Novel proteins that regulate cell extension formation in fibroblasts.

Cell extensions are critical structures that enable matrix remodeling in wound healing and cancer invasion but the regulation of their formation is not well-defined. We searched for new proteins that mediated cell extension formation over collagen by tandem mass tagged mass spectrometry analysis of purified extensions in 3T3 fibroblasts. Unexpectedly, importin-5, ENH isoform 1b (PDLIM5) and 26 S protease regulatory subunit 6B (PSMC4) were more abundant (> 10-fold) in membrane-penetrating cell extensions than cell bodies, which was confirmed by immunostaining and immunoblotting and also observed in human gingival fibroblasts. After siRNA knockdown of these proteins and plating cells on grid-supported floating collagen gels for 6 h, formation of cell extensions and collagen remodeling were examined. Knockdown of importin-5 reduced collagen compaction (1.9-fold), pericellular collagen degradation (~ 1.8-fold) and number of cell extensions (~ 69%). Knockdown of PSMC4 reduced collagen compaction (~ 1.5-fold), pericellular collagen degradation (~ 1.7-fold) and number of cell extensions (~ 42%). Knockdown of PDLIM5 reduced collagen compaction (~ 1.6-fold) and number of cell extensions (~ 21%). Inhibition of the TGF-ß RI kinase, Smad3 or ROCK-II signaling pathways reduced the abundance of PDLIM5 in cell extensions but PSMC4 and importin-5 were reduced only by Smad3 or ROCK-II inhibitors. We conclude that these novel proteins are required for cell extension formation and their recruitment into extensions involves the Smad3 and ROCK signaling pathways.

Bipolar disorder type I and II show distinct relationships between cortical thickness and executive function.

OBJECTIVE: Frontal cortical abnormalities and executive function impairment co-occur in bipolar disorder. Recent studies have shown that bipolar subtypes differ in the degree of structural and functional impairments. The relationships between cognitive performance and cortical integrity have not been clarified and might differ across patients with bipolar disorder type I, II, and healthy subjects. METHOD: Using a vertex-wise whole-brain analysis, we investigated how cortical integrity, as measured by cortical thickness, correlates with executive performance in patients with bipolar disorder type I, II, and controls (N = 160). RESULTS: We found focal associations between executive function and cortical thickness in the medial prefrontal cortex in bipolar II patients and controls, but not in bipolar I disorder. In bipolar II patients, we observed additional correlations in lateral prefrontal and occipital regions. CONCLUSIONS: Our findings suggest that bipolar disorder patients show altered structure-function relationships, and importantly that those relationships may differ between bipolar subtypes. The findings are line with studies suggesting subtype-specific neurobiological and cognitive profiles. This study contributes to a better understanding of brain structure-function relationships in bipolar disorder and gives important insights into the neuropathophysiology of diagnostic subtypes.

Sharing pain and relief: neural correlates of physicians during treatment of patients.

Patient-physician interactions significantly contribute to placebo effects and clinical outcomes. While the neural correlates of placebo responses have been studied in patients, the neurobiology of the clinician during treatment is unknown. This study investigated physicians' brain activations during patient-physician interaction while the patient was experiencing pain, including a 'treatment', 'no-treatment' and 'control' condition. Here, we demonstrate that physicians activated brain regions previously implicated in expectancy for pain-relief and increased attention during treatment of patients, including the right ventrolateral and dorsolateral prefrontal cortices. The physician's ability to take the patients' perspective correlated with increased brain activations in the rostral anterior cingulate cortex, a region that has been associated with processing of reward and subjective value. We suggest that physician treatment involves neural representations of treatment expectation, reward processing and empathy, paired with increased activation in attention-related structures. Our findings further the understanding of the neural representations associated with reciprocal interactions between clinicians and patients; a hallmark for successful treatment outcomes.

Cognitive flexibility is associated with sickness resilience.

