[Pharmacogenetics in anesthesia and intensive care medicine : Clinical and legal challenges exemplified by malignant hyperthermia].

Anaesthesist. 2016 May 3;

Authors: Klingler W, Pfenninger E

Abstract
Pharmacotherapy is a key component of anesthesiology and intensive care medicine. The individual genetic profile influences not only the effect of pharmaceuticals but can also completely alter the mode of action. New technologies for genetic screening (e.g. next generation sequencing) and increasing knowledge of molecular pathways foster the disclosure of pharmacogenetic syndromes, which are classified as rare diseases. Taking into account the high genetic variability in humans and over 8000 known rare diseases, up to 20 % of the population may be affected. In summary, rare diseases are not rare. Most pharmacogenetic syndromes lead to a weakening or loss of pharmacological action. In contrast, malignant hyperthermia (MH), which is the most relevant pharmacogenetic syndrome for anesthesia, is characterized by a pharmacologically induced overactivation of calcium metabolism in skeletal muscle. Volatile anesthetic agents and succinylcholine trigger life-threatening hypermetabolic crises. Emergency treatment is based on inhibition of the calcium release channel of the sarcoplasmic reticulum by dantrolene. After an adverse pharmacological event patients must be informed and a clarification consultation must be carried out during which the hereditory character of MH is explained. The patient should be referred to a specialist MH center where a predisposition can be diagnosed by the functional in vitro contracture test from a muscle biopsy. Additional molecular genetic investigations can yield mutations in the genes for calcium-regulating proteins in skeletal muscle, e.g. ryanodine receptor 1 (RyR1) and calcium voltage-gated channel subunit alpha 1S (CACNA1S). Currently, an association to MH has only been shown for 35 mutations out of more than 400 known and probably hundreds of unknown genetic variations. Furthermore, MH predisposition is not excluded by negative mutation screening. For anesthesiological patient safety it is crucial to identify individuals at risk and warn genetic relatives; however, the legal requirements of the Patients Rights Act and the Human Genetic Examination Act must be strictly adhered to. Specific features of insurance and employment law must be respected under consideration of the Human Genetic Examination Act.

PMID: 27142362 [PubMed - as supplied by publisher]

Non-cholesterol Sterols in the Diagnosis and Treatment of Dyslipidemias: A Review.

Curr Med Chem. 2016 May 3;

Authors: Baila-Rueda L, Cenarro A, Civeira F

Abstract
Non-cholesterol sterols have been used as markers of cholesterol intestinal absorption and hepatic synthesis, leading to a better understanding of cholesterol homeostasis in humans. This review discusses the main non-cholesterol sterols that are clinically useful, different methods to quantify the factors associated with blood concentration, and the potential role of non-cholesterol sterols in the diagnosis and treatment of different types of dyslipidemia. The main indication is the use of non-cholesterol sterols for the diagnosis of rare diseases associated with defects in cholesterol synthesis or anomalies in the absorption and/or elimination of phytosterols. However, other potential uses, including the diagnosis of certain hypercholesterolemias and the individualization of lipid-lowering therapies, are promising as they could help treat a wider population.

PMID: 27142287 [PubMed - as supplied by publisher]

Clinicopathological features and prognosis of Kimura's disease with renal involvement in Chinese patients.

Clin Nephrol. 2016 May 4;

