Abnormal white‐matter rich‐club organization in obsessive–compulsive disorder

Rich‐club organization is key to efficient global neuronal signaling and integration of information. Alterations interfere with higher‐order cognitive processes, and are common to several psychiatric and neurological conditions. A few studies examining the structural connectome in obsessive–compulsive disorder (OCD) suggest lower efficiency of information transfer across the brain. However, it remains unclear whether this is due to alterations in rich‐club organization. In the current study, the structural connectome of 28 unmedicated OCD patients, 8 of their unaffected siblings and 28 healthy controls was reconstructed by means of diffusion‐weighted imaging and probabilistic tractography. Topological and weighted measures of rich‐club organization and connectivity were computed, alongside global and nodal measures of network integration and segregation. The relationship between clinical scores and network properties was explored. Compared to healthy controls, OCD patients displayed significantly lower topological and weighted rich‐club organization, allocating a smaller fraction of all connection weights to the rich‐club core. Global clustering coefficient, local efficiency, and clustering of nonrich club nodes were significantly higher in OCD patients. Significant three‐group differences emerged, with siblings displaying highest and lowest values in different measures. No significant correlation with any clinical score was found. Our results suggest weaker structural connectivity between rich‐club nodes in OCD patients, possibly resulting in lower network integration in favor of higher network segregation. We highlight the need of looking at network‐based alterations in brain organization and function when investigating the neurobiological basis of this disorder, and stimulate further research into potential familial protective factors against the development of OCD.     

Confirmatory factor analysis of the Dutch Intolerance of Uncertainty Scale: Comparison of the full and short version

BACKGROUND AND OBJECTIVES: The Intolerance of Uncertainty Scale (IUS) was developed for assessing reactions to ambiguous situations, uncertainty, and future events. The IUS has been validated in different languages, but equivocal factor structures, in combination with highly interrelated items and factors, resulted in a redundancy of the items of the English version. In the current study, the psychometric properties of the Dutch version of the IUS were examined, and compared with the shortened 12-item version (IUS-12). METHODS: Confirmatory factor analyses were used to investigate different factor structures of both the full and short version of the IUS. RESULTS: Results indicated that the IUS-12 model with two factors (Prospective Anxiety and Inhibitory Anxiety) provides the best fit. The reduced measure has equally good internal consistency, and is highly correlated with the full version. LIMITATIONS: Future research could investigate whether the current findings generalize to clinical populations. CONCLUSION: To summarize, the usage of the short 12-item version of the IUS should be encouraged in future research concerning intolerance of uncertainty.     

A nonsurgical porcine model of left ventricular dysfunction. Validation of myocardial viability using dobutamine stress echocardiography and positron emission tomography

BACKGROUND: Although several shortterm animal models of stunning and hibernation have been studied extensively, it has been difficult to produce a consistent animal model of chronic hibernation. The aim of the present study was to develop a nonsurgical porcine stent model of coronary stenosis in order to investigate the relationship between chronic dysfunctional myocardium and viability using 2D-echo, dobutamine stress echo (DSE) and positron emission tomography (PET). METHODS AND RESULTS: Focal progressive coronary stenosis was induced by implantation of an oversized stent in the left anterior descending (LAD) and/or circumflex (LCX) coronary artery in a total of 115 pigs, according to various experimental protocols: copper stent in the LAD (group I, n = 5); noncoated stainless steel stent in the LAD combined with balloon overstretch (group II, n = 7); poly(organo)phosphazene-coated stent in the LAD (group III, n = 77); and poly(organo)phosphazene-coated stent in both the LAD and the LCX (group IV, n = 26). Occurrence of left ventricular dysfunction was evaluated weekly by 2D-echo. At the time of left ventricular dysfunction the presence of viable myocardium within the dysfunctional region was investigated with DSE and PET, and confirmed by histology. The degree of coronary artery stenosis was measured by quantitative coronary angiography and morphometry. Severe coronary artery stenosis in the presence of dysfunctional, but viable, myocardium was induced in groups III and IV (47% and 11% of the animals, respectively). CONCLUSIONS: The authors developed a nonsurgical porcine stent model of progressive coronary stenosis using an oversized polymer-coated stent resulting in chronically decreased myocardial function, with residual inotropic reserve and viable myocardium. This condition may arise from repetitive periods of ischemia, or from sustained hypoperfusion, or a combination of these processes eventually leading to myocardial hibernation. (Int J Cardiovasc Intervent 2000; 3: 111-120)     

Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population

Objective: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS.

Methods: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years.

Results: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10–20?mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period.

Conclusions: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.     

Discovery of a cholecystokinin-gastrin-like signaling system in nematodes

Members of the cholecystokinin (CCK)/gastrin family of peptides, including the arthropod sulfakinins, and their cognate receptors, play an important role in the regulation of feeding behavior and energy homeostasis. Despite many efforts after the discovery of CCK/gastrin immunoreactivity in nematodes 23 yr ago, the identity of these nematode CCK/gastrin-related peptides has remained a mystery ever since. The Caenorhabditis elegans genome contains two genes with high identity to the mammalian CCK receptors and their invertebrate counterparts, the sulfakinin receptors. By using the potential C. elegans CCK receptors as a fishing hook, we have isolated and identified two CCK-like neuropeptides encoded by neuropeptide-like protein-12 (nlp-12) as the endogenous ligands of these receptors. The neuropeptide-like protein-12 peptides have a very limited neuronal expression pattern, seem to occur in vivo in the unsulfated form, and react specifically with a human CCK-8 antibody. Both receptors and ligands share a high degree of structural similarity with their vertebrate and arthropod counterparts, and also display similar biological activities with respect to digestive enzyme secretion and fat storage. Our data indicate that the gastrin-CCK signaling system was already well established before the divergence of protostomes and deuterostomes.     

The Influence of Social Threat on Pain,Aggression, and Empathy in Women

Only one published study has investigated the effect of a threatening social context on the perception and expression of pain, showing that social threat leads to increased pain reports but reduced nonverbal pain expression. The current study aimed to replicate and extend these findings to further explore the effects of a threatening social context. Healthy, female participants (N?=?71) received 10 electrocutaneous stimuli delivered by a confederate. They were led to believe that the confederate was requested to administer 10 painful stimuli (control group) or that the confederate deliberately chose to deliver 10 painful stimuli when given the choice to deliver between 1 to 10 painful stimuli (social threat group). Self-reported pain intensity, unpleasantness, threat value of pain, and painful facial expression were assessed. Additionally, empathy and aggression toward the confederate were investigated. Social threat did not affect painful facial expression or self-reported pain intensity, but led to increased aggression toward the confederate. Moreover, perceived social threat predicted the threat value of pain and reduced empathy toward the confederate. We were not able to replicate the previously reported dissociation between pain reports and pain expression as a result of social threat. However, social threat was associated with an increased threat value of pain, increased aggression, and reduced empathy.