Psychological constructs related to health outcomes and well-being, such as metacognitive beliefs, have been linked to executive functions in general, and cognitive flexibility more specifically. However, such effects have previously only been discussed on a theoretical level and behavioral flexibility has most often been measured through self-report, only approximating information processing capacities. Objectively measured executive functions may be a more potent predictor of health outcomes. We set out to test whether cognitive flexibility capacity was associated with sick leave in a medium sized company. We included 111 subjects of widely different occupations and assessed their executive functions using Delis-Kaplan Executive Function System test battery (D-KEFS). To assess cognitive flexibility capacity, we included Design Fluency (DF) and Verbal Fluency (VF) and computed these into an index of cognitive flexibility (DFVF). Detailed information on sick leave for the last 5 years was gathered from the company. Our results showed that there was a significant negative correlation between DFVF and sick leave [rs(109) = -0.23, p = 0.015] in the full group as well as in the group that had at least 1 day of sick leave [rs(72) = -0.25, p = 0.03]. The results withstood adjustment for sex, age, occupation, and several core executive functions as well as autistic and ADHD-traits. The results remained for separate analyses using DF or VF. Our main findings were conceptually replicated in a group of bipolar disorder patients. This study shows that objectively measured capacity of cognitive flexibility is associated with key health outcomes such as sick leave.

COVID-19 conspiracy ideation is associated with the delusion proneness trait and resistance to update of beliefs.

The rapid spread of conspiracy ideas associated with the recent COVID-19 pandemic represents a major threat to the ongoing and coming vaccination programs. Yet, the cognitive factors underlying the pandemic-related conspiracy beliefs are not well described. We hypothesized that such cognitive style is driven by delusion proneness, a trait phenotype associated with formation of delusion-like beliefs that exists on a continuum in the normal population. To probe this hypothesis, we developed a COVID-19 conspiracy questionnaire (CCQ) and assessed 577 subjects online. Their responses clustered into three factors that included Conspiracy, Distrust and Fear/Action as identified using principal component analysis. We then showed that CCQ (in particular the Conspiracy and Distrust factors) related both to general delusion proneness assessed with Peter's Delusion Inventory (PDI) as well as resistance to belief update using a Bias Against Disconfirmatory Evidence (BADE) task. Further, linear regression and pathway analyses suggested a specific contribution of BADE to CCQ not directly explained by PDI. Importantly, the main results remained significant when using a truncated version of the PDI where questions on paranoia were removed (in order to avoid circular evidence), and when adjusting for ADHD- and autistic traits (that are known to be substantially related to delusion proneness). Altogether, our results strongly suggest that pandemic-related conspiracy ideation is associated with delusion proneness trait phenotype.

Psychedelic drug use and schizotypy in young adults.

Despite recently resurrected scientific interest in classical psychedelics, few studies have focused on potential harms associated with abuse of these substances. In particular, the link between psychedelic use and psychotic symptoms has been debated while no conclusive evidence has been presented. Here, we studied an adult population (n = 1032) with a special focus on young (18-35 years) and healthy individuals (n = 701) to evaluate the association of psychedelic drug use with schizotypy and evidence integration impairment typically observed in psychosis-spectrum disorders. Experimental behavioural testing was performed in a subsample of the subjects (n = 39). We observed higher schizotypy scores in psychedelic users in the total sample. However, the effect size was notably small and only marginally significant when considering young and healthy subjects (Cohen's d = 0.13). Controlling for concomitant drug use, none of our analyses found significant associations between psychedelic use and schizotypal traits. Results from experimental testing showed that total exposure to psychedelics (frequency and temporal proximity of use) was associated with better evidence integration (Cohen's d = 0.13) and a higher sensitivity of fear responses (Cohen's d = 1.05) to the effects instructed knowledge in a reversal aversive learning task modelled computationally with skin conductance response and pupillometry. This effect was present even when controlling for demographics and concomitant drug use. On a group level, however, only difference in sensitivity of fear responses to instructed knowledge reached statistical significance. Taken together, our findings suggest that psychedelic drug use is only weakly associated with psychosis-like symptoms, which, in turn, is to a large extent explained by psychiatric comorbidities and use of other psychoactive substances. Our results also suggest that psychedelics may have an effect on flexibility of evidence integration and aversive learning processes, that may be linked to recently suggested therapeutic effects of psychedelic drugs in non-psychotic psychiatric populations.