Authors: Chen Y, Wang J, Xu F, Zeng C, Liu Z

Abstract
AIMS: Kimura's disease (KD) with renal involvement is a rare disease. Optimal treatments are still not well established. It is necessary to analyze clinicopathological features, treatment responses, and prognosis for improving KD diagnosis and treatment.
MATERIALS AND METHODS: Clinicopathological data, treatment responses, and prognosis were collected and analyzed retrospectively.
RESULTS: The patients consisted of 27 males and 2 females, with an average age of 35.5 ± 15.1 (13 - 61) years. 27 exhibited proteinuria ranging from 0.730 to 14.1 g/24 h (5.98 ± 3.40 g/24 h). Hypertension, renal insufficiency (serum creatinine (Scr) > 1.24 mg/dL), and microhematuria occurred in 4 (13.8%), 11 (37.9%), and 13 (44.8%) cases, respectively. Light microscopy (LM) identified mesangium proliferation, minimal change, focal and segmental glomerulosclerosis (FSGS), membranous glomerulonephritis, membranoproliferative glomerulonephritis (MPGN), and acute tubular necrosis in 14, 8, 3, 2, 1, and 1 cases, respectively. All were treated with Tripterygium wilfordii (TW), prednisone, leflunomide (LEF), tacrolimus (FK506), myophenolate mofetil (MMF), or renin-angiotensin system blockers (RASI). 26 patients were followed up for 1.60 - 108.7 months (39.6 ± 28.7). After treatments, urinary red blood cells (RBC) decreased in all. The amount of 24-hour urinary protein (24-hUPE) decreased in 24 patients. 22 reached complete remission (CR), 4 partial remissions (PR). The patients who did not relapse were younger than those who relapsed.
CONCLUSIONS: KD with renal involvement occurs predominantly among 35 - 50 year old Chinese patients with male predilection. The most common features are proteinuria, hypertension, micro hematuria with minimal change, and mesangial proliferative glomerulonephritis. Most were responsive to treatment, but could relapse. Gender, age, and hypertension are associated with KD recurrence. The prognosis is good mostly.

PMID: 27142199 [PubMed - as supplied by publisher]

Challenges of access to medicine and the responsibility of pharmaceutical companies: a legal perspective.

Daru. 2016;24(1):13

Authors: Ahmadiani S, Nikfar S

Abstract
The right to health as a basic human right- and access to medicine as a part of it- have been a matter of attention for several decades. Also the responsibilities of different parties- particularly pharmaceutical companies- in realization of this right has been emphasized by World Health Organization. This is while many companies find no incentive for research and development of medicines related to rare diseases. Also some legal structures such as "patent agreements" clearly cause huge difficulties for access to medicine in many countries. High prices of brand medicine and no legal production of generics can increase the catastrophic costs- as well as morbidity-mortality of medication in lower income countries. Here we evidently review the current challenges in access to medicine and critically assess its legal roots. How societies/governors can make the pharmaceutical companies responsible is also discussed to have a look on possible future and actions that policy makers- in local or global level- can take.

PMID: 27141958 [PubMed - in process]

The Undiagnosed Diseases Program--Reply.

JAMA. 2016 May 3;315(17):1904

Authors: Gahl WA, Wise AL, Ashley EA

PMID: 27139070 [PubMed - indexed for MEDLINE]

The Undiagnosed Diseases Program.

JAMA. 2016 May 3;315(17):1903-4

Authors: Drolet BC, Brower JP

PMID: 27139068 [PubMed - indexed for MEDLINE]

Policymaking for Orphan Drugs and Its Challenges.

AMA J Ethics. 2015 Aug;17(8):776-9

Authors: Rhee TG

PMID: 26270879 [PubMed - indexed for MEDLINE]

Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain.

Brain. 2015 Dec;138(Pt 12):e400

Authors: Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, Rojas-García R, García-Redondo A, Povedano M, Lladó A, Álvarez V, Sánchez-Juan P, Pardo J, Jericó I, Vázquez-Costa J, Sevilla T, Cardona F, Indakoechea B, Moreno F, Fernández-Torrón R, Muñoz-Llahuna L, Moreno-Grau S, Rosende-Roca M, Vela Á, Muñoz-Blanco JL, Combarros O, Coto E, Alcolea D, Fortea J, Lleó A, Sánchez-Valle R, Esteban-Pérez J, Ruiz A, Pastor P, López De Munain A, Pérez-Tur J, Clarimón J, Dementia Genetics Spanish Consortium (DEGESCO)

PMID: 26152333 [PubMed - indexed for MEDLINE]