Effects of weaning age and pace on blood metabolites, cortisol concentration, and mRNA abundance of inflammation-related genes in gastrointestinal, adipose, and liver tissue of Holstein dairy calves.

The objective of this study was to evaluate the effects of weaning age and pace on blood metabolites, cortisol concentration, and mRNA abundance of inflammation-related genes in Holstein dairy calves. A total of 70 1-d-old calves (38.8 ± 4.4 kg BW ± SD), blocked by sex and birth BW, were randomly assigned to a 2 × 2 factorial arrangement of treatments. The first factor was weaning age, which was either early (6 wk) or late (8 wk). The second factor was weaning pace, which was either abrupt (4 steps down over 3 d; the initial milk replacer was 7.6 L, which was reduced by 1.9 L in each step-down) or gradual (7 steps down over 14 d; the initial milk replacer was 7.6 L, which was reduced by 1.09 L in each step-down), generating early-abrupt (EA), early-gradual (EG), late-abrupt (LA), and late-gradual (LG) treatments. All treatments had 10 female and 8 male calves, except EA that had 1 fewer male calf. Milk replacer (24% CP, 17% fat) was bottle fed, up to 1,200 g/d, twice daily (0600 h and 1800 h). The EA and EG treatment calves received 46.2 kg of milk replacer, and the LA and LG treatment calves received 63 kg of milk replacer. The study had 2 cohorts (2020, n = 40; 2021, n = 31), and each cohort included all treatments. Blood was collected from the jugular vein at 0900 h at 3 and 7 d of age, and a day before starting and a day after weaning completion. Male calves were humanely killed a day after weaning. Rumen, jejunum, large intestine, liver, omental adipose and perirenal adipose tissues were sampled to determine the mRNA abundance of inflammation-related genes. Weaning pace, age, pace × age, birth BW, and sex were included as fixed and cohort was included as random effects in the model. Blood metabolites and cortisol were analyzed as repeated measures, and sampling day, pace × sampling day, and age × sampling day were also included as additional fixed effects. Significance was noted at P ≤ 0.05 and tendencies when 0.05

Direct Structural Identification and Quantification of the Split-Vacancy Configuration for Implanted Sn in Diamond.

We demonstrate formation of the ideal split-vacancy configuration of the Sn-vacancy center upon implantation into natural diamond. Using ß^{-} emission channeling following low fluence ^{121}Sn implantation (2×10^{12} atoms/cm^{2}, 60 keV) at the ISOLDE facility at CERN, we directly identified and quantified the atomic configurations of the Sn-related centers. Our data show that the split-vacancy configuration is formed immediately upon implantation with a surprisingly high efficiency of ≈40%. Upon thermal annealing at 920 °C ≈30% of Sn is found in the ideal bond-center position. Photoluminescence revealed the characteristic SnV^{-} line at 621 nm, with an extraordinarily narrow ensemble linewidth (2.3 nm) of near-perfect Lorentzian shape. These findings further establish the SnV^{-} center as a promising candidate for single photon emission applications, since, in addition to exceptional optical properties, it also shows a remarkably simple structural formation mechanism.

Lattice Location of Mg in GaN: A Fresh Look at Doping Limitations.

Radioactive ^{27}Mg (t_{1/2}=9.5 min) was implanted into GaN of different doping types at CERN's ISOLDE facility and its lattice site determined via ß^{-} emission channeling. Following implantations between room temperature and 800 °C, the majority of ^{27}Mg occupies the substitutional Ga sites; however, below 350 °C significant fractions were also found on interstitial positions ∼0.6 Å from ideal octahedral sites. The interstitial fraction of Mg was correlated with the GaN doping character, being highest (up to 31%) in samples doped p type with 2×10^{19} cm^{-3} stable Mg during epilayer growth, and lowest in Si-doped n-GaN, thus giving direct evidence for the amphoteric character of Mg. Implanting above 350 °C converts interstitial ^{27}Mg to substitutional Ga sites, which allows estimating the activation energy for migration of interstitial Mg as between 1.3 and 2.0 eV.

Genetic variation in PTX3 and plasma levels associated with hepatocellular carcinoma in patients with HCV.

