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1.  Comparison of two modes of vitamin B12 supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: a cluster randomized controlled trial. a study protocol [ISRCTN 02694183] 
Nutrition Journal  2011;10:100.
Background
Older people have a high risk of vitamin B12 deficiency; this can lead to varying degrees of cognitive and neurological impairment. CBL deficiency may present as macrocytic anemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. Less is known about subclinical vitamin B12 deficiency and concurrent neuroconduction and cognitive impairment. A Programme of Complementary Feeding for the Older Population (PACAM) in Chile delivers 2 complementary fortified foods that provide approximately 1.4 μg/day of vitamin B12 (2.4 μg/day elderly RDA). The aim of the present study is to assess whether supplementation with vitamin B12 will improve neuroconduction and cognitive function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of clinical deficiency.
Methods
We designed a cluster double-blind placebo-controlled trial involving community dwelling people aged 70-79 living in Santiago, Chile. We randomized 15 clusters (health centers) involving 300 people (20 per cluster). Each cluster will be randomly assigned to one of three arms: a) a 1 mg vitamin B12 pill taken daily and a routine PACAM food; b) a placebo pill and the milk-PACAM food fortified to provide 1 mg of vitamin B12; c) the routine PACAM food and a placebo pill.
The study has been designed as an 18 month follow up period. The primary outcomes assessed at baseline, 4, 9 and 18 months will be: serum levels of vitamin B12, neuroconduction and cognitive function.
Conclusions
In view of the high prevalence of vitamin B12 deficiency in later life, the present study has potential public health interest because since it will measure the impact of the existing program of complementary feeding as compared to two options that provide higher vitamin B12 intakes that might potentially may contribute in preserving neurophysiologic and cognitive function and thus improve quality of life for older people in Chile.
Trial registration
ISRCTN: ISRCTN02694183
doi:10.1186/1475-2891-10-100
PMCID: PMC3195703  PMID: 21952034
cobalamin; vitamin B12; cyanocobalamin; elderly; neurophysiology; cognitive disorders; nerve conduction; cluster randomized controlled trial; public health; Chile
2.  Subnormal vitamin B12 concentrations and anaemia in older people: a systematic review 
BMC Geriatrics  2010;10:42.
Background
Pernicious anaemia is undeniably associated with vitamin B12 deficiency, but the association between subnormal vitamin B12 concentrations and anaemia in older people is unclear. The aim of this systematic review was to evaluate the association between subnormal vitamin B12 concentrations and anaemia in older people.
Methods
Clinical queries for aetiology and treatment in bibliographic databases (PubMed [01/1949-10/2009]; EMBASE [01/1980-10/2009]) were used. Reference lists were checked for additional relevant studies. Observational studies (≥50 participants) and randomized placebo-controlled intervention trials (RCTs) were considered.
Results
25 studies met the inclusion criteria. Twenty-one observational cross-sectional studies (total number of participants n = 16185) showed inconsistent results. In one longitudinal observational study, low vitamin B12 concentrations were not associated with an increased risk of anaemia (total n = 423). The 3 RCTs (total n = 210) were well-designed and showed no effect of vitamin B12 supplementation on haemoglobin concentrations during follow-up in subjects with subnormal vitamin B12 concentrations at the start of the study. Due to large clinical and methodological heterogeneity, statistical pooling of data was not performed.
Conclusions
Evidence of a positive association between a subnormal serum vitamin B12 concentration and anaemia in older people is limited and inconclusive. Further well-designed studies are needed to determine whether subnormal vitamin B12 is a risk factor for anaemia in older people.
doi:10.1186/1471-2318-10-42
PMCID: PMC2900261  PMID: 20573208
3.  The neuropsychiatry of megaloblastic anaemia. 
British Medical Journal  1980;281(6247):1036-1038.
