The study of intestinal permeability can provide important

The study of intestinal permeability can provide important

information regarding changes in the structure and function of the mucosal barrier after the procedure.

The urinary excretion rates of lactulose and mannitol after oral intake of both substances were evaluated. We also evaluated the MK-8776 in vitro lactulose/mannitol excretion ratio. Tests were performed during the preoperative period (T0), at the first postoperative month (T1), and at the sixth postoperative month (T6).

The study included 16 morbidly obese patients. The excretion rate of mannitol was significantly lower at T1 compared with T0 and T6 (p = 0.003). There was no significant difference in the excretion rates of lactulose or in the lactulose/mannitol ratio during the three periods. Six patients (37.5 %) exhibited a considerable increase in the excretion rate of lactulose at T6 (4-73 times higher than the preoperative value), accompanied by proportional variations in the lactulose/mannitol ratio.

The significant increase in mannitol excretion rate from T1 to T6 most likely reflects the occurrence of intestinal adaptation (mucosal hyperplasia), which would tend to

minimize the malabsorption of macronutrients. A subgroup of patients who undergo RYGB exhibit pronounced increase AS1842856 mouse in their intestinal permeability (assessed by the lactulose/mannitol ratio and the lactulose excretion rate) at T6.”
“Background: EVLA has proven to be very successful, but the optimum methods for energy delivery have still not been clarified. A better understanding of the mechanism of action may contribute

to achieving a consensus on the best laser method and the most effective use of laser parameters, resulting in optimal clinical outcomes, maintaining high success rates with minimal adverse events. The aim of this study is to assess the impact of wavelength, pullback speed and power level on the endovenous temperature profile in an experimental setting.

Methods: In an experimental setting, temperature measurements were performed using thermocouples. ABT-263 nmr The experimental set-up consisted of a transparent box in which a glass tube was fixed. Different laser parameters (wavelength and power) and 2 different pullback speeds (2 and 5 mm/s) were used. Thermocouples were placed at different distances from the fiber tip. Validity of the experimental setting was assessed by performing the same temperature measurements using a stripped varicose vein. The maximal temperature rise and the time span that the temperature was above collagen denaturation temperature were measured.

Results: The experiments showed that decreasing the pullback speed (2 mm/s) and increasing the power (up to 14 W) both cause higher maximal temperature and a longer time above the temperature for collagen denaturation. The use of different laser wavelengths (940 or 1470 nm) did not influence the temperature profile.

4 %) patients treated between 2 and 20 days Overall survival aft

4 %) patients treated between 2 and 20 days. Overall survival after 12 months was 50.2 % (110/219), while 65.8 % (144/219) were discharged from ICU.

Older age,

longer treatment at the ICU and increased simplified acute physiology score (SAPS) at admission were associated with decreased 12-month survival, while no statistical differences were observed for the underlying and malignant disease by univariate analysis.

The risk of death BB-94 was 29, 56 and 61 % for patients treated 2-4, 5-19 and a parts per thousand yen20 days at the ICU. Decreased survival of patients treated for 5-19 and a parts per thousand yen20 days were confirmed by logrank test (p = 0.001).

Patients with long-term ICU stay showed decreased survival than patients who are treated less than 5 days but similar survival as patients which stayed between 5 and 19 days. Malignant disease is not associated with an unfavourable 12-month survival while older age, higher SAPS index at discharge and longer stay at ICU are. Long-term ICU survivors have no increased risk to succumb after discharge from ICU.”
“Hypothesis In this developmental research study that aimed to develop tympanic membrane regeneration therapy, we devised a method of sustained bFGF formulation release using gelatin hydrogel

in a guinea pig eardrum perforation model.

Background Basic fibroblast growth factor (bFGF) can promote perforation closure. In addition, several studies of bFGF formulations have Selleckchem BEZ235 used gelatin hydrogel-bFGF coupled electrostatically to a gelatin polymer. BFGF is released gradually as a result of degradation of the gelatin polymer, and studies have shown that Geneticin the long-term pharmacologic effects of bFGF can be maintained.