Hepatitis C virus (HCV) is the main cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC) worldwide. The risk to develop HCC increases with the severity of liver inflammation and fibrosis. Long pentraxin 3 (PTX3) is a soluble pattern-recognition receptor produced by phagocytes and nonimmune cells at sites of inflammation or injury. The aim of the present study was to determine the association of PTX3 polymorphisms and its plasma levels with HCC occurrence among patients with HCV. Samples from 524 patients with chronic hepatitis C were evaluated in this study. Two polymorphisms (rs1840680 and rs2305619) in the PTX3 gene were determined by real-time PCR. PTX3 plasma levels were measured by Enzyme-linked Immunosorbent Assay (ELISA). Our data show a significant association between PTX3 polymorphisms and HCC occurrence in univariate and multivariate analysis (P = 0.024). Patients with HCC had higher PTX3 plasma levels compared to individuals with mild or severe fibrosis (P < 0.0001 and P = 0.002, respectively). In addition, PTX3 rs2305619 polymorphism and plasma levels were correlated with Child-Pugh scores B and C in HCC individuals. PTX3 seems to be a risk factor for HCC occurrence in chronic hepatitis C. This is the first study that evaluates PTX3 in the context of hepatitis C.

High tumor necrosis factor-α/interleukin-10 ratio is associated with hepatocellular carcinoma in patients with chronic hepatitis C.

Hepatitis C virus (HCV) is the main cause of chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC) worldwide. The risk for the development of HCC increases with the severity of liver inflammation and fibrosis. The hepatic inflammation caused by HCV involves host regulatory immune response, which is mediated by cytokines with anti-viral role upon the interaction of viral polypeptides with innate and adaptive immunity. Two cytokines; tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) play key roles in the regulation of cellular immune response in HCV infection. The aim of the present study was to determine the levels of IL-10 and TNF-α, as well as the ratio of TNF-α and IL-10 serum levels in patients with HCV and HCC caused by HCV (HCC-HCV). The study included 173 patients with chronic HCV. TNF-α and IL-10 serum levels were measured by ELISA (R&D Systems, Inc.). In the present study, 54 patients presented liver mild fibrosis, 68 had severe fibrosis and 51 patients had HCC. After adjustment in the multivariate regression analysis, the following variables remained significantly associated with HCC-HCV occurrence: diabetes (p=0.012 OR 10.44 CI 1.66-65.60), IL-10 lower levels (p<0.0001 OR 0.83 CI 0.78-0.89) and TNF-α higher levels (p<0.0001 OR 1.19 CI 1.11-1.28). Individuals with HCC presented higher TNF-α/IL-10 ratio than those with fibrosis grade F4, F3 or F0+F1+F2 (p=0.0003, p<0.0001, p<0.0001, respectively). Patients with HCC were associated to higher index TNF-α/IL-10 ratio, suggesting that the unbalanced production of these cytokines may represent progression to the liver disease severity in HCV infected patients.

Tuning quantum corrections and magnetoresistance in ZnO nanowires by ion implantation.

Using ion implantation, the electrical as well as the magnetotransport properties of individual ZnO nanowires (NWs) can be tuned. The virgin NWs are configured as field-effect transistors which are in the enhancement mode. Al-implanted NWs reveal a three-dimensional metallic-like behavior, for which the magnetoresistance is well described by a semiempirical model that takes into account the presence of doping induced local magnetic moments and of two conduction bands. On the other hand, one-dimensional electron transport is observed in Co-implanted NWs. At low magnetic fields, the anisotropic magnetoresistance can be described in the framework of weak electron localization in the presence of strong spin-orbit scattering. From the weak localization, a large phase coherence length is inferred that reaches up to 800 nm at 2.5 K. The temperature-dependent dephasing is shown to result from a one-dimensional Nyquist noise-related mechanism. At the lowest temperatures, the phase coherence length becomes limited by magnetic scattering.

A new thrombospondin-related anonymous protein homologue in Neospora caninum (NcMIC2-like1).

