Safety Assessment and Power Analyses in Published Anti-Vascular Endothelial Growth Factor Randomized Controlled Trials.

PURPOSE: To investigate a certain set of methodological limitations in published anti-vascular endothelial growth factor (VEGF) randomized controlled trials (RCTs). DESIGN: Descriptive methodological study. METHODS: We did a PubMed search with the terms "bevacizumab OR ranibizumab OR pegaptanib OR aflibercept" and the limitations "humans" and "randomized controlled trials" in 15 of the highest-impact-factor general medicine and ophthalmology journals. We included only RCTs published as original articles, where an anti-VEGF agent was used to treat eye disease. Two independent observers (O.A., P.K.) read through each article and classified the articles according to a predefined set of criteria. RESULTS: The PubMed search yielded 209 articles, and 93 were classified as eligible. In most of the studies, the study drug was bevacizumab (52.6%, n = 49), followed by ranibizumab (44.1%, n = 41), pegaptanib (7.5%, n = 7), and aflibercept (5.4%, n = 5). Basic epidemiologic data, including sex distribution (2.2%, n = 2) and mean age (3.2%, n = 3), were missing in 3.2% of the published RCTs. The power calculation for efficacy was mentioned in 48% (n = 45) of the published work, and a power calculation for safety was considered in only 1 study (1.1%). Only 6 RCTs (6.5%) reported negative results. CONCLUSIONS: Power calculations for efficacy, an important component of an RCT, were missing in 51% of the RCTs we surveyed, while a power calculation for safety was only present in 1.1%. Around 60% of the published RCTs were labeled as an "efficacy and safety trial," and none of those studies had a power calculation for safety.

Systematic Review of Central Post Stroke Pain: What Is Happening in the Central Nervous System?

Central poststroke pain (CPSP) is one of the most common central neuropathic pain syndromes seen after stroke. It is mainly related with vascular damage at certain brain territory and pain related to corresponding body areas. In the past, it was described as one of the definitive symptoms of thalamic lesion. However, recent findings suggest that it is not only seen after thalamic lesions but also seen after vascular lesions in any part of the central nervous system. Although there are certain hypotheses to explain physiopathologic mechanisms of CPSP, further evidence is needed. The majority of the cases are intractable and unresponsive to analgesic treatment. Electrical stimulation such as deep brain stimulation and repetitive transcranial magnetic stimulation seems to be effective in certain cases. In this systematic review, recent advancements related to CPSP mechanisms have been evaluated. Further investigations are needed in order to reveal the mystery of the pathophysiologic mechanisms of CPSP.

Pectus Excavatum and Pectus Carinatum: Associated Conditions, Family History, and Postoperative Patient Satisfaction.

BACKGROUND: Pectus excavatum (PE) and pectus carinatum (PC) are the most common chest wall deformities. In this study, we aimed to characterize how patients obtained information about these deformities, as well as patients' family history, associated medical problems, and postoperative satisfaction after the Nuss and Abramson procedures. METHODS: This cross-sectional retrospective study included patients who were operated by a single surgeon between 2006 and 2013. Follow-up calls were made after approval of our institution's ethics committee. We reached 207 of the 336 PE patients (61.6%) and 73 of the 96 PC patients (76%). RESULTS: The majority of the patients were male (85% of the PE patients and 91.8% of the PC patients). The age of diagnosis of PE was 14.52±0.51 years and the age at the time of operation was 17.89±0.42 years; for PC patients, the corresponding ages were 15.23±0.55 years and 16.77±0.55 years, respectively. A total of 70% of the PE patients and 63.8% of the PC patients obtained information about pectus deformities through the Internet. In 27.1% of the PE patients with an associated anomaly, 57.1% (n=13) had scoliosis, while 41.1% of the PC patients with an associated anomaly had kyphosis (n=5). Postoperative satisfaction, as evaluated on a scale from 0 to 10, was 8.17±0.15 for PE patients and 8.37±0.26 for PC patients. The postoperative pain duration was 51.93±5.18 days for PE patients and 38.5±6.88 days for PC patients. CONCLUSION: In this study, we found that most patients with pectus deformities were male. The Internet was an important resource for patients to learn about their deformities. Family history and associated anomalies were identified as important aspects for consideration in the clinical setting. The patients reported high levels of postoperative satisfaction, and pain management was found to be one of the most important elements of postoperative care.

Intrauterine diagnosed sternal cleft patient and her management.