The neuropsychiatric states of 50 patients with vitamin B12 deficiency and 34 patients with folate deficiency presenting with megaloblastosis in a general hospital were examined and compared. Abnormalities of the nervous system were found in two-thirds of both groups. Peripheral neuropathy was the most common condition associated with vitamin B12 deficiency and affective disorder with folate deficiency. The proportions of patients with organic mental change were similar in the two groups. Subacute combined degeneration of the cord was an uncommon complication and occurred only in the patients with vitamin B12 deficiency. There was no relation between haematological and neuropsychiatric abnormalities. The neuropsychiatry of megaloblastic anaemia seen in this study of patients presenting to haematologists or general physicians contrasts with that reported previously, before haematological techniques for separating the two deficiencies were introduced.
PMCID: PMC1714413  PMID: 6253016
4.  Vitamin D supplementation in older people (VDOP): Study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3 
Trials  2013;14:299.
The randomised, double blind intervention trial ‘Optimising Vitamin D Status in Older People’ (VDOP) will test the effect of three oral dosages of vitamin D given for one year on bone mineral density (BMD) and biochemical markers of vitamin D metabolism, bone turnover and safety in older people. VDOP is funded by Arthritis Research UK, supported through Newcastle University and MRC Human Nutrition Research and sponsored by the Newcastle upon Tyne Hospitals NHS Foundation Trust.a
Background
Vitamin D insufficiency is common in older people and may lead to secondary hyperparathyroidism, bone loss, impairment of muscle function and increased risk of falls and fractures. Vitamin D supplementation trials have yielded conflicting results with regard to decreasing rates of bone loss, falls and fractures and the optimal plasma concentration of 25 hydroxy vitamin D (25OHD) for skeletal health remains unclear.
Method/design
Older (≥70 years) community dwelling men and women are recruited through General Practices in Northern England and 375 participants are randomised to take 12,000 international units (IU), 24,000 IU or 48,000 IU of vitamin D3 orally each month for one year starting in the winter or early spring. Hip BMD and anthropometry are measured at baseline and 12 months. Fasting blood samples are collected at baseline and three-month intervals for the measurement of plasma 25OHD, parathyroid hormone (PTH), biochemical markers of bone turnover and biochemistry to assess the dose–response and safety of supplementation. Questionnaire data include falls, fractures, quality of life, adverse events and outcomes, compliance, dietary calcium intake and sunshine exposure.
Discussion
This is the first integrated vitamin D supplementation trial in older men and women using a range of doses given at monthly intervals to assess BMD, plasma 25OHD, PTH and biochemical markers of bone turnover and safety, quality of life and physical performance. We aim to investigate the vitamin D supplementation and plasma 25OHD concentration required to maintain bone health and to develop a set of biochemical markers that reflects the effect of vitamin D on bone. This will aid future studies investigating the effect of vitamin D supplementation on fracture risk.
#ISRCTN 35648481 (assigned 16 August 2012), EudraCT 2011-004890-10.
doi:10.1186/1745-6215-14-299
PMCID: PMC3848647  PMID: 24041337
Vitamin D supplementation trial; Bone mineral density; 25 hydroxy vitamin D; Parathyroid hormone; Bone markers; Older people
5.  Severe megaloblastic anaemia in an infant 
BMJ Case Reports  2011;2011:bcr0220113835.
Vitamin B12 or cobalamin deficiency, a rare clinical entity in pediatric age, is found most exclusively in breastfed infants, whose mothers are strictly vegetarian non-supplemented or with pernicious anaemia. In this article, the authors describe a 10-month-old infant admitted for vomiting, refusal to eat and prostration. The infant was exclusively breastfed and difficulties in introduction of new foods were reported. Failure to thrive since 5 months of age was also noticed. Laboratory evaluation revealed severe normocytic normochromic anaemia and cobalamin deficit. A diagnosis of α-thalassemia trait was also made. Maternal investigation showed autoimmune pernicious anaemia. This case shows the severity of vitamin B12 deficiency and the importance of adopting adequate and precocious measures in order to prevent potentially irreversible neurologic damage.
doi:10.1136/bcr.02.2011.3835
PMCID: PMC3097362  PMID: 22696751
6.  Platelet monoamine oxidase activity in megaloblastic anaemia. 
Journal of Clinical Pathology  1980;33(10):963-965.
