Monolateral hypoplasia of the motor vagal nuclei in a case of sudden infant death syndrome

During the development of motor vagal nuclei (MVN), the neuroblasts of the myeloencephalic basal plate migrate in the dorsolateral direction to form the dorsal motor vagal nucleus (DMVN) and ventrolaterally to form the ventral motor vagal nucleus (VMVN). Those neuroblasts that remain close to the median sulcus will form the hypoglossal nucleus. In support of the congenital origin of the alteration of the MVN in sudden infant death syndrome (SIDS), we report the case of an 8‐month‐old female child who was found dead in her cot. The neuropathological assessment revealed that the medullary triangle of the 4th ventricle floor was asymmetric, owing to the presence of three prominences to the left side of the median sulcus. The medial prominence corresponded to the hypoglossal nucleus, which showed a marked increase in the number of large neurons; the intermediate prominence corresponded to the DMVN whose large neurons were reduced and were recognizable mainly at the level of the medial fringe; the lateral prominence corresponded to the solitary nucleus. The left solitary tract showed a reduction of the transverse diameter. Also, the left VMVN showed marked reduction in the number of neurons. Inflammatory and astrocytic reactions were absent. We suggest that in SIDS cases the hypocellularity of the MVN and the increased number of neurons of the hypoglossal nucleus are intimately related, indicating a congenital alteration due to incomplete migration of the vagal neuroblasts with abnormality of the autonomic cardio‐respiratory control.     

Activity of tea tree oil and nerolidol alone or in combination against Pediculus capitis (head lice) and its eggs

Acanthamoeba castellanii causes amoebic keratitis which is a painful sight-threatening disease of the eyes. Its eradication is difficult because the amoebas encyst making it highly resistant to anti-amoebic drugs, but several medicinal plants have proven to be more effective than the usual therapy. This study aimed to evaluate the in vitro amoebicidal activity of ethanol extracts of Arachis hypogaea L. (peanut), Curcuma longa L. (turmeric), and Pancratium maritimum L. (sea daffodil) on A. castellanii cysts. Acanthamoeba were isolated from keratitic patients, cultivated on 1.5% non-nutrient agar, and then incubated with different concentrations of plant extracts which were further evaluated for their cysticidal activity. The results showed that all extracts had significant inhibitory effect on the multiplication of Acanthamoeba cysts as compared to the drug control (chlorhexidine) and non-treated control, and the inhibition was time and dose dependent. The ethanol extract of A. hypogaea had a remarkable cysticidal effect with minimal inhibitory concentration (MIC) of 100 mg/ml in all incubation periods, while the concentrations of 10 and 1 mg/ml were able to completely inhibit growth after 48 and 72 h, respectively. The concentrations 0.1 and 0.01 mg/ml failed to completely inhibit the cyst growth, but showed growth reduction by 64.4–82.6% in all incubation periods. C. longa had a MIC of 1 g and 100 mg/ml after 48 and 72 h, respectively, while the concentrations 10, 1, and 0.1 mg/ml caused growth reduction by 60–90.3% in all incubation periods. P. maritimum had a MIC of 200 mg/ml after 72 h, while the 20-, 2-, 0.2-, and 0.02-mg/ml concentrations showed growth reduction by 34–94.3% in all incubation periods. All extracts seemed to be more effective than chlorhexidine which caused only growth reduction by 55.3–80.2% in all incubation periods and failed to completely inhibit the cyst growth. In conclusion, ethanol extracts of A. hypogaea, C. longa, and P. maritimum could be considered a new natural agent against the Acanthamoeba cyst.     

The contribution of HERV-E clone 4-1 and other HERV-E members to the pathogenesis of rheumatic autoimmune diseases

Human endogenous retroviruses (HERV)-E consist of a family of more than 1300 elements, stably integrated in the human genome. Some of them are full-length proviruses able to synthesize the viral proteins gag, pol and env. The reactivation of HERV-E elements has been associated to placentation, cancer and autoimmunity. In this narrative review, we aimed to report the status of the art concerning the involvement of HERV-E in rheumatic autoimmune diseases. Following a research on PubMed database, a total of 87 articles were selected. The highest amount of evidence derives from studies on systemic lupus erythematosus (SLE), whereas a few to no data are available on other immune-mediated diseases. In SLE, the hyper-expression of HERV-E clone 4-1 in peripheral blood mononuclear cells or differentiated lymphocytes has been associated with disease activity and autoantibody production. It is likely that HERV-E take part to the pathogenesis of rheumatic autoimmune diseases but additional research is needed.     

