One such rare presentation was seen in a 23-year-old patient who presented with zosteriform skin coloured, occasionally painful cutaneous lesions over left shoulder region. Histopathology confirmed the diagnosis of cutaneous BLZ945 mw leiomyoma. He was symptomatically managed with non-steroidal anti-inflammatory agents and topical capcicum cream. Case is reported here due to rare occurrence of this benign cutaneous neoplasm in an atypical pattern and on uncommon site.”
“This work presents a new, readily implementable screen printing technique for the front side metallization of textured mono- and multi-crystal

line silicon solar cells. The use of a heated print chuck to increase the substrate temperature during the screen print process enables a significantly reduced printed line width for conventional and fine line screen printing. The influence of substrate temperature on the line definition is optically and electrically analysed. Within this work an efficiency gain of 1% relative as well as continuous printed lines showing a width below 60 mu m have been achieved on textured silicon surfaces at high throughput rates.

(C) 2009 Elsevier B.V. All rights reserved.”
“Noninvasive blood pressure measurements are difficult when arterial pulsations are reduced, as in patients supported by continuous flow left Sapanisertib ventricular assist devices (cf-LVAD). We evaluated the feasibility of measuring noninvasive arterial blood pressure MK-2206 chemical structure with the Nexfin monitor during conditions of reduced arterial pulsatility. During cardiopulmonary bypass (CPB) in which a roller pump based or a centrifugal pump based heart-lung machine generated arterial blood pressure with low pulsatility,

noninvasive arterial pressures (NAP) measured by the Nexfin Monitor were recorded and compared with invasively measured radial artery pressures (IAP). We also evaluated NAP in 10 patients with a cf-LVAD during a pump speed change procedure (PSCP). During CPB in 18 patients, the NAP-IAP average difference was -1.3 +/- 6.5 mm Hg. The amplitude of pressure oscillations were 4.3 +/- 3.8 mm Hg measured by IAP. Furthermore, in the cf-LVAD patients, increase in pump speed settings led to an increase in diastolic and mean arterial pressures (MAP) while the NAP acquired a sinusoidal shape as the aortic valve become permanently closed. In conclusion, NAP was similar to IAP under conditions of reduced arterial pulsatility. The device also measured the blood pressure waveform noninvasively in patients supported by a cf-LVAD. ASAIO Journal 2010; 56:221-227.”
“Objective: To test the hypothesis that there is no difference in the vertical alveolar bone levels and alveolar bone thickness around the maxillary and mandibular central incisors in surgically treated skeletal Class III malocclusion patients.

These observations support the conclusion that, during the nuclear cataract formation, alterations in protein packing are extensive and can result in pronounced density fluctuations. Aging causes the MLB cores to become increasingly different in their protein packing from the adjacent cytoplasm. These results support the hypothesis that the MLBs increase their scattering with age and nuclear cataract formation. (C) 2012 Elsevier Ltd. All rights reserved.”
“What is known and Objective: Invasive fungal infections are a major threat

to renal transplant recipients. Micafungin and voriconazole are two useful antifungal agents for treating such infections. Our objective is to evaluate the comparative efficacy and safety of micafungin and voriconazole in the initial treatment of such infections.\n\nMethods: Geneticin chemical structure In this prospective, multicentre, open-labelled, randomized, controlled trial, renal transplant recipients with invasive fungal infections were assigned to receive either micafungin or voriconazole. The enrolled

subjects received a kidney transplant between March 2008 and March 2010 at one of the two transplant centres in Henan Province, China. The efficacy and adverse effects of the two treatments were compared.\n\nResults and Discussion: The clinical trial enrolled 65 patients, of whom 31 were treated with micafungin, and 34 with voriconazole. The rates of microbiological evidence of infection in the micafungin and voriconazole groups were 64.5% and 70.5%, respectively, whereas the rates of Candida as the major cultured fungus were 80.0% and 75.0%, respectively. Complicated bacterial infection rates in the NCT-501 in vivo two treatment groups were 38.7% and 32.4%, respectively, whereas complicated CMV viral infection occurred at a rate of 19.2% and 23.5%, respectively. Fungal infection within one to 3 months after transplant was 83.6% (26/31) and 85.3% (29/34) in the micafungin and voriconazole groups, respectively. There was no significant difference between the two groups XMU-MP-1 in terms of efficacy, survival beyond 10 days