Neospora caninum is an Apicomplexan protozoan that has the dog as a definitive host and cattle (among other animals) as intermediate hosts. It causes encephalopathy in dogs and abortion in cows, with significant loss in worldwide livestock. As any Apicomplexan, the parasite invades the cells using proteins contained in the phylum-specific organelles, like the micronemes, rhoptries and dense granules. The aim of this study was the characterization of a homologue (denominated NcMIC2-like1) of N. caninum thrombospondin-related anonymous protein (NcMIC2), a micronemal protein previously shown to be involved in the attachment and connection with the intracellular motor responsible for the active process of invasion. A polyclonal antiserum raised against the recombinant NcMIC2-like1 functional core (thrombospondin and integrin domains) recognized the native form of NcMIC2-like1, inhibited the in vitro invasion process and localized NcMIC2-like1 at the apical complex of the parasite by confocal immunofluorescence, indicating its micronemal localization. The new molecule, NcMIC2-like1, has features that differentiates it from NcMIC2 in a substantial way to be considered a homologue.

Facial exercise therapy for facial palsy: systematic review and meta-analysis.

UNLABELLED: The effectiveness of facial exercises therapy for facial palsy has been debated in systematic reviews but its effects are still not totally explained. OBJECTIVE: To perform a systematic review with meta-analysis to evaluate the effects of facial exercise therapy for facial palsy. DATA SOURCES: A search was performed in the following databases: Cochrane Controlled Trials Register Library, Cochrane Disease Group Trials Register, MEDLINE, EMBASE, LILACS, PEDro, Scielo and DARE from 1966 to 2010; the following keywords were used: 'idiopathic facial palsy', 'facial paralysis', 'Bell's palsy', 'physical therapy', 'exercise movement techniques', 'facial exercises', 'mime therapy' 'facial expression', 'massage' and 'randomized controlled trials'. REVIEW METHODS: The inclusion criteria were studies with facial exercises, associated or not with mirror biofeedback, to treat facial palsy. RESULTS: One hundred and thirty-two studies were found but only six met the inclusion criteria. All the studies were evaluated by two independent reviewers, following the recommendations of Cochrane Collaboration Handbook for assessment of risk of bias (kappa coefficient = 0.8). Only one study presented sufficient data to perform the meta-analysis, and significant improvements in functionality was found for the experimental group (standardized mean difference (SMD) = 13.90; 95% confidence interval (CI) 4.31, 23.49; P = 0.005). CONCLUSION: Facial exercise therapy is effective for facial palsy for the outcome functionality.

Time-of-day effect on hip flexibility associated with the modified sit-and- reach test in males.

Flexibility is a key component of physical fitness. It has been suggested that measures of physical fitness components may vary throughout the day. The aim of this study was to analyse the effects of the time of day on flexibility performance. 26 men (mean age=25.4 years, SD=2.5) were evaluated by hip flexion on kinematic analysis and also by an absolute score in the modified Sit-and-Reach test during a repeated measure design. This was done during 3 experimental sessions, which took place at 8:00 a.m., 1:00 p.m. and 6:00 p.m., in random order. All subjects were previously familiarized with the test parameters. There was a diurnal variation only in the modified Sit-and-Reach test score between 8:00 a.m and 6:00 p.m. (P=0.01). There was no significant difference in the hip kinematic analysis between hours. These findings suggest that flexibility performance in the modified Sit-and-Reach test, in absolute scores, is affected by the time of day, with higher performance in the evening.

[Rate of genotypic mutations and resistance to antiretroviral drugs in a general hospital]. / Tasa de mutaciones genotípicas y resistencia a antirretrovirales en un hospital general.

OBJECTIVES: The objective is to describe the resistance mutation rate in protease and reverse transcriptase genes and sensitivity to different antiretrovirals in our environment. METHODS: We performed an observational descriptive study in which we examined the samples provided at the clinical immunology laboratory between April 2004 and April 2009. We analysed both the resistance tests and the sensitivity to different drugs in patients with therapeutic failure using trugene hiv01 genotyping kits(®). RESULTS: We registered samples from 242 patients, 61 of which had no detectable resistance. The most prevalent mutations according to drug families were: for nucleoside analog reverse transcriptase inhibitors T215A/C/D/F/L/N/S/Y (24.10%), M184G/I/V/W (14.66%), M41J/L/R/T/W (11.24%) and K219E/G/H/N/R/T/W (10.24%). The highest levels of resistance corresponded to stavudine and lamivudine/emtricitabine, and tenofovir produced the least resistance in our environment. The non-analogues were K103N/R (23.98%), V179D/E/I/M/T (10.82%), A98E/G/S (10.53%) y K101E/P/Q/R (9.06%). Nevirapine presented greater resistance than efavirenz. Protease inhibitors were L10F/I/V (15.95%), M36I/L (13.81%), A71I/T/V (13.10%) and 154L/S/V (7.38%). The combination darunavir/ritonavir combination was that which presented the least resistance, and tipranavir/ritonavir and lopinavir/ritonavir the most resistance. CONCLUSIONS: Antiretroviral resistance and sensitivity to retroviral treatment in our environment was similar to results from other studies in Spain, but differed in the high level of resistance to lamivudine/emtricitabine and lopinavir/ritonavir.