Methods Using a CO2 laser, total tympanic membrane perforations were created in 24 guinea pig ears and divided into 3 groups: the bFGF-gelatin hydrogel group(n = 8), the saline-gelatin hydrogel group (n = 8), and the control group (n = 8). Either a bFGF formulation or saline was impregnated into gelatin hydrogen and implanted into the perforated tympanic membrane.

Results All ear drums of the

control group showed large perforations at even the 30th postoperative day. The perforation persisted in 3 of 8 ears in the saline-gelatin hydrogel group, and the tympanic membranes that had achieved closure were thinned, whereas all ears in the bFGF-gelatin hydrogel group achieved closure of the perforation. In the ears in which a normal tympanic membrane had regenerated, histologic observation with hematoxylin and eosin staining revealed that, although mucosal and epithelial layer regeneration had occurred in the saline-gelatin hydrogel group, the bFGF-gelatin hydrogel group showed regeneration of the fibrous layer in addition to the other 2 layers.

Conclusion These data suggest that hydrogel impregnated with bFGF induces regeneration of the tympanic membrane and can conservatively treat tympanic membrane perforation.


“Purpose: PHA-739358 To retrospectively evaluate radiation dose, image quality, and the ability to differentiate urinary calculi of differing compositions by using low-dose dual-energy computed tomography (CT).

Materials and Methods: The institutional review board approved this retrospective study; informed consent was waived. A low-dose dual-energy CT protocol (tube voltage and reference effective tube current-time product, 140

kV and 23 mAs and 80 kV and 105 mAs; collimation, 64 x 0.6 mm; pitch, 0.7) for the detection of urinary calculi was implemented into routine clinical care. All patients (n = 112) who were examined with this protocol from July 2008 to August 2009 were included. The composition of urinary calculi was assessed by using commercially available postprocessing software and was compared with results of the reference standard (ex vivo infrared spectroscopy) in 40 patients for whom the reference standard was available. Effective doses were calculated. Image quality was rated subjectively and objectively

and was correlated with patient size expressed as body cross-sectional area at the level of acquisition by using Spearman correlation coefficients.

Results: One calcified learn more concrement in the distal ureter of an obese patient was mistakenly interpreted as mixed calcified and uric acid. One struvite calculus was falsely interpreted as cystine. All other uric acid, cystine, and calcium-containing calculi were correctly identified by using dual-energy CT. The mean radiation dose was 2.7 mSv. The average image quality was rated as acceptable, with a decrease in image quality in larger patients.

Conclusion: Low-dose unenhanced dual-source dual-energy CT can help differentiate between calcified, uric acid, and cystine calculi at a radiation dose comparable to that of conventional intravenous pyelography. Because of decreased image

quality in obese patients, only nonobese patients should JQ-EZ-05 manufacturer be examined with this protocol. (C) RSNA, 2010″
“Background: Magnetic resonance imaging (MRI) and MR spectroscopic imaging (MRSI) have been gaining acceptance as tools in the evaluation of prostate cancer. We compared the accuracy of transrectal ultrasound (TRUS)-guided biopsy and dynamic contrast-enhanced MRI combined with three-dimensional (3D) MRSI in locating prostate tumours and determined the influence of prostate weight on MRI accuracy. Patients and Methods: Between March 1999 and October 2006, 507 patients with localised prostate cancer underwent radical prostatectomy (RP) at the Jules Bordet Institute. Of these, 220 had undergone endorectal MRI (1.5 T Siemens Quantum Symphony) and 3D-MRSI prior to RP. We retrospectively reviewed data on tumour location and compared the results obtained by MRI and by TRUS-guided biopsy with those obtained on histopathology of the RP specimen. Results: Patient data were as follows: median age 62.4 years (45-74); median PSA 6.36 ng/ml (0.5-22.6); 73.

