Stiff substrates inhibit collagen accumulation via integrin α2ß1, FAK and Src kinases in human atrial fibroblast and myofibroblast cultures derived from patients with aortal stenosis.

The aim of the study was to confirm whether cell substrate stiffness may participate in the regulation of fibrosis. The involvement of integrin α2ß1, focal adhesion kinase (FAK) and Src kinase in signal transmission was investigated. Human atrial fibroblasts and myofibroblasts were cultured in both soft (2.23 ± 0.8 kPa) and stiff (8.28 ± 1.06 kPa) polyacrylamide gels. The cells were derived from the right atrium of patients with aortal stenosis undergoing surgery. The isolated cells, identified as fibroblasts or myofibroblasts, were stained positively with α smooth muscle actin, vimentin and desmin. The cultures settled on stiff gel demonstrated lower intracellular collagen and collagen type I telopeptide (PICP) levels; however, no changes in α1 chain of procollagen type I and III expression were noted. Inhibition of α2ß1 integrin by TC-I 15 (10-7 and 10-8 M) or α2 integrin subunit silencing augmented intracellular collagen level. Moreover, FAK or Src kinase inhibitors increased collagen content within the culture. Lower TIMP4 secretion was reported within the stiff gel cultures but neither MMP 2 nor TIMP-1, 2 or 3 release was altered. The stiff substrate cultures also demonstrated lower interleukin-6 release. Substrate stiffness modified collagen deposition within the atrial fibroblast and myofibroblast cultures. The elasticity of the cellular environment exerts a regulatory influence on both synthesis and breakdown of collagen. Integrin α2ß1, FAK and Src kinase activity participates in signal transmission, which may influence fibrosis in the atria of the human heart.

Leveraging Radiobiology for Arrhythmia Management: A New Treatment Paradigm?

Radiation therapy is a well-established approach for safely and non-invasively treating solid tumours and benign diseases with high precision and accuracy. Cardiac radiation therapy has recently emerged as a non-invasive treatment option for the management of refractory ventricular tachycardia. Here we summarise existing clinical and preclinical literature surrounding cardiac radiobiology and discuss how these studies may inform basic and translational research, as well as clinical treatment paradigms in the management of arrhythmias.

Disruption of histamine/H3 receptor signal reduces collagen deposition in cultures scar myofibroblasts.

A suitable inflammatory signal influences extracellular matrix accumulation and determines the quality of the myocardial infarction scar. The aim of the present study was to determine the influence of mast cell sonicates or histamine on collagen accumulation in heart myofibroblast culture and on the deposition of collagen in the myocardial infarction scar. The histamine receptor involved in the process was investigated. Myocardial infarction was induced by ligation of the left coronary artery. Myofibroblasts were isolated from the scar of myocardial infarction. The effects of mast cell sonicates, histamine and its receptor antagonists, i.e. ketotifen (H1-receptor inhibitor), ranitidine (H2-receptor inhibitor), ciproxifan (H3-receptor inhibitor), JNJ7777120 (H4-receptor inhibitor), imetit (H3 receptor agonist), were investigated. The mast cell sonicates or histamine (10-10 - 10-5M) augmented collagen content in myofibroblast cultures; however, histamine-induced elevation was reduced by ciproxifan (10-5M, 10-6M). Imetit (10-9 - 10-5M) elevated collagen content in the culture. H3 receptor expression on myofibroblasts was confirmed. Our findings indicate that histamine increases the deposition of collagen in cultures of myofibroblasts isolated from the myocardial infarction scar. This effect is dependent on H3 receptor activation.

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce. METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted. RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

Clinical decision support for hematology laboratory test utilization.

Clinical decision support (CDS) is the use of information and communication technologies to improve clinical decision making and patient care. CDS applications have been used in many aspects of health care, including medication ordering and diagnostic prediction algorithms. As economic and regulatory pressures place a strain on laboratory resources, the potential of CDS to improve utilization of laboratory testing has also begun to be realized. Hematology and coagulation laboratories stand to gain tremendously from the implementation of CDS interventions, given their mixture of high-volume, low-cost tests (eg CBC, PT, aPTT) and tests that carry a high potential of being misused or misinterpreted (eg lupus anticoagulant, erythrocyte sedimentation rate, heparin-induced thrombocytopenia testing). This brief review will define the key terms in the field of clinical decision support, provide instructive examples of CDS interventions to improve utilization of hematology and coagulation testing, introduce methods to implement these interventions effectively, and discuss metrics by which the success of these interventions can be evaluated.

