Tumor rupture (TR) occurred in the other 9 and LR occurred in sev

Tumor rupture (TR) occurred in the other 9 and LR occurred in seven (Yates’ P = 0.012). All 33 patients underwent type III resection with free margins without tumor rupture. LR occurred in five. 11 patients had type IV resection. Free margin without tumor rupture was accomplished in seven and LR occurred in three. TR occurred in the other four, and LR occurred in two (Yates’ P = 0.689). One patient underwent selleck products type V resection with free margin without tumor rupture and LR occurred. Postoperatively, less than 1/3 needed long-term urethral catheterization. No patients received colostomy

for postoperative fecal incontinence. All the patients were able to ambulate.

Our classification system and the corresponding surgical

approaches are helpful in dealing with primary malignant sacral tumors. Better oncologic results could be expected if free margin without tumor rupture was accomplished.”
“Although infrared laser was proven to be an alternative approach for neural stimulation, there is very little known about the neural response to infrared laser irradiation in visual cortex. This study is to investigate the effect of near-infrared laser irradiation on neural activities at the cortex level. A 850-nm pigtailed diode laser was applied to stimulate the rat primary visual cortex while the horizontal SBE-β-CD black and white stripe pattern was used as standard visual stimulation to evoke visual-evoked potential (VEP). Both amplitude and latency of VEP P100 was measured with or without infrared pulse stimulation applied in rat primary visual cortex. Paired t test and one-way analysis Proteasome inhibitor of variance were used to evaluate the impact of infrared irradiation and its pulse

width on the amplitudes and latencies of P100, respectively. The results from our preliminary study revealed that, the pulsed near-infrared laser depressed the VEP amplitude and shortened the latency of P100; with the increment of pulse width of infrared irradiation, further decline of VEP amplitude and much shortened latency of P100 were observed. The present work suggests that near-infrared laser irradiation can alter the neural activities in primary visual cortex transiently, and could provide a novel contactless artificial neural stimulus to brain cortex with high spatial selectivity.”
“Methanesulfonic acid (MSA) was compared with sulfuric acid for the conversion of glucose and xylose mixtures to produce levulinic acid and furfural. The interactions of glucose and xylose, the predominant sugars found in biomass, were found to influence product yields with furfural degradation reactions enhanced under higher reactant loadings. Fast heating rates allowed maximal yields (>60 mol%) of levulinic acid and furfural to be achieved under short reaction times. Under the range of conditions examined, sulfuric acid produced a slight increase in levulinic acid yield by 6% (P=0.02), although there was no significant difference (P=0.

The level of sCD36 in subjects with

glycosylated haemoglo

The level of sCD36 in subjects with

glycosylated haemoglobin (HbA(1C)) above the mean was higher than in those with HbA(1C) values below the mean.

Insulin sensitivity is a predictor of sCD36 in men with impaired glucose tolerance. IL-6 is related to sCD36 but does not predict sCD36 independent of insulin sensitivity and BMI.”
“Three kinds of insulin resistance cell models were used to. study how Agrimonia pilosa Ledeb (AP) extracts affect glucose uptake in cells. One flavone glycoside, tiliroside, was isolated from AP by bioassay-guided chromatographic fractionation and tested it on promoting glucose uptake. Adipocytes were used to identify the response of tiliroside on insulin resistance related mRNA expression. It was found that glucose transporter factor 4GLUT4 translocation and the number of IR Bafilomycin A1 concentration were enhanced by tiliroside

treatment. Our findings indicate that tiliroside from AP may be beneficial for diabetic complications through its enhanced adiponectin secretion and GLUT4 translocation.”
“The influence of preparation methodology of silymarin solid dispersions using a hydrophilic polymer on the dissolution performance of silymarin was investigated. Silymarin solid dispersions were prepared using HPMC E 15LV by kneading, spray drying and co-precipitation methods and characterized by FTIR, DSC, XRPD and SEM. Dissolution profiles were compared by statistical and model independent methods. The FTIR and DSC studies revealed weak hydrogen bond formation between the drug and polymer, while XRPD and SEM confirmed the amorphous nature of the drug in co-precipitated solid dispersion. Enhanced selleck dissolution compared to pure drug was found in the following order: co-precipitation > spray drying > kneading methodology (p < 0.05). All preparation methods enhanced silymarin dissolution from solid dispersions of different characteristics.