Sternal cleft is a rare chest wall deformity. It can be diagnosed in the intrauterine stage with ultrasonography. Newborn period is the optimal time for the surgical correction of sternal cleft, due to the elasticity of the sternum and minimal compression of underlying structures. Here we reported a newborn patient with sternal cleft which has been operated 5 days after labor. Good surgical outcome and long-term results were accomplished.

How pulmonary function changes after pectus excavatum correction surgery.

AIM: We aimed to determine the effects of minimally invasive repair of pectus excavatum on pulmonary function and quality of life. METHODS: Minimally invasive pectus excavatum repair was undertaken in 80 patients with a mean age of 16.91 ± 4.37 years (range 7-30 years) and a mean Haller index of 4.07 ± 1.39; 85% of the patients were male. They and their parents completed the Nuss Questionnaire Modified for Adults, and pulmonary function tests were performed on the patients before and 6 months after the operation. RESULTS: The mean Nuss score was 31.06 ± 6.78 before the operation and it increased to 37.1 ± 8.31 (p = 0.000) 6 months after the operation. Forced vital capacity decreased from 3.70 ± 1.23 to 3.48 ± 1.03 L (p = 0.05) postoperatively. The percentage of expected forced vital capacity decreased from 83.21% ± 16.97% to 76.52% ± 20.98% (p = 0.01). There was no significant change in forced expiratory volume in 1 s. The mean ratio of forced expiratory volume in 1 s to forced vital capacity was 86% preoperatively and it increased to 91% postoperatively (p = 0.000). CONCLUSIONS: Minimally invasive pectus excavatum repair has a positive impact on the quality of life of pectus excavatum patients, but a negative impact on forced vital capacity. Follow-up studies are needed to assess the long-term changes in pulmonary function after this operation.

Visualization of Sensory Neurons and Their Projections in an Upper Motor Neuron Reporter Line.

Visualization of peripheral nervous system axons and cell bodies is important to understand their development, target recognition, and integration into complex circuitries. Numerous studies have used protein gene product (PGP) 9.5 [a.k.a. ubiquitin carboxy-terminal hydrolase L1 (UCHL1)] expression as a marker to label sensory neurons and their axons. Enhanced green fluorescent protein (eGFP) expression, under the control of UCHL1 promoter, is stable and long lasting in the UCHL1-eGFP reporter line. In addition to the genetic labeling of corticospinal motor neurons in the motor cortex and degeneration-resistant spinal motor neurons in the spinal cord, here we report that neurons of the peripheral nervous system are also fluorescently labeled in the UCHL1-eGFP reporter line. eGFP expression is turned on at embryonic ages and lasts through adulthood, allowing detailed studies of cell bodies, axons and target innervation patterns of all sensory neurons in vivo. In addition, visualization of both the sensory and the motor neurons in the same animal offers many advantages. In this report, we used UCHL1-eGFP reporter line in two different disease paradigms: diabetes and motor neuron disease. eGFP expression in sensory axons helped determine changes in epidermal nerve fiber density in a high-fat diet induced diabetes model. Our findings corroborate previous studies, and suggest that more than five months is required for significant skin denervation. Crossing UCHL1-eGFP with hSOD1G93A mice generated hSOD1G93A-UeGFP reporter line of amyotrophic lateral sclerosis, and revealed sensory nervous system defects, especially towards disease end-stage. Our studies not only emphasize the complexity of the disease in ALS, but also reveal that UCHL1-eGFP reporter line would be a valuable tool to visualize and study various aspects of sensory nervous system development and degeneration in the context of numerous diseases.

Validity and reliability of the Turkish version of the nuss questionnaire modified for adults.

BACKGROUND: Pectus excavatum (PE) is the most common chest wall deformity. The Nuss Questionnaire modified for Adults (NQmA) is a disease-specific health-related quality of life assessment tool for patients with pectus deformities. The aim of this study is to adapt the NQmA into Turkish. METHODS: Two hundred and sixty-five patients with PE were participated, with an age range of 14 to 29 years. All patients underwent a physical examination and had not undergone corrective surgery. The Turkish version of the NQmA was completed by patients and their parents. RESULTS: The content validity index based on expert opinions was 91% for the patient questionnaire and 96% for the parent questionnaire. The Cronbach's alpha value for the NQmA was found to be 0.805 for the patient questionnaire and 0.800 for the parent questionnaire. Exploratory factor analysis was used to assess construct validity. Two factors explained 51.1% of the total variance in the patient questionnaire (psychosocial: 31.145%, Cronbach's alpha=0.818; physical: 19.955%, Cronbach's alpha=0.862). In the parent questionnaire, two factors explained 51.422% of the total variance (psychosocial: 26.097%, Cronbach's alpha=0.743; physical: 25.325%, Cronbach's alpha=0.827). Construct validity was confirmed by confirmatory factor analysis. CONCLUSION: The Turkish version of the NQmA was found to be valid and reliable for the assessment of quality of life in patients with PE.