Evidence for the involvement of SDF-1 and CXCR4 in the disruption of endothelial cell-branching morphogenesis and angiogenesis by TNF-alpha and IFN-gamma

Vigorous inflammatory responses are associated with tissue damage, particularly when toxic levels of inflammatory cytokines are produced. Despite proangiogenic factors being present early at sites of inflammation, vascular repair occurs toward the end of the inflammatory response, suggesting modulation of the proangiogenic response. Endogenous inhibitors of angiogenesis induced during acute inflammation are poorly characterized. Here, we looked for endothelial cell-derived modulators of angiogenesis that may account for delayed neovascularization during inflammation. Gene profiling of endothelial cells showed that the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) selectively promote expression of the antiangiogenic molecules, IFN-inducible protein-10, monokine induced by IFN-gamma, tryptophanyl-tRNA synthetase, and tissue inhibitor of metalmetalloproteinase-1, and inhibit expression of the proangiogenic molecules, platelet-endothelial cell adhesion molecule-1, vascular endothelial growth factor receptor-2, stromal cell-derived factor-1 (SDF-1), collagen type IV, endothelial cell growth factor-1, and carcinoembryonic antigen-related cell adhesion molecule-1. Reduced endothelial cell expression of SDF-1 protein by TNF-alpha and IFN-gamma disrupts extracellular matrix-dependent endothelial cell tube formation, an in vitro morphogenic process that recapitulates critical steps in angiogenesis. Replacement of SDF-1 onto the endothelial cell surface reconstitutes this morphogenic process. In vivo, TNF-alpha and IFN-gamma inhibit growth factor-induced angiogenesis and SDF-1 expression in endothelial cells. These results demonstrate that SDF-1/CXC chemokine receptor-4 constitutes a TNF-alpha- and IFN-gamma-regulated signaling system that plays a critical role in mediating angiogenesis inhibition by these inflammatory cytokines.     

Variations in the NMDA receptor subunit 2B gene (GRIN2B) and schizophrenia: a case-control study.

A well established model for the pathophysiology of schizophrenia postulates a role for the NMDA-mediated glutamate transmission. The human gene coding for the 2B subunit of the NMDA receptor (GRIN2B) is considered a candidate based on its selective expression in brain. To evaluate the hypothesis that GRIN2B acts as a major gene in determining susceptibility to schizophrenia, a case-control association study was performed. Five single nucleotide polymorphisms (SNPs) were genotyped in 188 Italian patients and 156 control subjects. The association study showed a marginally significant excess of homozygosity for the polymorphism located in the 3'UTR region (P = 0.04). No other difference in genotype and allele frequencies was found in schizophrenics as compared to the control series. The case-control study was also carried out on estimated haplotypes, confirming a trend for association (P = 0.04). These results suggest that GRIN2B variations might be linked with susceptibility to schizophrenia. Replication studies on larger samples are warranted to further test this hypothesis.     

Craniofacial dyssynostosis: case report and review

Craniofacial dyssynostosis (CFD) is a rare disorder related to premature closure of the lambdoid suture and the posterior part of the sagittal suture. Epilepsy, mental retardation, abnormalities of the corpus callosum, and short stature have been reported. We studied a patient with CFD, hydronephrosis, and partially empty sella turcica; the latter two features are reported for the first time. We discuss the brain anomalies and their neurologic sequelae, which are part of the CFD phenotype.     

Characterisation of in vivo ovarian cancer models by quantitative 1H magnetic resonance spectroscopy and diffusion-weighted imaging