and discontinuation of treatment because of lack of efficacy (P > 0.05). Mortality rates in the micafungin and voriconazole groups were 9.7% (3/31) and 12.1% (4/33), respectively. Rates of adverse effects in the two groups were 41.9% and 51.6% (P > 0.05), respectively.\n\nWhat is new and Conclusions: This is the first comparison of micafungin and voriconazole in renal transplant patients. Our study shows that the effectiveness of micafungin was similar to that of voriconazole in such patients.”
“Aims: To compare the effects of lifestyle modification programs that prescribe low-glycemic load (GL) vs. low-fat diets in a randomized trial.\n\nMethods: Seventy-nine obese adults with type 2 diabetes received low-fat or low-GL dietary instruction, delivered in 40-week lifestyle modification programs with identical goals for calorie intake and physical activity.

4)-gamma-catalyst and HRTEM examination on the sulfided catalysts showed a decrease for the average stacking number and Selleck VX-689 for the average length of WS2 particles with the gallium content. Moreover, change of the promoter

(Ni2+) interaction with the support was induced by the affinity of gallium (at low loadings) to the tetrahedral sites of alumina, inducing an increase of the octahedral species of Ni in the oxidic state of the catalysts as evidenced from UV-vis and to a higher amount of the NiWS mixed phase in the sulfided samples as deduced from XPS analysis. (C) 2012 Elsevier B.V. All rights reserved.”
“Homogeneous and patchy inputs of inorganic and organic nitrogen (N) are common in grazed grasslands, but little is known about the interactions between spatial pattern and form of N inputs for plant and soil processes. Understanding coupled plant and soil responses to heterogeneous N inputs is a critical step towards the improved prediction of field-scale ecosystem function. We compared impacts of uniform and patchy N addition on plant and soil properties using three N forms of increasing complexity (inorganic N; a simple amino acid, glycine; a complex protein, BSA) in an in situ grassland experiment. One month after N addition, patchy N treatments increased plant production but

decreased biomass produced per gram nitrogen (a proxy of N use efficiency) compared with uniform N treatments. Contrary to expectations, plant production showed limited differences among N

form treatments. However, microbial biomass and dissolved organic see more carbon showed significant N form x pattern interactions, with strongest responses to patchy inputs of complex organic N. Irrespective of N form, plant responses to patchy N inputs occurred over a larger spatial area than soil microbe responses, consistent with optimal foraging by plant roots. Unlike plants, microbial responses to patchy N inputs were still observed after six months. Overall, our results indicate that patchy inputs of N promote the uncoupling of PCI-32765 solubility dmso plant and soil properties, with greatest differences observed for complex organic N inputs. The spatial and temporal asynchrony between plant production and microbial biomass observed may have significant implications for the competitive balance of plants and soil microbes in space, as well as for plant soil feedbacks involved with the regulation of biogeochemical cycling. (C) 2014 Elsevier Ltd. All rights reserved.”
“Background: The standard clinical protocol of image-guided IMRT for prostate carcinoma introduces isocenter relocation to restore the conformity of the multi-leaf collimator (MLC) segments to the target as seen in the cone-beam CT on the day of treatment. The large interfractional deformations of the clinical target volume (CTV) still require introduction of safety margins which leads to undesirably high rectum toxicity.