Platelet monoamine oxidase activity has been measured in 17 patients with megaloblastic anaemia due to either vitamin B12 or folate deficiency, and in 20 healthy subjects. There was a highly significant increase in patients compared with controls. In two patients, platelet activity decreased following successful treatment. A significant correlation between platelet activity and the severity of bone marrow megaloblastic change, assessed by the deoxyuridine suppression test and bone marrow morphology, was also observed. If the change in activity also occurs in the nervous system, this may contribute to the mental disturbance associated with vitamin B12 or folate deficiency.
PMCID: PMC1146294  PMID: 7430361
7.  Effects of vitamin E supplementation during erythropoietin treatment of the anaemia of prematurity 
Aims: To evaluate the effects of vitamin E supplementation on haemoglobin concentration and the requirement for transfusion in premature infants treated with erythropoietin and iron.
Methods: Randomised, double blind, placebo controlled trial. Thirty infants ≤32 weeks gestation and ≤1250 g birth weight, who were defined as stable based on minimal requirements for respiratory support and phlebotomy, and absence of major congenital anomalies were enrolled. All were treated with erythropoietin and iron, and were randomised to receive, in addition, either vitamin E 50 IU/day or placebo for eight weeks or until discharge, whichever came first.
Results: Despite higher vitamin E (α-tocopherol) levels in the experimental group in weeks 3 (49.0 v 28.1 µmol/l) and 8 (66.2 v 38.5 µmol/l), there were no differences in haemoglobin, reticulocyte count, iron concentration, or transfusion requirement.
Conclusions: Oral vitamin E supplementation at 50 IU/day does not increase the response of preterm infants to erythropoietin and iron. Vitamin E obtained through standard nutrition may have been sufficient or higher doses may be required.
doi:10.1136/fn.88.4.F324
PMCID: PMC1721575  PMID: 12819167
8.  Immunoglobulin deficiency responding to vitamin B12 in two elderly patients with megaloblastic anaemia. 
Postgraduate Medical Journal  1985;61(722):1065-1066.
Two elderly patients with vitamin B12 deficiency were found to have low immunoglobulin levels. These returned to normal on treatment with vitamin B12.
PMCID: PMC2418537  PMID: 4095049
9.  Effects of Vitamin A Supplementation on Iron Status Indices and Iron Deficiency Anaemia: A Randomized Controlled Trial 
Nutrients  2013;6(1):190-206.
Iron deficiency anaemia (IDA) is the most common nutritional deficiency in the world including developed and developing countries. Despite intensive efforts to improve the quality of life of rural and aboriginal communities in Malaysia, anaemia and IDA are still major public health problems in these communities particularly among children. A randomized, double-blind, placebo-controlled trial was conducted on 250 Orang Asli (aboriginal) schoolchildren in Malaysia to investigate the effects of a single high-dose of vitamin A supplementation (200,000 IU) on iron status indices, anaemia and IDA status. The effect of the supplement was assessed after 3 months of receiving the supplements; after a complete 3-day deworming course of 400 mg/day of albendazole tablets. The prevalence of anaemia was found to be high: 48.5% (95% CI = 42.3, 54.8). Moreover, 34% (95% CI = 28.3, 40.2) of the children had IDA, which accounted for 70.1% of the anaemic cases. The findings showed that the reduction in serum ferritin level and the increments in haemoglobin, serum iron and transferrin saturation were found to be significant among children allocated to the vitamin A group compared to those allocated to the placebo group (p < 0.01). Moreover, a significant reduction in the prevalence of IDA by almost 22% than prevalence at baseline was reported among children in the vitamin A group compared with only 2.3% reduction among children in the placebo group. In conclusion, vitamin A supplementation showed a significant impact on iron status indices and IDA among Orang Asli children. Hence, providing vitamin A supplementation and imparting the knowledge related to nutritious food should be considered in the efforts to improve the nutritional and health status of these children as a part of efforts to improve the quality of life in rural and aboriginal communities.
doi:10.3390/nu6010190
PMCID: PMC3916855  PMID: 24384995
clinical trial; vitamin A supplementation; iron deficiency anaemia; children; Malaysia
10.  Acidosis and severe megaloblastic anaemia 
Journal of Clinical Pathology  1982;35(9):984-985.
