Vitamin K status in cystic fibrosis

Appearance of PIVKA-II (protein induced by vitamin K absence-II) in serum is a biochemical sign of insufficient vitamin K-dependent carboxylation of prothrombin. Plasma concentrations of PIVKA-II and vitamin K1 were determined in 24 children with cystic fibrosis. Eight were supplemented with vitamin K1. The purpose of the study was to determine the occurrence of vitamin K deficiency in cystic fibrosis and to evaluate the effect of vitamin K supplementation. PIVKA-II was detectable in only one unsupplemented child. In this patient, the concentration of vitamin K1 was below the limit of detection of 60 ng/l. Vitamin K1 levels in the other unsupplemented children were normal (mean 476 ng/l = 1 mmol/l). The supplemented patients showed extremely high levels of vitamin K1 (mean 22445 ng/l = 50 nmol/l). In conclusion, vitamin K deficiency occurs infrequently in cystic fibrosis. Checking the coagulation system is advised, but routine vitamin K supplementation is not recommended. If additional vitamin K is needed, the starting dose should not exceed 1 mg daily.     

Erythrocyte membrane acetylcholinesterase, Na+, K+-ATPase and Mg2+-ATPase activities in patients with classical galactosaemia

BACKGROUND: Classical galactosaemia is commonly presented by high blood galactose (Gal) and galactose-1-phosphate (Gal-1-P) levels followed by mental retardation, seizures, etc. dependent on the mutation of the patients. AIM: To evaluate Gal and Gal-1-P in the blood of patients and to correlate their levels with their erythrocyte membrane acetylcholinesterase (AChE), Na+,K+-ATPase and Mg2+-ATPase activities. METHODS: Blood was obtained from nine patients on poor diet (group B) followed by a 30-d strict diet (group A) and controls (group C) in order to evaluate Gal and Gal-1-P in Guthrie cards and to correlate their concentrations with the above enzyme activities, which were measured spectrophotometrically. RESULTS: With the patients on a "loose" diet, AChE, Na+,K+-ATPase and Mg2+-ATPase activities were found to be decreased, as compared with those on strict diet and controls. Significantly (p<0.01) inverse correlation coefficients of the enzyme activities were found with Gal-1-P levels. CONCLUSION: (a) AChE, Na+,K+-ATPase and Mg2+-ATPase activities were determined to be decreased in poorly controlled patients with classical galactosaemia. (b) The enzyme activities were inversely correlated with the Gal-1-P blood levels. (c) Since Na+,K+-ATPase in the erythrocyte membranes is the isomer of Na+,K+-ATPase distributed in many tissues and in the brain, evaluation of the enzyme activity in the erythrocytes could be a useful peripheral marker of Gal-1-P toxicity.     

The effect of vitamin K supplementation on biochemical markers of bone formation in children and adolescents with cystic fibrosis

Introduction Impaired vitamin K status in cystic fibrosis (CF) has been considered as a newly emerged pathogenetic factor for reduced bone mineral density (BMD).Objectives Our aim was to evaluate the effectiveness of vitamin K supplementation in managing bone formation abnormalities in children and adolescents with CF.Materials and methods The statuses of vitamins K and D in relation to biochemical markers of bone metabolism and BMD were examined in 20 CF children receiving vitamin D supplements but not vitamin K supplements. Laboratory tests were carried out at the beginning of the study period and after 1 year of vitamin K supplementation (10 mg single oral dose/week) and the results were compared; the results were also compared with those of 25 healthy controls.Results and discussion Ten of the CF patients had BMD z-score ≤2.5 (n=5) or between −1 and −2.5 (n=5). Biochemical tests on patients before vitamin K supplementation revealed that the levels of osteoblastic activity markers, namely, bone alkaline phosphatase (BAP), serum osteocalcin (Gla-OC), serum carboxy-terminal propeptide of type I procollagen (PICP) and serum amino-terminal propeptide of type I procollagen (PINP), were significantly reduced compared with those of the controls. These patients had also lower 25-hydroxy-vitamin D (25(OH)D) and vitamin K serum levels, higher undercaboxylated osteocalcin (Glu-OC) and parathormone (PTH) levels and a higher calcium to creatinine ratio (Ca/Cr) than the controls. Vitamin K intake was associated with an increase in Gla-OC, PINP, PICP levels and a decrease in Glu-OC levels. PTH levels were lower after vitamin K supplementation without any difference in BMD z-scores.Conclusion Our data indicate that vitamin K supplementation may have a beneficial role in bone health in CF children.     