Subsequent intake of a tocotrienol-free diet with or without alpha-tocopherol for 7 days depleted concentrations of alpha- and gamma-tocotrienol in serum and tissues, which was accompanied by a decrease in the excretion of gamma-tocotrienol metabolite. However, neither the tocotrienol concentration nor gamma-tocotrienol metabolite excretion was affected by dietary alpha-tocopherol. These data showed that dietary INCB28060 manufacturer alpha-tocopherol did not accelerate the depletion of gamma-tocopherol and tocotrienol

and their metabolite excretions, suggesting that the positive effect of alpha-tocopherol on vitamin E omega-hydroxylase is not sufficient to affect the other isoform concentrations in tissues.”
“Several immune functions are markers of health, biological age and predictors of longevity. A chronic oxidative and inflammatory state is the main cause of ageing and the immune system is involved in the rate of ageing. Thus, several murine models of premature ageing have been proposed owing to their early immunosenescence

and oxidative stress, such as ovariectomised rats and mice, obese rats and anxious mice. In the last model, the most extensively studied by us, mice showing anxiety have an aged immune function and redox status as well Pitavastatin research buy as a shorter longevity in comparison with animals without anxiety of the same chronological age, being denominated prematurely ageing mice. A confirmation of the above is that the administration of diets supplemented with antioxidants improves the redox status and immune functions and increases the longevity of prematurely ageing mice. Antioxidant precursors of glutathione such as thioproline or N-acetylcysteine, which have a relevant role in ageing, have been the most widely investigated in adult prematurely ageing mice in our laboratory. In the present work, we have studied the effects of the ingestion for 5 weeks of a diet supplemented with 0.1% (w/w) thioproline + N-acetylcysteine on several functions of find more leucocytes from chronological old (69-73

weeks of age) prematurely ageing mice of two strains (Swiss and BALB/c). The results show an improvement of the immune functions, with their values becoming closer to those in adult animals (24 +/- 2 weeks). Thus, an adequate nutrition with antioxidants, even in aged subjects, could be a good strategy to retard ageing.”
“Matrix metalloproteinase 9 (MMP-9) has been implicated in airway injury in chronic obstructive pulmonary disease (COPD), lung inflammation, and lung cancer and plays a major role in tumor necrosis factor-alpha (TNF-alpha)-stimulated tumor invasion and lung inflammation. MMP-9 activity is promoted by the pro-inflammatory cytokine TNF-alpha. GMI, cloned from Ganoderma microsporum and purified, is one of the recombinant fungal immunomodulatory proteins.

“
“Depletion of podocytes, common to glomerular diseases AMN-107 molecular weight in general, plays a role in the pathogenesis of glomerulosclerosis. Whether podocyte injury in adulthood can be repaired has not been established. Here, we demonstrate that in the adult human kidney, CD133+CD24+ cells consist of a hierarchical population of progenitors that are arranged in a precise sequence within Bowman’s capsule and exhibit heterogeneous potential for differentiation and regeneration. Cells localized

to the urinary pole that expressed CD133 and CD24, but not podocyte markers (CD133+CD24+PDX- cells), could regenerate both tubular cells and podocytes. In contrast, cells localized between the urinary pole and vascular pole that expressed both progenitor and podocytes markers (CD133+CD24+PDX+) could regenerate only podocytes. Finally, cells localized to the vascular pole did not exhibit progenitor markers, but displayed phenotypic features of differentiated podocytes (CD133-CD24-PDX+ cells). Injection of

CD133+CD24+PDX- cells, but not CD133+CD24+PDX+ or CD133-CD24- cells, into mice with adriamycin-induced nephropathy reduced proteinuria and improved chronic glomerular CBL0137 solubility dmso damage, suggesting that CD133+CD24+PDX- cells could potentially treat glomerular disorders characterized by podocyte injury, proteinuria, and progressive glomerulosclerosis.”
“Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a

genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic GS-7977 supplier testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20x, with average read depths overlapping targets ranging from 322x to 798x. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes.