Level of play and coach-rated game intelligence are related to performance on design fluency in elite soccer players.

Executive brain functions are innate mechanisms for regulating behavior. While the impact of suboptimal executive functions has been characterized in patients, their contribution to individual success has not been elucidated. We set out to understand how executive functions relate to successful human behavior by examining their relation to game intelligence in sport - the ability to read a game and quickly adapt the behavior. In elite soccer players (n = 51), those playing in national teams (national team players) significantly outperformed those only playing at premier league level (premier league players) in Design Fluency (DF), a complex visuo-spatial executive function test that includes measures of creativity and cognitive flexibility. Their result showed a moderate correlation with coach rated game intelligence, remained also when correcting for low level cognitive capacity and was most evident when considering cognitive flexibility. DF capacity also correlated with number of assists made during the season but not with number of made goals during the same period, linking the fast planning of several steps in DF to fast planning of several steps in the soccer game. Altogether, our data suggests that DF capacity relates to success in soccer both on a subjective and on an objective level.

Pain-related cerebral activation is altered by a distracting cognitive task.

It has previously been suggested that the activity in sensory regions of the brain can be modulated by attentional mechanisms during parallel cognitive processing. To investigate whether such attention-related modulations are present in the processing of pain, the regional cerebral blood flow was measured using [(15)O]butanol and positron emission tomography in conditions involving both pain and parallel cognitive demands. The painful stimulus consisted of the standard cold pressor test and the cognitive task was a computerised perceptual maze test. The activations during the maze test reproduced findings in previous studies of the same cognitive task. The cold pressor test evoked significant activity in the contralateral S1, and bilaterally in the somatosensory association areas (including S2), the ACC and the mid-insula. The activity in the somatosensory association areas and periaqueductal gray/midbrain were significantly modified, i.e. relatively decreased, when the subjects also were performing the maze task. The altered activity was accompanied with significantly lower ratings of pain during the cognitive task. In contrast, lateral orbitofrontal regions showed a relative increase of activity during pain combined with the maze task as compared to only pain, which suggests the possibility of the involvement of frontal cortex in modulation of regions processing pain.

A PET activation study of dynamic mechanical allodynia in patients with mononeuropathy.

The objective of this study was to investigate the central processing of dynamic mechanical allodynia in patients with mononeuropathy. Regional cerebral blood flow, as an indicator of neuronal activity, was measured with positron emission tomography. Paired comparisons were made between three different states; rest, allodynia during brushing the painful skin area, and brushing of the homologous contralateral area. Bilateral activations were observed in the primary somatosensory cortex (S1) and the secondary somatosensory cortex (S2) during allodynia compared to rest. The S1 activation contralateral to the site of the stimulus was more expressed during allodynia than during innocuous touch. Significant activations of the contralateral posterior parietal cortex, the periaqueductal gray (PAG), the thalamus bilaterally and motor areas were also observed in the allodynic state compared to both non-allodynic states. In the anterior cingulate cortex (ACC) there was only a suggested activation when the allodynic state was compared with the non-allodynic states. In order to account for the individual variability in the intensity of allodynia and ongoing spontaneous pain, rCBF was regressed on the individually reported pain intensity, and significant covariations were observed in the ACC and the right anterior insula. Significantly decreased regional blood flow was observed bilaterally in the medial and lateral temporal lobe as well as in the occipital and posterior cingulate cortices when the allodynic state was compared to the non-painful conditions. This finding is consistent with previous studies suggesting attentional modulation and a central coping strategy for known and expected painful stimuli. Involvement of the medial pain system has previously been reported in patients with mononeuropathy during ongoing spontaneous pain. This study reveals a bilateral activation of the lateral pain system as well as involvement of the medial pain system during dynamic mechanical allodynia in patients with mononeuropathy.

