Givosiran to treat acute porphyria.

Porphyrias are a family of rare diseases chiefly due to inborn errors of heme biosynthesis. The porphyrias are generally characterized either by the main site of overproduction of heme precursors (hepatic or erythropoietic) or the main clinical manifestations (acute or cutaneous). The regulation of 5- (or δ)-aminolevulinic acid synthase 1 (ALAS1) plays a key role in the pathway of normal hepatic heme synthesis, providing insight into the pathophysiologic mechanisms and potential therapeutic targets for the treatment of the porphyrias. Givosiran (Givlaari; Alnylam Pharmaceuticals) is an ALAS1-directed small interfering RNA (siRNA) which has been developed for the treatment of acute hepatic porphyria (AHP). It was first approved in 2019 by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with AHP, and it received also approval in the E.U. in 2020 for the treatment of AHP in adults and adolescents aged 12 years and older.

A systematic review examining nutrition support interventions in patients with incurable cancer.

PURPOSE: Recent guidelines by the European Society for Clinical Nutrition and Metabolism (ESPEN) have advocated increased attention to nutritional support in all patients with cancer; however, little is known about the optimal type of nutritional intervention. The aim of this review was to assess the current evidence for nutrition support in patients with incurable cancer. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Embase, MEDLINE and CINAHL were searched from 1990 to 2018. Evidence was appraised using a modified risk of bias table, based on guidance from the Cochrane Handbook for Systematic Reviews of Interventions. RESULTS: Sixty studies were assessed of which twelve met the eligibility criteria. Eleven studies examined body composition, with six studies reporting improvements in weight. Six studies examined nutritional status with three studies reporting an improvement. Nine studies examined nutritional intake with six showing improvements including significant improvements in dietary and protein intake. Ten studies examined quality of life, with six studies reporting improvements following intervention. The most common nutritional interventions examined were nutrition counselling and dietary supplementation. CONCLUSIONS: There is moderate quality evidence to support the need for increased attention to nutrition support in patients with incurable cancer; however, despite some statistically significant results being reported, the clinical effects of them were small. Key questions remain as to the optimal timing for these interventions to be implemented (e.g. cachexia stage, illness stage and timing with anticancer therapy) and the most appropriate endpoint measures.

In vitro evaluation of the contractile response to endothelin-1 of the circular and longitudinal myometrial layers of the uterine horn of nongravid mares.

OBJECTIVE: To characterize the in vitro response of circular and longitudinal myometrial layers of the uterine horn (CMLH and LMLH, respectively) of horses to endothelin (ET)-1 by use of specific ETA (BQ-123) and ETB (IRL-1038) receptor antagonists. SAMPLE POPULATION: Uteruses from 10 nongravid mares in anestrus. PROCEDURE: Muscle strips from the CMLH and LMLH were suspended in tissue baths and connected to force-displacement transducers interfaced with a polygraph. Strips were incubated for 45-minute intervals with no antagonist (control specimens), and 3 concentrations (10(-9), 10(-7), and 10(-5)M) of BQ-123, IRL-1038, or BQ-123 and IRL-1038 before concentration-response curves to ET-1 were generated. Contractile response to cumulative concentrations of ET-1 (10(-9) to 10(-6)M) was quantified by measuring change in the area under the curve (AUC) for the 3-minute period after each ET-1 dose. RESULTS: ET-1 caused concentration-dependent contraction of the CMLH and LMLH specimens. Application of BQ-123 decreased AUC values for both layers. Application of IRL-1038 increased the AUC value for LMLH specimens but did not affect the CMLH value. The combination of BQ-123 and IRL-1038 decreased the AUC value for LMLH tissue and increased that for CMLH tissue. CONCLUSIONS AND CLINICAL RELEVANCE: ET-1 causes contraction of the CMLH and LMLH in nongravid horses. In both layers, ETA receptors mediate contraction but the role of ETB receptors remains unclear. In the LMLH, ETA receptors have a dominant role; the presence of another receptor or receptor subtype within this layer is suggested. These findings support a physiologic role for ET-1 in uterine contractility.

Laparoscopic repair of ruptured urinary bladder in a stallion.

A 12-year-old stallion was evaluated because of pollakiuria; endoscopy of the urinary tract during general anesthesia revealed that the urinary bladder was intact. After recovery, the stallion developed clinical and biochemical signs of bladder rupture, which was confirmed by endoscopy. Cystoplasty in adult stallions represents a unique surgical dilemma; the large distance between the incision site and the bladder necessitates the repair be accomplished under maximum tension with minimal exposure. Because traditional surgical approaches through ventral midline or paramedian incisions provide limited access and viewing, laparoscopy was used to provide a definitive diagnosis, good viewing, easy access, tension-free dissection, and a secure repair. Lack of surgical complications and postoperative discomfort, rapid and uncomplicated healing, and patient-client satisfaction make laparoscopic cystoplasty the preferred method for surgical repair of ruptured urinary bladder in adult stallions.