Association of variant alleles of MBL2 gene with vasoocclusive crisis in children with sickle cell anemia.

Vasoocclusive crisis (VOC) is the major cause of morbidity and mortality in sickle cell anemia (SCA), which is caused by the occlusion of blood vessels, followed by ischemia or infarct, resulting in progressive damage to organs. However, this clinical manifestation is variable, indicating that this process could be influenced by modifier genes. The gene MBL2 which codes for mannose-binding lectin (MBL) has been associated with modifications in the progression of infectious and inflammatory vascular diseases. The aim of this study was to determine the frequency of the polymorphisms of exon 1 (alleles A/O) and promoter region -221 (alleles Y/X) of MBL2 in children with SCA and to verify their association with VOC. The determination of the polymorphism of exon 1 and the promoter region of MBL2 was performed by SYBR GREEN((R)) and Taqman((R)) system, respectively. In the patients with SCA, the frequency of the genotype related to high production of MBL was 0.46 (YA/YA) and for intermediate/low production was 0.54 (YA/XA, XA/XA, YA/YO, XA/YO, YO/YO). The frequency of the genotypes and haplotypes of MBL2 in patients with SCA did not differ from control individuals. The populations were in Hardy-Weinberg equilibrium. The patients were divided into two groups. The groups were separated by the frequency of VOC, which was defined by the total of VOC episodes divided by the age of the children at the end of this study. Since, we choose a cut point in FVOC <1 (n=48) (which we considered of mild presentation of disease) and FVOC >or=1 (n=39) (higher severity). In children with SCA, the frequency of the genotypes of MBL2 of intermediate/low expression for MBL was associated with FVOC >or=1 (p=0.0188 OR=3.15 CI=1.19-8.50). The results suggest that MBL2 polymorphism at promoter and first exon of MBL2 associated with low serum levels and structural alterations of MBL could modify the phenotype of the child with SCA related to VOC.

Health burden of co-morbid asthma and allergic rhinitis in West Indian children.

BACKGROUND: Co-morbid allergic rhinitis (AR) and asthma has not been studied in Caribbean countries where there is a high prevalence of childhood asthma. METHODS: Using the International Primary Care Airways Group (IPAG) guidelines to determine AR, care-givers of 393 (response rate=100%) children attending asthma clinics in selected public sector health facilities in Trinidad, West Indies, were interviewed. RESULTS: Children (393) were between 2-17 years and included 239 (60.8%) boys and 154 (39.2%) girls. As many as 53.9% of children sampled (95% CI 45.9-55.8) suffered from AR. Children exposed to household smoking were nearly twice as likely to have AR (p<0.0041, OR=1.9, CI 1.22-2.88). Significantly (p<0.01) more asthmatics with AR (154, 58.6%) visited Accident and Emergency (A&E) in the past 12 months. The odds of visiting A&E at least once in the past 12 months for asthmatics with AR were 1.75 (95% CI 1.15-2.68). The average frequency of A&E visits was higher in children who also suffered from AR (1.75 vs 1.36, p<0.04). Age was negatively correlated (-0.21, p<0.005) with exacerbation frequency for asthmatics without AR suggesting A&E visits are independent of age in co-morbid disease. More children with AR (>60%) suffer day and night symptoms (p<0.001), and miss school (59.8%) (p<0.03) at least once a week (p<0.002) than asthmatics without AR (OR=1.5, 95% CI=1.03-2.30). CONCLUSIONS: AR is prevalent in 53.9% of Trinidadian children with asthma. The burden of co-morbid disease in asthmatic children is associated with increased likelihood of asthma-related A&E visits, day and night symptoms and absence from school.