The co-precipitation method proved to be best and provided a stable amorphous solid dispersion with 2.5 improved dissolution compared to the pure drug.”
“The objectives VX-680 of the study were to determine whether identifying patients with metabolic syndrome (MetS) (as defined by International Diabetes Federation [IDF] criteria) among patients with diabetes would affect the decision to prescribe statin for primary prevention of cardiovascular disease (CVD), based on currently available public health guidelines.

We analysed the most recent recorded CVD risk profiles obtained from electronic patient files from 304 general practices in England and Wales. Of 60,258 patients with diabetes, 11,005 men and women aged 30-74 years fulfilled criteria for primary CVD prevention and were not on lipid-lowering drugs. Outcome data were extrapolated to an estimated national diabetes prevalence of 3.6%.

Identifying MetS in this group of patients would produce an additional 29,536 (8.

Data were analyzed using a Hierarchical Generalized Linear Model

Data were analyzed using a Hierarchical Generalized Linear Model (HGLM) with species richness and presence of individual species as response variables and distance to nature reserve and application of AES as factors, controlling

for possible confounding factors. Results were interpreted as the effects of AES on seed and site limitation of the species. The results showed that plant diversity decreased significantly with distance from source populations. There were considerable differences in species diversity between AES and non-AES ditch banks, with the former showing greater plant diversity especially in the first 200 m from nature reserves. Presences of all individual species decreased with distance to nature reserve, find more but the strength buy GSK J4 of this relationship and the AES effects differed among species. AES ditch banks had lower site limitations for most plant species, but did not have lower seed limitation. (C) 2009 Elsevier Ltd. All rights reserved.”
“An optical switch based on liquid crystal dielectric loaded surface plasmon polariton waveguides is proposed and theoretically analyzed. The infiltration of the plasmonic structure with a nematic liquid crystalline material serving as the dielectric loading

is shown to allow for extensive electrical tuning of its waveguiding characteristics. Both the electrical switching and optical properties of the proposed waveguide are investigated in the context of designing a directional coupler optical switch, which is found to combine efficient voltage control, low power consumption, high extinction ratio, and relatively low insertion losses. (C) 2011 American Institute of Physics. [doi:10.1063/1.3658247]“
“Zonisamide is an antiepileptic selleck compound drug that acts on voltage-sensitive sodium and calcium channels, with a modulatory

effect on GABA-mediated neuronal inhibition and an inhibitory effect on carbonic anhydrase. It is used mainly for the treatment of partial seizures, and is generally well tolerated at therapeutic doses. The most common reported adverse effects are somnolence, anorexia, dizziness, and headache. There are limited data on zonisamide overdose in the literature, and no case of zonisamide mono-intoxication has been published to date. We describe the first case of zonisamide mono-intoxication in a 25-year-old woman who ingested 12.6 g of this substance with suicidal intent. Despite a plasma zonisamide concentration of 182 mg/L on admission, the patient exhibited a benign clinical course with vomiting and central nervous system depression, requiring brief intubation. Somnolence persisted for 50 hours, and normal-anion-gap metabolic acidosis and polyuria for several days. Complete recovery may be expected with supportive care, even after ingestion of large zonisamide overdoses. (C) 2011 Elsevier Inc. All rights reserved.

The method can extract artefact- and EEG-free single trial ERP wa

The method can extract artefact- and EEG-free single trial ERP waveforms, offers improved ERP averages by selecting the trials on the basis of their BICs, and is applicable to other evoked potentials, conditions and diseases.”
“Melanins CHIR98014 in vivo are a heterogeneous group of polymers formed by enzymatic reactions in vegetable tissues that contain phenolic or polyphenolic

molecules. Recent studies have discovered some beneficial properties of melanins on health, making that not only its elimination should be reconsidered, but also its addition could be proposed to functional food of new creation. A further knowledge about the kinetic mechanism of melanogenesis is required prior to its possible industrial utilization. In this work, the kinetics of melanogenesis from 4-methylcatechol using mushroom tyrosinase and measuring the absorbance of the solution has been analyzed. The reaction pathway Taselisib mouse has been divided in two steps, and a mathematical expression has been developed to describe each one of them. The first one, an enzymatic reaction from the o-diphenol to colorless intermediate products. The second one, a polymerization of these intermediates leading to melanin chains. These expressions allow describing melanin formation as a function of reaction time, including some important parameters such as the extinction coefficient.

