RGR variants in different forms of retinal diseases: The undetermined role of truncation mutations.

Mol Med Rep. 2016 Nov;14(5):4811-4815

Authors: Li J, Xiao X, Li S, Jia X, Guo X, Zhang Q

Abstract
It has been previously reported that mutations in retinal G protein coupled receptor (RGR) are associated with retinitis pigmentosa. The present study aims to systemically analyze the potential role of variants of RGR in retinal diseases. Variants in coding regions and splice sites of RGR were selected from a whole exome sequencing dataset of 820 probands with various forms of genetic ocular diseases. Potential variants of RGR were further confirmed by Sanger sequencing and analyzed in available family members. Clinical data was reviewed for patients with RGR variants. As a result, a total of five variants in RGR were detected in six probands with different types of ocular diseases. Of the five variants, two were novel heterozygous truncation variations, c.266C>A (p.S89*) and c.722_723delCC (p.S241Yfs*29), identified in two probands with high myopia and confirmed by Sanger sequencing. Segregation analysis on available family members demonstrated p.S89* and p.S241Yfs*29 were also present in unaffected relatives. The other three variants of RGR were heterozygous missense variants randomly occurring in patients with different genetic ocular diseases. No homozygous or compound heterozygous variants were detected. The results of the present study suggested that the heterozygous truncation variants in RGR were less likely to be pathogenic. Further studies are expected to evaluate the pathogenicity of variants in RGR.

PMID: 27748892 [PubMed - indexed for MEDLINE]

The first Japanese case of leukodystrophy with ovarian failure arising from novel compound heterozygous AARS2 mutations.

J Hum Genet. 2016 Oct;61(10):899-902

Authors: Hamatani M, Jingami N, Tsurusaki Y, Shimada S, Shimojima K, Asada-Utsugi M, Yoshinaga K, Uemura N, Yamashita H, Uemura K, Takahashi R, Matsumoto N, Yamamoto T

Abstract
Even now, only a portion of leukodystrophy patients are correctly diagnosed, though various causative genes have been identified. In the present report, we describe a case of adult-onset leukodystrophy in a woman with ovarian failure. By whole-exome sequencing, a compound heterozygous mutation consisting of NM_020745.3 (AARS2_v001):c.1145C>A and NM_020745.3 (AARS2_v001):c.2255+1G>A was identified. Neither of the mutations has been previously reported, and this is the first report of alanyl-transfer RNA synthetase 2 mutation in Asia. We anticipate that further studies of the molecular basis of leukodystrophy will provide insight into its pathogenesis and hopefully lead to sophisticated diagnostic and treatment strategies.

PMID: 27251004 [PubMed - indexed for MEDLINE]

De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux.

J Hum Genet. 2016 Sep;61(9):835-8

Authors: Fujita A, Isidor B, Piloquet H, Corre P, Okamoto N, Nakashima M, Tsurusaki Y, Saitsu H, Miyake N, Matsumoto N

Abstract
MEIS2 aberrations are considered to be the cause of intellectual disability, cleft palate and cardiac septal defect, as MEIS2 copy number variation is often observed with these phenotypes. To our knowledge, only one nucleotide-level change-specifically, an in-frame MEIS2 deletion-has so far been reported. Here, we report a female patient with a de novo nonsense mutation (c.611C>G, p.Ser204*) in MEIS2. She showed severe intellectual disability, moderate motor/verbal developmental delay, cleft palate, cardiac septal defect, hypermetropia, severe feeding difficulties with gastro-esophageal reflux and constipation. By reviewing this patient and previous patients with MEIS2 point mutations, we found that feeding difficulty with gastro-esophageal reflux appears to be one of the core clinical features of MEIS2 haploinsufficiency, in addition to intellectual disability, cleft palate and cardiac septal defect.

PMID: 27225850 [PubMed - indexed for MEDLINE]

A PDE3A mutation in familial hypertension and brachydactyly syndrome.