Ten patients with severe megaloblastic anaemia were studied to investigate whether the causative metabolic defects might predispose them to lactic or other acidosis. One patient had compensated acidosis with hyperlactataemia before treatment but there were obvious causes other than anaemia. No other patient developed an acidosis. Neither anaemia per se nor the metabolic defects of vitamin B12 or folic acid deficiency are likely to cause clinically significant lactic acidosis or hyperlactataemia.
PMCID: PMC497849  PMID: 7119130
11.  The direct antiglobulin (Coombs) test in megaloblastic anaemia 
Journal of Clinical Pathology  1965;18(1):119-120.
Folic acid deficiency with the picture of a megaloblastic bone marrow may develop in haemolytic anaemia, and, on the other hand, both vitamin B12 and folic acid deficiency may produce signs of haemolysis. As the correct interpretation of a positive antiglobulin reaction associated with megaloblastic erythropoiesis is particularly important, the effect of deficiency of vitamin B12 and folic acid on the results of the test was investigated in 32 patients with vitamin B12 or folic acid deficiency and a positive antiglobulin reaction was obtained in ten. There was no correlation between the result of the test and the degree of anaemia, and there was no significant difference between the incidence of positive results associated with deficiency of vitamin B12 or folic acid. In determining the significance of a positive result, the time interval before agglutination occurs is sometimes of greater value than the strength of the reaction or the result of the gamma globulin neutralization test.
PMCID: PMC472844  PMID: 14247693
12.  Effectiveness of the National Program of Complementary Feeding for older adults in Chile on vitamin B12 status in older adults; secondary outcome analysis from the CENEX Study (ISRCTN48153354) 
Nutrition Journal  2013;12:124.
Background
Older people are at increased risk of vitamin B12 deficiency and the provision of fortified foods may be an effective way to ensure good vitamin B12 status in later life.
Aim
To evaluate the effectiveness of a vitamin B12 fortified food provided by a national program of complementary food for older people on plasma vitamin B12 levels.
Subjects and methods
A random sub-sample of 351 subjects aged 65-67y from a large cluster randomised controlled trial provided blood samples at baseline and after 24 months of intervention. The intervention arm (10 clusters 186 participants) received a vitamin B12 fortified food designed to deliver 1.4 μg/day, while the control arm did not receive complementary food (10 clusters, 165 participants). Serum vitamin B12 and folate levels determined by radioimmunoassay were used to estimate the effect of intervention on vitamin B12 levels, adjusting for baseline levels and sex.
Results
Attrition at 24 months was 16.7% and 23.6% in the intervention and control arms respectively (p = 0.07). Over 24 months of intervention, mean (95% CI) serum vitamin B12 decreased from 392 (359–425) pmol/dL to 357 (300–414) pmol/dL (p < 0.07) in the intervention arm and from 395 (350–440) pmol/dL to 351 (308–395) pmol/dL in the control arm. There was no significant effect of the intervention on folate status.
