Four probands have high low-density lipoprotein cholesterol (LDL-

Four probands have high low-density lipoprotein cholesterol (LDL-C) levels, ranging from 14.65 to 27.66 mmol/L. Their heterozygous

parents had relatively tow levels. B-mode ultrasound supplemented by Doppler was used to examine aortic/mitral valve structural alterations and carotid intima-media thickness (ITM) in all probands. The ITM values were between 1.2 and 2.3 mm, much higher than the normal value of < 0.8 mm.

Conclusion: Our data demonstrated that all the probands were associated with severe hypercholesterolemia, thick carotid IMT and a low CFVR (coronary flow velocity reserve) value. The novel mutation (C120Y) is a disease causing mutation. (c) 2008 Elsevier B.V. All rights reserved.”
“Study Design. Case report.

Objective. To describe the case of a Klippel-Feil anomaly associated with carotid agenesis.

Summary of Background Data.

Klippel-Feil anomaly is a spinal malformation characterized by fusion Selleck Barasertib of the cervical vertebrae. mTOR inhibitor Four subtypes have been identified for this congenital disorder with different severity of vertebral fusion and different extra-axial anomalies. Most cases are sporadic, although autosomal dominant and autosomal recessive cases are recognized. It can cause neurologic disorders and is associated to vascular abnormalities. However, agenesis of internal carotid and Klippel-Feil syndrome is an unusual association.

Methods. A 49-year-old woman came to our attention for recurrent transitory ischemic attacks presenting with weakness of left limbs associated with sensory abnormalities. Neurologic examination revealed mild left limb weakness and tactile hypoesthesia.

Results. Tipifarnib Brain magnetic resonance (MR) and MR angiography demonstrated absence of the right internal carotid and the

middle right cerebral artery was filled from the basilar artery. Fusion of vertebral bodies was documented at MR and confirmed at spinal CT scan. The day after the admission the neurologic examination became normal. Ticlopidine was then started.

Conclusion. Literature of vascular abnormalities in association with Klippel-Feil syndrome takes the form of anecdotal reports. Aortic coarctation, vertebral artery dissection, aneurysms, persistent trigeminal artery, and abnormal origin of internal carotid are described. An unusual association of carotid internal agenesis and Klippel-Feil syndrome is reported with a literature review.”
“Background and aims: To determine whether triglyceride/high-density lipoprotein chotesterol ratio (TG/HDL-C), which has been shown to be an indicator of the Metabolic syndrome (MetS) and insulin resistance, can predict coronary heart disease (CHD) independently of total cholesterol (TC) and other risk factors in an Iranian population with a high prevalence of MetS and tow HDL-C.

Methods and results: Between February 1999 and August 2001, 1824 men >= 40 years old, free of clinical cardiovascular diseases at baseline, were followed.

Similar enhancement in neuroprotective effect was also observed i

Similar enhancement in neuroprotective effect was also observed in primary cortical cultures after NMDA or Zn(2+) treatment or oxygen glucose deprivation. Together, these results indicate that combination treatment of ethyl pyruvate and aspirin affords synergistic neuroprotection in the postischemic brain with a wide therapeutic window, in part via differential modulation of the NF-kappa B signaling pathway.”
“An in situ thickness measurement method of dielectric films (dual frequency method) was developed, and the thicknesses were measured in an inductively coupled plasma. This method uses a small ac bias voltage with two frequencies for thickness measurement. The dielectric thickness is obtained from

measuring the amplitudes check details of the two frequency ac currents through a sensor, as well as using an equivalent circuit model describing impedance of the dielectric film and the plasma sheath. In the experiment, the thicknesses of Al2O3 film could be accurately

measured in real time. To check the measurement reliability, the dual frequency method was compared with reflection spectrophotometry as a technique for optical thickness Sonidegib molecular weight diagnostics. It was found that the dual frequency method agrees closely with reflection spectrophotometry at various rf powers and pressures. In addition, this method is very simple and can be installed anywhere in plasma reactors, in contrast with optical methods; therefore, it is expected to be applied to in situ surface diagnostics for various processing plasmas.”
“Case Description-An 11-year-old spayed female Siberian Husky was evaluated because of a 2-week history of progressive paraparesis.