J Hum Genet. 2016 Aug;61(8):701-3

Authors: Boda H, Uchida H, Takaiso N, Ouchi Y, Fujita N, Kuno A, Hata T, Nagatani A, Funamoto Y, Miyata M, Yoshikawa T, Kurahashi H, Inagaki H

Abstract
Hypertension and brachydactyly syndrome (HTNB) with short stature is an autosomal-dominant disorder. Mutations in the PDE3A gene located at 12p12.2-p11.2 were recently identified in HTNB families. We found a novel heterozygous missense mutation c.1336T>C in exon 4 of the PDE3A gene in a Japanese family with multiple HTNB patients. This mutation was found to be completely linked to the family members who inherited this condition. The mutation, resulting in p.Ser446Pro, was located within the cluster region of reported mutations. This mutation may also affect the phosphodiesterase activity of PDE3A to reduce the cyclic AMP level in the cell and thereby influencing the development of limbs and the function of the cardiovascular system.

PMID: 27053290 [PubMed - indexed for MEDLINE]

De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures.

J Hum Genet. 2016 May;61(5):381-7

Authors: Fukai R, Saitsu H, Tsurusaki Y, Sakai Y, Haginoya K, Takahashi K, Hubshman MW, Okamoto N, Nakashima M, Tanaka F, Miyake N, Matsumoto N

Abstract
The voltage-gated Kv10.1 potassium channel, also known as ether-a-go-go-related gene 1, encoded by KCNH1 (potassium voltage-gated channel, subfamily H (eag related), member 1) is predominantly expressed in the central nervous system. Recently, de novo missense KCNH1 mutations have been identified in six patients with Zimmermann-Laband syndrome and in four patients with Temple-Baraitser syndrome. These syndromes were historically considered distinct. Here we report three de novo missense KCNH1 mutations in four patients with syndromic developmental delay and epilepsy. Two novel KCNH1 mutations (p.R357Q and p.R357P), found in three patients, were located at the evolutionally highly conserved arginine in the channel voltage-sensor domain (S4). Another mutation (p.G496E) was found in the channel pore domain (S6) helix, which acts as a hinge in activation gating and mainly conducts non-inactivating outward potassium current. A previously reported p.G496R mutation was shown to produce no voltage-dependent outward current in CHO cells, suggesting that p.G496E may also disrupt the proper function of the Kv channel pore. Our report confirms that KCNH1 mutations are associated with syndromic neurodevelopmental disorder, and also support the functional importance of the S4 domain.

PMID: 26818738 [PubMed - indexed for MEDLINE]

SOFT syndrome caused by compound heterozygous mutations of POC1A and its skeletal manifestation.

J Hum Genet. 2016 Jun;61(6):561-4

Authors: Ko JM, Jung S, Seo J, Shin CH, Cheong HI, Choi M, Kim OH, Cho TJ

Abstract
SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis, which is caused by biallelic mutations in the POC1A gene. Only 19 patients with mutation-confirmed SOFT syndrome have been reported to date, all of whom carried homozygous variants that were strongly associated with consanguineous marriages. We report an 8.5-year-old boy with SOFT syndrome showing primordial dwarfism, no effect of growth-hormone therapy and skeletal dysplasia. This is the first report of compound heterozygous variants in POC1A, one previously reported and the other novel. A characteristic skeletal manifestation is reported.

PMID: 26791357 [PubMed - indexed for MEDLINE]

Tadalafil Facilitates the Distal Ureteral Stone Expulsion: A Meta-Analysis.

J Endourol. 2017 Apr 06;:

Authors: Bai Y, Yang Y, Wang X, Tang Y, Han P, Wang J

Abstract
OBJECTIVE: To assess the efficacy and safety of tadalafil in facilitating the spontaneous passage of distal ureteral stones.
METHODS: The relevant studies were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to November 2016. Randomized controlled trials evaluating effects of tadalafil for distal ureteral stones were included.
RESULTS: Six publications involving 921 patients were included. Compared with tamsulosin monotherapy, tadalafil monotherapy or combined with tamsulosin has a significantly higher stone expulsion rate (relative risk [RR], 1.16; 95% confidence interval [CI], 1.05 to 1.29; p = 0.004; RR, 1.24; 95% CI, 1.09 to 1.42; p = 0.001, respectively) and shorter time to stone expulsion (mean difference [MD], -1.33 days; 95% CI, -2.44 to -0.23; p = 0.02; MD, -1.98 days; 95% CI, -3.08 to -0.88; p = 0.0004, respectively). Statistically significant differences were noted in pain episodes and analgesic use in favor of group tadalafil alone compared to group tamsulosin alone. The analgesic use was significantly lower in the combined group than in the tamsulosin alone group. Although the occurrence of drug-related adverse events in the tadalafil alone or combined with tamsulosin was higher than that in the use of tamsulosin-alone group, the most common adverse events were mild and tolerable.
CONCLUSIONS: Our study suggested that medical expulsive therapy for the distal ureteral stones using tadalafil alone or combined with tamsulosin is safe, efficacious, and well tolerated.