Identification of novel mutations in Arabs with cystic fibrosis and their impact on the cystic fibrosis transmembrane regulator mutation detection rate in Arab populations

The cystic fibrosis transmembrane regulator (CFTR) gene in Arab patients with cystic fibrosis (CF) (sweat chloride >60 mmol/l) from 61 unrelated families was screened for mutations in exons 3, 4, 5, 7, 10, 11, 16 and 19 and for mutations W1282X, N1303K and 3849 + 10kbC → T. Eight novel mutations were identified. These are: in exon 4: a) 425del42 (an in-frame 42 bp deletion that removes 14 amino acids and causes Gln₉₈ → His at the point of deletion), b) 475G → T (Glu₁₁₅ → Stop) and c) 548A → T (His₁₃₉ → Leu); in intron 5, 711 + 1G → A (splice site mutation); in exon 10, 1548delG (deletion of a “G” nucleotide causing a frameshift mutation that alters the amino acid sequence at residue 473 and results in translation termination at residue 526); in exon 11, a) 1729T → C (Ph₅₃₃E → Leu) and b) 1811 + 2 (splice site mutation) and finally in exon 19, 3361A → T (Lys₁₁₇₇ → Stop). All mutations were detected by heteroduplex analysis and identified by sequencing. Of more than 850 known CFTR mutations, only 9 were encountered. The comparative frequencies of the most common mutations are: 1548delG> I123V=ΔF508=3120 + 1G → A > H139L. Screening for these five mutations identifies 60% of the CF alleles in Arab populations. The novel mutation 1548delG is the most frequent (17%) among Arabs. Conclusion Novel Arab-specific mutations were identified in the CFTR gene underlying cystic fibrosis. As a result of this study, the CFTR mutation detection rate among Arabs with cystic fibrosis is now comparable to that of other populations. Received: 18 December 1998 / Accepted: 14 May 1999     

Birth distribution in cystic fibrosis and phenylketonuria

The present study of 977 cystic fibrosis (CF) patients showed a bimodal birth distribution with peaks in April to July and October to January. After adjustment to the monthly variation of the birth rate of all liveborn children there was no significant deviation from the expected distribution. The 387 phenylketonuria (PKU) patients showed no seasonal birth variation.     

Serum immunoreactive trypsin and pancreatic lipase in cystic fibrosis

Serum immunoreactive trypsin (IRT) and pancreatic lipase have been measured in 59 patients with cystic fibrosis (age 1 month-27 years). Follow-up values were obtained from 49 patients. Their serum enzyme levels were compared to those of 120 healthy children of all age groups. Faecal fat excretion was determined in selected patients (n=23) to elucidate the relationship between serum enzyme levels and pancreatic exocrine function.In cystic fibrosis IRT and lipase showed a very similar agecorrelated pattern: in infancy levels were markedly elevated. During the following years the concentrations of both enzymes decreased rapidly and were found to be far below the normal range after the 10th year of life. Elevated enzyme levels in infancy as well as low levels in all age groups coincided with steatorrhaea. Older patients (11–27 years) without severe pancreatic insufficiency however, had IRT and lipase levels in or above the normal range.In healthy children there was no age dependency of IRT levels, whereas in the first 12 months of life lipase levels were significantly lower than in later childhood.Abbreviations IRT Serum immunoreactive trypsin - CF Cystic fibrosis     