Clinical Findings-Results Ralimetinib mouse of neurologic examination were consistent

with a T3-L3 myelopathy. There were no abnormalities on CBC, and hypercalcemia was noted on serum biochemical analysis. Several hypoechoic splenic nodules were evident on abdominal ultrasonography, and results of fine-needle aspiration cytology were consistent with splenic extramedullary hematopoiesis (EMH). Two compressive, extradural masses in the dorsal epidural space of the thoracolumbar region of the spinal cord were seen on MRI images.

Treatment and Outcome-A dorsal laminectomy was performed to remove the extradural spinal masses. Results of histologic examination of tissue samples were consistent with EMH. Following surgery, clinical signs of paraparesis resolved, and there was no recurrence of the masses 24 months after surgery.

Clinical Relevance-Extramedullary hematopoesis should be considered as a differential diagnosis in dogs in which results of diagnostic imaging indicate a epidural mass. In human patients, spinal EMH usually occurs secondary to an underlying hematologic disease, but it can also occur spontaneously. Treatment options reported for humans include surgical decompression, radiation therapy, chemotherapy, and blood transfusion.

These results suggest that the succinylation treatment could be a

These results suggest that the succinylation treatment could be applied to modify the mechanical properties of legume proteins, especially in the case that requires excellent flexibility of cast films. (c) 2010 Wiley Periodicals, Inc. J Appl Polym Sci 120: 1934-1941,

2011″
“Since the advent of uterine compression suture by B-Lynch, GSK-3 inhibitor numerous techniques have been advocated. We aim to discuss these various techniques with respect to their efficacy, safety, complications, complexity of the technique itself, future fertility and menstrual periods. Since no randomized controlled trials are available, the conclusions are based on weak data derived from observational studies and case series. A success rate of 91.7% has been reported for various uterine compression sutures. There are concerns regarding closure of uterine cavity and blood entrapment resulting in infection, pyometra and adhesions as the uterus will be MK-8931 ic50 transfixed from front to back in some of the suturing techniques. Long-term follow-up regarding fertility of patients who had uterine compression sutures

is urgently needed. Data on menstrual periods after uterine compression sutures is limited. Our review is limited in nature due to lack of consistent data on many important outcomes and also preclinical variables.”
“Childhood asymmetry labium majus enlargement (CALME) is a disctinctive clinicopathologic entity of pre- and early puberty first described in 2005. It is defined as an expansion of normal soft tissues of the vulva. Although CALME is not a rare lesion, it has been called lipoma, fibroma, hamartoma, and fibrous hyperplasia. CALME is not a true neoplasm and is a physiologic growth in response to hormone. It may tend to resolve spontaneously and recur after surgical resection. We report four cases of CALME with a review of the literature. To the best of the knowledge, this

is the first Korean report.”
“Macroporous styrene-divinylbenzene copolymers with different degree of crosslinking were prepared by suspension polymerization in presence of different binary mixtures of toluene and heptane, as diluent. Specific surface area, SBC-115076 inhibitor bulk and apparent densities, and pore volume of the resulting beads were determined experimentally. Applying the least square method to the experimental data, correlations for prediction of these properties were obtained. Effects of divinylbenzene concentration, diluent to comonomer volume ratio, and composition of the diluent mixture were considered in developing the aforementioned correlations. The influence of the reaction recipe on porous structure of the samples was also studied using scanning electron microscope (SEM). (c) 2010 Wiley Periodicals, Inc.

Discrepancies were discussed with a third reviewer and scored by<

Discrepancies were discussed with a third reviewer and scored by

consensus. Finally, a level of evidence approach was used to synthesize the results and study quality.

Results Our search strategy identified a total of 2,588 articles. Forty-six articles, reporting 79 unique studies, met inclusion criteria. Ten instruments quantifying mindfulness as a unidimensional scale (n = 5) or as a set of 2-5 subscales (n = 5) were reviewed. The Mindful Attention Awareness Scale was evaluated by the most studies (n = 27) and had positive overall quality ratings for most of the psychometric properties reviewed. The Five Facet Mindfulness Questionnaire received the highest possible rating (“”consistent findings in multiple studies of good methodological quality”") for two properties, internal consistency ACY-738 in vitro and construct validation by hypothesis testing. However, none of the instruments had sufficient evidence of content validity. Comprehensiveness of construct coverage had not been assessed; qualitative methods to confirm understanding and

relevance were absent. In addition, estimates of test-retest reliability, responsiveness, or measurement error to guide users in protocol development or interpretation of scores were lacking.

