Whole-brain CT perfusion measurement of perfused cerebral blood volume in acute ischemic stroke: probability curve for regional infarction

PURPOSE: To determine the probability curve for regional cerebral infarction as a function of percentage normalized perfused cerebral blood volume (pCBV) in patients with acute ischemic stroke. MATERIALS AND METHODS: The authors retrospectively analyzed whole-brain computed tomographic (CT) perfusion scans from 28 patients with acute stroke (<6 hours) due to major arterial occlusion, without intracranial hemorrhage. Each patient had a positive follow-up CT scan 1-4 days later, without interval thrombolysis. Normalized pCBV, expressed as a percentage of contralateral normal brain pCBV, was determined in the core infarction and in regions just inside and outside the boundary between infarcted and noninfarcted brain. These regions were dichotomized into infarcted (core and inner band) and noninfarcted (outer band) categories. Logistic regression analysis was then used to create a reference curve of probability of infarction as a function of percentage normalized pCBV. RESULTS: Normalized pCBV values in the core, inner band, and outer band were 24.5% +/- 2.3, 36.3% +/- 2.4, and 72.1% +/- 2.4, with corresponding probabilities of infarction of .99, .96, and .11. The normalized pCBV at which the probability of survival reached .5 was 58.0% +/- 0.5. Sensitivity, specificity, and accuracy of the reference probability curve were 90.5% (209 of 231), 89.5% (212 of 237), and 90.0% (421 of 468), respectively. Negative and positive predictive values were 90.6% (212 of 234) and 89.3% (209 of 234), respectively. R2 was 0.73, and differences in perfusion between core and inner and outer bands were highly significant (P <.0001). CONCLUSION: A probability of infarction curve can help predict the likelihood of infarction as a function of percentage normalized pCBV.     

Long-term oral treatment with BAY 41-2272 ameliorates impaired corpus cavernosum relaxations in a nitric oxide-deficient rat model

Study Type – Therapy (case control)
Level of Evidence 3b What’s known on the subject? and What does the study add? Erectile dysfunction is defined as the persistent inability to achieve and/or maintain an erection sufficient for satisfactory sexual performance. Nitric oxide (NO) is the main transmitter released from nitrergic nerves and endothelial cells involved in the erectile erection. NO activates the soluble guanylyl cyclase (sGC) in cavernosal smooth muscle to generate cyclic GMP (cGMP) that in turn promotes relaxation and penile erection. Erectile dysfunction genesis can be attributed to a variety of factors such as stress, ageing, drugs, and certain pathological conditions including arterial hypertension, atherosclerosis, dyslipidemia and diabetes mellitus. Inhibitors of phosphodiesterase‐5 (PDE5) like sildenafil (viagra^TM), vardenafil (levitra^TM) and tadalafil (cialis^TM) remain the main oral therapy for erectile dysfunction. These compounds inhibit the cGMP hydrolysis thereby preserving cGMP thus causing an enhancement of corporeal smooth muscle relaxation. The existence of a new NO‐independent regulatory site on sGC has been described. BAY 41‐2272 is a novel compound that generates significant amounts of cGMP by stimulating the sGC in the absence of NO. Compound BAY 41‐2272 also synergize with endogenous NO producing higher cGMP‐dependent cell responses. Using a model of chronic NO deficiency in rats to produce erectile dysfunction, we show that long‐term oral treatment of with BAY 41‐2272 prevents the erectile dysfunction in the NO‐deficient rats. Therefore, this compound may have great therapeutic potential to erectile dysfunction treatment.

OBJECTIVE

? To investigate the potential beneficial effects of 4‐week oral treatment with 5‐cyclopropyl‐2‐[1‐(2‐fluoro‐benzyl)‐1Hpyrazolo[3,4‐b]pyridin‐3‐yl]‐pyrimidin‐4‐ylamine (BAY 41‐2272), a nitric oxide (NO)‐independent soluble guanylate cyclase activator, on impaired rat corpus cavernosum relaxations in NO‐deficient rats.

MATERIAL AND METHODS

? Male Wistar rats were divided into four groups: Control, N (G)‐nitro‐L‐ arginine methyl ester (L‐NAME; 20 mg/rat/day), BAY 41‐2272 (20 mg/kg/day) and L‐NAME + BAY 41‐2272. ? Rats were treated with L‐NAME concomitantly with BAY 41‐2272 for 4 weeks. ? Concentration–response curves to acetylcholine (ACh) and sodium nitroprusside (SNP), along with the nitrergic relaxations (1–32 Hz) were obtained in rat corpus cavernosum (RaCC). ? The RaCC contractile responses to the α₁‐adrenoceptor agonist phenylephrine (PE) were obtained.