In addition, the effect of pH and substrate concentration has been assayed in melanogenesis from two kinds of tyrosinase substrates: monophenolic (L-tyrosine) and o-diphenolic (4-methylcatechol). (C) 2010 Elsevier Ltd. All rights reserved.”
“Myotonic dystrophy type 1 (DM1) and myotonic

dystrophy type 2 (proximal muscular myopaty/DM2) are caused by similar dynamic mutations at two distinct genetic loci. The two diseases also lead to similar phenotypes but different clinical severity. Dysregulation of alternative splicing has been suggested as the common pathogenic mechanism. Here, we investigate the molecular differences between DM1 and DM2 using reverse transcriptase-polymerase chain reaction of troponin T (TnT) and the insulin receptor selleck chemicals (IR), as well as immunoblotting of TnT in muscle biopsies from DM1 and DM2 patients. We found that: (a) slow TnT was encoded by two different transcripts in significantly different ratios in DM1 and DM2 muscles; (b) DM2 muscles exhibited a higher degree of alternative splicing dysregulation for fast TnT transcripts when compared to DM1 muscles; (c) the distribution of TnT proteins was significantly skewed towards higher molecular weight species in both diseases; (d) the RNA for the insulin-independent IR-A isoform was significantly increased and appeared related to the fibre-type composition in the majority of the cases examined. On the whole, these data should give a better insight on pathogenesis of DM1 and DM2.

Conclusion: The results of this study demonstrate a late diagnosi

Conclusion: The results of this study demonstrate a late diagnosis and an increasing frequency of this neoplasia in the oral cavity.”
“Two major ginsenosides, ginsenoside-Rg(1) (1) and ginsenoside-Rb-1 (2), were transformed by the fungus Fusarium oxysporum f. sp. Lycopersici (Z-001). 1 was converted into five metabolites, ginsenoside-F-1 (3), 6a, 12 beta-dihydroxydammar-3-one-20(S)-O-beta-D-glucopyranoside (4), 3a-oxa-3a-homo-6 alpha, 12 beta-dihydroxydammar-3-one-20(S)-O-beta-D-glucopyranoside

Screening Library in vitro (5), 20(S)-protopanaxatriol (6), and 3-oxo-20(S)-protopanaxatriol (7). 2 was converted into four metabolites, ginsenoside-Rd (8), ginsenoside-F-2 (9), compound K (10), and 12 beta-hydroxydammar-3-one-20(S)-O-beta-D-glucopyranoside (11). The structures of these metabolites were determined by the analysis of extensive spectroscopic data. Among them, 4 and 5 were two new compounds. Deglycosylation and ketonization at C-3 were recognized as the characteristic reactions of this strain.”
“Prior to the late 1960s, a variety of studies suggested

that a general zonal pattern existed within the cerebellar cortex. The hypothesis proposed by Voogd, based on the organization of the subcortical white matter, indicated that this pattern may be very detailed, and he noted that “”a further analysis of the corticonuclear projection is still necessary.”" This brief paper chronicles the approach used by the author to formulate a plan, initiate a large series of experiments (over 250), and follow the sometimes confusing ML323 results to finally arrive at an understanding of the details of cerebellar corticonuclear projections. It was discovered that a series of mediolateral cortical zones were present that were topographically related to the underlying cerebellar nuclei, and within each zone, the cortex projected in a rostrocaudal sequence to a specific cerebellar nucleus. The hypothesis proposed by Voogd was fundamentally proven.”
“The present study was find more designed to monitor extrapyramidal

symptoms (EPS) elicited by the oral administration of haloperidol at clinically recommended doses and to compare it with EPS produced when the drug is injected intraperitoneally at doses used in animal research. Rats injected with haloperidol at a dose of 1 mg/kg daily for 5 weeks exhibited akinesia in an open field and impaired motor coordination. Effects of the drug on motor coordination but not on open field akinesia were attenuated gradually from 2-5 weeks of treatment. Oral administration of haloperidol in drinking water at clinically recommended dose exhibited decreased exploratory activity without producing akinesia. Motor coordination was impaired maximally after 3 weeks and tolerance was developed in the drug induced motor impairment after 5 weeks of treatment. Intensity of vacuous chewing movements (VCMs) and tardive VCMs was greater by oral administration than intraperitoneal injections of haloperidol.