septempunctata and H. axyridis exhibited a type II functional

response for predation toward adult soybean aphids at 26 +/- 1 degrees C. In C. septempunctata, the functional response curve of adult males differed from those of third instars and adult females, but MAPK inhibitor there was no difference between third instars and adult females. In H. axyridis,, the functional response curves of larvae, adult females, and adult males all differed significantly. Third instars and adult females consumed significantly more soybean aphids than did adult males at prey densities of 150 and 180 aphids per arena for C. septempunctata and at prey densities of 60, 90, 120, 150, and 180 aphids per arena for H. axyridis. The theoretical maximum daily predation rate of adult aphids by C. septempunctata was predicted to be 204 per third instar, 277 per adult female, and 166 per adult male, and 244, 156, and 73, respectively, for H. axyridis. Third instars and adult females of both species consumed significantly more aphids than did adult males on soybean plants with the recommended action threshold of 250 soybean aphids per plant. Both C. septempunctata and H. axyridis have high predation capacities and are important in suppressing soybean aphid populations.”
“Metastasis is the main cause of cancer-related death. It is surprising then that the exact nature of metastasisthe process by which cancer cells leave the primary tumor to reach

distant organs, and resume proliferation-is not fully understood. Moreover, the different conditions under Selleckchem Rabusertib which the immune system can either promote or suppress metastasis are only now beginning to be uncovered. In recent years, our understanding of metastasis as a genocentric, cell-autonomous process has shifted toward a systemic model in which interactions between cancer cells and their surrounding microenvironments lead to dissemination and metastasis. In silico modeling of the various steps involved in metastasis can help provide an understanding of how tumor properties emerge from the complex interplays between tumor cells and their microenvironment. In silico models can also be useful in identifying the selective

forces that selleck kinase inhibitor favor the outcomes of cancer cells with metastatic potential.”
“Norovirus is a major cause of viral gastroenteritis and a common cause of foodborne and waterborne outbreaks. Norovirus outbreaks are responsible for economic losses, most notably to the public health and food industry field. Norovirus has characteristics such as low infectious dose, prolonged shedding period, strong stability, great diversity, and frequent genome mutations. Besides these characteristics, they are known for rapid and extensive spread in closed settings such as hospitals, hotels, and schools. Norovirus is well known as a major agent of food-poisoning in diverse settings in South Korea. For these reasons, nationwide surveillance for norovirus is active in both clinical and environmental settings in South Korea.

We determined the prevalence of self-reported depression and memory dysfunction in ARDS survivors.\n\nMethods: Six to 48 (median 22) months after ICU discharge, we administered A-1210477 supplier instruments assessing depression symptoms (Beek Depression Inventory-II [BDI-II]) and memory dysfunction (Memory Assessment Clinics Self-Rating Scale [MAC-S]) to 82 ARDS patients who were enrolled in a prospective cohort study in four university-affiliated ICUs.\n\nResults: Sixty-one (74%), 64 (78%), and 61 (74%) patients fully

completed the BDI-II, MAGS (Ability subscale), and MAGS (Frequency of Occurrence subscale) instruments. Responders (similar to nonresponders) were young (median 42 years, interquartile range [IQR] 35 to 56), with high admission illness severity

and organ dysfunction. The median BDI-11 score was 12 (IQR 5 to 25). Twenty-five (41%) patients reported moderate-severe depression symptoms and were less likely to return to work than those with minimal-mild symptoms (8/25 [32%] vs 25/36 [69%]; p = 0.005). Median MAGS (Ability) and MAGS (Frequency selleck products of Occurrence) scores were 76 (IQR 61 to 93) and 91 (IQR 77 to 102), respectively; 8%, 16%, and 20% scored > 2, > 1.5, and > 1 SD(s), respectively, below age-adjusted population norms for each subscale. BDI-II and MAGS scores were negatively correlated (Spearman coefficient -0.58 and -0.50 for Ability and Frequency of Occurrence subscales, respectively; p < 0.0001). Univariable analyses showed no demographic or illness-severity predictors of BDI-II (including the Cognitive subscale) or MAGS (both subscales); results were similar when restricted to patients whose primary language was English.\n\nConclusions: ARDS survivors report a high prevalence of depression symptoms