Discussion
Our findings suggest that foods fortified with 1.4 μg/daily vitamin B12 as provided by Chile’s national programme for older people are insufficient to ensure adequate vitamin B12 levels in this population. Chile has a long and successful experience with nutrition intervention programs; however, the country’s changing demographic and nutritional profiles require a constant adjustment of the programs.
doi:10.1186/1475-2891-12-124
PMCID: PMC3848755  PMID: 24016218
Older people; Fortified foods; Nutrition programme; Vitamin B12
13.  Does Early Treatment Prevent Deafness in Thiamine-Responsive Megaloblastic Anaemia Syndrome? 
Thiamine-responsive megaloblastic anaemia (TRMA; OMIM 249270) syndrome is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anaemia, and sensorineural deafness. Progressive hearing loss is one of the cardinal findings of the syndrome and is known to be irreversible. Whether the deafness in TRMA syndrome can be prevented is not yet known. Here, we report a four-month-old female infant diagnosed with TRMA syndrome at an early age. There was no hearing loss at the time of diagnosis. The patient’s initial auditory evoked brainstem response measurements were normal. Although she was given thiamine supplementation regularly following the diagnosis, the patient developed moderate sensorineural hearing loss at 20 months of age, indicating that early diagnosis and treatment with oral thiamine (100 mg/day) could not prevent deafness in TRMA syndrome. It would be premature to draw general conclusions from one case, but we believe that further patient-based observations can shed light on the pathophysiology of this rare syndrome as well as prediction of its prognosis.
Conflict of interest:None declared.
doi:10.4274/jcrpe.v3i1.08
PMCID: PMC3065315  PMID: 21448333
Thiamine-responsive megaloblastic anaemia; Diabetes; deafness
14.  Pigmentation in Megaloblastic Anaemia Associated with Pregnancy and Lactation 
British Medical Journal  1969;2(5659):737-739.
Generalized skin pigmentation in five African women with megaloblastic anaemia in the postnatal period was associated with low serum folate levels, as distinct from vitamin B12 deficiency. It is suggested that the occurrence of pigmentation in both folate and vitamin B12 deficiency may reflect a common abnormality of metabolism.
Images
PMCID: PMC1983534  PMID: 5795778
15.  Improving Mobility and Reducing Disability in Older People Through Early High-Dose Vitamin D Replacement Following Hip Fracture: A Protocol for a Randomized Controlled Trial and Economic Evaluation 
Hypovitaminosis D is particularly common among older people with a proximal femoral (hip) fracture and has been linked with poorer lower extremity functioning, falls, and fractures. There is evidence that disability severity and fall rates may be reduced by adequate vitamin D replacement. However, the ideal regimen for vitamin D administration to have these benefits in older people who have been in the hospital has not been established. This randomized controlled trial will investigate the effects of an oral vitamin D loading dose with maintenance oral vitamin D and calcium on lower extremity function (gait velocity), correction of hypovitaminosis D, falls, and fractures among older people after hip fracture surgery. The cost-effectiveness of the REVITAHIP program from the health and community service provider’s perspective will also be established, as will predictors of adherence with the treatment. A total of 450 older people who have recently had a hip fracture requiring surgical intervention will be screened to achieve 250 participants for the study. Participants will have no medical contraindications to vitamin D replacement. The primary outcome measure will be mobility-related disability as measured with the 2.4-m gait velocity test. Secondary measures will be 25-hydroxyvitamin D (25-OHD) levels at 2, 4, and 26 weeks, number of falls and fractures, and additional measures of mobility, disability, quality of life, health system and community–service contact, adherence to the intervention, and adverse events. After surgical fixation and being deemed medically stable, participants will be randomly allocated to an intervention or placebo-control group. Participants of the intervention group will receive initial oral 250 000 IU (5 × 50 000 IU) vitamin D3 tablets. Both groups will receive oral maintenance vitamin D3 and calcium and will follow the usual hip fracture rehabilitation pathway. The study will determine the impact of a vitamin D loading dose on mobility-related disability in older people following hip fracture and will discuss the efficacy and cost-effectiveness of a loading dose vitamin D replacement more generally. The results will have direct implications for future use of vitamin D therapy for this high-risk group.
doi:10.1177/2151458511406723
PMCID: PMC3597307  PMID: 23569677
fragility fractures; geriatric medicine; hospitalist; metabolic bone disorders; osteoporosis; physical medicine and rehabilitation; trauma surgery
16.  Vitamin K in hand osteoarthritis: results from a randomised clinical trial 
Annals of the rheumatic diseases  2008;67(11):1570-1573.