Isolation and characterization of erythrocyte membrane Ca2+-ATPase in cystic fibrosis

Ca2+-ATPase was purified from erythrocyte membranes prepared from cystic fibrosis (CF) blood samples (n = 10) and from age/sex-matched control blood samples (n = 10). The kinetics of calcium activation of the purified enzyme was investigated in the presence of asolectin phospholipids and found to be virtually identical for both CF and control preparations: VCa2+ = 3.01 +/- 0.24 mumol ATP hydrolyzed/mg pure enzyme/min (mean +/- SE) and 3.09 +/- 0.20 for CF and control Ca2+-ATPase, respectively; KCa2+ = 0.328 +/- 0.046 mu molar free calcium and 0.333 +/- 0.040 for CF and control enzyme, respectively. The preparative procedure used (one-step purification by calmodulin-affinity chromatography) allowed quantitative recovery of essentially 100% of the Ca2+-ATPase present in detergent-solubilized erythrocyte membranes, enabling expression of the yield of purified enzyme in terms of the quantity of starting membrane protein: 0.127% +/- 0.006% (w/w) and 0.140% +/- 0.007% for CF and control enzyme preparations, respectively. None of the parameters evaluated showed a statistically significant difference (p less than 0.05) between the CF and control groups. Furthermore, when CF and control purified Ca2+-ATPase samples were analyzed by high-resolution gradient SDS-polyacrylamide gel electrophoresis, no differences in mobility were observed (mol wt = 128 kdaltons). Thus, Ca2+-ATPase purified from CF erythrocyte membranes and assayed in the presence of asolectin appears to be quantitatively similar to control purified enzyme in amount, molecular weight, and kinetics of activation by calcium. These data suggest that Ca2+-ATPase may not be the defective gene product in CF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pubertal growth and development in cystic fibrosis: a retrospective review

AIM: Normal growth patterns are seen throughout the first decade in children with cystic fibrosis (CF). Growth in the second decade is, however, less satisfactory and may reflect pubertal delay. This study was performed to assess the extent of pubertal delay, to examine factors that influence the timing and magnitude of the pubertal growth spurt, and to establish whether the final height for most CF patients differed significantly from the normal population. METHODS: Thirty subjects (16 male) attending a single centre were studied. Peak height velocity (PHV), final height and ages when achieved were compared with population norms. Outcome data were correlated with disease severity using Shwachman and Chrispin-Norman scores and forced expiratory volume in 1 s. RESULTS: PHV was significantly later in both genders in this CF population compared with Tanner and Whitehouse standards: boys 14.6 y (95% confidence interval (95% CI) 12.4-16.8, p < 0.01) and girls 12.6 y (95% CI 10.5-14.7, p < 0.01). Mean PHV was also lower in both genders (boys 7.7 cm y(-1) and girls 6.4 cm y(-1), both p<0.001). However, final heights did not differ significantly from Freeman standards (height standard deviation scores: males--1.2, females--0.1); 52% of final heights equalled or exceeded the mid-parental centile. CONCLUSION: CF patients showed suboptimal PHVs with a later pubertal growth spurt influenced by disease severity, but eventually achieved a normal final height.     