Conclusions Current mindfulness scales have important conceptual differences, and none can be strongly recommended based solely on superior psychometric properties. Important limitations in the field are the absence of qualitative evaluations and accepted external referents to support construct validity. Investigators need to proceed cautiously before optimizing any mindfulness intervention based on the existing scales.”
“Semitransparent this website IWR-1 chemical structure composite films

were prepared made from TiO(2) nanotubes in chitosan (CS) matrix. Hydrothermally synthesized titanium nanotubes (TiNTs) were dispersed in chitosan matrix in order to produce film-forming solutions at 0.05 and 0.10% w/v. Structural, topological, optical and thermal properties of these films were evaluated. The antimicrobial activity of films against Salmonella enterica serovar Typhimurium, Escherichia coli (Gram-negatives) and Staphylococcus aureus (Gram-positive) was also investigated. Fourier transform infrared (FTIR) spectra showed effective site-selective interactions between chitosan and TiNTs. TiNTs prevented the degradation of films, avoiding the oxidization of the glucosamine ring. Characterizing techniques such as, Scanning electron microscopy energy dispersive spectroscopy (SEM-EDS) line profile and atomic force microscopy (AFM) were used to examine the TiNTs dispersion within the film. The morphological analysis indicated that the TiNTs were well dispersed and became clustered proportionally to the weight percentage of TiNTs used in the composites. The UV-Vis spectra showed that TiNTs increased the film absorption in the UV region and the light barrier properties of films remained stable over the storage period.

Patients received twice-daily cyclosporine 0 05% in 1 eye and an

Patients received twice-daily cyclosporine 0.05% in 1 eye and an artificial tear in the other eye from 1 month before to 2 months after second-eye surgery. Outcomes were evaluated at baseline and 2 months

after second-eye surgery.

RESULTS: The study enrolled 28 eyes of 14 patients. At baseline, there were no statistically P5091 mouse significant between-group differences in outcome measures. Two months postoperatively, the cyclosporine group had significantly lower mean uncorrected distance visual acuity than the artificial tear group (0.11 logMAR +/- 0.03 [SD] [20/25 Snellen equivalent] versus 0.19 +/- 0.05 logMAR [20/30]; P = .045) as well as significantly lower mean corrected distance visual acuity (0.0 +/- 0.02 logMAR [20/20] versus 0.1 +/- 0.02 logMAR [20/25]; P = .005) and corneal staining scores (0.210 +/- 0.07 versus 0.645 +/- 0.18; P = .034). Treatment with cyclosporine

0.05% also improved contrast sensitivity, conjunctival staining, and tear breakup time. Significantly more patients preferred the eye treated with cyclosporine 0.05% to the eye treated with artificial tears (57.1% versus 14.3%; P = .007).

CONCLUSION: Cyclosporine 0.05% therapy reduced dry-eye signs and improved visual quality after multifocal IOL implantation.”
“The present study describes the behaviour of photosystem II (PSII) in Amaranthus hypochondriacus buy WH-4-023 and Amaranthus hybridus under water stress conditions, assessed by the analyses of the polyphasic rise in chlorophyll a fluorescence (O-J-I-P). We determined the adaptive behaviour in relation to the regulation of the different functional and structural parameters of PSII, which was a direct and rapid response due to changes in soil water status indicated by a decrease in leaf water potential and relative water content. It allows for the identification of specific key or limiting chlorophyll fluorescence parameters which could be used to identify traits conveying tolerance. For the above partial processes of PSII

function studied, it seems that A. hybridus remained the more stable upon water stress (after 17 PF-562271 days of withholding water), concerning the specific energy fluxes of absorption/reaction centre (ABS/RC) apparent (antenna size) and trapping/reaction centre (TR/RC) (maximum trapping flux), as well as the density of the reaction centres/cross section (RC/CS) and the phenomenological trapping flux/cross section (TR(o)/CS). It was clear that amaranth adjusts the non-photochemical (k(n)) deactivation constant of PSII and to a less extend also the photochemical (k(p)) deactivation constant by means of photoregulation, which forms the basis of the quenching of chlorophyll a fluorescence.

