Folate-deficient human lymphoblasts: changes in deoxynucleotide metabolism and thymidylate cycle activities

Peripheral blood lymphocytes of healthy volunteers cultured with phytohaemagglutinin in folate-deficient medium exhibit megaloblastic maturation with reduced intracellular folate content. We have employed this in vitro model for megaloblastic maturation to determine accompanying changes in cellular thymidylate cycle activities and deoxynucleotide levels. Folate-deficient cells exhibit a two-fold increase in thymidine kinase and thymidylate synthase activities. These increased activities were reduced to those of folate-replete cells by co-culture of folate-deficient cells with thymidine. Folate deficiency was accompanied by reduced cellular levels of thymidine triphosphate (TTP) and deoxyguanosine triphosphate (dGTP). Exogenous deoxyuridine produced no increase in the reduced levels of TTP of folate-deficient cells but effected a two-fold increase in cellular deoxycytidine triphosphate. Exogenous thymidine increased the reduced TTP levels of folate-deficient cells and corrected the reduced dGTP level; the increase in cellular TTP accompanying exogenous thymidine was more pronounced in folate-deficient cells. These in vitro findings are compatible with a block in de novo thymidylate synthesis and explain in part the reported in vivo changes for the deoxynucleotide pool in megaloblastic marrow cells due to folate or vitamin B12 deficiency.     

Age-related differences in care receipt and symptom experience of elderly cancer patients dying at home: Lessons from the DEATH project

Background:   Data on the differences between older and younger elderly cancer patients dying at home is sparse. To clarify age-related differences in symptom experience and care receipt of elderly cancer patients at end-of-life, we conducted a subanalysis study of the Dying Elderly at Home (DEATH) project, a multicenter study of 240 elderly aged 65 and older dying at home.
Methods:   We assessed the frequency of symptom experience and end-of-life care receipt in home elderly patients during the last 2 days of their lives and evaluated the differences between younger elderly (aged 65–74) and older elderly (aged 75+) cancer decedents. The general practitioners were asked to fill out a questionnaire immediately after the death of study patients. A total of 66 younger and 51 older elderly cancer decedents were included in the analysis.
Results:   Coma and dementia were common among younger and older elderly patients. Older decedents were less likely to experience anxiety, but, after adjustment for baseline characteristics, this age-related difference did not clearly appear. Older decedents were also less likely to receive opioids than younger decedents. There were no significant differences in volume of i.v. hydration between the two groups.
Conclusions:   Our results suggested that there were no differences in symptom experience and care receipt among older and younger decedents, except in opioid use, at end-of-life. These findings imply a similar need of end-of-life care for younger and older elderly cancer patients who opt for home death.     

Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation

Objective: Microsatellite instability (MSI) detected in non-neoplastic mucosa of patients with ulcerative colitis has been ascribed to an excess of DNA damage associated with chronic inflammation. Folate deficiency, commonly found in patients with long-standing disease, could further contribute to this defect because folate is essential for DNA replication and repair. We evaluated MSI in the colonic mucosa of 26 patients with ulcerative colitis for  >10 yr  and 10 patients with Crohn's colitis and correlated MSI with folate status.
Methods: DNA was amplified using primers directed at nine different loci. Folate concentrations in serum, whole blood, and colonic mucosa were determined using the Lactobacillus casei assay.
Results: MSI was found in 3/23 patients (13%) with ulcerative colitis and in none of the patients with Crohn's colitis. All three patients with MSI had inactive histological disease, whereas all patients with active disease were negative for MSI (   p = 0.08  ). Serum, whole blood, and colonic concentrations of folate were 30–50% lower in patients with MSI (   p > 0.05  ), and folate supplements had been administered less frequently during the past 5-yr (   p = 0.06  ). One of the patients with MSI was randomized to receive folate 5 mg/d for 6 months, and a clear change in MSI pattern was observed in three of six markers.
Conclusions: A defect in DNA repair associated with a low folate status may be one additional cause for patients with ulcerative colitis exhibiting MSI in non-neoplastic mucosa.     

