Anomalie cerebellari fetali: confronto tra ecografia e risonanza magnetica prenatale e follow up a distanza

Cerebellar malformation are increasingly diagnosed in utero. To assess the effectiveness of ultrasound and fetal magnetic resonance in the antenatal prediction of long term neurodevelopmental delay. STUDY DESIGN: We collected 105 cases of cerebellum malformation in the period 2000-2010 in Bologna and Bari University. Classification included cystic anomalies of posterior fossa and cerebellar hypoplasia. RESULTS: The greater group included Blake’s pouch cysts and mega cisterna magna cases (58/105). These cases seemed to have a good prognosis with a good outcome both in association with other anomalies and isolated. In cases of Dandy Walker malformation, vermis hypoplasia and cerebellum hypoplasia there were few survivors, so it was so difficult to outline some conclusion for child outcome. Despite great neuroimaging advances, in our study, ultrasound and MR reached a similar sensitivity (62-63%) for the diagnosis of posterior fossa anomalies, but the number of MR was lower compared with ultrasonography. CONCLUSION: Ultrasonography remains the screening method of choice for evaluation of cerebellum anatomy but probably MR imaging can improve some details expecially in the third trimester. Despite the data on Dandy Walker, vermis hypoplasia and cerebellum hypoplasia were conflicting and uncertain, for Blake and mega cisterna magna we can considered a rather good outcome.

Il ruolo dell’ecografia prenatale nella diagnosi precoce delle anomalie fetali della fossa cranica posteriore

Obiettivo: Valutare il ruolo brainstem-vermis angle (BV angle) a 16-18 settimane per la diagnosi precoce delle anomalie cistiche della fossa cranica posteriore. Metodi: Uno studio prospettico, multicentrico, osservazionale. Volumi ecografici tridimensionali della testa fetale sono stati acquisiti in feti a 16-18 settimane. Tre operatori di simile esperienza hanno misurato il BV angle nel piano sagittale come precedentemente descritto1,2 e hanno annotato se il quarto ventricolo era aperto sul piano assiale. Un follow-up dettagliato è stato ottenuto in tutti i casi. Risultati: Tra novembre 2009 e marzo 2011, 150 volumi sono stati acquisiti ad un’epoca gestazionale media di 16 settimane. A causa di una scarsa qualità delle immaginai, 49 volumi sono stati esclusi, con una popolazione finale di 101 casi. Di questi, 6 hanno ricevuto successivamente una diagnosi di malformazione di Dandy-Walker (DWM) e 2 di cisti della tasca di Blake (BPC), gli altri erano normali. In tutti i feti con anomalie cistiche della fossa cranica posteriore, il BV angle è risultato significativamente più ampio rispetto ai controlli (57.3+23.0° vs 9.4+7.7°, U-Mann Whitney test p<0.000005). Nel 90.3% dei feti normali, il BV angle era <20° e il quarto ventricolo era chiuso sul piano assiale. In 9 feti normali e nei casi con BPC, l’angolo era >20° ma <45° (25.8+5.6°) e il quarto ventricolo era aperto posteriormente sul piano assiale, ma solo utilizzando una scansione non convenzionale. In tutti i feti con DWM, il BV angle era >45° (67.9+13.9°) e il quarto ventricolo era aperto anche sul piano assiale standard. Conclusioni: Fino ad ora la diagnosi di anomalie cistiche della fossa cranica posteriore è stata consideratea difficile o impossibile prima di 20 settimane, a causa del presunto sviluppo tardivo del verme cerebellare. La nostra esperienza suggerisce che la misurazione del BV angle consente un’identificazione precisa di queste condizioni già a 16 settimane.

Effetti dell'acido urico sulle cellule glomerulari mesangiali: meccanismi intracellulari di trasduzione del segnale e possibili implicazioni nella progressione del danno renale e nella sindrome infiammatoria in corso di nefropatie croniche

Uric acid is a major inducer of inflammation in renal interstitium and may play a role in the progression of renal damage in hyperuricemic subjects with primary nephropathies, renal vascular disease, and essential hypertension. At the same time, UA also acts as a water-soluble scavenger of reactive oxygen species. We evaluated the cellular effects of UA on cultured HMC as a potential interstitial target for abnormally elevated levels in acute and chronic renal disease. Intracellular free Ca2+ ([Ca2+]i) was monitored by microfluorometry of fura 2-loaded cells, while oxidation of intracellularly trapped non-fluorescent 2’,7’-dichlorofluorescein diacetate (DCFHDA, 20 uM) was employed to assess the generation of reactive oxygen species during 12-hr incubations with various concentrations of UA or monosodium urate. Fluorescent metabolites of DCFH-DA in the culture media of HMC were detected at 485/530 nm excitation/emission wavelengths, respectively. UA dose-dependently lowered resting [Ca2+]i (from 102±9 nM to 95±3, 57±2, 48±6 nM at 1-100 uM UA, respectively, p <0.05), leaving responses to vasoconstrictors such as angiotensin II unaffected. The effect was not due to Ca2+/H+ exchange upon acidification of the bathing media, as acetate, glutamate, lactate and other organic acids rather increased [Ca2+]i (to max. levels of 497±42 nM with 0.1 mM acetate). The decrease of [Ca2+]i was abolished by raising extracellular Ca2+ and not due to effects on Ca2+ channels or activation of Ca2+-ATPases, since unaffected by thapsigargin. The process rather appeared sensitive to removal of extracellular Na+ in combination with blockers of Na+/Ca2+ exchange, such as 2’,4’-dichlorobenzamil, pointing to a countertransport mechanism. UA dose-dependently prompted the extracellular release of oxidised DCFH (control 37±2 relative fluorescence units (RFU)/ml, 0.1uM 47±2, 1 uM 48±2, 10 uM 51±4, 0.1 mM 53±4; positive control, 10 uM sodium nitroprusside 92±5 RFU/ml, p<0.01). In summary, UA interferes with Ca2+ transport in cultured HMC, triggering oxidative stress which may initiate a sequence of events leading to interstitial injury and possibly amplifying renal vascular damage and/or the progression of chronic disease.

