Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity.

Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort (n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation (P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery (P = 0.0298) and replication (n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion.

A founder mutation in COL4A3 causes autosomal recessive Alport syndrome in the Ashkenazi Jewish population.

Alport syndrome is an inherited progressive nephropathy arising from mutations in the type IV collagen genes, COL4A3, COL4A4, and COL4A5. Symptoms also include sensorineural hearing loss and ocular lesions. We determined the molecular basis of Alport syndrome in a non-consanguineous Ashkenazi Jewish family with multiple affected females using linkage analysis and next generation sequencing. We identified a homozygous COL4A3 mutation, c.40_63del, in affected individuals with mutant alleles inherited from each parent on partially conserved haplotypes. Large-scale population screening of 2017 unrelated Ashkenazi Jewish samples revealed a carrier frequency of 1 in 183 indicating that COL4A3 c.40_63del is a founder mutation which may be a common cause of Alport syndrome in this population. Additionally, we determined that heterozygous mutation carriers in this family do not meet criteria for a diagnosis of Thin Basement Membrane Nephropathy and concluded that carriers of c.40_63del are not likely to develop benign familial hematuria.

Feline exocrine pancreatic carcinoma: a retrospective study of 34 cases.

Thirty-four cases were reviewed in this retrospective study for information on clinical presentation, prognostic indicators, survival time and response to various therapies. The most common presenting clinical signs were weight loss, decreased appetite, vomiting, palpable abdominal mass and diarrhoea. Metastatic disease was confirmed in 11 cats. The overall median survival was 97 days. The median survival times for patients who received chemotherapy or had their masses surgically removed was 165 days. Those patients who had an abdominal effusion present at the time of diagnosis survived a median of 30 days. Cats that received non-steroidal anti-inflammatory drug therapy had a median survival of 26 days. This study confirms that exocrine pancreatic carcinoma in cats is an aggressive tumour with a high metastatic rate and poor prognosis, although three patients survived over 1 year. Fifteen percent of the patients were diabetic, which raises the question as to what the link between diabetes and pancreatic cancer in people and cats may be.

Ecological degradation in protected areas: the case of Wolong Nature Reserve for giant pandas.

It is generally perceived that biodiversity is better protected from human activities after an area is designated as a protected area. However, we found that this common perception was not true in Wolong Nature Reserve (southwestern China), which was established in 1975 as a "flagship" protected area for the world-renowned endangered giant pandas. Analyses of remote sensing data from pre- and post-establishment periods indicate that the reserve has become more fragmented and less suitable for giant panda habitation. The rate of loss of high-quality habitat after the reserve's establishment was much higher than before the reserve was created, and the fragmentation of high-quality habitat became far more severe. After the creation of the reserve, rates of habitat loss and fragmentation inside the reserve unexpectedly increased to levels that were similar to or higher than those outside the reserve, in contrast to the situation before the reserve was created.

Serum alanine aminotransferase levels and prevalence of hepatitis A, B, and delta in outpatients.

We investigated the relationship between alanine aminotransferase (ALT) levels and the prevalence of serologic markers of hepatitis A, hepatitis B, and delta hepatitis in an outpatient population. Sera submitted for routine biochemical testing from 4669 patients were grouped according to ALT level (normal and 1 to 2.5, 2.5 to 5.0, and more than five times the upper limit of normal). Serologic evidence of acute hepatitis A or acute or chronic hepatitis B was detected in 6.1% of specimens with elevated ALT levels compared with 1.3% with normal ALT levels. Patients with ALT levels greater than 2.5-fold and fivefold elevated were associated with a 9.3% and a 15.1% prevalence, respectively, of markers of acute or chronic hepatitis. Antibody to delta hepatitis was detected in nine subjects, all of whom also had serologic evidence of chronic hepatitis B. A retrospective chart review of 80 patients with serologic evidence of acute or chronic hepatitis revealed that 51% of cases were previously undiagnosed, most of which were in the low ALT groups. Hepatitis serologic testing may be indicated in outpatients with unexplained elevations of the ALT level.