Magnetic resonance imaging (MRI) and spectroscopy (MRS) offer powerful approaches for detecting physiological and metabolic alterations in malignancies and help investigate underlying molecular mechanisms. Research on epithelial ovarian carcinoma (EOC), the gynaecological malignancy with the highest death rate characterised by frequent relapse and onset of drug resistance, could benefit from application of these molecular imaging approaches. In this study, MRI/MRS were used to characterise solid tumour models obtained by subcutaneous (s.c.) or intraperitoneal (i.p.) implantation of human SKOV3.ip cells in severe combined immunodeficiency (SCID) mice. In vivo MRI/MRS, ex vivo magic-angle-spinning (MAS), and in vitro (1)H-NMR measurements were carried out at 4.7 T, 9.4 T, and 9.4/16.5 T, respectively. MRI evaluation was performed by T1-, T2-, and diffusion-weighted (DW) multislice spin-echo imaging. The in vivo (1)H spectra of all tumour models showed a prominent resonance of total choline-containing metabolites (tCho). Quantitative in vivo MRS of both i.p. and s.c. SKOV3.ip xenografts showed that the mean tCho content was in the 2.9-4.5 mM range, with a mean PCho/tCho ratio of 0.99 ± 0.01 [23 examinations, 14-34 days post injection (dpi)], in good agreement with ex vivo and in vitro analyses. Myo-inositol ranged between 11.7 and 17.0 mM, with a trend towards higher values in i.p. xenografts at 14-16 dpi. The average apparent diffusion coefficient (ADC) values of SKOV3.ip xenografts [1.64 ± 0.11 (n = 9, i.p.) and 1.58 ± 0.03 x10(-3) mm(2)/s (n = 7, s.c.)] were in agreement with values reported for tumours from patients with EOC, while the mean vascular signal fraction (VSF) was lower (≤ 4%), probably due to the more rapid growth of preclinical models. Both s.c. and i.p. xenografts are valuable preclinical models for monitoring biochemical and physiopathological changes associated with in vivo EOC tumour growth and response to therapy, which may serve as the basis for further clinical development of noninvasive MR approaches.     

Facioscapulohumeral muscular dystrophy: new insights from compound heterozygotes and implication for prenatal genetic counselling

Background Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disease with a prevalence of 1 in 20?000. Almost all patients with FSHD carry deletions of integral copies of tandem 3.3 kb repeats (D4Z4) located on chromosome 4q35. However, FSHD families have been reported in which individuals carrying a D4Z4-reduced allele remain asymptomatic. Recently, it has been proposed that the D4Z4-reduced allele is pathogenic only in association with the permissive haplotype, 4APAS. Methods and results Through the Italian National Registry for FSHD (INRF), genotype-phenotype correlations were extensively studied in 11 non-consanguineous families in which two D4Z4-reduced alleles segregate. Overall, 68 subjects carrying D4Z4-reduced alleles were examined, including 15 compound heterozygotes. It was found that in four families the only FSHD-affected subject was the compound heterozygote for the D4Z4-reduced allele, and 52.6% of subjects carrying a single D4Z4-reduced 4A161PAS haplotype were non-penetrant carriers; moreover, the population frequency of the 4A161PAS haplotype associated with a D4Z4-reduced allele was found to be as high as 1.2%. Conclusions This study reveals a high frequency of compound heterozygotes in the Italian population and the presence of D4Z4-reduced alleles with the 4A161PAS pathogenic haplotype in the majority of non-penetrant subjects in FSHD families with compound heterozygosity. These data suggest that carriers of FSHD-sized alleles with 4A161PAS haplotype are more common in the general population than expected on the basis of FSHD prevalence. These findings challenge the notion that FSHD is a fully penetrant autosomal dominant disorder uniquely associated with the 4A161PAS haplotype, with relevant repercussions for genetic counselling and prenatal diagnosis.     

Recombinant LH administration in subsequent cycle after “unexpected” poor response to recombinant FSH monotherapy.

Poor ovarian response (POR) is most frequently linked to the condition known as diminished ovarian reserve, but it can also occur in the absence of pathological ovarian reserve tests (“unexpected” POR). Because possible explanations include theca cells function deficiency, our aim was to evaluate the effect of r-LH administration in “unexpected” poor responders.

A retrospective, single-centre, cohort study was conducted on 65 patients with AMH >0.5?ng/ml and/or AFC >5 with POR in their first cycle. Patients underwent a second IVF cycle with same protocol (long- or antagonist) and same starting dose of r-FSH used in the first cycle, plus daily addiction of 150?IU of r-LH from day 1.

Compared to the first cycle, r-LH addition in the second cycle determined an increase in number of oocytes retrieved (p?p?2 levels at hCG triggering (p?p?=?0.002). A 15% clinical pregnancy rate was also observed in the second cycle.

Our results suggest that patients with non-pathological ovarian reserve tests and previous “unexpected” POR seem to benefit from r-LH addition in subsequent cycles without the need to increase the r-FSH starting dose, possibly due to an underlying occult theca cells deficiency.