Proline at the P2 position in protein C is important for calcium- mediated regulation of protein C activation and secretion

Protein C is a vitamin K-dependent plasma serine protease zymogen, which upon activation, functions as an anticoagulant. Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM). This activation is Ca(2+)-dependent, but Ca2+ inhibits protein C activation by thrombin alone. In most proteases, specificity is determined primarily by the residues that lie near the scissile bond. In protein C, the P2 position is Pro, whereas in the fibrinogen A chain, P2 is Val. We have expressed a Pro-->Val mutant of protein C (P168V) in mammalian cells. At saturating Ca2+, the P168V and wild-type proteins were activated by the T-TM complex equivalently, but half maximal rates of activation were obtained at 50 mumol/L Ca2+ for wild type and approximately 5 mmol/L Ca2+ for the P168V mutant. In the absence of TM, Ca2+ no longer inhibited the activation of the P168V mutant. These results indicate that Pro168 influences the Ca(2+)- dependent conformational changes in protein C that control activation. Recently, a patient with thrombotic complications has been identified with a Pro168-->Leu substitution. Both the P168V and the P168L mutation lead to impaired secretion caused by retention within the cell.     

Exercise tolerance in obese vs. lean adolescents: a systematic review and meta‐analysis

To prescribe feasible and medically safe exercise interventions for obese adolescents, it remains to be determined whether exercise tolerance is altered and whether anomalous cardiopulmonary responses during maximal exercise testing are present. Studies that examined cardiopulmonary responses to maximal exercise testing in obese adolescents were searched: cardiopulmonary exercise tests with respiratory gas exchange measurements of peak oxygen uptake (VO_2peak) were performed and comparisons between obese and lean adolescents were made. Study quality was assessed using a standardized item list. By meta‐analyses VO_2peak, peak cycling power output (W_peak) and peak heart rate (HR_peak) were compared between groups. Nine articles were selected (333 obese vs. 145 lean adolescents). VO_2peak (L min^?1), HR_peak and W_peak were not different between groups (P ≥ 0.10), while a trend was found for a reduced VO_2peak (mL min^?1 kg^?1 lean tissue mass) (P = 0.07) in obese vs. lean adolescents. It remained uncertain whether anomalous cardiopulmonary responses occur during maximal exercise testing in obese adolescents. In conclusion, a trend was found for lowered VO_2peak (mL min^?1 kg^?1 lean tissue mass) in obese vs. lean adolescents. Whether cardiopulmonary anomalies during maximal exercise testing would occur in obese adolescents remains uncertain. Studies are therefore warranted to examine the cardiopulmonary response during maximal exercise testing in obese adolescents.     

Long-term goals for oral health

The current, optimistic prognosis is that newborns will reach an average age of 100 years. This increased life-expectancy requires a renewed vision of long-term goals for oral health. The starting-point could be a prospective end-point with minimal oral function which should be reached, for example, in the last years of one's life. The consequence is that adequate oral healthcare for the elderly starts in childhood. Choices such as the extraction of premolars for orthodontic reasons and the dental re-restoration cycle have a great negative impact on reaching this goal. The average sustainability of dental restorations or prosthetic constructions is commonly much shorter than the life-expectancy of a patient. If oral treatment is necessary, it is recommended to give priority to maintaining a minimally functional dentition up to an advanced age, instead offocusing on short- or medium-term goals.     

Dissociable fronto-striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility

Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor (DRD2) in flexible behavioral adaptation, mostly shown in reward-based learning paradigms. Recent evidence from imaging genetics indicates that also intentional cognitive flexibility, associated with lateral frontal cortex, is affected by variations in DRD2 signaling. In the present functional magnetic resonance imaging (MRI) study, we tested the effects of a direct pharmacological manipulation of DRD2 stimulation on intentional flexibility in a task-switching context, requiring switches between cognitive task rules and between response hands. In a double blind, counterbalanced design, participants received either a low dose of the DRD2 agonist bromocriptine or a placebo in two separate sessions. Bromocriptine modulated the blood-oxygen-level-dependent (BOLD) signal during rule switching: rule-switching-related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo, at comparable performance levels. Fronto-striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions. Hand-switching-related activity, in contrast, was reduced under bromocriptine in sensorimotor regions. Our results provide converging evidence for an involvement of DRD2 signaling in fronto-striatal mechanisms underlying intentional flexibility, and indicate that the neural mechanisms underlying different types of flexibility (cognitive vs motor) are affected differently by increased dopaminergic stimulation.     

Pharmacotherapy and nutritional supplements for seasonal affective disorders: a systematic review

Introduction: A seasonal affective disorder (SAD) is a subtype of unipolar and bipolar major depressive disorders. It is characterized by its annual recurrence of depressive episodes at a particular season, mostly seen in winter and is responsible for 10–20% of the prevalence of major depressive disorders. Some pathophysiological hypotheses, such as the phase delay and the monoamine depletion hypotheses, have been postulated but the exact cause has not been fully unraveled yet. Studies on treatment for SAD in the last decade are lacking. To tackle this chronic disease, attention needs to be drawn to the gaps in this research field.

Areas covered: In this systematic review, the authors give a broad overview of the pharmacological therapy available for SAD. Also, nutritional substances fitting well with the postulated hypotheses are reviewed for the treatment and prevention of SAD. There is a specific focus on the quality of the currently performed studies.

Expert opinion: Light therapy and fluoxetine are the only proven and effective acute treatment options for SAD, while bupropion is the only registered drug for prevention of SAD. This area of research is in dire need of valid large-scale and sufficiently reproducible randomized control trials.     

Facial nerve injury during temporal artery biopsy

Temporal artery biopsy is considered the gold standard investigation of giant cell arteritis and is recommended in suspected cases despite a sensitivity of 81–91%. This review highlights the potential risk of facial nerve injury during temporal artery biopsy and introduces recent advances in the emerging role of imaging modalities. When these non-invasive techniques are used in conjunction with American College of Rheumatology scoring, which includes clinical features and biochemical test results, temporal artery biopsy may be avoided in selected cases.