严重脓毒症大鼠肺内水通道蛋白-1及Na+-K+-ATP酶变化的研究

目的探讨严重脓毒症大鼠肺内水通道蛋白-1(AQP-1)及Na -K -ATP酶表达的变化及其在肺水肿形成中的作用。方法健康雄性Wistar大鼠(160～210g)16只,以抽签方式随机分为两组,即严重脓毒症组和正常对照组,每组8只。间隔5h分两次注射灭活大肠杆菌,建立严重脓毒症大鼠模型。2h后收集肺组织标本,观察肺组织病理形态和计算肺损伤病理评分,并采用免疫组化法观察肺内AQP-1、Na -K -ATP酶、糖皮质激素受体(GR)的表达。结果肺损伤生物学标志[肺湿/干重比(g/g)、肺泡灌洗液蛋白水平(mg/L)和肺泡通透指数(10-3)],严重脓毒症组(4.76±0.10,278.96±60.45,4.73±0.60)显著高于正常对照组(4.10±0.07,67.46±13.27,1.12±0.15),两组间差异有非常显著性(P<0.001);肺损伤病理评分,严重脓毒症组(11.13±1.13)显著高于正常对照组(0.50±0.53),差异有非常显著性(P<0.001)。肺内AQP-1、Na -K -ATP酶及GR表达面积比严重脓毒症组(0.02±0.02,0.02±0.01,0.04±0.04)显著低于正常对照组(0.09±0.04,0.10±0.06,0.12±0.04),差异有非常显著性(P<0.001)。指标间相关性分析提示,GR与AQP-1和Na -K -ATP酶表达均存在明显直线正相关关系(r=0.43,P=0.007;r=0.31,P=0.015)。结论严重脓毒症期间,肺内AQP-1及Na -K -ATP酶表达存在下调,是肺水肿形成的原因之一,而二者下调原因可能与GR表达下调有关。     

原发性高血压患儿红细胞膜三磷酸腺苷酶活性及血液黏度改变的意义

目的 探讨原发性高血压患儿红细胞膜Na 、K -ATP酶、Ca2 、Mg2 -ATP酶活性及血液黏度改变的意义.方法 对本院2004年11-12月坚持随访的50例原发性高血压患儿进行红细胞膜Na 、K -ATP酶、Ca2 、Mg2 -ATP酶活性(比色法)及血液黏度测定,并与30例健康儿童作对照,采用SPSS 12.0软件进行t检验及直线相关分析.结果 原发性高血压组患儿红细胞膜Na 、K -ATP酶、Ca2 、Mg2 -ATP酶活性[(6.12±1.30) μmolpi/(gHb·h)和(4.59±1.40) μmolpi/(gHb·h)]较健康对照组[(7.46±1.30) μmolpi/(gHb·h)和(5.81±1.20) μmolpi/(gHb·h)]显著降低(Pa＜0.01);血液黏度较健康对照组显著升高(Pa＜0.01).原发性高血压组Na 、K -ATP酶、Ca2 、Mg2 -ATP酶活性与血液黏度均呈负相关(P＜0.05,0.01).结论 Na 、K -ATP酶、Ca2 、Mg2 -ATP酶活性降低及血液黏度升高可能在儿童高血压发病机制中起重要作用.     

Developmental and psychosocial issues in cystic fibrosis

Cystic fibrosis (CF) is a multisystemic life-limiting genetic disorder, primarily affecting respiratory functioning. Most patients with CF are diagnosed by 2 years of age, and the current median predicted survival rate is 37.4 years old, with 95% of patients dying from complications related to pulmonary infection. Given the chronic, progressive, and disabling nature of CF, multiple treatments are prescribed, most on a daily basis. Thus, this illness requires children, with the aid of their families, to adopt multiple health-related behaviors in addition to managing more typical developmental demands. The morbidity and mortality factors pose cognitive, emotional, and behavioral challenges for many children with CF and their families. This article applies a developmental perspective to describing the psychosocial factors affecting psychological adjustment and health-related behaviors relevant to infants, preschool and school-age children, and adolescents with CF. Topics particularly pertinent to developmental periods and medical milestones are noted, with clinical implications highlighted.     