Patients who acquired their anti-diabetic drugs from a Brazilian

Patients who acquired their anti-diabetic drugs from a Brazilian community pharmacies chain were invited to participate in the PCP. The recruited patients were monthly interviewed and information about pharmacotherapy,

comorbidities, diet, physical activity, body mass index (BMI), blood pressure (BP), and waist circumference (WC) were obtained. Evaluation of glycemia, glycated hemoglobin Alc (HbAlc), and lipid profile analyses was done after the first interview and repeated every four months until finish the PCP. The 51 (91.1 %) patients who completed the PCP (12 months) showed improvement in the nutritional habits, physical GW3965 in vivo activity, pharmacoterapeutic follow-up, HbAlc, lipid profile, BP, WC, and BMI. Thus, the PCP was

applicable to the type 2 diabetic patients improving diabetes education and reducing modifiable risk factors of chronic complications.”
“Objective: To compare the maternal and fetal characteristics and perinatal outcome in mild and severe preeclampsia cases with and without uterine artery Doppler abnormalities.

Methods: Two hundred and fifty-nine mild and severe preeclampsia cases were evaluated retrospectively. Doppler measurements were done in the section where uterine artery raised from the hypogastric artery. Pulsatility index above the 95th percentile of the corresponding gestational age was accepted as abnormal.

Results: In mild and severe preeclampsia cases with abnormal Doppler (AD), the rate of intrauterine growth restriction, preterm birth PLX-4720 cell line and low birth weight was higher than, but the neonatal intensive care unit stay was similar to the cases with normal Doppler. Base excess was higher in selleckchem the AD group, in mild and severe preeclampsia. The rate of low Apgar score at 5 min and perinatal mortality was higher in the AD group, in the mild preeclampsia. The strongest independent predictor of the perinatal morbidity and mortality was the presence of prematurity and of the prematurity was the presence of abnormal uterine artery Doppler.

Conclusions: Maternal and perinatal morbidity and perinatal mortality increase in mild to severe preeclampsia cases

with abnormal uterine artery Doppler. The abnormal uterine artery Doppler increases the morbidity and mortality by increasing the risk of prematurity.”
“The purpose of this study was to design a novel vaginal delivery system composed of metronidazole microspheres dispersed within a bioadhesive gel. Microspheres were prepared by solvent evaporation method using Eudragit RS-100 and RL-100 polymers with different drug/polymer ratios. Micro spheres were characterized by SEM, DSC, FT-IR and particle size analysis and evaluated for morphology, drug loading and in vitro drug release in simulated vaginal fluid. The % yield, actual drug loading and encapsulation were found to range between 79 +/- 0.5 to 94 +/- 0.6%, 19.6 +/- 0.27 to 35.91 +/- 0.

In WT scions, the rootstock had no effect on detached leaf ethyle

In WT scions, the rootstock had no effect on detached leaf ethylene evolution or xylem concentrations of ABA or the ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC). In fic scions, although the WT rootstock suppressed stomatal conductance of individual leaves, there was no detectable effect on whole plant transpiration rate. However, leaf area of flc/WT (scion/rootstock) plants increased 1.6-fold compared to fic self-grafts. WT rootstocks increased xylem ABA concentration in fic scions

(relative to fic self-grafts) up to 3-fold, and resulted in xylem ACC concentrations and detached leaf ethylene evolution similar to WT scions. Since the WT rootstock normalized shoot ethylene relations but only partially restored the leaf area of fic scions

(relative to that of WT scions), shoot ABA biosynthesis can directly promote leaf area via an unknown, ethylene-independent, PXD101 mechanism.”
“Background: Subtle variations selleck chemicals in acetabular morphology have been implicated in several pathologic hip conditions. Although it is understood that the acetabulum forms at the junction of the ilium, ischium, and pubis at the triradiate cartilage, the ossification and development pattern of the posterior wall of the acetabulum is unknown. Standard radiographs and computed tomographic scans used in evaluation of the adolescent hip do not allow a complete assessment of the non-ossified portions of the developing acetabulum. The purpose of this study was to define the currently unknown ossification pattern and development of the posterior wall of the acetabulum and to determine when conventional imaging, with use of computed tomography and radiographs, is appropriate.