Reversible Dementia and Neuropathy Associated with Folate Deficiency 16 Years After Partial Gastrectomy

A 57-year-old woman developed dementia and peripheral neuropathy 16 years after a partial gastrectomy (Billroth II). Serum cobalamin was 198 pmol/l (reference interval 150–550), and the vitamin B₁₂ absorption test (Schilling) showed decreased absorption (1.7% without and 2.2% with intrinsic factor). In spite of 20 months' therapy with vitamin B₁₂, the neurological symptoms progressed. Folate deficiency was suggested by a very low erythrocyte folate and a slightly abnormal FIGLU test. There were no other signs of general malabsorption. A few months' treatment with folic acid significantly improved the massive neurological manifestations which were verified neurophysiologically as well as histologically. A common role of vitamin B₁₂ and folate in the development of neuropathy is suggested.     

An analysis of the outcomes of treatment of small cell lung cancer in the elderly

Abstract Background: Many cases of small cell lung cancer will occur in the elderly population but optimal management of the disease in this age group remains uncertain.
Aims: To evaluate treatment of small cell lung cancer in the elderly in Australia and to compare treatment received and outcomes with those of younger patients. To draw insights from these observations into the optimal management of small cell lung cancer in the elderly.
Methods: A retrospective review of treatment charts and case notes for 51 elderly patients and 102 younger patients was undertaken.
Results: Elderly patients had similar baseline parameters with respect to disease stage and performance status. Elderly patients were mostly treated uniformly with combination chemotherapy, but suffered more dose reductions than younger patients. Benefits of chemotherapy were seen even in patients with poor performance status. Despite the dose reductions, response rates and survival times for elderly patients were usually similar to younger patients.
Conclusions: Combination chemotherapy is beneficial to elderly patients with small cell lung cancer. Optimal therapy for the elderly may be different from that for younger patients and should be defined through prospective randomised clinical trials.     

Folate, Vitamin B12, Homocysteine, and Depressive Symptoms in a Population Sample of Older Chinese Adults

OBJECTIVES: To investigate the independent associations between folate, B12, and homocysteine levels and depressive symptoms in older adults.
DESIGN: Cross-sectional study.
SETTING: Resident population in southeast Singapore.
PARTICIPANTS: Six hundred sixty-nine community-living noninstitutionalized Chinese adults aged 55 and older.
MEASUREMENTS: Laboratory values of folate, vitamin B12, and homocysteine were examined for their independent relationships with depressive symptoms (Geriatric Depression Scale (GDS) score ≥5).
RESULTS: Respondents with depression (n=178) had lower mean serum folate concentrations (21.5 nmol/L) than those without (n=491, 24.0 nmol/L, P =.04). There was a linear relationship between descending quartiles of folate concentrations and increasing odds of association with depressive symptoms, independent of other risk factors (demographic, psychosocial, alcohol and smoking, chronic morbidity, functional status, nutritional risk, albumin, anemia, depression-inducing medications, use of antidepressants and vitamin supplements), including B12 and homocysteine ( P for trend=.02). The odds ratio (OR) of association between low folate (lowest quartile: <14.6 nmol/L) and depressive symptoms independent of other risk factors, including homocysteine and B12, was 1.72 (95% confidence interval (CI)=1.11–2.66). Vitamin B12 across a range of values did not show a linear association, but B12 deficiency (<180 pmol/L) appeared to be significantly associated with depressive symptoms (OR=2.68, 95% CI=1.20–6.00), independent of folate and homocysteine.
CONCLUSION: Decreasing and low levels of serum folate and deficient levels of B12 were associated with greater risk of depressive symptoms in older Chinese adults.     