Quality-of-life in children and adolescents with cystic fibrosis managed in both regional outreach and cystic fibrosis center settings in Queensland

OBJECTIVES: To assess the health-related quality-of-life (HRQOL) of children/adolescents with cystic fibrosis (CF) and compare HRQOL in children managed by cystic fibrosis outreach service (CFOS) with those treated in a cystic fibrosis center (CFC). To compare HRQOL of children with CF in Queensland with previously published HRQOL data from the United States and examine the relationship between HRQOL scores and pulmonary function. STUDY DESIGN: Participants were children/adolescents with CF and their parents managed by the Royal Children's Hospital Queensland at a CFC or CFOS. Two HRQOL surveys were used: PedsQL and Cystic Fibrosis Questionnaire (CFQ). RESULTS: There were 91 CFC and 71 CFOS participants with similar demographics. PedsQL total summary score was statistically higher in CFOS, P=.05. There was no significant difference in CFQ scores between groups. Queensland parents reported lower HRQOL for their children compared with US parents (P<.01) despite similar pulmonary function. Declining pulmonary function correlated with worse CFQ scores in adolescents, P<.05. CONCLUSIONS: Children living in regional Queensland reported as good as or slightly better HRQOL compared with children attending a CFC. Parent proxy HRQOL scores were generally low suggesting a reduced perception of HRQOL by parents for their children.     

Hyperglycaemia and insulinopenia in a neonate with cystic fibrosis

Abnormal glucose tolerance is a frequent late complication of cystic fibrosis (CF), but the prevalence of CF-related diabetes mellitus (CFRD) in children less than 10 y old is less than 2%. The youngest child with CFRD reported to date was 6 mo of age. Insulinopenia is the primary cause of abnormal glucose tolerance/CFRD, but it is unknown whether it may begin in the neonatal period. We describe a case of a neonate with CF who presented with hyperglycaemia in the diabetic range and marked insulinopenia. Insulinopenia and impaired glucose tolerance were permanent findings at 6 and 15 mo of age. CONCLUSION: This case suggests that abnormal glucose tolerance/diabetes may occur much earlier in the course of CF, even during neonatal age. Careful follow-up and further studies in CF infants could reveal that the real incidence of glucose intolerance and diabetes in this age group has been underestimated.     

高胆红素血症新生大鼠脑组织Na~+-K~+-ATP酶活力的研究

目的：探讨胆红素神经毒性的作用环节,研究胆红素脑病发病机理。方法：72只新生7d SD大鼠随机分为对照组(C组)和实验组(T组),T组又根据腹腔注射胆红素剂量的依次增加分为T1,T2,T3,T4和T5组。检测各组脑组织和血清中胆红素含量,定磷法测定脑组织中Na+ K+ ATP酶(Na+ K+ ATPase)活力。结果：给药后4 h和8 h均随着腹腔注射胆红素量的增加,血清总胆红素浓度、脑组织内胆红素含量逐渐增加,脑组织Na+ K+ ATPase活力则逐渐降低,除T1组外余各组与对照组相比差异均有显著性(P0.05),但脑组织内胆红素含量、Na+ K+ ATPase活力除T1组外各组4 h,8 h之间差异有显著性(P0.05),脑组织内胆红素含量与Na+ K+ ATPase活力呈负相关(r=-0.86,P<0.01)。结论：脑组织内胆红素对Na+ K+ ATPase活力有抑制作用。     

Essential fatty acid deficiency and predisposition to lung disease in cystic fibrosis

Essential fatty acid (EFA) deficiency is a predisposing factor for pulmonary infection with Staphylococcus aureus and Pseudomonas aeruginosa , the two major pathogenic microorganisms in cystic fibrosis (CF). Objective : The goal of this study was to investigate the essential fatty acid status of CF patients from infancy to 20 years old. Materials and methods. Plasma fatty acid profiles for phospholipid (PL) were determined for cord ( n = 6), 4 months ( n = 40), 16 months ( n = 25), 3 y ( n = 8), 5-10 y ( n = 10), and 10-20 y ( n = 10) aged CF patients and compared to their respective control; cord ( n = 22), 1-36 months ( n = 38) and adult ( n = 100). Significance was established by Student's t-test ( p < 0.05). Results : The plasma PL fatty acid profile for all CF patients, except cord, revealed consistent deficiency in ω3 and ω6 EFAs. These deficiencies were most marked at infancy and more pronounced for patients with meconium ileus. Conclusions and relevance : EFA deficiency may contribute to the predisposition of CF infants to develop respiratory disease and to the excess cytotoxic activity found in bronchoalveolar lavage fluid at 2 months of age in the majority of screened infants.     