“Background:


“Background: TH-302 Glenoid component loosening is a common cause of failure of total shoulder arthroplasty. It has been proposed that the heat generated during glenoid preparation may reach temperatures capable of producing osteonecrosis at the bone-implant interface. We hypothesized that temperatures sufficient to induce thermal necrosis can be produced with routine drilling and reaming during glenoid preparation for shoulder arthroplasty in vivo. Furthermore, we hypothesized that irrigation of the glenoid during reaming can reduce this temperature increase.

Methods: Real-time, high-definition, infrared thermal video imaging was used to determine the temperatures produced,by drilling and reaming

during glenoid preparation in ten consecutive patients undergoing total shoulder arthroplasty. The maximum temperature and the duration of temperatures greater than the established thresholds for thermal necrosis were documented. The first five arthroplasties were performed without irrigation and were compared with the second five GSK3235025 mw arthroplasties, in which continuous bulb irrigation was

used during drilling and reaming. A one-dimensional finite element model was developed to estimate the depth of penetration of critical temperatures into the bone of the glenoid on the basis of recorded surface temperatures.

Results: Our first hypothesis was supported by the recording of maximum surface temperatures above the 56 degrees C threshold during reaming in four of the five arthroplasties done without irrigation and during drilling in two of selleck compound the five arthroplasties without irrigation. The estimated depth of penetration of the critical temperature (56 degrees C) to produce instantaneous osteonecrosis was beyond 1 mm (range, 1.97 to 5.12 mm) in four of these patients during reaming and one of these patients during drilling, and two had estimated temperatures above 56 degrees

C at 3 mm. Our second hypothesis was supported by the observation that, in the group receiving irrigation, the temperature exceeded the critical threshold in only one specimen during reaming and in two during drilling. The estimated depth of penetration for the critical temperature (56 degrees C) did not reach a.depth of 1 mm in any of these patients (range, 0.07 to 0.19 mm).

Conclusions: Temperatures sufficient to induce thermal necrosis of glenoid bone can be generated by glenoid preparation in shoulder arthroplasty in vivo. Frequent irrigation may be effective in preventing temperatures from reaching the threshold for bone necrosis during glenoid preparation.

Level of Evidence: Therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence.”
“Background : Human pituitary adenoma (PA) is a common intracranial tumor, but the mechanism underlying tumorigenesis has not been established.

RESULTS: The ionic liquid showed excellent catalytic performance

RESULTS: The ionic liquid showed excellent catalytic performance exhibiting 95.4% conversion of propylene oxide (PO) and 94.6% selectivity to 1-methoxy-2-propanol. It is also an effective catalyst for the reaction of PO with other primary alcohols to yield corresponding

ethers. In addition this catalyst can be recovered and reused.

CONCLUSION:The high activity and selectivity can probably be ascribed to its basicity and/or the strong polarity and electrostatic field of the reaction medium caused by the ionic liquid. These findings are very rare in synthesis of propylene glycol https://www.selleckchem.com/products/cbl0137-cbl-0137.html ether to our knowledge. (C) 2010 Society of Chemical Industry”
“Keloids are a proliferative fibrotic disease characterized by abnormal

accumulation GSK1210151A in vivo of extracellular matrix in the dermis. Keloid lesions lack skin plasticity due to deficiencies in elastic fiber formation in the extracellular matrix. The loss of elastic fiber is caused by excessive accumulation of chondroitin sulfate (CS), a sulfated glycosaminoglycan. However, there is no radical cure for keloids. Using a model system, we show herein that treatment of keloid tissues with chondroitinase ABC, an enzyme that specifically digests CS, improves clinical features of keloids. Keloid tissues obtained from patients were grafted on nude mice, and chondroitinase ABC was injected into the grafted keloid tissues. Chondroitinase ABC treatment significantly reduced the volume of keloid implants concomitant with recovery of elastic fiber formation. These results suggest that chondroitinase ABC injection is an effective therapy

for keloid.”
“BACKGROUND: The capability of cyanobacteria to convert carbon dioxide into carbohydrates offers a promising carbon-neutral energy solution. Unfortunately, the lifespan of cyanobacteria based photoelectrochemical cells is poor because BVD-523 purchase discharge current drops to zero within days. The primary factor that limits lifespan was believed to be the toxicity of an artificial mediator that extracts electrons from cyanoacteria to electrode. It is critical to experimentally identify the true limiting factor such that we could prolong the lifespan for practical use.