Different changes of bone mineral density and nutritional status after hospitalization between vascular dementia and Alzheimer's disease in elderly female patients

Background:   Bone fractures strongly influence morbidity and mortality in elderly patients with dementia. The goal of this study was to examine whether difference in the type of dementia affects changes of bone mineral density (BMD) during hospitalization with rehabilitation programs.
Methods:   Ninety-four Japanese elderly female patients were enrolled. BMD, Mini-Mental State Examination (MMSE) scores, and levels of serum albumin, calcium-related factors and urinary calcium excretion were measured.
Results:   Multivariable analyses indicated that serum albumin levels and MMSE scores were positively correlated with changes in BMD after 2 years hospitalization. Significant reduction of BMD levels after hospitalization were observed in patients with severe dementia (MMSE scores, <10) or with severe malnutrition (serum albumin, <2.0). We next classified our subjects into three groups according to the 4th edn of the Diagnostic and Statistical Manual criteria: non-dementia (ND), Alzheimer's disease (AD) and vascular dementia (VaD). Although there were no significant differences in age and physical activities among the groups; the levels of BMD were maintained in AD as well as ND but not in VaD. Notably, calcium excretion levels were significantly decreased after hospitalization in AD as well as ND but not in VaD. Serum 25(OH)D levels were also restored in AD but not in VaD. In addition, the nutritional status significantly improved in AD but not in VaD.
Conclusion:   The levels of BMD were maintained and the nutritional status was improved in AD but not in VaD for 2 years hospitalization with rehabilitation programs. These results suggest that different programs including nutritional support may be necessary for maintaining BMD levels in VaD as compared with AD during hospitalization.     

Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study

Abstract. Hooshmand B, Solomon A, Kåreholt I, Rusanen M, Hänninen T, Leiviskä J, Winblad B, Laatikainen T, Soininen H & Kivipelto M (Aging Research Center, Karolinska Institutet, Stockholm, Sweden; KI Alzheimer’s Disease Research Center (KI‐ADRC), Karolinska Institutet, Stockholm, Sweden; National Institute for Health and Welfare (THL), Helsinki, Finland; University of Eastern Finland, Institute of Clinical Medicine, and University Hospital, Kuopio, Finland). Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 2012; 271 : 204–212. Objectives. To examine the associations between serum homocysteine (tHcy), holotranscobalamin (holoTC, the biologically active fraction of vitamin B12) and folate and cognitive functioning in a longitudinal population‐based study of Finnish elderly subjects. Subjects and design. tHcy, holoTC and folate were measured at baseline in 274 dementia‐free subjects aged 65–79 years from the Cardiovascular Risk Factors, Aging and Dementia study. Subjects were re‐examined 7 years later, and global cognition, episodic memory, executive functioning, verbal expression and psychomotor speed were assessed. Results. Higher baseline tHcy levels were associated with poorer performance in global cognition, relative difference: 0.90 [95% confidence interval (CI) 0.81–0.99]; episodic memory: 0.87 (95% CI 0.77–0.99); executive functions: 0.86 (95% CI 0.75–0.98); and verbal expression: 0.89 (95% CI 0.81–0.97) at follow‐up. Increased holoTC levels were related to better performance on global cognition: 1.09 (95% CI 1.00–1.19); executive functions: 1.11 (95% CI 1.01–1.21); and psychomotor speed: 1.13 (95% CI 1.01–1.26). After excluding 20 cases of incident dementia, increased tHcy remained associated with poorer performance in episodic memory, execution functions and verbal expression. Higher holoTC levels tended to be related to better performance in executive functions and psychomotor speed, while elevated serum folate concentrations were significantly related to higher scores in global cognition and verbal expression tests. Conclusions. tHcy, holoTC and folate levels are related to cognitive performance 7 years later even in nondemented elderly subjects. Randomized trials are needed to determine the impact of vitamin B12 and folate supplementation on preventing cognitive decline in the elderly.     

Association between cholesterols, homocysteine and silent brain infarcts

Background:  The aim of this study was to assess the relationship between total plasma homocysteine, cholesterol levels, vitamin B₁₂, folate, thyroid hormones, urea, ferritin, uric acid, C-reactive protein, cardiovascular risk factors and silent brain infarct (SBI) in patients without any neurological disorder. Whether the factors of interest were associated with SBI is investigated.
Methods:  One hundred and forty-two subjects with a mean age of 52.1 ± 13.1 years (21–87 years) without any history of stroke, transient ischaemic attack and neurological abnormality were enrolled in this cross-sectional study. The subjects underwent brain magnetic resonance imaging and blood chemistry determinations. Student's t -test was used to compare differences in means of laboratory results between the groups with and without SBI. The χ²-test was used for categorized variables. Multiple logistic regression analysis was used to determine the independent predictors of SBI.
Results:  The group comprised 56 men and 86 women. SBI were found in 40 patients (28%). The low-density lipoprotein levels were significantly higher in the infarct group ( P  = 0.019), homocysteine concentrations were significantly higher in the men-infarct group ( P  = 0,029) and total cholesterol levels were significantly higher in the women-infarct group than the women non-infarct group ( P  = 0.006).
Conclusion:  Serum low-density lipoprotein, total cholesterol and homocysteine levels were associated with SBI.     