Around 6-20% of monostotic FD occurs in the ribs The objective o

Around 6-20% of monostotic FD occurs in the ribs. The objective of this study was to report our experience in the management of the monostotic FD of the ribs. Between January 2004 and December 2009, seven cases of FD of the rib (six men and one woman, mean age 30.4 years, range 17-40 years) were operated on. The patients were evaluated with plain radiographs and computer tomography (CT). All our patients were symptomatic; two patients presented chest pain and swelling and other patients presented only chest pain. One rib was involved in all our

patients (monostotic form): the site was fifth rib (four cases), sixth rib (two cases) or second rib (one case). Radio logically, plain Selleckchem Autophagy inhibitor films and selleck kinase inhibitor CT showed an expansible lesion with a ground-glass centre and thinning of the cortex. Rib resection was performed in all patients; there were no postoperative complications and no recurrence in all cases at mean 43 month follow-up. In symptomatic monostotic FD of ribs, the involved segment of bone

may be excised to rule out malignancy and for painful lesions.”
“Fiber separation from corn flour could increase ethanol productivity and increase energy value as feed for non-ruminants (swine and poultry). Elusieve process, a combination of sieving and air classification, has been found to be effective in separating fiber. The objectives of this study were to determine the operating air velocities for corn particles and to compare physical properties of corn particles with that of DDGS particles from an earlier study. The operating air velocities for large,

medium and small corn size fractions were 2.9-3.8,2.8-3.0 and 2.5-2.6 m/s, respectively. Densities of nonfiber particles for corn flour were higher selleck chemicals llc than for DDGS (earlier study). Compared to DDGS, the difference between fiber and nonfiber particle terminal velocities was higher for corn, which signifies relative ease of operability for fiber separation from corn flour. (C) 2012 Elsevier B.V. All rights reserved.”
“Biogenic volatile organic compounds (BVOCs), released by practically all plants, have important atmospheric and ecological consequences. Because BVOC-emission measurements are especially tedious, complex and extremely variable between species, two approaches have been used in scientific studies to try to estimate BVOC-emission types and rates from plant species. The first, which has known little success, involves grouping species according to plant-taxonomy criteria (typically, genus and family). The second involves studying the correlation between BVOC content and emission (i.e. how leaf content could be used to estimate emissions). The latter strategy has provided controversial results, partly because BVOCs are amazingly chemically diverse, and, as a result, techniques used to study plant BVOC content, which we review, cannot be equally adequate for all analytes.

“” The primitive sebaceous germinative cells in sebaceoma may sti

“” The primitive sebaceous germinative cells in sebaceoma may still have the ability to undergo

apocrine differentiation. Most of the reports so far on sebaceoma with apocrine differentiation, including the present case, describe a ripple/carcinoid pattern, thus suggesting that ripple/carcinoid pattern sebaceoma is composed of more primitive sebaceous germinative cells than conventional RG-7112 inhibitor sebaceoma.”
“Background: The proportion of high school sports-related injuries requiring surgery, which pose monetary and time loss burdens, has significantly increased during the last decade. The objective was to investigate the epidemiology of high school athletic injuries requiring surgery.

Methods: High school sports-related injury data were collected for nine sports from 2005 to 2010 from 100 nationally selleck representative US high schools.


Athletes sustained 1,380 injuries requiring surgery for a rate of 1.45 injuries per 10,000 athlete exposures. Boys’ football had the highest injury rate (2.52) followed by boys’ wrestling (1.64). Among gender comparable sports, girls’ sports has a higher injury rate (1.20) than boys’ (0.94) (rate ratio, 1.28; 95% confidence interval, 1.08-1.51; p = 0.004). The rate of injuries was higher in competition (3.23) than practice (0.79) (rate ratio, 4.08; 95% confidence interval, 3.67-4.55; p < 0.001) overall and in each sport. Commonly injured body sites were the knee (49.4%), head/face/mouth (9.7%), and shoulder (8.7%). Common diagnoses were

complete ligament strain (32.1%) and fracture (26.4%). Nearly half (48.0%) resulted in medical disqualification for the season.