Vitamin A deficiency and nocturnal vision in teenagers with cystic fibrosis

The aim of this study was to document plasma retinol status and nocturnal vision in ten eutrophic adolescents with cystic fibrosis (CF) receiving daily retinol supplementation. Plasma retinol, α and β carotenes and retinol binding protein were measured in ten clinically stable CF patients (mean age: 14.3 years; Shwachman score: 80–100). Nocturnal vision evaluation was performed with a Beyne optometer. Plasma retinol (mean 0.42 ± 0.16 mg/l), α carotene and β carotene levels were below the lower limit of normal in all but one patient. Five out of ten patients with normal standard opthalmological examination presented a poor (n=3 patients) or a pathological (n=2) dark adaptation test. These two patients showed a dramatic increase in nocturnal vision after 1 year of adapted retinol supplementation. Conclusion Low vitamin A levels occur frequently in clinically stable, eutrophic and retinol supplemented CF adolescents. Since vitamin A deficiency is asso-ciated with poor nocturnal vision and since this pattern can be reversed by adapted retinol supplementation, we recommend monitoring plasma vitamin A levels in CF patients and evaluation of dark adaptation in retinol deficient patients. Received: 6 December 1996 / Accepted in revised form: 18 June 1997     

Pseudo-Bartter's syndrome revealing cystic fibrosis in an infant caused by 3849 + 1G>A and 4382delA compound heterozygosity

Pseudo-Bartter's (PB) syndrome characterized by hypokalemic metabolic alkalosis and persistent failure to thrive constitutes a rare typical presentation of cystic fibrosis (CF) with prevalence of 16.8%. We present a case of CF presenting with failure to thrive, dehydration, PB syndrome associated with chest infection and primo-colonization with Pseudomonas aeruginosa. Sweat chloride test was 102 mmol/L. DNA analysis identified 2 mutations 3849 + 1G>A (intron 19) and 4382delA (exon 24) present in heterozygous status. To the best of our knowledge, our case is the first reported case in the literature of CF manifested by PB syndrome associated with chest infection and primo-colonization with Pseudomonas aeruginosa. CONCLUSION: The genotype 3849 + 1G>A/4382delA found in our patient is described for the first time in the literature. It explains the lung involvement with the dehydration and electrolyte disturbances. The role of the mutation in exon 24 in cases of CF with PB syndrome remains to be determined.     

The incidence and presentation of cystic fibrosis in Victoria 1955–1978

The minimum incidence of cystic fibrosis in Victoria, Australia over a 24 year period based on diagnosed cases was 1:2556 live births. There was no significant variation in incidence during the period.
The percentage of patients presenting with chest infection fell from 45% in the first 6 years of the study to 32% in the last 6 years and the percentage presenting with gastrointestinal symptoms rose from 19% in the first 6 years to 32% in the last 6 years. During the 24 year period 18% of patients presented with meconium ileus.     

Bronchial constriction after nebulized tobramycin preparations and saline in patients with cystic fibrosis

To asses the airway response to inhaled tobramycin we measured flow volume curves in 12 patients with cystic fibrosis. Immediately and/or 2 min after tobramycin inhalations there was a significant fall in lung function regardless of the concentration used; isotonic saline caused similar obstruction but not a complete cessation of peripheral air-flows. The baseline oxygen saturation was significantly correlated with the fall in lung function. Ten minutes after inhalation lung function tests returned to baseline values.CH-81-441313 CH-81-434014