Microsomal metabolism of picene.

Picene, a polycyclic aromatic hydrocarbon (PAH) of environmental relevance has recently been predicted to be carcinogenic, based on quantum mechanical calculation, although in several animal studies no carcinogenicity could be detected. In order to find out if the metabolism of this PAH can provide an explanation for its lack of carcinogenicity, picene was incubated with the hepatic microsomal fraction of Sprague-Dawley rats, which had been pretreated with Aroclor 1254. Sixteen ethyl acetate-extractable metabolites could be separated by reversed-phase high-performance liquid chromatography. Comparison of the chromatographic behavior and the UV and mass spectral properties of the metabolites with those of synthetic derivatives of picene allowed the identification of trans-1,2-, -3,4-, -5,6-dihydrodiol as well as 2- and 4-phenol as microsomal metabolites of picene. At a substrate concentration of 2.7 microM and an amount of 68 micrograms microsomal protein per ml incubation volume, 4-picenol was the main microsomal metabolite with 32.2% of total metabolic conversion, followed by the 1,2-(bay-region)dihydrodiol with 16.7%, the 3,4-(M-region)dihydrodiol with 15.9%, 2-picenol with 9.1% and the 5,6-(K-region)dihydrodiol with 1.6%. In this respect the metabolism of picene is not significantly different from that of the carcinogenic PAH benzo[a]pyrene and dibenz[a,h]anthracene. The M-region dihydrodiols, potential precursors of electrophilically reactive dihydrodiol bay-region epoxides, are formed from all three PAHs at 11-16% of total metabolic conversion. From the 2.8- to 4.4-fold lower amounts of polar and water-soluble metabolites of picene as compared to dibenz[a,h]anthracene and benzo[a]pyrene it is deduced that dihydrodiol epoxides are generated from picene to a much smaller extent than from the two carcinogenic PAHs. The lacking carcinogenicity of picene could therefore result from the inability of microsomal enzymes to transform its M-region dihydrodiol to dihydrodiol bay-region epoxides in amounts necessary to initiate carcinogenesis.

Control of ventricular rate by interatrial septal incision and crista terminalis myotomy in the patients with atrial fibrillation undergoing mitral valve replacement.

The aim of the study was to analyze the effect of surgical moderation of conduction from the atrium to the atrio-ventricular (AV) node on ventricular response in 30 patients with atrial fibrillation (AF) undergoing mitral valve replacement (MVR). Besides the usual diagnostics, echocardiographic evaluation of the size of the left atrium was performed in all patients, as a parameter of stability of rhythm conversion by drugs. Surgical treatment was applied exclusively in cases where, judging by these parameters, there was little chance for drug treatment to be effective. All patients (mean age 50 years) had severe mitral valve disease (NYHA III and IV), chronic AF and irregular ventricular rate, and underwent mitral valve replacement with mechanical valve. The patients were divided into three groups of ten patients each. In group I: MVR was combined with interatrial septal incision (IASI) to study the effect of the moderation of conduction from the interatrial septum to the AV node; in group II: after MVR, IASI was combined with crista terminalis myotomy (CTM) to study the additional effect of the moderation of conduction along the crista terminalis to the AV node; in group III (control): MVR was performed through left atriotomy, without antiarrhythmic incisions. Ventricular response was studied in two phases: In the immediate postoperative period (up to 7 days), using continuous electrocardiographic (ECG) monitoring, and 2 months postoperatively, using 24 h Holter monitoring with the results compared to a preoperative 24 h recording. Postoperative AF occurred in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Initial clinical experience with PerDUCER device: promising new tool in the diagnosis and treatment of pericardial disease.