Objectives:
Vitamin K has bone and cartilage effects, and previously shown to be associated with radiographic osteoarthritis. We evaluated vitamin K's effect on hand osteoarthritis in a randomised controlled trial.
Methods:
This was an ancillary study to a randomised controlled trial assessing the effects of phylloquinone supplementation (vitamin K arm) versus placebo on bone loss and vascular calcification among older adults regardless of their vitamin K status. At the final 3-year study visit, we assessed the effects of vitamin K versus placebo on hand x-ray features of osteoarthritis using logistic regression and intention to treat, and also restricted analysis to the subgroup that had insufficient vitamin K concentrations at baseline.
Results:
This ancillary study had 378 participants (193 in vitamin K arm, 185 in placebo arm). There were no effects of randomisation to vitamin K for radiographic osteoarthritis outcomes. Those with insufficient vitamin K at baseline who attained sufficient concentrations at follow-up had trends towards 47% less joint space narrowing (p = 0.02).
Conclusions:
There was no overall effect of vitamin K on radiographic hand osteoarthritis. Subjects that were insufficient in vitamin K at baseline who attained sufficient concentrations at follow-up may have had a benefit in joint space narrowing. A clinical trial in those who are vitamin K insufficient may be warranted.
Trial registration number:
NCT00183001.
doi:10.1136/ard.2008.094771
PMCID: PMC2584352  PMID: 18625626
17.  THE ABSORPTION OF VITAMIN B12 IN MEGALOBLASTIC ANAEMIA ASSOCIATED WITH PREGNANCY 
Journal of Clinical Pathology  1960;13(5):394-395.
The absorption of 60CoB12 has been studied in a group of patients suffering from megaloblastic anaemia associated with pregnancy and in a control group.
The mean urinary excretion of 60CoB12 in the patients with megaloblastic anaemia is not significantly different from that of the control group. Five of the 30 patients showed a value towards the lower limit of normal, but the serum vitamin B12 content in this group was within the normal range.
Malabsorption of vitamin B12 does not appear to play a significant role in the pathogenesis of this form of megaloblastic anaemia.
PMCID: PMC480109  PMID: 13769903
18.  Plasma lactate dehydrogenase in megaloblastic anaemia 
Journal of Clinical Pathology  1966;19(1):51-54.
Raised plasma lactate dehydrogenase (LDH) values were found in 26 patients with marked megaloblastic anaemia due either to vitamin B12 or folic-acid deficiency or a combination of these factors.
Minor megaloblastic changes were not usually accompanied by plasma LDH elevation. Serial LDH estimations were as valuable as serial reticulocyte counts in assessing the response to physiological doses of folic acid and therefore in deciding whether megaloblastic anaemia is partially or completely due to folic acid deficiency.
PMCID: PMC473158  PMID: 5904983
19.  AMINOACIDURIA AND MEGALOBLASTIC ANAEMIA 
Journal of Clinical Pathology  1960;13(3):230-231.
Urinary amino-acid chromatograms from 23 patients with megaloblastic anaemia have been studied before and after therapy. The most consistent abnormality was an increased taurine or increased taurine/glycine ratio. This was not related directly to deficiency of vitamin B12 or folic acid or to the degree of anaemia.
PMCID: PMC480056  PMID: 13824214
20.  Minimal criteria for the diagnosis of megaloblastic anaemia of pregnancy 
Journal of Clinical Pathology  1961;14(5):536-539.
The routine examination of buffy coat films is a valuable diagnostic aid to screening large numbers of specimens of blood and is applicable to hospital and general practice, provided that a bottle of sequestrinated venous blood can be examined in the laboratory within 24 hours.
The diagnosis of folic-acid deficiency anaemia of pregnancy can be made, in many cases, before the appearance of megaloblasts in the peripheral blood by finding macrocytes, polylobing of polymorphonuclear leucocytes, and `out of step' haemoglobinization of normoblasts in the buffy coat film.