血浆同型半胱氨酸水平与帕金森病相关研究

目的探讨血浆同型半胱氨酸（homocysteine,Hcy）水平与帕金森病（Parkinson＇s disease,PD）之间的相关性,观察B族维生素、恩他卡朋治疗左旋多巴诱导的高同型半胱氨酸血症的疗效。方法选择年龄及性别基本匹配的PD病例90例（未治疗的病例15例、非左旋多巴治疗的病例21例、左旋多巴治疗的病例54例）。体检健康老年人90例。检测PD患者、健康老年人的血浆同型半胱氨酸、维生素B12和叶酸水平。将左旋多巴治疗的PD病例采用随机数字表法随机分为3组,分别给予口服安慰剂、B族维生素（维生素B12 1 mg/d、叶酸500 ug/d）和恩他卡朋200 mg/d,检测三组用药前后的血浆Hcy水平。结果各组血浆Hcy水平差异有统计学意义（F=25.580,P=0.001）。PD患者血浆Hcy水平高于健康老年人组（P〈0.05）。左旋多巴治疗PD组血浆Hcy水平高于未治疗PD组和非左旋多巴胺治疗PD组（P〈0.05）。PD组叶酸水平低于健康老年人组（P〈0.05）。维生素B12、叶酸和恩他卡朋均能使左旋多巴治疗的PD患者血浆Hcy水平下降（P〈0.05）。相关分析显示,PD患者血浆Hcy水平与叶酸水平呈负相关（r=-0.425,P=0.000）。结论高同型半胱氨酸血症可能是帕金森病的危险因素之一,并与缺乏B族维生素和使用左旋多巴治疗有一定的联系。B族维生素、恩他卡朋可能降低左旋多巴引起的高同型半胱氨酸血症。     

Alogliptin Use in Elderly People: A Pooled Analysis from Phase 2 and 3 Studies

OBJECTIVES: To compare the efficacy and safety of alogliptin, a dipeptidyl peptidase-4 (DPP-4) enzyme inhibitor, in elderly (≥65) and younger (<65) patients with type 2 diabetes mellitus.
DESIGN: Pooled analysis of six randomized, double-blind, placebo-controlled studies of alogliptin.
PARTICIPANTS: Patients aged 18 to 80 with type 2 diabetes mellitus and inadequate glycemic control.
INTERVENTIONS: Elderly (mean age 70.0; n=455) and younger (mean age 51.8; n=1,911) patients received alogliptin 12.5 mg (n=922), alogliptin 25 mg (n=910), or placebo (n=534) for 26 weeks (12 weeks in a Phase 2 study). The studies evaluated alogliptin as monotherapy and coadministered with pioglitazone, glyburide, metformin, or insulin.
MEASUREMENTS: Efficacy endpoints included change from baseline in glycosylated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, and lipid values. Safety variables included hypoglycemic events, adverse events, and blood pressure.
RESULTS: Least-squares mean HbA1c decreased from baseline by 0.7% and 0.8% in elderly patients receiving alogliptin 12.5 and 25 mg, respectively, and 0.5% and 0.6%, respectively, in younger patients ( P <.001 for both alogliptin doses vs placebo for both age groups P =.70 for 12.5 mg and .68 for 25 mg for differences between age groups). Results were similar for FPG. Incidence of hypoglycemia was 8.3% or less in all alogliptin groups (≤10.5% for placebo), with no apparent difference between elderly and younger patients. Changes in weight were negligible in all treatment groups in both age categories. The safety profiles of alogliptin were similar in the age and dose groups.
CONCLUSION: Alogliptin was effective and well tolerated in the elderly patients enrolled in these studies. Improvements in HbA1c were similar to those seen in younger patients, and no increase in the risk of hypoglycemia, weight gain, or other adverse events was apparent in elderly patients.     