RESULTS: Systematic tests on cell physiology and current discharge were performed in autotrophic and heterotrophic conditions. Contrary to previous belief, results for cell viability, chlorophyll content and growth curve of Cyanobacterium Synechocystis PCC 6714 under continuous vitamin K(3)-mediated current discharge did not exhibit any toxic effect. The role of glucose was then investigated. Surprisingly, discharge current dropped to zero although there was significant intracellular glycogen (2.5 x 10(-10) mg cell(-1)).

The present study was undertaken to determine the morphological a

The present study was undertaken to determine the morphological and biochemical changes ATM Kinase Inhibitor of FL cells induced by OA, Results indicated that externalization of phosphatidylserine, cytoskeletal disruption, DNA strand breaks and decrease of Bcl-2 protein expression levels as well as increase of PP2A-A subunit protein were all involved in the apoptosis of

FL cells induced by OA. This work not only provided further evidence of apoptosis induced by OA but also suggested that PP2A might play a pivotal role in apoptosis induced by protein phosphatases inhibitors. (C) 2008 Wiley Periodicals, Inc. Environ Toxicol 24: 437-445, 2009.”
“Objective: The aim of the current study was to analyze the relationships between plasma hormones, body weight parameters and stressful life events in anorexia nervosa (AN).

Material and Methods: 72 females in the active phase of AN were evaluated. 52 healthy women constituted the control group. RIA kits were used to measure plasma hormone levels.

Results: The concentrations of leptin, insulin, IGF-1, triiodothyronine, LH, FSH, estradiol, and testosterone were significantly lower and those of cortisol and growth hormone significantly higher in the AN than the control group. No hormonal differences between restrictive and binge-purging AN subtypes were found. Leptin, IGF-1,

gonadotropins, and sex steroids correlated significantly negatively and growth hormone positively learn more with total reduction of body weight or the degree of undernutrition. Associations were also found between lower insulin concentration and family violence, lower cortisol and psychiatric diseases in the family, higher testosterone and patient’s alcohol or drug abuse.

Discussion: The changed

activity of the somatotropin-somatomedin, gonadal, and corticotrophin axes corresponds to the clinical stage of AN. Plasma IGF-1 seems to be the most sensitive and useful independent hormonal marker of cachexia.”
“Capillary-liquid chromatography (CLC) and nano-LC are miniaturized techniques with great potential in the analytical field. They have been applied in different areas – pharmaceuticals, biomedicine, environment and recently food and agrochemicals. CLC and nano-LC separations are carried out in capillaries of narrow internal diameter (10-320 mu m) containing selected stationary phases. Short analysis time, high mass sensitivity, Selleck EX 527 minute volumes of samples and mobile phases, and easy coupling with mass spectrometry are the main features. We review the general principles of the two miniaturized techniques, their advantages over conventional LC, and the most important applications in food analysis. (C) 2013 Elsevier Ltd. All rights reserved.”
“Objective: The aim of this study was to report speech performance in quiet and in noise, sound localization with cochlear implanted children bilaterally. Their performances were compared also in unilateral conditions. In addition, speech and language evaluation was analyzed.

Currently, the preferred method of HSC mobilization for subsequen

Currently, the preferred method of HSC mobilization for subsequent transplantation is treatment of the donor with granulocyte colony-stimulating VX-809 concentration factor. The mobilizing effect of granulocyte colony-stimulating factor is not completely understood, but recent studies suggest that its capacity to mobilize HSCs, at least in part, is a consequence of alterations to the hematopoietic niche. The present article reviews some of the key mechanisms mediating HSC mobilization, highlighting recent advances and controversies in the field.”
“Vertigo and migraine are known to be frequently associated. However, only recently,

the etiological links between the two diseases are being investigated and explained. More and more interest is being attracted by migrainous vertigo, an isolated entity that might deserve inclusion in the International Classification of Headache Disorders. The authors briefly review the main links between migraine and vertigo.”
“Here, we propose a new method for estimating the extent of curing of thermosetting prepregs. In the proposed method, the extent of curing