Conclusions: Rates and patterns of injuries requiring surgery differ by sport, type of exposure, and gender. Future studies should identify sport-specific risk factors to drive effective interventions to decrease the incidence and severity of such injuries.”
“For Torin 2 the first time, biocomposites from wheat by-products, i.e. wheat gluten and wheat straw fibers, were prepared using a thermomechanical process. Three types of wheat straw fibers displaying contrasted sizes (median diameter d(50) = 1.1 mm, 62 mu m and 8 mu m), morphologies and surface reactivities were prepared by successive grinding processes (cut milling (CM), impact milling (IM) and ball milling (BM), respectively). The main objectives of the present study were (i) to gain further scientific knowledge about the impact of fibers characteristics on the mechanical properties of these composite materials, and (ii) to evaluate in which extent the addition of wheat straw fibers could decrease the final cost of materials without altering their mechanical properties. Mechanical properties were assessed through tensile tests and discussed in relation to the structure of materials, especially to the interfacial adhesion between the fiber and the matrix. Globally, an increasing fiber content up to 11.

Other factors such as birthweight, breastfeeding, socioeconomic s

Other factors such as birthweight, breastfeeding, socioeconomic status and region of birth

have also been demonstrated to contribute to risk. ACPA status is associated with specific environmental factors and is therefore important to incorporate into present and future studies.”
“Introduction and Hypothesis A terminology and standardized classification has yet to be developed for those complications related to native tissue female pelvic floor surgery. Methods: This report on the terminology and classification combines the input of members of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International BI 2536 Continence Society (ICS) and a Joint IUGA/ ICS Working Group on Complications Terminology, assisted at intervals by many external referees. A process of rounds of internal and external review took place with decision- making by collective opinion (consensus). Results: A terminology and classification of complications related to native tissue female pelvic floor surgery has been developed, with the classification based on category (C), time (T), and site (S) classes and divisions, that should encompass all conceivable scenarios for describing operative complications and healing abnormalities. The CTS code for each complication, involving three (or four) letters and three numerals,

is likely to be very suitable for any surgical audit or registry, particularly one DAPT manufacturer that is procedure- specific. Users of the classification have been assisted by case examples, color charts, and online aids (www. icsoffice. org/ ntcomplication). Conclusions: A consensus- based terminology and classification report for complications in native tissue female pelvic floor surgery has been produced. It is aimed at being a significant aid to clinical practice and particularly to research. Neurourol. Urodynam. 31: 406-414, 2012. (C) 2012 Wiley Periodicals, CBL0137 Inc.”
“Objectives: To investigate whether physicians’ prescribing preferences

were valid instrumental variables for the antidepressant prescriptions they issued to their patients.

Study Design and Setting: We investigated whether physicians’ previous prescriptions of (1) tricyclic antidepressants (TCAs) vs. selective serotonin reuptake inhibitors (SSRIs) and (2) paroxetine vs. other SSRIs were valid instruments. We investigated whether the instrumental variable assumptions are likely to hold and whether TCAs (vs. SSRIs) were associated with hospital admission for self-harm or death by suicide using both conventional and instrumental variable regressions. The setting for the study was general practices in the United Kingdom.

Results: Prior prescriptions were strongly associated with actual prescriptions: physicians who previously prescribed TCAs were 14.9 percentage points (95% confidence interval [CI], 14.4, 15.4) more likely to prescribe TCAs, and those who previously prescribed paroxetine were 27.

81, P < 0 001) but there was no correlation among the CG patie

81, P < 0.001) but there was no correlation among the CG patients (r = 0.14, P = 0.73).