Exercise: a potential contributing factor to the relationship between folate and dementia

OBJECTIVES: To investigate whether exercise confounds the relationship between folate and cerebrovascular events, all-cause dementia, and Alzheimer's disease. DESIGN: Prospective cohort study. SETTING: Multiple centers in Canada. PARTICIPANTS: In the Canadian Study of Health and Aging, 466 people reported exercise levels, had folate measurements, and were not demented at baseline. After 5 years, 194 had adverse cerebrovascular events, and 65 had dementia (Alzheimer's disease in 47). MEASUREMENTS: Associations between folate and cerebrovascular outcomes were examined using logistic regression in the presence and absence of exercise and other confounders. RESULTS: Folate was associated with greater risk of Alzheimer's disease (odds ratio (OR)=2.12, 95% confidence interval (CI)=1.01-4.54) and cerebrovascular outcomes (OR=2.05, 95% CI=1.11-3.78) in adjusted analyses before the inclusion of exercise and neared significance with all-cause dementia (OR=1.80, 95% CI=0.94-3.45). After the inclusion of exercise, the association between folate and dementia and Alzheimer's disease was 29% and 25% lower, respectively, and neither association was any longer significant (Alzheimer's disease: OR=1.91, 95% CI=0.89-4.11; all-cause dementia: OR=1.62, 95% CI=0.84-3.15). Exercise was a significant confounder in the relationship between folate and Alzheimer's disease (P=.03) and dementia (P=.003) but not cerebrovascular outcomes (P=.64). Unlike folate, exercise was significantly associated with Alzheimer's disease (OR=0.43, 95% CI=0.19-0.98) and dementia (OR=0.35, 95% CI=0.17-0.72) in adjusted analyses. CONCLUSION: Exercise seems to account for much of the relationship between folate and incident dementia and Alzheimer's disease.     

Folate Deficiency in an Urban Safety Net Population

PurposeSince mandatory fortification of grain products with folic acid in the United States in 1998, folate deficiency has become rare. Some have suggested that serum folate levels should be tested rarely in countries with mandatory folic acid fortification, given low rates of deficiency, high cost per deficiency diagnosis, and low rates of supplementation for those diagnosed as deficient. Given persistent racial, ethnic, and socioeconomic disparities in folate deficiency, these suggestions may not apply to all populations. We examine the rate at which serum testing detected folate deficiency in an urban safety net hospital and the characteristics of folate-deficient patients.MethodsWe reviewed the charts of all inpatients and emergency department patients with low serum folate results at a safety net hospital in Boston in 2018. We collected data concerning demographics, social determinants of health, clinical factors, and whether folate supplementation was prescribed. Finally, we performed a cost analysis.ResultsOf 1368 patients tested, 76 (5.5%) met criteria for folate deficiency. Overall, 86.8% of these patients were anemic, and 17.1% had macrocytic anemia; 42% were diagnosed with malnutrition. Common social determinants in folate-deficient patients included birth outside of the United States, homelessness, and alcohol use disorder. Of folate-deficient patients, 88% were newly prescribed folic acid supplementation at discharge. The estimated charge per deficient test was $1278.ConclusionCompared with a nearby institution, serum folate testing at our safety net hospital detected deficiency at a higher rate, incurred a lower charge per deficient test, and was more likely to impact management.     