Sindrome di Down e fattori di rischio nel declino neurocognitivo

Down syndrome (DS) or Trisomy 21, occurring in 1/700 and 1/1000 livebirths, is the most common genetic disorder, characterized by a third copy of the human chromosome 21 (Hsa21). DS is associated with various defects, including congenital heart diseases, craniofacial abnormalities, immune system dysfunction, mental retardation (MR), learning and memory deficiency. The phenotypic features in DS are a direct consequence of overexpression of genes located within the triplicated region on Hsa21. In addition to developmental brain abnormalities and disabilities, people with DS by the age of 30-40 have a greatly increased risk of early-onset of Alzheimer’s disease (AD) and an apparent tendency toward premature aging. Many of the immunological anomalies in DS can be enclosed in the spectrum of multiple signs of early senescence. People with DS have an increased vulnerability to oxidative damage and many factors, including amyloid beta protein (Abeta), genotype ApoE4, oxidative stress, mutations in mitochondrial DNA (mtDNA), impairment of antioxidant enzymes, accelerated neuronal cell apoptosis, are related to neuronal degeneration and early aging in DS. SUBJECTS and METHODS: Since 2007 a population of 50 adolescents and adults with DS, 26 males and 24 females (sex-ratio: M/F = 1.08), has been evaluated for the presence of neurological features, biomarkers and genetic factors correlated with neuronal degeneration and premature aging. The control group was determined by the mother and the siblings of the patients. A neuropsychiatric evaluation was obtained from all patients. The levels of thyroid antibodies (antiTg and antiTPO) and of some biochemical markers of oxidative stress, including homocysteine (tHcy), uric acid, cobalamin, folate were measured. All patients, the mother and the siblings were genotyped for ApoE gene. RESULTS: 40% of patients, with a mild prevalence of females aged between 19 and 30 years, showed increased levels of antiTg and antiTPO. The levels of tHcy were normal in 52% patients and mildly increased in 40%; hyperomocysteinemia was associated with normal levels of thyroid antibodies in 75% of patients (p<0.005). The levels of uric acid were elevated in 26%. Our study showed a prevalence of severe MR in patients aged between 1-18 years and over 30 years. Only 3 patients, 2 females and one male, over 30 years of age, showed dementia. According to the literature, the rate of Down left-handers was high (25%) compared to the rest of population and the laterality was associated with increased levels of thyroid antibodies (70%). 21.5% of patients were ApoE4 positive (ApoE4+) with a mean/severe MR. CONCLUSIONS: Until now no biochemical evidence of oxidative damage and no deficiency or alteration of antioxidant function in our patients with DS were found. mtDNA sequencing could show some mutations age-related and associated with oxidative damage and neurocognitive decline in the early aging of DS. The final aim is found predictive markers of early-onset dementia and a target strategy for the prevention and the treatment of diseases caused by oxidative stress. REFERENCES: 1) Rachidi M, Lopes C: “Mental retardation and associated neurological dysfunctions in Down syndrome: a consequence of dysregulation in critical chromosome 21 genes and associated molecular pathways.” - Eur J Paediatr Neurol. May;12(3):168-82 (2008). 2) Lott IT, Head E: “Down syndrome and Alzheimer's disease: a link between development and aging.” - Ment Retard Dev Disabil Res Rev, 7(3):172-8 (2001). 3) Lee HC, Wei YH: “Oxidative Stress, Mitochondrial DNA Mutation, and Apoptosis in Aging.” - Exp Biol Med (Maywood), May;232(5):592-606 (2007).

Sindrome di Buschke-Ollendorff: clinica e genetica

Buschke Ollendorff syndrome (BOS) is a rare autosomal dominant genodermatosis, with high penetrance and variable expressivity, characterized by the association of connective tissue naevi and osteopoikilosis. Both cutaneous and osseous manifestations are usually asymptomatic. The disease is caused by a loss-of-function mutation in the gene LEMD3, that is located on chromosome 12q13. Differential diagnosis mainly includes pseudoxantoma elasticum, morphea, lipoid proteinosis, papular elastorrhexis, juvenile elastoma, papular mucinosis. The 2 cases of BOS here reported are an example of segmental type 2 autosomal dominant genodermatosis, that is due to the loss of heterozygosity occurring at an early developmental stage in a heterozygous patient, causing a segmental homozygosity. Such patients usually have pronounced segmental lesions in the first years of life and later develop disseminated symmetrical lesions.