Conclusions: Patients with severe CAP had high levels of PNE, which was closely

correlated with PVPI. PNE may be involved in the pathogenesis of severe pneumonia.”
“OBJECTIVES: Both renal function and immune system function decline with age. Although controversial, a significant number of studies have shown that the decline in kidney function is associated with the worsening of the immune system. These findings are reinforced by the increased susceptibility to infections and deficient immunization coverage after vaccination both in patients with chronic renal disease Elafibranor and in elderly individuals. Our objective was to evaluate a non-institutionalized elderly population from Sao Paulo City and

correlate the estimated glomerular filtration rate with the percentage of lymphocytes in circulation.

METHODS: A random population of 237 individuals (107 men and 130 women), ranging in age from 60 to 101 years, who were enrolled in the Health, Well-Being and Aging Study was evaluated for renal function (Modification on Diet in Renal Disease formula) and lymphocyte percentage (flow cytometry).

RESULTS: Aging was associated with a decrease in the estimated glomerular filtration rate in both male and female individuals. We did not identify a significant correlation between the estimated glomerular filtration rate and either the percentage of CD4, click here CD8, and B cells or JQ1 datasheet CD4/CD8 ratio. The median percentage of CD8+ T cells was significantly lower in individuals with an estimated glomerular filtration rate >= 60 mL/min/1.73 m(2).

CONCLUSIONS: In this study, no statistical correlation was found between the estimated glomerular filtration rate and either the lymphocyte phenotype (CD4+, CD8+, and

CD19+ cells) or the CD4/CD8 ratio in blood.”
“Essential oil extracted from aerial parts of two Ocimum species (O. canum and O. kilimanascharicum) was investigated using gas chromatography and gas chromatography/mass spectrometry techniques on DB-5 (5% dipheny1-95% dimethylpolysiloxane) and beta-cyclodextrin (6-tertiarybutyldimethylsiliyl-2,3-diethy-beta-cyclodextrin) capillary columns. Essential oil extracted from O. canum contained camphor, limonene, camphene and myrtenol as most abundant constituents among monoterpenoids, whereas beta-selinene, a-selinene, maaliol and beta-caryophyllene were identified under sesquiterpenoids class. On contrary, two folds higher camphor was recorded in O. kilimandscharicum. Maaliol (6.4%) was characterized in O. canum for the first time with the help of extensive 1D and 2D-NMR experiments. Therefore, maaliol can be considered as a marker constituent to differentiate both the camphor rich oils. Further, when the oils were subjected to chiral analysis on beta-cyclodextrin column; a high enantiomeric excess for (1R)-(+)-camphor was recorded.

62 (CI 95%: 1 2-2 19; P < 0 002) for men with KDM

62 (CI 95%: 1.2-2.19; P < 0.002) for men with KDM Cl-amidine in vivo and 1.75 for women with KDM (CI 95%: 1.26-2.43; P < 0.001),

respectively. Conclusion. Current study indicates that increasing levels of altered carbohydrate metabolism are accompanied by a trend towards decreasing quality of life, mainly in women, in a representative sample of Spanish population.”
“Placental mesenchymal dysplasia (PMD) is a rare placental vascular anomaly which resembles partial molar pregnancy by 2-D ultrasonography. It is challenging but clinically important to distinguish between them in order to avoid unnecessary termination of pregnancy. A patient was referred to our centre at 13 weeks of gestation and 2-D ultrasound of the placenta showed a widespread vesicular pattern mixed with normal appearing placenta. Amniotic fluid volume was normal, and the fetus appeared to be an appropriate size for gestation without obvious structural abnormalities. 3-D reconstruction imaging of the placenta showed a large multi-cystic area YM155 arising from the chorionic plate which was adjacent to normal-appearing placenta. 3-D imaging rendered with inversion mode’ revealed multiple fluid-filled structures with different sizes and appearances. Her serum hCG level was slightly elevated. All findings taken together,