RESULTS

? Acetylcholine (0.01–1000 µmol/L) produced concentration‐dependent relaxing responses in RaCC that were significantly enhanced (P < 0.05) in BAY 41‐2272‐treated rats. ? The ACh‐induced relaxations were largely reduced in L‐NAME‐treated rats, and co‐treatment with BAY 41‐2272 failed to significantly modify these impaired relaxations. ? The SNP‐induced relaxations were modified neither by L‐NAME nor by co‐treatment with BAY 41‐2272. ? The nitrergic relaxations were significantly amplified in BAY 41‐2272‐treated rats (at 16 and 32 Hz). A significant reduction in the nitrergic relaxations was observed in L‐NAME‐treated rats, an effect largely restored by co‐treatment with BAY 41‐2272. ? The contractile RaCC responses produced by PE (0.001–100 µmol/L) were significantly higher (P < 0.05) in L‐NAME‐treated rats, and co‐treatment of L‐NAME with BAY 41‐2272 nearly restored these enhanced contractile responses.

CONCLUSION

? Four‐week therapy with BAY 41‐2272 prevents the impaired corpus cavernosum relaxations of rats treated chronically with L‐NAME, indicating that accumulation of cyclic guanosine monophosphate into erectile tissue counteracts the NO deficiency.     

Genetic analysis and effect of triiodothyronine and prednisone trial on bone turnover in a patient with craniotubular hyperostosis

Craniotubular hyperostosis are a group of high bone mass disorders related to mutations in the LRP5 and SOST genes, although other causative genes remain to be identified. Little is known about the bone turnover and the response to T3 or glucocorticoids in these patients. We describe a patient with craniotubular hyperostosis, including mutation analyses of the LRP5, SOST, DKK1 and KRM1 genes. We also studied bone turnover and bone mineral density (BMD), before and after a trial with T3 (75 microg/d for 28 weeks) and T3 and prednisone (T3 100 microg/d for 2 weeks, followed by 10 weeks on prednisone 10 mg/d, and a final 2 weeks period off of medicactions, completing 3 cycles in 42 weeks. Mutation analysis of the complete coding region and flanking highly conserved sequences of SOST, evaluation of the presence of the 52-kb deletion associated with Van Buchem disease in Dutch patients and mutation analysis of exons 2-4 of LRP5, and the coding regions of DKK1 and KRM1 did not reveal any disease-causing mutations. A baseline 5 to 7 fold increase in osteocalcin and in deoxypiridinoline was detected. After 4 weeks on 75 microg/d of T3, osteocalcin decreased 36%, but at week 28, it returned to basal. Deoxypiridinoline did not change. After the first cycle on T3 and prednisone, osteocalcin decreased 72%, and at the end of the third cycle it remained 44% below basal value. Deoxypiridinoline was stable and high during the three cycles; no changes in BMD were observed. As we failed to identify any disease-causing mutations in our patient with craniotubular hyperostosis, we suggest that another gene must be involved in the pathogenesis of his condition. This study provides additional data about the high bone turnover described in craniotubular hyperostosis, and also suggests an abnormal response to T3 excess in this condition.     

Resistance Training with Instability in Multiple System Atrophy: A Case Report

This case report assessed quality of life, activities of daily living, motor symptoms, functional ability, neuromuscular parameters and mRNA expression of selected genes related to muscle protein synthesis and degradation in a patient with Multiple System Atrophy (MSA). The patient underwent resistance training with instability devices (i.e., bosu, dyna disk, balance disk, Swiss ball) for six months twice a week. After the six months training, the patient’s left and right quadriceps muscle cross-sectional area and leg press one-repetition maximum increased 6.4%, 6.8%, and 40%, respectively; the patient’s timed up and go, sit to stand, dynamic balance, and activities of daily living improved 33.3%, 28.6%, 42.3%, and 40.1%, respectively; the patient’s severity of motor symptoms and risk of falls decreased 32% and 128.1%, respectively. Most of the subscales of quality of life demonstrated improvements as well, varying from 13.0% to 100.0%. mRNA expression of mechanogrowth factor and mammalian target of rapamycin increased 12.7-fold and 1.5-fold, respectively. This case report describes likely the first nonpharmacological therapeutic tool that might be able to decrease the severity of motor symptoms and risk of falls, and to improve functional ability, neuromuscular parameters, and quality of the life in a patient with MSA.

Key points

• Six months of resistance training with instability alleviate the MSA-related effects and improve the quality of life in a patient with MSA.
• High complexity exercise intervention (i.e., resistance training with instability) may be very beneficial to individuals with impaired motor control and function as MSA patients.
• Caution should be exercised when interpreting our findings as they cannot be generalized to the entire MSA population and they do not allow establishing causal conclusions on the effects of this mode of exercise on MSA.

