Clinical Utility of Genetic Testing with Geographical Locations in ADPKD: Describing New Variants.

Background: Our study aims to comment on all ADPKD variants identified in our health area and explain how they are distributed geographically, to identify new variants, and relate the more frequent variants with their renal phenotype in terms of kidney survival. Materials and Methods: We identified patients suffering from ADPKD in a specialized consultation unit; genealogical trees were constructed from the proband. According to the ultrasound-defined modified Ravine-Pei criteria, relatives classified as at risk were offered participation in the genetic study. Socio-demographic, clinical, and genetic factors related to the impact of the variant on the survival of the kidney and the patient, such as age at RRT beginning and age of death, were recorded. Results: In 37 families, 33 new variants of the PKD1 gene were identified, which probably produce a truncated protein. These variants included 2 large deletions, 19 frameshifts, and 12 stop-codons, all of which had not been previously described in the databases. In 10 families, six new probably pathogenic variants in the PKD2 gene were identified. These included three substitutions; two deletions, one of which was intronic and not associated with any family; and one duplication. A total of 11 missense variants in the PKD1 gene were grouped in 14 families and classified as probably pathogenic. We found that 33 VUS were grouped into 18 families and were not described in the databases, while another 15 were without grouping, and there was only 1 in the PKD2 gene. Some of these variants were present in patients with a different pathogenic variant (described or not), and the variant was probably benign. Renal survival curves were compared to nonsense versus missense variants on the PKD1 gene to check if there were any differences. A group of 328 patients with a nonsense variant was compared with a group of 264 with a missense variant; mean renal survival for truncated variants was lower (53.1 ± 0.46 years versus non-truncated variant 59.1 ± 1.36 years; Log Rank, Breslow, and Tarone Ware, p < 0.05). Conclusions: To learn more about ADPKD, it is necessary to understand genetics. By describing new genetic variants, we are approaching creation of an accurate genetic map of the disease in our country, which could have prognostic and therapeutic implications in the future.

Proactive monitoring of anti-TNF agents improves follow-up of paediatric patients with Crohn disease.

INTRODUCTION AND AIMS: The incidence of paediatric inflammatory bowel disease has increased in recent decades. The aim of the present study was to evaluate the role of proactive and serial monitoring of tumour necrosis factor (TNF) inhibitor levels to maintain clinical remission and mucosal healing in the follow-up of paediatric patients with Crohn disease (CD). METHODS: Prospective study that included all patients diagnosed with CD and treated with adalimumab or infliximab between May 2015 and November 2020 who underwent serial and proactive monitoring of TNF inhibitor levels. RESULTS: The study included 30 patients, 21 male (70%). The mean age at diagnosis was 11.3 years (SD, 2.0), the mean age at initiation of TNF inhibitors was 12.6 years (SD, 1.9) with a mean duration of follow-up of 27.1 ±â€¯9.1 months. Clinical remission was defined as a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) of less than 12.5 and mucosal healing as a Mucosal Inflammation Non-invasive Index (MINI) of less than 8. During the follow-up, patients were in clinical remission in 87.1% of the visits, presented with mild disease in 11.4% and with moderate disease in 1.5%, and mucosal healing was assumed in 83% of the visits. The rates of clinical remission and mucosal healing at 1, 2, and 3 years of follow-up were 83.3%, 95.8%, 92.8%, and 86.7%, 87.5% and 85.7%, respectively. CONCLUSIONS: Proactive and serial monitoring of serum TNF inhibitor levels may make it possible for patients to maintain clinical remission and mucosal healing in the maintenance phase, with individualised optimization of the required dosage and minimization of secondary loss of response.

The role of oxidative stress in neurodegenerative diseases and potential antioxidant therapies.

Objectives: The central nervous system (CNS) is essential for homeostasis and controls the physiological functions of the body. However, the biochemical characteristics of the CNS make it especially vulnerable to oxidative damage (OS). This phenomenon compromises correct CNS functioning, leading to neurodegeneration and neuronal death. Contents: OS plays a crucial role in the physiopathology of neurodegenerative diseases. It is involved in multiple mechanisms of nucleic acid, protein, and lipid oxidation, thereby contributing to progressive brain damage. These mechanisms include mitochondrial dysfunction; excessive production of reactive oxygen and nitrogen species; deficiency of antioxidant defenses; protein oligomerization; cytokine production and inflammatory response; blood-brain barrier abnormalities; and proteasome dysfunction. All these dysfunctions are involved in the pathogenesis of neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Huntington's disease, or amyotrophic lateral sclerosis. Summary and outlook: A curative treatment is currently not available. Research is focused on the search for therapies that reduce oxidative damage and delay disease progression. In the recent years, researchers have focused their attention on the effects of antioxidant therapies.