Therapeutic advances in ADPKD: the future awaits

Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder included in ciliopathies, representing the fourth cause of end stage renal disease (ESRD), with an estimated prevalence between 1:1000 and 1:2500. It is mainly caused by mutations in the PKD1 and PKD2 genes encoding for polycystin 1 (PC1) and polycystin 2 (PC2), which regulate differentiation, proliferation, survival, apoptosis, and autophagy. The advances in the knowledge of multiple molecular pathways involved in the pathophysiology of ADPKD led to the development of several treatments which are currently under investigation. Recently, the widespread approval of tolvaptan and, in Italy, of long-acting release octreotide (octreotide-LAR), represents but the beginning of the new therapeutic management of ADPKD patients. Encouraging results are expected from ongoing randomized controlled trials (RCTs), which are investigating not only drugs acting on the calcium/cyclic adenosin monoposphate (cAMP) pathway, the most studied target so far, but also molecules targeting specific pathophysiological pathways (e.g. epidermal growth factor (EGF) receptor, AMP-activated protein kinase (AMPK) and KEAP1-Nrf2) and sphingolipids. Moreover, studies on animal models and cultured cells have also provided further promising therapeutic strategies based on the role of intracellular calcium, cell cycle regulation, MAPK pathway, epigenetic DNA, interstitial inflammation, and cell therapy. Thus, in a near future, tailored therapy could be the key to changing the natural history of ADPKD thanks to the vigorous efforts that are being made to implement clinical and preclinical studies in this field. Our review aimed to summarize the spectrum of drugs that are available in the clinical practice and the most promising molecules undergoing clinical, animal, and cultured cell studies. Graphical abstract: [Figure not available: see fulltext.

I-21 Current therapeutic guidelines in Duchenne Muscular Dystrophy to prolong life

Duchenne's myopathy is an X-linked disease with well defined evolutionary phases, characterized by degradation of the walking function, development of evolutive scoliosis and progressive decline of the respiratory function leading patients to premature death. In 1985 Y. Rideau in France carried out a new global therapeutic strategy for treatment of lower limb deformities, scoliosis deformity and progressive restrictive syndrome. The indication for surgery at the lower limbs is made very early, at the onset of the first signs of disease. The procedures are carried out at the same time and always bilaterally; they include: (i) hip section of superficial flexors; (ii) iliotibial band resection; (iii) subcutaneous tenotomy of semitendineous and gracilis; (iv) subcutaneous lengthening of Achilles tendons. In the post-operative period, the patient begins exercises of active and passive mobility in few days and after three weeks recovers his performances; ambulation will remain almost normal for several years. A comparison of two groups of patients, the first precociously operated on the lower limbs, the other one not operated, shows better performances in the operated group. The indications for surgical treatment of Duchenne scoliosis must be made after the loss of ambulation and not too late, to avoid the concurrent respiratory restrictive syndrome makes the patient inoperable. Over ten years ago, in Poitiers, a specific instrumentation for Duchenne scoliosis was created, providing for cylindrical rods fixed by peduncular screws at the sacro-lumbar level. On the dorso-lumbar level, the rod becomes flat to allow more flexibility of the trunk. The complications observed in a group of 55 patients operated for scoliosis, consisted in 2 cases of breaking of rods and 1 superficial infection. The surgery approach in DMD has the double aim to prolong the time of the autonomous ambulation and to avoid the evolution of scoliosis, limiting the harmful effects of the scoliosis on the respiratory function. However, the surgery alone is unable to prolong the life expectancy in these patients, without treating the restrictive respiratory syndrome, first by nasal ventilation and then by elective tracheotomy, essential for the survival of the patient

(+/-)-Gelliusines A and B, two diastereomeric brominated tris-indole alkaloids from a deep water New Caledonian marine sponge (Gellius or Orina sp.)

Two new diastereomeric brominated tris-indole alkaloids occurring as enantiomeric pairs, (±)-gelliusine A (I) and its isomer (±)-gelliusine B, have been isolated from a deep water New Caledonian sponge (Gellius or Orina sp.), whose crude ext. exhibited cytotoxicity against KB cells. Their structures were elucidated by spectroscopic methods including one- and two-dimensional NMR spectroscopy. The major compd., I, which showed very weak cytotoxicity, proved to be active at the serotonin receptor

Clinical findings and prognosis of interference injuries to the palmar aspect of the forelimbs in Standardbred racehorses: A study on 74 cases

Information on interference injuries in racehorses is lacking

The Neural Basis of Social Cognition in Typically Developing Children and Its Relationship to Social Functioning

Theory of mind (ToM), the ability to think about the perspectives, beliefs, and feelings of another, develops throughout childhood and adolescence and is an important skill for social interactions. This study examines neural activity in typically developing children during a novel ToM task – the Movie Mentalizing Task– and tests its relations to ToM behavioral performance and social functioning. In this fMRI task, children ages 8–13years (N=25) watched a brief movie clip and were asked to predict a character’s mental state after a social interaction. Engaging in the Movie Mentalizing Task activated the ToM neural network. Moreover, greater neural activity in the ToM network, including the superior temporal gyrus and inferior frontal gyrus, was associated with better behavioral performance on independent ToM tasks and was related to better social functioning, though these results do not survive correction for multiple comparisons. Results offer a new affective theory of mind task for children in the scanner that robustly recruits activity in theory of mind regions

Stepwise shortening of agalsidase beta infusion duration in Fabry disease: Clinical experience with infusion rate escalation protocol

Background: Although enzyme replacement therapy with agalsidase beta resulted in a variety of clinical benefits, life-long biweekly intravenous infusion may impact on patients’ quality of life. Moreover, regular infusions are time-consuming: although a stepwise shortening of infusion duration is allowed up to a minimum of 1.5 hr, in most centers it remains ≥3 hr, and no data exists about the safety and tolerability of agalsidase beta administration at maximum tolerated infusion rate. Methods: In this study, we reported our experience with a stepwise infusion rate escalation protocol developed in our center in a cohort of 53 Fabry patients (both already receiving and treatment-naΪve), and explored factors predictive for the infusion rate increase tolerability. Results: Fifty-two patients (98%) reduced infusion duration ≤3 hr; of these, 38 (72%) even reached a duration ≤2 hr. We found a significant difference between the mean duration reached by already treated and naΪve patients (p <.01). More severely affected patients (male patients and those with lower enzyme activity) received longer infusions for higher risk of infusion-associated reactions (IARs). A significant correlation between anti-agalsidase antibodies and IARs was found. Conclusion: Our infusion rate escalation protocol is safe and could improve patient compliance, satisfaction and quality of life