and a lower prevalence of memory dysfunction 6 to 48 months after ICU discharge. Depression symptoms may hinder the return to work, or patients may report these symptoms because of inability to re-enter the workforce.”
“Context: Erectile dysfunction (ED) and premature ejaculation (PE) are the two most prevalent male sexual dysfunctions.\n\nObjective: To present the updated version of 2009 European Association of Urology NSC 683864 (EAU) guidelines on ED and PE.\n\nEvidence acquisition: A systematic review of the recent literature on the epidemiology, diagnosis, and treatment of ED and PE was performed. Levels of evidence and grades of recommendation were assigned.\n\nEvidence synthesis: ED is highly prevalent, and 5-20% of men have moderate to severe ED. ED shares common risk factors with cardiovascular disease. Diagnosis is based on medical and sexual history, including validated questionnaires. Physical examination and laboratory testing must be tailored to the patient’s complaints and risk factors. Treatment is based on phosphodiesterase type 5 inhibitors (PDE5-Is), including sildenafil, tadalafil, and vardenafil. PDE5-Is have high efficacy and safety rates, even in difficult-to-treat populations such as patients with diabetes mellitus.

Future research should further investigate the pathogenesis BI 6727 mw of antisynthetase

syndrome which could identify new therapeutic targets. It will be also important to study whether patients with AS are at increased risk of cancer and whether certain antisynthetase antibodies have any association with the risk of malignancy.”
“Background: Sarcoidosis is an inflammatory granulomatous disease affecting multiple organ systems. Neurosarcoidosis (CNS involvement) is seen in approximately 25% of patients with systemic sarcoidosis, although it is subclinical in most of these cases. Because of its rarity, exposure of neurologists to the clinical spectrum of NS is limited to case reports or short case series.\n\nPatients Selleck CCI-779 and Methods: A database of 3900 patients treated at the Vanderbilt Multiple Sclerosis Clinic between 1995 and 2008 was searched for ‘neurosarcoidosis’, ‘neurosarcoid’, ‘sarcoidosis’

and ‘sarcoid’. Of the 162 patient records that were retrieved, 54 patients were found to meet the criteria for definite, probable or possible neurosarcoidosis and were reviewed, including their clinical presentation, Cerebrospinal fluid (CSF) findings, Magnetic resonance imaging (MRIs), biopsy results, treatment, and where available, outcomes 4 months to 20 years after onset of the presenting illness.\n\nResults: Clinical presentations and imaging findings in NS were varied. Cranial nerve abnormalities were the most common clinical presentation and involvement of the optic nerve in particular was associated with a poor prognosis for visual recovery. Isolated involvement of lower cranial nerves had a more favorable outcome. T(2) hyperintense parenchymal lesions were the most common imaging finding followed by meningeal enhancement. Long-term

treatment consisted of prednisone and/or other immunomodulators (azathioprine, methotrexate or mycophenolate mofetil).\n\nConclusions: Unlike systemic sarcoidosis, there is difficulty in making tissue diagnosis when involvement of CNS is suspected. MRI and CSF studies are sensitive in PR-171 inhibitor the detection of CNS inflammation but lack specificity, making the ascertainment of neurosarcoidosis a clinical challenge. In addition the low prevalence of the disease makes clinical trials difficult and therapeutic decisions are likely to be made from careful reporting from case studies.”
“Background\n\nThe discovery that glial activation plays a critical role in the modulation of neuronal functions and affects the spinal processing of nociceptive signalling has brought new understanding on the mechanisms underlying central sensitization involved in chronic pain facilitation.