BACKGROUND: The idea to enter the normal pericardial sac safely was unrealistic until recently. The development of a novel instrument (PerDUCER pericardial access device) for percutaneous access to the pericardium could potentially have a significant impact, not only on patients with pericardial diseases but even more, or primarily, on diagnosis and treatment of myocardial and coronary disease and arrhythmias. HYPOTHESIS: The overall objective of the present study was to evaluate the feasibility and safety of the percutaneous pericardial access with PerDUCER in patients with pericardial disease, and to analyze our initial experience with this new technique, with particular emphasis on sequential procedural steps. METHODS: The device was studied in five patients with pericardial disease (two men, mean age 50.4 years, range 30-68, four with normal body mass index). The procedure consists of two distinct techniques: (1) access to the mediastinal space, and (2) pericardial capture, puncture, and insertion of the guidewire. Access to the mediastinal space includes the introduction of a blunt cannula, a 0.038 guidewire, a dilator-introducer sheath set, and insertion of the PerDUCER device. Key points of the PerDUCER procedure are as follows: introduction of the blunt cannula without resistance, placement of the dilator-introducer sheath at the upper third of the heart, systolic movements of the PerDUCER device, successful vacuum and capture of pericardium, puncture and introduction of the intrapericardial guidewire. RESULTS: Access to the mediastinal space was accomplished in four of five patients, as were pericardial capture and probably puncture. However, despite numerous successful captures and probably punctures of pericardium, we were not able to confirm introduction of the intrapericardial guidewire into the pericardial cavity in any of our patients (0/5). The procedure was very well tolerated in all patients (5/5). No major complications developed during the procedure, bearing in mind that the intrapericardial placement of the guidewire was not achieved. Minor complications included pain at the dilator-introducer sheath entry site (5/5) and mild transient fever (2/5). CONCLUSIONS: According to the present experience, we believe that, with minor modifications, the PerDUCER device could be successfully implemented for pericardial entry in patients with pericardial disease. Further studies are needed to evaluate the feasibility and safety of this new instrument in patients with a normal pericardium. This could open a most exciting spectrum of possible implementations of the device in the future.

The surgical anatomy of the perforating branches of the anterior choroidal artery.

BACKGROUND: The available information about certain microanatomic features of the AChA perforators is incomplete. Precise knowledge of these vessels is necessary to understand the consequences of their occlusion and to safely operate in their region. METHODS: The AChA perforators were microdissected and examined under the stereoscopic microscope in 10 vascular casts and in 20 hemispheres injected with india ink or radiopaque substance. RESULTS: The perforating branches ranged in number from 2 to 9 (mean, 4.6) and in diameter between 90 microm and 600 microm (mean, 317 microm). The most proximal perforator arose 3.2 mm on average caudal to the AChA origin. The most distal (capsulothalamic) perforator varied in size from 200 microm to 610 microm (mean, 431 microm). One or more of the perforators always originated from the AChA (100%), but some of them also from the uncal (33.3%) or parahippocampal branch (10%) of the AChA, either as individual vessels only (70%) or from common trunks (30%). The perforators gave off the peduncular (20%), optic (23.3%), or uncal side branches (26.7%). CONCLUSIONS: Our findings concerning the origin, position, number, size, branching, penetration site, and relationships of the AChA perforators gave the anatomic basis for safe operations in patients with AChA aneurysms or mediobasal limbic epilepsy.

Fractures of the clavicle and injuries of the sub-clavian artery. Report of 10 cases.

During four years, the authors have observed ten lesions of the sub-clavian artery associated with a fracture of the clavicle. The clinical picture in one case out of two was that of an acute ischemia of the upper limb. The surgical repair has been performed in 8 cases. The thoracic approach was necessary three times. The clavicle was resected in most cases. The prognosis of these lesions depends on the rapidity of their recognition, and of their treatment, and on the fact whether the brachial plexus is involved or not

Clinical and functional evaluation of the Carbomedics Prosthetic Heart Valve in the mitral position. Preliminary results.

The Carbomedics Prosthetic Heart Valve is a new bileaflet pyrolite carbon prosthesis. This paper reports the preliminary results in 40 patients who underwent mitral valve replacement (MVR) using the Carbomedics Valve in 1988. The operative mortality rate was 5% and the early results have been encouraging, with no valve related complications observed in the first post-operative year.