PMID: 28384011 [PubMed - as supplied by publisher]

Adverse drug reactions in therapeutic hypothermia after cardiac arrest.

Ther Adv Drug Saf. 2017 Mar;8(3):101-111

Authors: Witcher R, Dzierba AL, Kim C, Smithburger PL, Kane-Gill SL

Abstract
BACKGROUND: Therapeutic hypothermia (TH) improves survival and neurologic function in comatose survivors of cardiac arrest. Many medications used to support TH have altered pharmacokinetics and pharmacodynamics during this treatment. It is unknown if or at what frequency the medications used during TH cause adverse drug reactions (ADRs).
METHODS: A retrospective chart review was conducted for patients admitted to an intensive care unit (ICU) after cardiac arrest and treated with TH from January 2009 to June 2012 at two urban, university-affiliated, tertiary-care medical centres. Medications commonly used during TH were screened for association with significant ADRs (grade 3 or greater per Common Terminology Criteria for Adverse Events) using three published ADR detection instruments.
RESULTS: A total of 229 patients were included, the majority being males with median age of 62 presenting with an out-of-hospital cardiac arrest in pulseless electrical activity or asystole. The most common comorbidities were hypertension, coronary artery disease, and diabetes mellitus. There were 670 possible ADRs and 69 probable ADRs identified. Of the 670 possible ADRs, propofol, fentanyl, and acetaminophen were the most common drugs associated with ADRs. Whereas fentanyl, insulin, and propofol were the most common drugs associated with a probable ADR. Patients were managed with TH for a median of 22 hours, with 38% of patients surviving to hospital discharge.
CONCLUSIONS: Patients undergoing TH after cardiac arrest frequently experience possible adverse reactions associated with medications and the corresponding laboratory abnormalities are significant. There is a need for judicious use and close monitoring of drugs in the setting of TH until recommendations for dose adjustments are available to help prevent ADRs.

PMID: 28382198 [PubMed - in process]

Sappanone A protects mice against cisplatin-induced kidney injury.

Int Immunopharmacol. 2016 Sep;38:246-51

Authors: Kang L, Zhao H, Chen C, Zhang X, Xu M, Duan H

Abstract
Cisplatin (CP) is an anti-cancer drug that often causes nephrotoxicity due to enhanced inflammatory response and oxidative stress. Sappanone A (SA), a homoisoflavanone isolated from the heartwood of Caesalpinia sappan, has been known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the protective effects and mechanism of SA on CP-induced kidney injury in mice. The results showed that treatment of SA improved CP-induced histopathalogical injury and renal dysfunction. SA also inhibited CP-induced MPO, MDA, TNF-α and IL-1β production and up-regulated the activities of SOD and GSH-PX decreased by CP. SA significantly inhibited the apoptosis rate of kidney tissues induced by CP. Furthermore, SA was found to inhibit CP-induced NF-κB activation. Treatment of SA up-regulated the expression of Nrf2 and HO-1 in a dose-dependent manner. In vitro, SA dose-dependently inhibited CP-induced TNF-α and IL-1β production and NF-κB activation in HK-2 cells. In conclusion, these results suggested that SA inhibited CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation. SA was a potential therapeutic drug for treating CP-induced kidney injury.

PMID: 27318179 [PubMed - indexed for MEDLINE]

Improving drug safety with a systems pharmacology approach.