Hypovitaminosis D in widespread pain: its effect on pain perception, quality of life and nerve conduction studies.

The aim of the study was to investigate the effects of hypovitaminosis D on pain, quality of life (QoL) and nerve conduction studies (NCSs) in patients with chronic widespread pain (CWP). We randomly selected 83 female patients with CWP according to their vitamin D levels in this cross-sectional study. Patients were divided into two groups as sufficient vitamin D level (above 20 ng/ml) and deficient vitamin D level (below 20 ng/ml, hypovitaminosis D). Various pain scales and Nottingham Health Profile (NHP) were used. NCSs were also done. In patients with hypovitaminosis D, there were significantly higher pain scores for all scales (p value range 0.002-0.027). The subscale and total NHP scores were significantly higher in hypovitaminosis D group (p = 0.048-0.001) except social isolation subscale (p = 0.553). Vitamin D levels were in negative correlation with right and left median and/or ulnar motor nerve amplitudes, left tibial motor amplitude. This study confirm that hypovitaminosis D is related with higher pain intensity and lower QoL scores in patients with CWP when compared with control group. Additionally, we identified for the first time that there were negative correlations between vitamin D levels and some findings of NCSs.

Quality of life improves after minimally invasive repair of pectus excavatum.

BACKGROUND: Pectus excavatum is the most common chest wall deformity. This deformity may cause physical limitations and psychosocial problems. In this study, we aimed to investigate the effect of minimally invasive repair of pectus excavatum on the quality of life. METHODS: This study included 88 patients, aged 18.44 ± 3.93 years (85.2% male), who underwent minimally invasive repair of pectus excavatum; 40.9% had an associated anomaly or disease, and 17.0% had scoliosis. The patients and their parents completed the patient and parent forms of the Nuss questionnaire modified for adults preoperatively and 6 months after the operation. RESULTS: The patients' median Nuss score increased from 31 (interquartile range 31-35) preoperatively to 43 (interquartile range 43-46) at 6 months after the operation (p = 0.000). The parents' preoperative score of 33 (interquartile range 29-36) increased to 38 (interquartile range 34-41; p = 0.000). Improvements in the physical and psychosocial component scores of the Nuss questionnaire were also significant in the patient (p = 0.000, p = 0.000, respectively) and parent forms (p = 0.005, p = 0.000, respectively). CONCLUSIONS: Minimally invasive repair of pectus excavatum significantly improved the physical and psychosocial wellbeing of patients. Longitudinal studies are needed to determine the long-term changes related to quality of life.

Ameliorative effect of chronic moderate exercise in smoke exposed or nicotine applied rats from acute stress.

INTRODUCTION: Physical activity has been found to be related with many health benefits. Our aim was to investigate the effect of chronic moderate exercise from acute stress on nicotine and cigarette smoke exposed rats. METHODS: Male Sprague Dawley rats (200-250g, n = 48) were divided into 6 groups as non-exercised, exercised, smoke exposed, smoke exposed and exercised, nicotine applied, and nicotine applied and exercised. Nicotine bitartarate was applied intraperitoneally (0.1mg/kg/day) for 5 weeks, and cigarette smoke was exposed in a ventilated chamber. After 1 week of nicotine application or smoke exposure, moderate exercise training protocol was applied to exercise groups. At the end of the experiments, acute stress induction was made to all groups by electric foot shock. Holeboard tests were performed before and after the experiments. Biochemical and histological analyses were performed in lung, liver, colon, stomach, and gastrocnemius tissues. RESULTS: Malondialdehyde levels were increased in all tissues of smoke exposed group (p < .05-.01) except gastrocnemius tissue compared to non-exercised group and were decreased with exercise (p < .05-.001). Myeloperoxidase levels were increased in lung, liver and colon tissues of smoke exposed group (p < .05-.001) and liver and colon tissues of nicotine applied rats (p < .01-.001) and decrease with exercise in liver and colon tissues of both smoke exposed or nicotine applied groups (p < .05-.01). In all tissue samples, increased histological injury scores (p < .05-.001) decreased significantly with exercise (p < .01-.001). CONCLUSION: Biochemical parameters and histological scoring indicated increased tissue injury due to nicotine application and cigarette smoke exposure and exercise training ameliorated these effects in most of the tissues of acute stress induced rats.

Reconstruction of sternal cleft with autologous cartilage graft in an adult.