is estimated with the curing index P5091 (C-i), defined as the ratio of the glass-transition temperature (T-g) to the ultimate glass-transition temperature of the material. The advantages of this new method over the conventional degree of conversion (alpha) for estimating the extent of curing of thermosetting prepregs are discussed in detail. C-i and alpha of a toughened epoxy prepreg (977-2 unidirectional) were obtained for a wide range of isothermal curing temperatures with a differential scanning calorimeter. The ultimate heat of reaction varied inconsistently with decreasing curing temperature; this resulted in erratic behavior of alpha. However, C-i provided a more consistent estimate of the extent of curing because T-g, unlike alpha, did not need to be modified on the basis of the curing history of the material

and was measured directly with the heat-flow data from differential scanning calorimetry. (C) 2011 Wiley Periodicals, Inc. J Appl Polym Sci 121: 883-891, 2011″
“Introduction: Local synthesis of interferon within B16 tumors Cl-amidine inhibitor mediates anti-tumor effects. Based on reports that stem cells are recruited to tumors, and because systemic administration of interferon causes dose-limiting undesirable side effects, we wanted to improve the anti-tumor effects of interferon while simultaneously minimizing its systemic side effects by employing mesenchymal stem cells (MSCs) as tumor-localized ectopic producers of interferon. Many vectors exist to fulfill this purpose, but their transfection efficiency and resulting expression levels vary considerably.

Methods: To follow both the recruitment to tumors and the synthesis of interferon by MSCs, we designed a bicistronic vector system that permits fluorescent visualization of vector-transfected and interferon-producing MSCs.

However, excessive manipulations are reported to cause rare but s

However, excessive manipulations are reported to cause rare but serious complications such as tetraplegia, vertebral artery dissection, epidural hematoma, and phrenic nerve injury.

Methods.

Clinical history, physical examination, and radiographic findings of the patient were described. Anterior cervical discectomy at the C3/C4 level and interbody fusion with a Caspar plate-screw system for fixation, were performed.

Results. A favorable Selleck SRT1720 surgical outcome was obtained. The Brown-Sequard syndrome improved and the patient regained full muscle power at a 3-months follow-up.

Conclusion. Cervical intradural disc herniation after SMT is rare and most often cause Brown-Sequard syndrome. Definite diagnosis and prompt surgery usually achieves a satisfactory outcome. Anterior discectomy with interbody fusion is recommended. The OPLL associated with degenerative disc reminds us of the increased risk of intradural disc herniation. Those high-risk groups should be more cautious with spinal manipulation therapy due to its serious sequelae.”
“To evaluate the long-term outcomes and hysterectomy rates after hysteroscopic endometrial resection with or without myomectomy for menorrhagia.

Fifty-three women who had submucous myomas with intramural extension of less than 50% and smaller

than 5 cm in diameter underwent endometrial resection and concomitant hysteroscopic myomectomy. Each of them was matched with a patient LCL161 who had no submucous myomas and who had been treated by endometrial resection only. These two groups were compared for operative outcomes, additional procedures, outcome of menstrual bleeding and for subsequent hysterectomy, which was the endpoint of this study.

During the mean follow-up period of 6.5 years, 18 (34.6%) women with endometrial resection and myomectomy and 21 (39.6%) without myomectomy underwent at least one gynecological procedure. Hysterectomy was performed in 26.9% [95% confidence interval

(CI) 16.8-40.3] of the patients with myomectomy https://www.selleckchem.com/products/a-1210477.html and in 17.0% (95% CI 9.2-29.2) of the patients without myomectomy (P = 0.22). The main indications for hysterectomy were pain and spotting bleeding in seven out of 14 cases with myomectomy and in four out of nine with endometrial resection only. Leiomyomas were found in 12 out of the 14 women who had hysterectomy after hysteroscopic myomectomy and in four out of nine with hysterectomy after endometrial resection only (P = 0.06). Most (75.6%) of the 82 women who had not required hysterectomy had reached menopause. All the patients without hysterectomy in both groups reported amenorrhea or slight bleeding, and this response maintained for years after the treatment.

Endometrial resection may be combined with hysteroscopic myomectomy without a significant increase or decrease in hysterectomy rates during a long-term follow-up.