Results of 132 PTFE (Gore-Tex) bifurcated graft implantations.

One hundred and thirty-two PTFE bifurcated prosthetic grafts were implanted during the course of a bicentre study conducted at the abovenamed institutions from 1982 to 1986. The study included 118 males and 14 females with an average age of 62 years. One hundred and eighteen patients suffered from aorto-iliac occlusive disease and 14 from abdominal aortic aneurysms (AAA). Five patients had already undergone previous surgery (redo operations), with extirpation of thrombosed Dacron prostheses. Proximal end to end anastomoses were fashioned in 94 cases (71.2%), while end to side anastomoses were performed in 38 cases (28.8%). The distal anastomoses were to the iliac arteries in 11 cases, the common femoral artery in 89 cases and the deep femoral artery in 32 cases.

Anatomy of the cavernous sinus region.

The cavernous region was examined in 20 fetuses, injected with Micropaque, and in 5 adults. The lateral wall of the cavernous region in fetuses was noticed to have four layers. The superficial membrane represents the dural sheath. The second membrane of dense connective tissue involves the trochlear nerve. The third layer, formed by loose connective tissue, involves the oculomotor nerve, and the ophthalmic and maxillary division. The fourth layer, which represents the lateral wall of the cavernous sinus, involves the abducent nerve. The meningohypophyseal trunk can be complete or incomplete. The inferolateral trunk and its branches were found to supply the cavernous portions of the mentioned cranial nerves. The obtained data make the anatomic basis for neurosurgical operations in the cavernous region.

Unruptured congenital aneurysm of the right sinus of Valsalva. Dissecting into the interventricular septum.

We report the case of a congenital aneurysm of the right sinus of Valsalva dissecting into the interventricular septum in a 21-year-old man. This condition was diagnosed by echocardiography and magnetic resonance imaging. In particular, transthoracic and transesophageal color-coded Doppler echocardiography showed that there was no communication between the aneurysm and the surrounding heart chambers. The findings were confirmed by angiography. Heart enlargement and other symptoms and signs of heart failure indicated surgical repair of the lesion. Early postoperative dehiscence of the sutured orifice was accurately diagnosed with Doppler echocardiography and angiography. Reintervention was successful in filling and sealing the septal cavity. This case confirms the reported difficulties in the surgical correction of aneurysms of sinus of Valsalva lying within the interventricular septum.

[Biochemical changes in hypertensive patients during a 1-year cross-over study of treatment with hydrochlorothiazide and propranolol]. / Biokemijske promjene u hipertonicara tijekom jednogodisnjeg krizanog lijecenja hidroklorotiazidom i propranololom.

A prospective, randomized, cross-over trial comparing the antihypertensive efficacy and biochemical changes during treatment with either hydrochlorothiazide (HTZ: 25 mg o.d.) or propranolol (PRO: 40 mg t.i.d.), included 55 mild to moderate hypertensives (diastolic blood pressures ranged from 90 to 110 mmHg), aged 25-65 years. Forty patients completed the study; during the first six months 20 of them (12 males and 8 females) were taking HTZ, and the remaining 20 (13 males and 7 females) PRO. After a one-week wash-out period, for the next six months the alternative drug was administered. Antihypertensive efficacy of both drugs was nearly equal: systolic and diastolic blood pressure significantly decreased already after the first month (approximately by 10%), and kept unchanged until the end of the study. The analyzed biochemical parameters, i.e. blood glucose, cholesterol, and triglycerides did not increase significantly, while serum potassium level remained almost unchanged during the trial. Furthermore, during PRO in group B, cholesterol significantly decreased (3rd month), as well as blood glucose during HTZ treatment (10th month). Only the uric acid level, although unsignificantly, increased in group A (from 326.2 to 365.3 +/- 125.2 on HTZ, and to 391.4 +/- 120.0 mumol/l on PRO). It is concluded that HTZ and PRO are comparably effective antihypertensives. During the long-term treatment in small doses these drugs do not induce significant biochemical disturbances.