Intermediate veins in swine (Sus scrofa domestica) kidney: authors' own anatomical classification.

BACKGROUND: The use of domestic swine as an experimental animal is increasing steadily. Swine organs are the best animal model for urological experiments. The aim of the study was to evaluate the course and size of intermediate veins in a swine kidney. The research results were compared with the results obtained from studies on venous vascularisation of human kidneys. The knowledge of the above-mentioned vessels is important both in human and veterinary medicine and will enable researchers to compare and notice differences between human and swine organs. MATERIALS AND METHODS: The study was conducted on 94 kidneys, 47 right ones and 47 left ones, taken from adult domestic swines (Sus scrofa domestica). The kidneys were prepared and corrosion casts were made. RESULTS: The average lumen diameter of secondary intermediate veins was 7.96 mm. The average diameter of the primary intermediate veins directly inserted in the renal vein (type A) and primary intermediate veins inserted in the secondary intermediate veins (type B) amounted to 6.7 mm and 4.75 mm, respectively. The average length of primary intermediate veins of type A was 21.91 mm. Secondary intermediate veins were shorter - on average 19.83 mm. Primary intermediate veins of type B were on average 12.91 mm long. CONCLUSIONS: Intermediate veins are formed in the area of vascular anastomoses on the level of renal papillae. The following veins can be distinguished: primary intermediate veins of type A and type B, as well as secondary intermediate veins. Secondary intermediate veins and primary intermediate veins of type A run only on the ventral side of the renal pelvis. Only the primary intermediate veins of type B can run on the dorsal side. From the anatomy point of view, intermediate veins of swine kidneys are very similar to equivalent vessels in human kidneys as regards their run and anastomoses.

Infraorbital groove localisation for the endoscopic decompression of the orbit in Graves' disease.

BACKGROUND: The aim of our study was to determine the localisation of the inferior margin of the optic canal in relation to the infraorbital canal/groove complex (IOC/G complex) and zygomaticoorbitale (ZO) as the potential useful landmarks for reducing dangerous complications following surgical and invasive procedures. MATERIALS AND METHODS: Sixty-four orbits of thirty-two human skulls were investigated. The distances between: the inferior margin of the optic canal and the posterior margin of the infraorbital groove measured at its medial border (OC-S); the inferior margin of the optic canal and the posterior margin of the roof of the infraorbital canal (OC-C); the inferior margin of the optic canal and the zygomaticoorbitale (OC-ZO) - were measured. The left/ /right symmetry ratio and the asymmetry index were counted. The symmetry between the contralateral measurements was analysed and statistical analysis was performed. RESULTS: On the right side the mean distance from the inferior margin of the optic canal to: the posterior margin of the infraorbital groove measured at its medial border; to the posterior margin of the roof of the infraorbital canal; and to the zygomaticoorbitale were: 23.41 ± 3.10 mm; 34.44 ± 5.30 mm; and 47.53 ± 4.13 mm, respectively. On the left side the mean distance from the inferior margin of the optic canal to: the posterior margin of the infraorbital groove measured at its medial border; to the posterior margin of the roof of the infraorbital canal; to the zygomaticoorbitale were 23.69 ± 2.80 mm; 36.75 ± 5.10 mm; 46.84 ± 3.24 mm, respectively. CONCLUSIONS: The presented measurements may be particularly helpful for endoscopic decompression in patients with the thyroid ophthalmopathy to avoid the complications.

Development of new antiatherosclerotic and antithrombotic drugs utilizing F11 receptor (F11R/JAM-A) peptides.

