGR1) gene, and all but one died of overwhelming mycobacterial infection. The population of Malta has high rates of infection with intracellular pathogens; leishmania, brucellosis and tuberculosis are all endemic, while leprosy, which was previously endemic, has only recently been eradicated. We hypothesised that heterozygous carriers of the IFNGR1 gene mutation, while resistant to infection with poorly pathogenic organisms, may have increased susceptibility to infection with more virulent pathogens. Methodology and Result: Screening patients with a past history of intracellular infection and healthy newborns for the presence of the IFNGR1 A->C395 mutation, using sequence specific primer PCR, did not identify any carriers of the mutation. Conclusion: These results suggest that the IFNGR1 mutation is unlikely to be of public health significance on Malta.peer-reviewe

Principles for the post-GWAS functional characterisation of risk loci

Several challenges lie ahead in assigning functionality to susceptibility SNPs. For example, most effect sizes are small relative to effects seen in monogenic diseases, with per allele odds ratios usually ranging from 1.15 to 1.3. It is unclear whether current molecular biology methods have enough resolution to differentiate such small effects. Our objective here is therefore to provide a set of recommendations to optimize the allocation of effort and resources in order maximize the chances of elucidating the functional contribution of specific loci to the disease phenotype. It has been estimated that 88% of currently identified disease-associated SNP are intronic or intergenic. Thus, in this paper we will focus our attention on the analysis of non-coding variants and outline a hierarchical approach for post-GWAS functional studies

Topology of the pore-region of a K+ channel revealed by the NMR-derived structures of scorpion toxins

AbstractThe architecture of the pore-region of a voltage-gated K+ channel, Kv1.3, was probed using four high affinity scorpion toxins as molecular calipers. We established the structural relatedness of these toxins by solving the structures of kaliotoxin and margatoxin and comparing them with the published structure of charybdotoxin; a homology model of noxiustoxin was then developed. Complementary mutagenesis of Kv1.3 and these toxins, combined with electrostatic compliance and thermodynamic mutant cycle analyses, allowed us to identify multiple toxin-challel interactions. Our analyses reveals the existence of a shallow vestibule at the external entrance to the pore. This vestibule is ∼28−32A˚wide at its outer margin, ∼28−34A˚wide at its base, and ∼4−8A˚deep. The pore is 9–14A˚wide at its external entrance and tapers to a width of 4–5A˚at a depth of ∼5−7A˚from the vestibule. This structural information should directly aid in developing topological models of the pores of related ion channels and facilitate therapeutic drug design

Diagnostic evaluation of people with hypertension in low income country: cohort study of “essential” method of risk stratification

Objectives To explore the predictive power of a risk stratification method for people with hypertension based on “essential” procedures (that is, available in economically less developed areas of the world), comparing it in the same population with the results given by the method suggested by the 1999 World Health Organization-International Society of Hypertension (WHO-ISH) guidelines

Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues

: Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases

Randomized Clinical Trial on Ivermectin versus Thiabendazole for the Treatment of Strongyloidiasis

Strongyloidiasis is the infection caused by the worm Strongyloides stercoralis. Due to its peculiar life cycle Strongyloides may remain indefinitely in the host, if not effectively cured. Although the disease is usually mild, in case of weakening of the host's immune defenses the worm may invade virtually all organs and tissues (disseminated strongyloidiasis, almost invariably fatal). The treatment must then reach the goal of the complete elimination of the parasite. Small size clinical trials showed similar, high efficacy of the two drugs ivermectin (used as a single dose) and thiabendazole (used twice daily for two consecutive days). All trials used as the criterion for cure the absence of larvae in stool exams. The latter however may easily miss the infection, falsely suggesting that the infection has been cured. This trial, using a test detecting specific Strongyloides antibodies as an additional and more sensitive diagnostic tool, confirms previous reports: the two drugs have similar efficacy but ivermectin is better tolerated and is therefore the first choice. However the cure rate was lower than 70% for the standard, single dose. The authors then conclude that a larger, multi center trial is needed to find the optimal dose schedule of ivermectin

Epithelial TGFβ engages growth-factor signalling to circumvent apoptosis and drive intestinal tumourigenesis with aggressive features

The pro-tumourigenic role of epithelial TGFβ signalling in colorectal cancer (CRC) is controversial. Here, we identify a cohort of born to be bad early-stage (T1) colorectal tumours, with aggressive features and a propensity to disseminate early, that are characterised by high epithelial cell-intrinsic TGFβ signalling. In the presence of concurrent Apc and Kras mutations, activation of epithelial TGFβ signalling rampantly accelerates tumourigenesis and share transcriptional signatures with those of the born to be bad T1 human tumours and predicts recurrence in stage II CRC. Mechanistically, epithelial TGFβ signalling induces a growth-promoting EGFR-signalling module that synergises with mutant APC and KRAS to drive MAPK signalling that re-sensitise tumour cells to MEK and/or EGFR inhibitors. Together, we identify epithelial TGFβ signalling both as a determinant of early dissemination and a potential therapeutic vulnerability of CRC’s with born to be bad traits

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year