Functional significance of genetic polymorphisms

Natural genetic polymorphisms are gifts from nature and sources of variations at all levels. The postgenomic era permits new perspectives on interpreting genetic polymorphisms and also poses challenges for scientists to answer system questions. Rather than a comprehensive coverage of genetic polymorphisms up-to-date, this review attempts to present some of the results in a somewhat coherent manner to highlight the needs and potentials of pertinent studies.     

Novel mutation in N-terminal fragment of ryanodine receptor 2 causing catecholaminergic polymorphic ventricular tachycardia

CPVT is a rare inherited arrhythmogenic disorder characterized by bidirectional, polymorphic ventricular arrhythmias triggered by catecholamines released during exercise, stress, or sudden emotion in individuals with a normal resting electrocardiogram and structurally normal heart. Mutations in the ryanodine receptor 2 gene are the most common known etiology of this disorder. The c.1195A > G(p.Met399Val) variant in Exon 14 of RyR2 is currently classified as a Variant of Uncertain Significance. We present a case of CPVT caused by this novel disease-causing RyR2 variant and discuss its pathophysiology. The role of SSRIs in treating patients with CPVT unresponsive to mainstream therapies is also highlighted.     

Minimizing the cost of environmental management decisions by optimizing statistical thresholds

Environmental management decisions are prone to expensive mistakes if they are triggered by hypothesis tests using the conventional Type I error rate (α) of 0.05. We derive optimal α‐levels for decision‐making by minimizing a cost function that specifies the overall cost of monitoring and management. When managing an economically valuable koala population, it shows that a decision based on α = 0.05 carries an expected cost over $5 million greater than the optimal decision. For a species of such value, there is never any benefit in guarding against the spurious detection of declines and therefore management should proceed directly to recovery action. This result holds in most circumstances where the species’ value substantially exceeds its recovery costs. For species of lower economic value, we show that the conventional α‐level of 0.05 rarely approximates the optimal decision‐making threshold. This analysis supports calls for reversing the statistical ‘burden of proof’ in environmental decision‐making when the cost of Type II errors is relatively high.     

Prognostic significance of lysosomal cysteine proteases in the estimation of the effectiveness of the antitumor therapy

The influence of the antitumor drugs, cyclophosphamide (CPA) and nitrosomethylurea (NMU) on the activity of lysosomal cysteine proteases cathepsin B and L in tumor tissue has been investigated using CPA-sensitive (LS) and CPA-resistant mouse lymphosarcomas (RLS). (These drugs exhibit high and low antitumor efficiency towards LS and RLS mouse lymphosarcomas, respectively). Regression or reduction in the growth rate of LS and RLS lymphosarcomas caused by CPA or NMU administration was accompanied by the increase in the activity of cysteine proteases cathepsin B and L in the tumor tissue. The increase of cathepsin B and L activity in tumor tissue correlated with the therapeutic effect of these drugs. Data obtained suggest that activity of cathepsin B and L in tumor tissue has a prognostic significance for the estimation of the effectiveness of antitumor therapy.