we suspected PMD rather than partial molar pregnancy. Histological examinations of the placenta after termination at 15 weeks confirmed the diagnosis.”
“Obesity or overweight selleck affect most of patients with polycystic ovary syndrome (PCOS). Phenotypes are the clinical characteristics produced by the interaction of heredity and environment in a disease or syndrome. Phenotypes of PCOS have been described on the presence of clinical hyperandrogenism, oligoovulation and polycystic ovaries. The insulin resistance is present in the majority of patients with obesity and/or PCOS and it is more frequent and of greater magnitude in obese than in non obese PCOS patients. Levels of sexual hormone binding globulin are decreased, and levels of free androgens are increased in obese PCOS

patients. Weight loss treatment is important for overweight or obese PCOS patients, but not necessary for normal weight PCOS patients, who only need to avoid increasing their body weight. Obesity decreases or delays several infertility treatments. The differences in the hormonal and metabolic profile, as well as the different focus and response to treatment between obese and non obese PCOS patients suggest that obesity has to be considered as a characteristic for classification of PCOS phenotypes.”
“The syndrome of pregnancy-associated osteoporosis (PAO) is a rare disorder which occurs either in late pregnancy or early post-partum period leading to fragility fracture(s), most commonly in the vertebral bodies.

This study examines tourists’ attitude towards large-scale bark b

This study examines tourists’ attitude towards large-scale bark beetle infestation in the case of Bavarian Forest National Park, Germany. Three alternative conceptual models for predicting attitude are specified and compared using structural equation modelling (SEM) and a post-hoc modified model is derived. We find that tourists overall have

a neutral attitude towards the bark beetle and are slightly against controlling the insect in the park. Tourists with higher affinity GNS-1480 supplier for the national park, better knowledge about the bark beetle and who expect a recovery of the affected areas have a significantly more positive attitude. Our results support a policy of selective non-intervention in the case of natural disturbance. This should be combined with educational measures aimed at raising awareness of the ecological

mandate of protected areas and increasing tourists’ knowledge of the specific disturbance. (C) 2008 Elsevier Ltd. All rights reserved.”
“Previous work on mathematical models of cultural evolution has mainly focused on the diffusion of simple cultural elements. However, a CBL0137 nmr characteristic feature of human cultural evolution is the seemingly limitless appearance of new and increasingly complex cultural elements. Here, we develop a general modelling framework to study such cumulative processes, in which we assume that the appearance and disappearance of cultural elements are stochastic events that depend on the current state of culture. Five scenarios are explored: evolution of independent cultural elements, stepwise modification of elements, differentiation or combination of elements and systems of cultural elements. As one application of our framework, we study the evolution of cultural diversity (in time as well as between groups).”
“Plants, like almost all living organisms, spontaneously emit photons of visible light. We used a highly sensitive, low-noise cooled charge coupled device camera to image spontaneous photon emission (autoluminescence) of plants. Oxidative stress and wounding induced a long-lasting enhancement of plant autoluminescence, the origin of which is investigated here. This long-lived Nepicastat in vitro phenomenon can be distinguished from

the short-lived chlorophyll luminescence resulting from charge recombinations within the photosystems by pre-adapting the plant to darkness for about 2 h. Lipids in solvent were found to emit a persistent luminescence after oxidation in vitro, which exhibited the same time and temperature dependence as plant autoluminescence. Other biological molecules, such as DNA or proteins, either did not produce measurable light upon oxidation or they did produce a chemiluminescence that decayed rapidly, which excludes their significant contribution to the in vivo light emission signal. Selective manipulation of the lipid oxidation levels in Arabidopsis mutants affected in lipid hydroperoxide metabolism revealed a causal link between leaf autoluminescence and lipid oxidation.

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 Napabucasin order 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 BIX 01294 clinical trial 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 4EGI-1 mouse (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.