Drug utilization patterns in pregnant women: a case study at the Mount Hope Women's Hospital in Trinidad, West Indies.

OBJECTIVE: To explore drug (prescription, over-the-counter and herbal) utilization in pregnant women attending a public sector tertiary healthcare institution. METHODS: This was a cross-sectional case study in women attending antenatal clinics at the Mount Hope Women's Hospital. Women (506) who consecutively presented for routine care at the antenatal clinic were interviewed on the medication they took. Descriptive statistics and logistic regression for predictors of drug use were done using SPSS 16. RESULTS: There were 200 (39.5%) primigravidae, 306 (60.5%) multigravidae and 299 (59%) women were in the third trimester of pregnancy. Most women (69.8%) were between 20-35 years of age. Women took an average of 1.32, 1.22 and 0.94 prescribed drugs in each trimester respectively. Multivitamins (59.8%) and iron/folic acid (54.2%) were the most frequently prescribed drugs. Regardless of trimester only 20% of women took supplemental calcium. Very few women (2.4%) took herbal medications. Paracetamol was the most common over-the-counter (OTC) medication in all trimesters. Women with secondary level education were most likely to use OTC iron/folic acid (p = 0.02), paracetamol and histamine2 receptor antagonists [H2RAs] (p = 0.001). More primigravidae took non-steroidal anti-inflammatory drugs (p = 0.02) and more women in the first trimester used antiemetics (p = 0.001). Age group (p = 0.048), marital status (p = 0.001) and the trimester of pregnancy (p = 0.001) were predictors of drug utilization. CONCLUSION: Overall, women in tertiary healthcare institutions took medication as prescribed particularly multivitamins and iron/folic acid. More women with higher education took OTC paracetamol, iron/folic acid and vitamin supplements. Herbal supplements were rarely used. Research on drug utilization in primary care facilities is recommended.

Influence of Computer-aided Design/Computer-aided Manufacturing Diamond Bur Wear on Marginal Misfit of Two Lithium Disilicate Ceramic Systems.

CLINICAL RELEVANCE: Marginal misfit of monolithic lithium disilicate ceramic crowns obtained from a chairside computer-aided design/computer-aided manufacturing system is affected after successive millings using a single diamond bur set. This fact can be critical for the longevity of indirect restorations.

Structural polymorphism of the mannose-binding lectin 2 (MBL2 ) gene in HCV-infected patients with a serological marker for thyroid autoimmunity.

We studied the association of the mannose-binding lectin-2 (MBL2) polymorphism with anti-thyroid antibodies (ATA) in hepatitis C virus (HCV)-infected Brazilian patients (n = 162) and 124 healthy volunteers screened for ATA. Our results showed that patients with ATA had higher frequency of genotype 00 than controls. MBL may play a role as disease modifier in HCV infection.

Evaluation of asthma control using patient based measures and peak expiratory flow rate.

OBJECTIVE: Asthma control has not been formally evaluated in the Caribbean. This study evaluated disease control on The Asthma Control Test (ACT), The Royal College of Physicians "Three questions" for Assessing Asthma Control (RCP), peak expiratory flow rate (PEFR) and patients' self-assessment of control. SUBJECTS AND METHODS: Asthma control was examined in a cross-section of 205 asthmatics above 16 years of age using the ACT, RCP and on the PEFR % predicted. Scores below 20 and equal to or above 1 on the ACT and RCP respectively, and PEFR below 80% predicted indicated uncontrolled asthma. Patients stated whether they perceived their asthma was controlled or uncontrolled. RESULTS: Overall there were more females (63.9%, p < 0.001) than males (36.1%). Males aged between 17-30 years predominated (60.8%, p < 0.001) with gender reversal beyond 30 years of age (33.2%, p < 0.002) years. Self-assessed control was higher (69.3%, p < 0.001) than control evaluated by the ACT and RCP tests, which were comparable (p > 0.05). Fewer patients (13.2%) achieved control on PEFR > 80% predicted than on the ACT (22.4%) and RCP (18%). The Kappa statistic indicated good reproducibility of the RCP and ACT and concordance between the PEFR and RCP (0.63) and the PEFR and ACT (0.56). Higher education was associated with control on the ACT (p < 0.0005) and RCP (p < 0.002) but not on PEFR or self-assessment (p > 0.05). CONCLUSION: Approximately 80% of study asthmatics were uncontrolled, and patients tended to overestimate their disease control. The ACT and RCP instruments were comparable with the PEFR. Efforts to study their validity and formal evaluation of asthma control in Trinidad are recommended.