Peptides with enhanced resistance to proteolysis, based on the amino acid sequence of the F11 receptor molecule (F11R, aka JAM-A/Junctional adhesion molecule-A), were designed, prepared, and examined as potential candidates for the development of anti-atherosclerotic and anti-thrombotic therapeutic drugs. A sequence at the N-terminal of F11R together with another sequence located in the first Ig-loop of this protein, were identified to form a steric active-site operating in the F11R-dependent adhesion between cells that express F11R molecules on their external surface. In silico modeling of the complex between two polypeptide chains with the sequences positioned in the active-site was used to generate peptide-candidates designed to inhibit homophilic interactions between surface-located F11R molecules. The two lead F11R peptides were modified with D-Arg and D-Lys at selective sites, for attaining higher stability to proteolysis in vivo. Using molecular docking experiments we tested different conformational states and the putative binding affinity between two selected D-Arg and D-Lys-modified F11R peptides and the proposed binding pocket. The inhibitory effects of the F11R peptide 2HN-(dK)-SVT-(dR)-EDTGTYTC-CONH2 on antibody-induced platelet aggregation and on the adhesion of platelets to cytokine-inflammed endothelial cells are reported in detail, and the results point out the significant potential utilization of F11R peptides for the prevention and treatment of atherosclerotic plaques and associated thrombotic events.

Variations in the topography of the infraorbital canal/groove complex: a proposal for classification and its potential usefulness in orbital floor surgery.

BACKGROUND: The aim of the study was to precisely describe and classify the infraorbital canal/groove (IOC/G) complex in dry human skulls and to evaluate the presence of asymmetry in the IOC/G complex. MATERIALS AND METHODS: Seventy orbits of 35 human skulls were investigated.The following distances were measured: the distance between the posterior and anterior margin of the infraorbital groove (S-C); the posterior margin of the infraorbital canal and the infraorbital foramen (C-IOF); and the total length of the infraorbital canal-groove complex (S-C-IOF). The symmetry of the contralateral measurements was analysed. RESULTS: Three types of the IOC/G complex were distinguished: types I, II, III, whose respective incidences were 11.4%, 68.6%, 20.0%. The mean length of the infraorbital groove plus canal complex on the right and left with standard deviation were 27.78±3.69 mm and 28.06±3.37 mm, respectively. CONCLUSIONS: The results presented in this study may be particularly helpful for surgery in patients with blow-out fractures and different endoscopic and reconstructive procedures in the region of the inferior orbital wall. The type III IOC/G complex, according to our classification, seems the most likely to be exposed to trauma during surgical manipulations.

Organelles do not colocalize with mRNA granules in post-ischemic neurons.

Following global brain ischemia and reperfusion, it is well-established that neurons undergo a translation arrest that is reversible in surviving neurons, but irreversible in vulnerable neurons. We previously showed a correlation between translation arrest in reperfused neurons and the presence of granular mRNA-containing structures we termed "mRNA granules." Here we further characterized the mRNA granules in reperfused neurons by performing colocalization studies using fluorescent in situ hybridization for poly(A) mRNAs and immunofluorescence histochemistry for markers of organelles and mRNA-binding proteins. There was no colocalization between the mRNA granules and markers of endoplasmic reticulum, cis- or trans-Golgi apparatus, mitochondria, microtubules, intermediate filaments, 60S ribosomal subunits, or the HuR ligands APRIL and pp32. The mRNA granules colocalized with the neuronal marker NeuN regardless of the relative vulnerability of the neuron type. RNA immunoprecipitation of HuR from the cytoplasmic fraction of 8 h reperfused forebrains selectively isolated hsp70 mRNA suggesting the mRNA granules are soluble structures. Together, these results rule out several organelle systems and a known HuR pathway as being directly involved in mRNA granule function.

Adverse drug reactions (ADRs) associated with hospital admissions - elderly female patients are at highest risk.

BACKGROUND: ADRs represent a significant problem in drug utilisation. The prevalence of admissions caused by ADRs varies depending on the observational site, studied population, data collection method and the used definitions. Women seem to be more frequently affected than men. OBJECTIVE: To assess the incidence and quality of ADRs related to hospital admissions, to identify the drugs most commonly involved and to define risk factors and preventive strategies for those ADRs. MATERIAL AND METHODS: 3,190 medical records of all newly admitted internal ward patients were assessed in a prospective observational study in an internal hospital over 6 months. Potential ADRs at hospital admission were identified following a list of suspicious symptoms and laboratory results. Cases were evaluated by means of a computer tool and data-base specialized on detecting causality and severity of ADRs. RESULTS: 304 ADRs were identified in 242 patients (7.6%), with 60% directly leading to admission. More women than men encountered an ADR (10 vs. 6%, p < 0.005). Analyzed separately by age groups, this gender difference became significant at an age of ≥ 81 years. The most common ADRs were electrolyte imbalances and over-anticoagulation. Diuretics and vitamin K antagonists were significantly correlated with ADRs. 62% of all ADRs were severe or life-threatening. CONCLUSION: ADRs leading or related to hospital admission are highly prevalent. Older age and female gender are significantly associated with ADR related hospital admissions. Causative drugs are the ones prescribed most frequently. Multidisciplinary preventive strategies and surveillance methods are necessary to ensure better care and patient safety especially for elderly women.