Sternal cleft is a rare chest wall deformity associated with various malformations. Primary closure is the gold standard in the newborn period. Alternative techniques are possible for older patients. A 23-year-old woman with a partial sternal cleft and no additional deformity, underwent reconstruction using costal cartilage grafts. Postoperative physical and functional were excellent.

Functional stability of plasminogen activator inhibitor-1.

Plasminogen activator inhibitor-1 (PAI-1) is the main inhibitor of plasminogen activators, such as tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), and a major regulator of the fibrinolytic system. PAI-1 plays a pivotal role in acute thrombotic events such as deep vein thrombosis (DVT) and myocardial infarction (MI). The biological effects of PAI-1 extend far beyond thrombosis including its critical role in fibrotic disorders, atherosclerosis, renal and pulmonary fibrosis, type-2 diabetes, and cancer. The conversion of PAI-1 from the active to the latent conformation appears to be unique among serpins in that it occurs spontaneously at a relatively rapid rate. Latency transition is believed to represent a regulatory mechanism, reducing the risk of thrombosis from a prolonged antifibrinolytic action of PAI-1. Thus, relying solely on plasma concentrations of PAI-1 without assessing its function may be misleading in interpreting the role of PAI-1 in many complex diseases. Environmental conditions, interaction with other proteins, mutations, and glycosylation are the main factors that have a significant impact on the stability of the PAI-1 structure. This review provides an overview on the current knowledge on PAI-1 especially importance of PAI-1 level and stability and highlights the potential use of PAI-1 inhibitors for treating cardiovascular disease.

Electroencephalographic and behavioral effects of intracerebroventricular or intraperitoneal injections of toxic honey extract in adult Wistar rats and GAERS.

Toxic honey, containing grayanotoxin, is obtained from nectar and polen of rhododendron. Consumed in excess it produces seizures and convulsions. In order to investigate whether the toxic honey extract can be used as a seizure model, we examined the electroencephalographic (EEG) and motor effects of intracerebroventricular (icv) or intraperitoneal (ip) injection of toxic honey extract in Wistar rats or in genetic absence epilepsy rats from Strasbourg (GAERS). Male Wistar rats or GAERS were stereotaxically implanted with bilateral cortical recording electrodes in all ip groups and cannula in the icv groups. Based on the previous study, an extract was obtained from the non-toxic and toxic honey. After the injection of the non-toxic or toxic honey extract, seizure stages and changes in EEG were evaluated from 9 am to noon. The icv administration of toxic honey extract produced stage 4 seizures and bilateral cortical spikes within 30-60 min and these effects disappeared after 120 min in Wistar rats or GAERS. The mean of bilateral cortical spike acitivity in EEG of Wistar rats was 804.2 ± 261.0 s in the 3-h period. After the icv administration of toxic honey extract to GAERS, the mean duration of spike-and-wave discharges (SWDs) in GAERS significantly decreased during the first 60 min and then returned to baseline level. Ip injection of toxic honey extract caused no seizure and no change in EEG in either GAERS or Wistars. These results suggest that the icv administration of toxic honey extract can be used as a seizure model.

Fracture history in osteoporosis: risk factors and its effect on quality of life.

BACKGROUND: Fractures are one of the main outcomes in osteoporosis and have an important effect on the general health status. AIMS: The purpose of this study was to determine the effect of major fracture history on quality of life. We also investigated the important risk factors and their effect on bone mineral density and fracture history. STUDY DESIGN: Cross-sectional study. METHODS: We recruited 105 patients who were admitted to an osteoporosis outpatient clinic. Medical history, family history, calcium intake, physical activity level and biochemical tests were evaluated. Lumbar spine and femur neck bone mineral density were measured. The Qualeffo-41 questionnaire was also used for evaluating quality of life. RESULTS: The average age of the 105 patients included in the study was 56.04±13.73 and 89% of them were post-menopausal women. The average body mass index was 26.84±5.99, which means that the women were overweight. Also, 48.5% of the patients were diagnosed with osteoporosis and 51.5% of them were diagnosed as low bone density. A total of 34 patients had a fracture history with minor trauma and some of the patients had more than one fracture (12 ankle and foot, 10 forearm, 9 vertebral, 4 hand, 3 hip, 2 rib, 1 tibial). When the patients with and without fracture history were compared, the mean Qualeffo-41 score in patients with fracture was 43.85±2.57 and in the non-fracture group was 36.27±2.01. CONCLUSION: Forearm, ankle and foot fractures can be commonly seen in osteoporosis patients with fracture history. We suggest that it is important to recognise osteoporosis prior to first fracture and disease-specific quality of life assessment should be done.