Evaluation of the vaccination status in pediatric renal transplant recipients.

To assess the immunization status of pediatric renal transplant patients followed at a single center in Brazil, vaccination charts of all patients aged between one and 18 yr were analyzed both pre- and post-transplantation. Appropriate immunization was defined according to the National Immunization Program (routine vaccines) - for all Brazilian children - and the Special Immunobiological Agents Program that also includes special vaccines for immunodeficient or other high-risk children. A total of 46 patients was evaluated (mean age 13.7 yr; range 4-17 yr). Vaccination charts were found to be up to date in only two patients (4.3%) pretransplant and in two (4.3%) post-transplant. Although 36 patients (62.2%) in the pretransplant phase and 24 (52.1%) in the post-transplant phase had been vaccinated according to the National Immunization Program, they had not received the special vaccines indicated for their immunocompromised condition. Therefore, despite being followed at a referral center, almost all patients presented an incomplete immunization status pre- and post-transplant. This probably reflects missed opportunities and medical/parental apprehension related to vaccination of patients with chronic renal insufficiency, dialysis or kidney transplantation. Efforts should be made to ensure adequate vaccination in children with kidney diseases, especially before kidney transplantation.

Influence of single-nucleotide polymorphisms on C-reactive protein levels in chronic kidney disease before and after kidney transplantation.

INTRODUCTION: We sought to evaluate 2 single-nucleotide polymorphisms (SNPs) in the C-reactive protein (CRP) gene promoter region for their effects on CRP levels in chronic kidney disease (CKD) patients before and after a successful kidney transplantation. METHODS: Fifty CKD patients were evaluated before and at the first and second years after the graft. Two SNPs were studied, a bi-allelic (G-->A) at the -409 and a tri-allelic (C-->T-->A) variation at the -390 position in the CRP gene. RESULTS: All patients presented the -409GG genotype. At the -390 position, the "A" allele was not found; there were 15 "CC" patients, 11 "TT" patients, and 24 "CT" patients. CRP levels were different among patients with various genotypes (P < .019). Also the presence of the allele "T" was sufficient to determine differences in CRP levels both in pretransplantation (P = .045) and at 1 year posttransplantation (P = .011), but not at the second year (P = .448). CONCLUSION: SNPs at the -390 position of the CRP gene promoter region influence CRP basal levels in such a way that the "C" allele correlated with the lowest and the "T" with the highest. We did not observe this influence in our patients at the second year posttransplantation.

Chronic obstructive pulmonary disease is missed in asthmatics in specialty care in Trinidad, West Indies.

SETTING: Underdiagnosis of chronic obstructive pulmonary disease (COPD) in asthmatics attending specialty care in Trinidad, West Indies. OBJECTIVE: To determine the prevalence of COPD in diagnosed asthmatics receiving specialty respiratory care. DESIGN: In a cross-sectional study, 258 asthmatics were screened for lung function measures to examine forced expiratory volume after 1 second (FEV1), forced vital capacity (FVC) and post-bronchodilator FEV1/FVC (COPD was defined as FEV1/FVC < 70%). RESULTS: Of 165 patients evaluated (response rate 64.0%), 53 (32.1%, 95%CI 25.0-39.2) had a study diagnosis of COPD and a mean FEV1/FVC of 60.12 +/- 1.2. Proportionally, more males had COPD (50.9%) than asthma (24.1%, P < 0.001). Patients with COPD were 10 years older than asthmatics (P < 0.001). Persons with asthma who smoked were more likely to have COPD (56.0%) (OR 3.26, 95%CI 1.36-7.80, P = 0.006). In both sexes, FEV1/FVC was lower among older people (P < 0.001), with a greater effect (OR 2.75, 95%CI 1.00-7.56, P < 0.01) seen among men in this cross-sectional study. CONCLUSIONS: One third of diagnosed asthmatics in specialty care also have COPD. Lung function was lower among older persons. Early spirometric evaluation of elderly asthmatics who smoke can determine the presence of COPD and facilitate appropriate management.