Key words: Exercise training, risk of falls, motor symptoms, cross-sectional area     

Spatial learning and neurogenesis: Effects of cessation of wheel running and survival of novel neurons by engagement in cognitive tasks

Physical exercise stimulates cell proliferation in the adult dentate gyrus and facilitates acquisition and/or retention of hippocampal‐dependent tasks. It is established that regular physical exercise improves cognitive performance. However, it is unclear for how long these benefits last after its interruption. Independent groups of rats received both free access to either unlocked (EXE Treatment) or locked (No‐EXE Treatment) running wheels for 7 days, and daily injections of bromodeoxyuridine (BrdU) in the last 3 days. After a time delay period of either 1, 3, or 6 weeks without training, the animals were tested in the Morris water maze (MWM) either in a working memory task dependent on hippocampal function (MWM‐HD) or in a visible platform searching task, independent on hippocampal function (MWM‐NH). Data confirmed that exposure of rats to 7 days of spontaneous wheel running increases cell proliferation and neurogenesis. In contrast, neurogenesis was not accompanied by significant improvements of performance in the working memory version of the MWM. Longer time delays between the end of exercise and the beginning of cognitive training in the MWM resulted in lower cell survival; that is, the number of novel surviving mature neurons was decreased when this delay was 6 weeks as compared with when it was 1 week. In addition, data showed that while exposure to the MWM‐HD working memory task substantially increased survival of novel neurons, exposure to the MWM‐NH task did not, thus indicating that survival of novel dentate gyrus neurons depends on the engagement of this brain region in performance of cognitive tasks. © 2015 Wiley Periodicals, Inc.     

Impact of a multidisciplinary trauma team on the outcome of acute subdural haematoma

IntroductionTo review the outcome of patients with post-traumatic acute subdural haematoma (ASDH) before and after the establishment of a hospital trauma team at a designated trauma centre.MethodA retrospective analysis was conducted on 82 consecutive patients who underwent surgery for post-traumatic ASDH. The ‘PRE’ and ‘POST’ groups included patients admitted before and after the establishment of a hospital trauma team, respectively.Injury severity was assessed by the admission Glasgow coma score, imaging findings, and the revised trauma score. Clinical outcome measures were the hospital length of stay and the Glasgow outcome score (GOS) upon hospital discharge.ResultsThe overall mortality rate was 53.7%. No significant difference was found between the PRE and POST groups. The mean length of hospital stay was also comparable between the two groups. The functional status of those who survived acute hospital care was significantly better in the POST group. Good outcome (GOS of 4 or 5) was achieved in 66.7% of the survivors in the POST group, compared with 25.0% in the PRE group (p = 0.024).ConclusionPost-traumatic ASDH carried a poor prognosis. The mortality rate and hospital length of stay of patients were not found to be reduced after the establishment of a hospital trauma team. The latter, however, was associated with significantly better functional outcome amongst survivors. Although causality cannot be established due to the multitude of factors which may have affected patient outcome, our findings nonetheless provide further support for the introduction of a multidisciplinary hospital trauma team for the optimal care of trauma patients.     

Modeling Chagas Disease at Population Level to Explain Venezuela's Real Data

Objectives

In this paper we present an age-structured epidemiological model for Chagas disease. This model includes the interactions between human and vector populations that transmit Chagas disease.

Methods

The human population is divided into age groups since the proportion of infected individuals in this population changes with age as shown by real prevalence data. Moreover, the age-structured model allows more accurate information regarding the prevalence, which can help to design more specific control programs. We apply this proposed model to data from the country of Venezuela for two periods, 1961–1971, and 1961–1991 taking into account real demographic data for these periods.

Results

Numerical computer simulations are presented to show the suitability of the age-structured model to explain the real data regarding prevalence of Chagas disease in each of the age groups. In addition, a numerical simulation varying the death rate of the vector is done to illustrate prevention and control strategies against Chagas disease.

Conclusion

The proposed model can be used to determine the effect of control strategies in different age groups.     

Genetic polymorphisms of interleukin 20 (IL-20) in patients with ulcerative colitis

Interleukin (IL)-20 belongs to the IL-10 family and is a potent immunomodulatory cytokine with implications for pathogenesis in the inflammatory bowel disease (IBD). The interleukin 20 gene is located within a 200 kb region of q31-32 locus of chromosome 1. No previous studies have reported this novel association between ulcerative colitis (UC) and IL-20 polymorphisms. In the present work, we evaluated the role of IL-20 gene polymorphisms as susceptibility markers for UC. Three polymorphisms of IL-20 gene (rs2981573, rs2232360, rs1518108) were genotyped by 5′ exonuclease TaqMan genotyping assays on an ABI Prism 7900 HT Fast Real-Time PCR system in a group of 198 Mexican Mestizo patients with UC and 698 ethnically matched healthy unrelated individuals with no family history of UC. We found significant decreased frequencies of two IL-20 genotypes: GG (rs2981573) [10.6% vs. 17.6%, p = 0.017, OR = 0.55, 95% CI: 0.33–0.93] and GG (rs2232360) [10.6% vs. 17.6%, p = 0.017, OR = 0.55, 95% CI: 0.33–0.93] in UC patients as compared to healthy controls. No significant differences of gene frequencies were found between UC patients and healthy controls in the rs1518108 polymorphism. In the subgroup analysis, no differences were found between the IL-20 genotypes and the clinical characteristics of UC. The results suggest that the GG genotypes of the IL-20 polymorphisms (rs2981573 and rs2232360) might have an important role in the development of UC in the Mexican population.