In this work, we studied the zebrafish ortholog Nfix (nfixa) and its role in the proper switch to the secondary myogenic wave. This allowed us to highlight evolutionarily conserved and divergent functions of Nfix. In fact, the knock down of nfixa in zebrafish blocks secondary myogenesis, as in mouse, but also alters Anlotinib concentration primary slow muscle fiber formation. Moreover, whereas Nfix mutant mice are motile, nfixa knockdown zebrafish display impaired motility that probably depends upon disruption of the sarcoplasmic reticulum. We conclude that, during

vertebrate evolution, the transcription factor Nfix lost some specific functions, probably as a consequence of the different environment in which teleosts and mammals develop.”
“This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B

kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the AZD8186 purchase pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 VX-680 in vivo and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency. (C) 2012 Elsevier Ltd. All rights reserved.”
“The cell bodies of sensory neurons in

the dorsal root ganglion (DRG) are enveloped by satellite glial cells (SGCs). In an animal model of intervertebral foraminal stenosis and low-back pain, a chronic compression of the DRG (CCD) increases the excitability of neuronal cell bodies in the compressed ganglion. The morphological and electrophysiological properties of SGCs were investigated in both CCD and uninjured, control lumbar DRGs. SGCs responded within 12 h of the onset of CCD as indicated by an increased expression of glial fibrillary acidic protein (GFAP) in the compressed DRG but to lesser extent in neighboring or contralateral DRGs. Within I week, coupling through gap junctions between SGCs was significantly enhanced in the compressed ganglion. Under whole-cell patch clamp recordings, inward and outward potassium currents, but not sodium currents, were detected in individual SGCs. SGCs enveloping differently sized neurons had similar electrophysiological properties. SGCs in the compressed vs. control DRG exhibited significantly reduced inwardly rectifying potassium currents (Kir), increased input resistances and positively shifted resting membrane potentials.

Infection of macrophages with zmp1-deleted Mtb triggered activation of the inflammasome, resulting in increased Selleck Crenolanib IL-1 beta secretion, enhanced maturation of Mtb containing phagosomes, improved mycobacterial clearance by macrophages, and lower bacterial burden in the lungs of aerosol-infected mice. Thus, we uncovered a previously masked role for IL-1 beta in the control of Mtb and a mycobacterial system that prevents inflammasome and, therefore, IL-1 beta activation.”
“The ruthenium (II) polypyridyl

complexes (RPC), Delta-[(phen)(2)Ru(tatpp)]Cl-2 (Delta-[3]Cl-2) and Delta Delta-[(phen)(2)Ru (tatpp)Ru(phen)(2)]Cl-4(Delta Delta-[4]Cl-4, are a new generation of metal-based antitumor agents. These RPCs bind DNA via intercalation of the tatpp ligand, which itself is redox-active and is easily reduced at biologically relevant potentials. We have previously shown that RPC 4(4+) cleaves DNA when reduced by glutathione to a radical species and that this DNA cleavage is potentiated under hypoxic conditions in vitro. Here, we show that 3(2+) also

exhibits free radical-mediated DNA cleavage in vitro and that 3(2+) and 4(4+) both exhibit selective cytotoxicity toward cultured malignant cell lines and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs3(2+) and 4(4+) (maximum tolerable doses similar to 65 mu mol/kg) is comparable with that for cisplatin (LD50 similar to 57 mu mol/kg), but unlike cisplatin, RPCs are generally cleared from the body unchanged via renal excretion without selleck compound appreciable

metabolism or nephrotoxic side effects. RPCs3(2+) and 4(4+) are shown to suppress growth of human non-small cell lung carcinoma (similar to 83%), show potentiated cytotoxicity 3-deazaneplanocin A in vivo in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biologic activity suggest a promising new anticancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials. (c) 2013 AACR.”
“Hunter syndrome is a rare, X-linked disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase. In the absence of sufficient enzyme activity, glycosaminoglycans accumulate in the lysosomes of many tissues and organs and contribute to the multisystem, progressive pathologies seen in Hunter syndrome. The nervous, cardiovascular, respiratory, and musculoskeletal systems can be involved in individuals with Hunter syndrome. Although the management of some clinical problems associated with the disease may seem routine, the management is typically complex and requires the physician to be aware of the special issues surrounding the patient with Hunter syndrome, and a multidisciplinary approach should be taken.