Eur J Pharm Sci. 2016 Oct 30;94:84-92

Authors: Schotland P, Bojunga N, Zien A, Trame MN, Lesko LJ

Abstract
Systems pharmacology is used to mechanistically analyze drug-adverse drug reaction (ADRs) pairs and is a promising solution to the complex problem of understanding mechanisms of toxicity. In this research, we have explored the feasibility of retrospectively mapping population-level adverse events from the FDA Adverse Event Reporting System (FAERS) to chemical and biological databases to identify drug safety signals and the underlying molecular mechanisms. We used an analytic platform - Molecular Analysis of Side Effects (MASE™). For this purpose, we selected the adverse event of severe and potentially fatal cutaneous reactions (SCARs) that are associated with acetaminophen (APAP). SCARs encompass the continuum between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). We found a statistically significant association between APAP and TEN, the most severe form of SCARs. We also explored the influence of APAP on other classes of drugs commonly associated with SCARs. We found that APAP significantly reduced the risk of SCARs commonly associated with carbamazepine (CBZ). We used molecular docking simulations to propose a mechanism for APAP's reduction in CBZ-induced SCARs which is competitive inhibition of the binding of CBZ to HLA-B*15:02. We conclude that systems pharmacology can complement established surveillance methodologies by providing a means to undertake an independent investigation and review of the mechanisms by which drugs cause adverse events.

PMID: 27287422 [PubMed - indexed for MEDLINE]

Systems pharmacology to predict drug safety in drug development.

Eur J Pharm Sci. 2016 Oct 30;94:93-95

Authors: Trame MN, Biliouris K, Lesko LJ, Mettetal JT

Abstract
Ensuring that drugs are safe and effective is a very high priority for drug development and the US Food and Drug Administration review process. This is especially true today because of faster approval times and smaller clinical trials, especially in oncology and rare diseases. In light of these trends, systems pharmacology is seen as an essential strategy to understand and predict adverse drug events during drug development by analyzing interactions between drugs and multiple targets rather than the traditional "one-drug-one-target" approach. This commentary offers an overview of the current trends and challenges of using systems pharmacology to reduce the risks of unintended adverse events.

PMID: 27251780 [PubMed - indexed for MEDLINE]

A Systematic Approach to Assess the Burden of Drug Interactions in Adult Kidney Transplant Patients.

Curr Drug Saf. 2016;11(2):156-63

Authors: Bril F, Castro V, Centurion IG, Espinosa J, Keller GA, Gonzalez CD, Riera MC, Saubidet CL, Di Girolamo G, Pujol GS, Alvarez PA

Abstract
AIM: Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population.
METHODS: A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs.
RESULTS: As a consequence of the high number of medications per patient (7.8±0.2 drugs), a considerable number of drugdrug interactions were observed in this population, with an average of 5.6±0.4 drug interactions per patient. Moreover, a significant percentage of admissions (~10%) of kidney transplant patients were related to probable ADRs. Almost all these patients had at least one drug interaction that could have potentially contributed to the probable ADR. Of note, clinically significant (i.e. severe) drug interactions were more frequent among patients with ADRs (29% vs. 15%, p<0.01). Also, patients with ADRs were more likely to have started a medication 30 days before admission (38.5% vs. 10.4%, p < 0.01). Non-immunosuppressive drugs most commonly involved in severe interactions were omeprazole, magnesium sulphate, and statins. The most commonly observed interactions were: tacrolimus and omeprazole, mycophenolate and omeprazole, sirolimus and enalapril, mycophenolate and antivirals, and mycophenolate and magnesium sulphate.
CONCLUSION: Drug interactions were extremely frequent among kidney transplant recipients, and responsible for potentially avoidable ADRs. They should be carefully considered when following kidney transplant recipients.

PMID: 27194037 [PubMed - indexed for MEDLINE]

Computed Biological Relations among Five Select Treatment-Related Organ/Tissue Toxicities.

Chem Res Toxicol. 2016 05 16;29(5):914-23

Authors: Sakellaropoulos T, Herod TJ, Alexopoulos LG, Bai JP

Abstract
Drug toxicity presents a major challenge in drug development and patient care. We set to build upon previous works regarding select drug-induced toxicities to find common patterns in the mode of action of the drugs associated with these toxicities. In particular, we focused on five disparate organ toxicities, peripheral neuropathy (PN), rhabdomyolysis (RM), Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), lung injury (LI), and heart contraction-related cardiotoxicity (CT), and identified biological commonalities between and among the toxicities in terms of pharmacological targets and nearest neighbors (indirect effects) using the hyper-geometric test and a distance metric of Spearman correlation. There were 20 significant protein targets associated with two toxicities and 0 protein targets associated with three or more toxicities. Per Spearman distance, PN was closest to SJS/TEN compared to other pairs, whereas the pairs involving RM were more different than others excluding RM. The significant targets associated with RM outnumbered those associated with every one of the other four toxicities. Enrichment analysis of drug targets that are expressed in corresponding organ/tissues determined proteins that should be avoided in drug discovery. The identified biological patterns emerging from the mode of action of these drugs are statistically associated with these serious toxicities and could potentially be used as predictors for new drug candidates. The predictive power and usefulness of these biological patterns will increase with the database of these five toxicities. Furthermore, extension of our approach to all severe adverse reactions will produce useful biological commonalities for reference in drug discovery and development.