Accurate haemoglobin estimations at intervals throughout pregnancy, and particularly in the last three months, are an important and in some cases essential part of ante-natal care. Any haemoglobin found to be below 75% (11·1 g.%) should be followed by the examination of a series of buffy coat films while the anaemia is being treated.
PMCID: PMC480280  PMID: 14490286
21.  Prevention of falls and fractures in old people by administration of calcium and vitamin d. randomized clinical trial 
BMC Public Health  2011;11:910.
Background
There are many studies that associate vitamin D serum levels in older persons with muscle strength, physical performance and risk of fractures and falls. However, current evidence is insufficient to make a general recommendation for administrating calcium and vitamin D to older persons. The objective of this study is to determine the effectiveness of calcium and vitamin D supplementation in improving musculoskeletal function and decreasing the number of falls in person aged over 65 years.
Methods/Design
Phase III, randomized, double blind, placebo-controlled trial to evaluate the efficacy of already marketed drugs in a new indication. It will be performed at Primary Care doctor visits at several Healthcare Centers in different Spanish Health Areas. A total of 704 non-institutionalized subjects aged 65 years or older will be studied (sample size calculated for a statistical power of 80%, alpha error 0.05, annual incidence of falls 30% and expected reduction of 30% to 20% and expected loss to follow up of 20%). The test drug containing 800 IU of vitamin D and 1000 mg of calcium will be administered daily. The control group will receive a placebo. The subjects will be followed up over two years. The primary variable will be the incidence of spontaneous falls. The secondary variables will include: consequences of the falls (fractures, need for hospitalization), change in calcidiol plasma levels and other analytical determinations (transaminases, PTH, calcium/phosphorous, albumin, creatinine, etc.), change in bone mass by densitometry, change in muscle strength in the dominant hand and change in musculoskeletal strength, risk factors for falls, treatment compliance, adverse effects and socio-demographic data.
Discussion
The following principles have been considered in the development of this Project: the product data are sufficient to ensure that the risks assumed by the study participants are acceptable, the study objectives will probably provide further knowledge on the problem studied and the available information justifies the performance of the study and its possible risk for the participants.
If calcium and vitamin D supplementation is effective in the prevention of falls and fractures in the elderly population, a recommendation may be issued with the aim of preventing some of the consequences of falls that affect quality of life and the ensuing personal, health and social costs.
Trial Registration
ClinicalTrials.gov: NCT01452243
Clinical trial authorized by the Spanish Medicines Agency: EudraCT number 2006-001643-63.
doi:10.1186/1471-2458-11-910
PMCID: PMC3267804  PMID: 22151975
22.  Effect of abnormal liver function on vitamin E status and supplementation in adults with cystic fibrosis. 
Gut  1986;27(6):714-718.
Patients with cystic fibrosis tend to have reduced serum concentrations of vitamin E and are therefore at risk of developing the neurological complications associated with vitamin E deficiency. Improved survival in cystic fibrosis has resulted in an increasing number of older patients who may develop hepatobiliary complications which may further impair the absorption of vitamin E. In this study the vitamin E status and results of supplementation with oral vitamin E were compared in adult patients with and without evidence of liver involvement as assessed by routine liver function tests. The serum vitamin E concentrations were reduced below normal in 24 of 25 patients. The mean serum vitamin E concentration was significantly lower (p less than 0.05) in those patients with abnormal liver function. When vitamin E status was assessed as the serum vitamin E/cholesterol ratio, however, there was no significant difference between those patients with normal and abnormal liver function. After supplementation with oral vitamin E, either 10 mg/kg/day for one month or 200 mg/day (equivalent to 3.4 to 4.4 mg/kg/day) for up to three months, there was no significant difference in the vitamin E status between the two groups. The results of this study indicate that in general, patients with cystic fibrosis and abnormal liver function do not require increased supplements of vitamin E compared with those with normal liver function.
PMCID: PMC1433330  PMID: 3721295
23.  Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial 
Nutrition Journal  2007;6:10.