Methods: One hundred and eighty magnetic resonance imaging examinations in patients who were four to fifteen years old were evaluated by a musculoskeletal radiologist for ossification patterns of the posterior wall of the acetabulum and triradiate cartilage.

Correlations were made with available radiographs.

Results: Posterior acetabular wall ossification lags behind anterior wall ossification throughout development. https://www.selleckchem.com/products/azd6738.html On average, the posterior wall of the acetabulum began to ossify at the chronological age of eight years, followed by a discrete rim of posterior calcification (posterior rim sign) at the patient age of twelve years, just prior to the fusion of the posterior acetabular wall elements to the pelvis. This preceded the closure of the triradiate cartilage in all subjects. On average, male patients had fusion of the posterior wall of the acetabulum one to 1.5 years after female patients.

Conclusions: The ossification of the posterior wall of the acetabulum is completed in a predictable manner prior to closure of the triradiate cartilage.

We have demonstrated a solution to this problem that harnesses th

We have demonstrated a solution to this problem that harnesses the computational power of today’s large massively parallel computers by combining a CA-4948 classical Wang-Landau Monte-Carlo calculation [F. Wang and D. P. Landau, Phys. Rev. Lett. 86, 2050 (2001)] with our first principles multiple scattering electronic structure code [Y. Wang et al., Phys. Rev. Lett. 75, 2867 (1995)] that allows the energy calculation of constrained magnetic states [M. Eisenbach et al.,

Proceedings of the Conference on High Performance Computing, Networking, Storage and Analysis (ACM, New York, 2009)]. We present our calculations of finite temperature properties of Fe and Fe3C using this approach and we find the Curie temperatures to be 980 and 425K, respectively. (C) 2011 American Institute of Physics. [doi: 10.1063/1.3562218]“
“An emulsion polymerization method was employed to prepare pulverized expandable graphite (pEG)-poly(methyl methacrylate-acrylic acid) copolymer [(PMA)] composite particles, and then the pEG-P(MA) particles were used for a flame retardant of the rigid polyurethane foam (RPUF). Fourier transform infrared (FTIR) spectroscopy data demonstrated

the Epigenetics inhibitor existence of P(MA) in the pEG-P(MA) particles, and the result of the thermogravimetric analysis (TGA) indicated that the content of P(MA) was 24.3 wt %. Morphological observation showed that the pEG particles were encapsulated by a layer of polymer coating to form typical core-shell composite particles. Due to the possible reaction between -COOH of pEG-P(MA) and R-CNO of isocyanate, the compatibility between the selleckchem composite particles

and the RPUF matrix was highly enhanced. In contrast to the pEG, the limiting oxygen index (LOI), the horizontal and vertical burning tests showed the pEG-P(MA) composite particles could improve the flame retardancy effectively. The improved flame retardancy of the RPUF matrix was attributed to the increased expansion volume ratio of pEG-P(MA) particles as exposed to fire. The dynamical mechanical analysis (DMA) showed that the incorporation of the core-shell particles could improve the storage modulus and tan delta of the RPUF composites. (C) 2011 Wiley Periodicals, Inc. J Appl Polym Sci 122: 932-941, 2011″
“The regulation of gene expression is an important determinant of organismal phenotype and evolution. However, the widespread recognition of this fact occurred long after the synthesis of evolution and genetics. Here, we give a brief sketch of thoughts regarding gene regulation in the history of evolution and genetics.

The value of IONM in prognosticating neural function and in intra

The value of IONM in prognosticating neural function and in intraoperative decision making regarding proceeding to bilateral surgery is also well-known. Initial data on recent extensions of IONM in the form of SLN monitoring and continuous vagal nerve monitoring are promising. Continuous vagal nerve monitoring expands the utility of IONM by providing real-time electrophysiological

buy LGX818 information, allowing surgeons to take a corrective action in impending neural injury.”
“Objective. Functional transcranial Doppler sonography (fTCD) enables reliable quantification of cerebral blood flow modulation during neural activation processes. Its high-time resolution, relatively simple technical arrangement, and low costs could make fTCD a useful tool in the investigation of brain activity underlying pain experience in fundamental and clinical research. The present pilot study explored the suitability of this technique to investigate cerebral hemodynamics during the processing of experimental heat pain.