PMID: 27063352 [PubMed - indexed for MEDLINE]

Patterns of Adverse Drug Reaction in the Medical Wards of a Teaching Hospital: A Prospective Observational Cohort Study.

Curr Drug Saf. 2016;11(2):164-71

Authors: Peter JV, Varghese GH, Alexander H, Tom NR, Swethalekshmi V, Truman C, Kumar TR, Sivakumar T

Abstract
INTRODUCTION: According to the World Health Organization (WHO) definition, an Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis, and treatment of disease. The risk factors of ADR are multi-factorial and include poly-pharmacy, age, gender, race, genetics and inter-current disease.
PATIENTS AND METHODS: This was a hospital based, prospective, observational cohort study undertaken in a tertiary care hospital in south India to assess the different patterns of adverse drug reaction in medical wards over 6 months. The severity of ADR was assessed using Hartwig Siegel scale and causality by Naranjo and WHO UMC Scale. Preventability was assessed using Schumock and Thornton scale and other parameters such as incidence, onset, duration, management and outcome were also assessed. Risk factors were assessed by bi-variate logistic regression analysis and length of hospital stay by T test.
RESULTS: The incidence of ADR was 10.42% in medicine wards. The causality of ADR done by Naranjo scale showed that most of the ADRs were probable (7.38%). Anti-tubercular agents were the leading cause of ADR. Duration of hospitalization was significantly longer (7.18 ± 2.64 vs. 5.06 ± 2.13 days) in patients with ADR (Odds ratio 1.38, 95% Confidence interval 1.26 to 1.51). 7.28% of ADRs were moderately severe. Seriousness criteria assessment showed that 0.33% were serious reactions. Most of the ADRs were definitely preventable. Most of the ADRs were managed by discontinuing the suspected drug. The present study showed female gender predominance over males for ADRs and no relationship with age.
CONCLUSION: Adverse drug reactions impose significant burden on hospitals through prolonging patient stay and by increasing admission rates. The occurrence of ADR in this study was higher when compared to that reported in previous studies. This study highlights the importance of ADR reporting among ADR reporting among health care professionals in hospital.

PMID: 26916785 [PubMed - indexed for MEDLINE]

Incidence of Adverse Drug Reactions in Indian Hospitals: A Systematic Review of Prospective Studies.

Curr Drug Saf. 2016;11(2):128-36

Authors: Patel TK, Patel PB

Abstract
This systematic review estimated the incidence of ADRs that lead to hospitalization (ADRAd) and that developed during hospitalization (ADRIn) and factors affecting in Indian population. Two independent investigators searched the electronic databases describing ADRs. Due to high heterogeneity, incidence of ADRAd and ADRIn were presented as median (interquartile range-IQR). We performed the subgroup analysis of incidence based on characteristics of the included studies. The meta-analysis (generic inverse variance method with random effect model) was possible for the fatal ADR incidence. The risk factors for ADRs were also explored from the included studies. We used 'Review manager software version 5.0' and 'Graph Pad Prism version 6.0' for the analysis. Of 77 fully evaluated references, 21 prospective studies were selected. The median incidence of ADRAd and ADRIn were 2.85% (IOR: 1.25 - 3.93%) and 6.34% (IQR: 3.36 - 16.37%), respectively. The subgroup analysis found high incidence rate with studies conducted in intensive care units, elderly age groups, with intensive monitoring, duration of > 1 year and multidisciplinary team. The fatal ADR incidence was 0.08% (95% CI: 0.00-0.15%). Important risk factors for ADRs included elderly, female sex and polypharmacy. The hospitalized patients have a significant burden of ADRs. The multiple factors may have affected their occurrence.

PMID: 26391424 [PubMed - indexed for MEDLINE]

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