BK virus associated renal cell carcinoma: case presentation with optimized PCR and other diagnostic tests.

Polyomaviruses, including BK and JC viruses, have been associated with graft failure, but have not commonly been associated with malignancy. We present a case of renal cell carcinoma arising in an allograft kidney, in which the tumor and metastasis contain viral DNA. Tumor and biopsy specimens from this patient were examined with hematoxylin & eosin, immunohistochemistry (IHC) and in situ hybridization (ISH). The results were confirmed by real-time polymerase chain reaction (PCR) analysis with BKV primers. Other viruses including herpes simplex 1-2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and varicella zoster were not detected. The presence of BKV DNA in a renal cell carcinoma, including a metastatic focus, adds to the evidence that this virus may play a role in cancers of the kidney and urinary tract.

Pharmacokinetics of ibuprofen sodium dihydrate and gastrointestinal tolerability of short-term treatment with a novel, rapidly absorbed formulation.

OBJECTIVE: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. MATERIAL AND METHOD: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 x 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 x 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. RESULTS: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar C(max) to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the t(max) for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. CONCLUSIONS: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.

Laparoscopic repair of inguinal hernias with higher risk for recurrence: independent assessment of results from 121 repairs.

This study attempts to determine by independent review the results of laparoscopic transabdominal preperitoneal (TAPP) inguinal hernia repair for hernias with increased risk for recurrence. Indicators used for increased recurrence risk were recurrent hernias or simultaneously repaired bilateral inguinal hernias. Office and hospital records of all such patients who had undergone TAPP repair were reviewed from one surgeon's 242-patient laparoscopic inguinal hernia database from 1992 to 1998. All were called for assessment by an independent surgeon at least 4 months postoperatively (median 34 months). Those unable to come in person were interviewed by telephone. There were 121 hernias: 34 recurrent and 100 bilateral (13 overlap). Recurrence rate was 3 per cent, which was similar for repair of bilateral and recurrent hernias. All recurrences occurred within 3 months of surgery. No unknown recurrence was detected by the independent observer. Laparoscopic TAPP inguinal hernia repair, often claimed as the method of choice for bilateral and recurrent hernia repair, is indeed a safe and effective procedure with a low early recurrent rate in these higher-risk situations.

Technique and early results of outpatient laparoscopic mesh onlay repair of ventral hernias.

BACKGROUND: This report describes the technique and early results of a simple outpatient laparoscopic ventral hernia repair. METHODS: Data were gathered prospectively for all laparoscopic ventral hernia repairs from January 1996 to December 1997 at a 228-bed hospital. Prolene mesh was stapled to the peritoneal surface of the abdominal wall, leaving sac in situ and mesh uncovered. Patients were seen by the operating surgeon within 2 months, and by an impartial surgeon (J.S.) after 3 to 14 months (average, 7 months; median, 6 months). RESULTS: Repairs involved 44 hernias with orifice sizes 2 to 20 cm in diameter, and an average area of 20 cm(2). Of these 44 hernias, 36 were postoperative and 8 primary. Furthermore, 20% were recurrent hernias. There were four conversions. The outpatient rate was 98%, with one readmission for ileus. The early recurrence rate was 5%. CONCLUSIONS: Laparoscopic mesh onlay repair is a safe, easy, and effective procedure with minimal discomfort and a low early recurrence rate that can be performed safely on an outpatient basis.

Variation of CYP1A2-dependent caffeine metabolism during menstrual cycle in healthy women.

BACKGROUND AND OBJECTIVES: The activity of the human cytochrome P450 CYP1A2 is decreased by female sex hormones during pregnancy or treatment with oral contraceptives. However, the influence of menstrual cycle on CYP 1A2 activity is not clear. METHODS: CYP1A2 activity was monitored in 15 women (13 with confirmed ovulatory cycles, 2 smokers, age (mean +/- SD) 27.8 +/- 3.8 years, body mass index 23.8 +/- 3.8 kg x m-2) using the specific substrate caffeine (mean doses 149 mg). After a run-in period started one week prior to expected onset of menses, daily saliva samples were taken 7.3 +/- 0.7 hours after caffeine intake throughout the cycle, and caffeine clearance was estimated from the paraxanthine to caffeine ratio therein. Ovulation was confirmed by progesterone serum concentration above 3 ng/ml in the second half of the cycle. RESULTS: Initial (day 2) caffeine clearance (n = 15, geometric mean) was 1.37 ml/min/kg body weight (coefficient of variation (CV) 48%). The ratio of caffeine clearance for the luteal (day -9 to -4 prior to onset of the next menses) to the follicular phase (days 5-10) was (n = 13, point estimate) 1.03 (90% CI 0.95-1.12), indicating that there was no difference in CYP1A2 activity between these cycle phases. The median intraindividual CV in ovulatory cycles (n = 13) was 23% (range 11% to 39%). As an additional finding, there was evidence for long-term fluctuations of CYP1A2 activity in most individuals. CONCLUSIONS: A dose adaptation according to the phase of menstrual cycle based on pharmacokinetics is not required for CYP1A2 substrates.

Prompt Optical Observations of Gamma-Ray Bursts.

The Robotic Optical Transient Search Experiment (ROTSE) seeks to measure simultaneous and early afterglow optical emission from gamma-ray bursts (GRBs). A search for optical counterparts to six GRBs with localization errors of 1 deg2 or better produced no detections. The earliest limiting sensitivity is mROTSE>13.1 at 10.85 s (5 s exposure) after the gamma-ray rise, and the best limit is mROTSE>16.0 at 62 minutes (897 s exposure). These are the most stringent limits obtained for the GRB optical counterpart brightness in the first hour after the burst. Consideration of the gamma-ray fluence and peak flux for these bursts and for GRB 990123 indicates that there is not a strong positive correlation between optical flux and gamma-ray emission.

Efficacy of multimodality spinal cord monitoring during surgery for neuromuscular scoliosis.

STUDY DESIGN: This study determined the relative efficacy of somatosensory-evoked potentials and motor-evoked potentials in monitoring spinal cord function during surgery for patients with idiopathic versus neuromuscular scoliosis. OBJECTIVES: To determine whether patients with idiopathic versus neuromuscular scoliosis demonstrate significantly different somatosensory-evoked potentials and motor-evoked potentials recorded during surgery. SUMMARY OF BACKGROUND DATA: Ashkenaze et al (1993) and others have reported that cortical somatosensory-evoked potentials are unreliable when used to monitor spinal cord function in patients with neuromuscular scoliosis. It was recommended that other neurophysiologic tests be used. METHODS: Somatosensory-evoked potentials and motor-evoked potentials were recorded from two groups of patients: those with idiopathic scoliosis and those with neuromuscular scoliosis. Somatosensory-evoked potentials were obtained before and during surgery. Motor-evoked potentials were obtained during surgery. Normal variability, as indicated from idiopathic scoliotic results, was compared with data obtained from patients with neuromuscular scoliosis. Motor-evoked potentials and somatosensory-evoked potentials were obtained sequentially during the duration of surgery. RESULTS: Single-channel cortical somatosensory-evoked potentials demonstrated a 27% positive rate, which was consistent with results (28%) from Ashkenaze et al. The use of multiple recording sites for the somatosensory-evoked potentials and the addition of motor-evoked potential procedures indicated that a reliable response could be obtained in more than 96% of the patients. It also was found that cortical somatosensory-evoked potentials were more affected by anesthetic agents when recorded from patients with neuromuscular scoliosis compared with patients with idiopathic scoliosis. CONCLUSIONS: Single-channel cortical somatosensory-evoked potentials demonstrated a high level of unreliability, which reduced their clinical effectiveness. However, by using multiple recording sites with the somatosensory-evoked potentials and by administering motor-evoked potential procedures, it was possible to monitor spinal cord function in neuromuscular patients and avoid postoperative neurologic deficits.