Design. In 46 healthy subjects, this website blood flow velocities in the anterior cerebral arteries (ACA) and middle cerebral arteries (MCA) of both hemispheres were recorded, while heat stimuli of 45 and 47 degrees C were applied to their left forearms (stimulus duration 20 seconds).

Subjective sensory and affective pain intensities were assessed using visual analog scales.

Results.

A biphasic right dominant blood flow increase arose in the ACA and MCA with maxima around 5 and 15 seconds after stimulus onset. The response was stronger under stimulation with 47 degrees C with respect to 45 degrees C, and the magnitude of the late response component correlated positively with sensory and affective pain intensity under the 45 degrees C condition.

Conclusions. The findings suggest that fTCD measurements prove sensitive both to different levels of physical intensity of painful stimuli and to interindividual differences in nociceptive responding. fTCD may be a valuable tool in clinical pain research, Selleck RG7112 for instance, when it comes to quantifying the temporal dynamics of exaggerated nociceptive responses in chronic pain, or evaluating treatment effects on nociceptive processing.”
“Background: Typical Williams-Beuren syndrome (WBS) is commonly caused by a similar to 1.5 Mb – similar to 1.8 Mb heterozygous deletion of contiguous genes at chromosome region 7q11.23. The majority of WBS cases occurs sporadically but few familial cases of autosomal dominant inheritance have been reported. Recent data demonstrated the existence of the paracentric inversion polymorphism at the WBS critical region in 7q11.23 in some of the progenitors transmitting the chromosome which shows the deletion in the affected child.

5 +/- 52 5 vs -4 8 +/- 44 0, P = 0 002) and LVESV (mL) (-34 0 +/-

5 +/- 52.5 vs -4.8 +/- 44.0, P = 0.002) and LVESV (mL) (-34.0 +/- 55.5 vs -9.9 +/- 45.8, Staurosporine inhibitor P = 0.002) and improvement in LVEF (%) (8.9 +/- 12.8 vs 4.5 +/- 9.0, P = 0.007) than patients without narrowing. In univariate analysis, female gender (P = 0.0002), percent QRS narrowing from baseline (P = 0.008), lack of nitrate (P < 0.0001) and antiarrhythmic medication use (P = 0.01), lack of a nonspecific intraventricular conduction delay (=0.02), nonischemic cardiomyopathy (P = 0.003), and lower pre-CRT LVEDV (P = 0.006) and LVESV [P = 0.01]) were associated with responders. In a multivariate model, QRS narrowing, indexed to

the baseline QRS duration, remained strongly associated with response (odds ratio 0.08 [0.01-0.56], P = 0.01).

Conclusions: After adjusting for potential confounders, QRS narrowing, indexed to baseline QRS duration, is associated with enhanced reverse ventricular

remodeling following CRT. (PACE 2011; 34:604-611).”
“Objective. The objective of this study was to evaluate immediate and late postoperative complications in treating zygomatic complex fractures by 2 modified approaches; namely, the modified lateral orbitotomy approach and the modified hemicoronal approach.

Study design. Twenty zygomatic complex fractures were treated, with 10 being treated with the modified lateral orbitotomy approach and the other 10 by the modified hemicoronal approach. Both groups were evaluated for postoperative complications, ie, hematoma, infection, swelling, and nerve injury. The incisions were also evaluated in PU-H71 datasheet all patients using clinical evaluation and visual analogue scales.

Results. Nocodazole in vivo Patients in both groups had temporary facial nerve injury that was primarily related to retraction of the nerve. There were no hematomas observed in any of the groups. As compared to the modified lateral orbitotomy approach, swelling was observed on more occasions with the modified hemicoronal approach. Infection was not observed in any of the groups. As far as the esthetics in relation to the incision was concerned, the patients accepted the

modified hemicoronal approach more strongly as compared with the modified lateral orbitotomy approach.

Conclusion. The modified hemicoronal approach seems to be preferred to the modified lateral orbitotomy approach with respect to treating zygomatic complex fractures. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2010; 109: 504-509)”
“Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent.