Therapeutic augmentation of NO-sGC-cGMP signalling: lessons learned from pulmonary arterial hypertension and heart failure

Heart Failure Reviews - The nitric oxide (NO)–guanylate cyclase (GC)–cyclic guanosine monophosphate (cGMP) pathway plays an important role in cardiovascular, pulmonary and renal...     

Differentiating poor validity from probable impairment on the medical symptom validity test: a cross-validation study

Aims: In neuropsychological evaluations, it is often difficult to ascertain whether poor performance on measures of validity is due to poor effort or malingering, or whether there is genuine cognitive impairment. Dunham and Denney created an algorithm to assess this question using the Medical Symptom Validity Test (MSVT). We assessed the ability of their algorithm to detect poor validity versus probable impairment, and concordance of failure on the MSVT with other freestanding tests of performance validity.

Methods: Two previously published datasets (n?=?153 and n?=?641, respectively) from outpatient neuropsychological evaluations were used to test Dunham and Denney’s algorithm, and to assess concordance of failure rates with the Test of Memory Malingering and the forced choice measure of the California Verbal Learning Test, two commonly used performance validity tests.

Results: In both datasets, none of the four cutoff scores for failure on the MSVT (70%, 75%, 80%, or 85%) identified a poor validity group with proportionally aligned failure rates on other freestanding measures of performance validity. Additionally, the protocols with probable impairment did not differ from those with poor validity on cognitive measures.

Conclusions: Despite what appeared to be a promising approach to evaluating failure on the easy MSVT subtests when clinical data are unavailable (as recommended in the advanced interpretation program, or advanced interpretation [AI], of the MSVT), the current findings indicate the AI remains the gold standard for doing so. Future research should build on this effort to address shortcomings in measures of effort in neuropsychological evaluations.     

C.B‐17 SCID mice develop epicardial calcinosis with unaltered cardiac function

Inbred mouse strains are the most widely used mammalian model organism in biomedical research owing to ease of genetic manipulation and short lifespan; however, each inbred strain possesses a unique repertoire of deleterious homozygous alleles that can make a specific strain more susceptible to a particular disease. In the current study, we report dystrophic cardiac calcinosis (DCC) in C.B‐17 SCID male mice at 10 weeks of age with no significant change in cardiac function. Acquisition of DCC was characterized by myocardial injury, fibrosis, calcification, and necrosis of the tissue. At 10 weeks of age, 38% of the C.B‐17 SCID mice from two different commercial colonies exhibited significant calcinosis on the ventricular epicardium, predominantly on the right ventricle. The frequency of calcinosis was more than 50% for mice obtained from Taconic's Cambridge City colony and 25% for mice obtained from Taconic's German Town colony. Interestingly, the DCC phenotype did not affect cardiac function at 10 weeks of age. No differences in echocardiography or electrocardiography were observed between the calcinotic and non‐calcinotic mice from either colony. Our findings suggest that C.B‐17 SCID mice exhibit DCC as early as 10 weeks of age with no significant impact on cardiac function. This strain of mice should be cautiously considered for the study of cardiac physiology.     

Natural Variant of Collagen-Like Protein A in Serotype M3 Group A Streptococcus Increases Adherence and Decreases Invasive Potential

Group A Streptococcus (GAS) predominantly exists as a colonizer of the human oropharynx that occasionally breaches epithelial barriers to cause invasive diseases. Despite the frequency of GAS carriage, few investigations into the contributory molecular mechanisms exist. To this end, we identified a naturally occurring polymorphism in the gene encoding the streptococcal collagen-like protein A (SclA) in GAS carrier strains. All previously sequenced invasive serotype M3 GAS possess a premature stop codon in the sclA gene truncating the protein. The carrier polymorphism is predicted to restore SclA function and was infrequently identified by targeted DNA sequencing in invasive strains of the same serotype. We demonstrate that a strain with the carrier sclA allele expressed a full-length SclA protein, while the strain with the invasive sclA allele expressed a truncated variant. An isoallelic mutant invasive strain with the carrier sclA allele exhibited decreased virulence in a mouse model of invasive disease and decreased multiplication in human blood. Further, the isoallelic invasive strain with the carrier sclA allele persisted in the mouse nasopharynx and had increased adherence to cultured epithelial cells. Repair of the premature stop codon in the invasive sclA allele restored the ability to bind the extracellular matrix proteins laminin and cellular fibronectin. These data demonstrate that a mutation in GAS carrier strains increases adherence and decreases virulence and suggest selection against increased adherence in GAS invasive isolates.