Background
Observational studies have frequently reported an association between cognitive function and nutrition in later life but randomised trials of B vitamins and antioxidant supplements have mostly found no beneficial effect. We examined the effect of daily supplementation with 11 vitamins and 5 minerals on cognitive function in older adults to assess the possibility that this could help to prevent cognitive decline.
Methods
The study was carried out as part of a randomised double blind placebo controlled trial of micronutrient supplementation based in six primary care health centres in North East Scotland. 910 men and women aged 65 years and over living in the community were recruited and randomised: 456 to active treatment and 454 to placebo. The active treatment consisted of a single tablet containing eleven vitamins and five minerals in amounts ranging from 50–210 % of the UK Reference Nutrient Intake or matching placebo tablet taken daily for 12 months. Digit span forward and verbal fluency tests, which assess immediate memory and executive functioning respectively, were conducted at the start and end of the intervention period. Risk of micronutrient deficiency at baseline was assessed by a simple risk questionnaire.
Results
For digit span forward there was no evidence of an effect of supplements in all participants or in sub-groups defined by age or risk of deficiency. For verbal fluency there was no evidence of a beneficial effect in the whole study population but there was weak evidence for a beneficial effect of supplementation in the two pre-specified subgroups: in those aged 75 years and over (n 290; mean difference between supplemented and placebo groups 2.8 (95% CI -0.6, 6.2) units) and in those at increased risk of micronutrient deficiency assessed by the risk questionnaire (n 260; mean difference between supplemented and placebo groups 2.5 (95% CI -1.0, 6.1) units).
Conclusion
The results provide no evidence for a beneficial effect of daily multivitamin and multimineral supplements on these domains of cognitive function in community-living people over 65 years. However, the possibility of beneficial effects in older people and those at greater risk of nutritional deficiency deserves further attention.
doi:10.1186/1475-2891-6-10
PMCID: PMC1872030  PMID: 17474991
24.  The impact of iron supplementation efficiency in female blood donors with a decreased ferritin level and no anaemia. Rationale and design of a randomised controlled trial: a study protocol 
Trials  2009;10:4.
Background
There is no recommendation to screen ferritin level in blood donors, even though several studies have noted the high prevalence of iron deficiency after blood donation, particularly among menstruating females. Furthermore, some clinical trials have shown that non-anaemic women with unexplained fatigue may benefit from iron supplementation. Our objective is to determine the clinical effect of iron supplementation on fatigue in female blood donors without anaemia, but with a mean serum ferritin ≤ 30 ng/ml.
Methods/Design
In a double blind randomised controlled trial, we will measure blood count and ferritin level of women under age 50 yr, who donate blood to the University Hospital of Lausanne Blood Transfusion Department, at the time of the donation and after 1 week. One hundred and forty donors with a ferritin level ≤ 30 ng/ml and haemoglobin level ≥ 120 g/l (non-anaemic) a week after the donation will be included in the study and randomised. A one-month course of oral ferrous sulphate (80 mg/day of elemental iron) will be introduced vs. placebo. Self-reported fatigue will be measured using a visual analogue scale. Secondary outcomes are: score of fatigue (Fatigue Severity Scale), maximal aerobic power (Chester Step Test), quality of life (SF-12), and mood disorders (Prime-MD). Haemoglobin and ferritin concentration will be monitored before and after the intervention.
Discussion
Iron deficiency is a potential problem for all blood donors, especially menstruating women. To our knowledge, no other intervention study has yet evaluated the impact of iron supplementation on subjective symptoms after a blood donation.
Trial registration
NCT00689793
doi:10.1186/1745-6215-10-4
PMCID: PMC2637271  PMID: 19149890
25.  A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I 
Journal of Medical Genetics  2000;37(9):669-673.
The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.


Keywords: TRMA syndrome; SLC19A2 gene; complex I deficiency
doi:10.1136/jmg.37.9.669
PMCID: PMC1734685  PMID: 10978358

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