Outcome and treatment in elderly patients with small cell lung cancer: A retrospective study

Aim:   The number of elderly patients with small cell lung cancer (SCLC) is expected to increase with the growing geriatric population. The aim of this study is to evaluate the safety and efficacy of standard chemotherapy or chemoradiotherapy in elderly patients with SCLC.
Methods:   In this retrospective study, we analyzed the data of 126 patients with SCLC diagnosed between 1996 and 2005 at our hospital, and compared the outcome of younger patients less than 70 years and elderly patients 70 years or older who were treated with etoposide and cisplatin (EP regimen) and cyclophosphamide, adriamycin and vincristine (CAV regimen). Patients with limited disease SCLC received thoracic radiotherapy (RT) following chemotherapy.
Results:   Overall response rates (complete and partial response) were not significantly different between patients less than 70 years and patients 70 years or older (69% vs 65%, P  = 0.591). The median survival time was 13 months for patients less than 70 years compared with 12 months for patients 70 years or older ( P  = 0.263), with 2- and 5-year survival rates of 37.8% and 8.2% vs 26.2% and 3.6%, respectively. Progression-free survival of patients 70 years or older was similar to that of patients less than 70 years ( P  = 0.445). Grade 3 and 4 hematological toxicities were more frequent among the elderly group (leukopenia, 48% vs 31%, P  = 0.049; neutropenia, 52% vs 32%, P  = 0.028; thrombocytopenia, 38% vs 21%, P  = 0.047).
Conclusion:   In spite of having more grade 3 and 4 hematological toxicity, elderly SCLC patients 70 years or older can benefit from the EP regimen and the CAV regimen with or without thoracic RT. Further investigations are needed to focus on ways to decrease toxicity, especially in the elderly.     

Mild hyperhomocysteinemia in adult patients with sickle cell disease: a common finding unrelated to folate and cobalamin status

Homocysteine has associations with both vitamin insufficiency and vascular complications, and its status is therefore of interest in sickle cell disease (SCD). However, information is limited, especially in adults. We studied plasma total homocysteine (tHcy) and three of its major modifiers, cobalamin, folate, and creatinine, in 90 adult patients with SCD and 76 control subjects. The patients had higher tHcy levels than did controls (P = 0.03) and had elevated tHcy more often (20% vs. 3%, P = 0.0005). None of the hyperhomocysteinemic patients had low cobalamin or folate levels; on the contrary, patients with SCD had high folate levels more often than control subjects (32% vs. 7%; P < 0.0001). Although serum creatinine values were lower in SCD patients than in control subjects (P = 0.03), high levels also tended to occur more often (8% vs. 1%; P = 0.054). Most importantly, creatinine levels correlated significantly with tHcy (P < 0.0001) and logistic regression analyses showed creatinine to be the only significant predictor of high tHcy levels in SCD (P = 0.01). Our results show that hyperhomocysteinemia affects 20% of adults with SCD despite routine folate supplementation and is independent of folate and cobalamin status. Creatinine was the major identifiable influence on tHcy, but renal insufficiency explained only 4 of the 18 elevated tHcy levels. Longitudinal studies will be needed to determine whether the frequent hyperhomocysteinemia of SCD influences the vascular complications in SCD. If reducing tHcy becomes advisable, then interventions other than folate therapy will be needed.     

Endocarditis in the elderly: clinical, echocardiographic, and prognostic features.

AIMS: Infective endocarditis (IE) is more and more frequent in elderly persons and it has been associated with various clinical, bacteriological, and prognostic features. The aim of the study was to define the clinical, echographic, and prognostic characteristics of IE in a large population of elderly patients from four European centres (three French, one Italian). METHODS AND RESULTS: Three hundred and fifteen consecutive patients with definite IE underwent clinical evaluation, echocardiography, blood cultures, and follow-up. Patients were separated into three groups: group A: 117 patients aged <50 years, group B: 111 patients aged >50 and <70 years, group C: 87 patients aged >70 years.Elderly patients (group C) presented more frequently than other groups with digestive or urinary portal of entry, pacemaker endocarditis, and anaemia. S bovis endocarditis was less frequent and S aureus endocarditis more frequent in younger (group A) patients than in other groups. No difference was observed among groups concerning echocardiographic data as well as the incidence and localization of embolic events. Elderly patients were operated on as frequently as younger patients and their operative risk was similar than in other groups (11%, 3%, and 5% in groups C, B, and A, respectively, P=ns). Overall mortality in elderly patients was low (17%) but significantly higher than in younger patients (10% in group A, 7% in group B, P=0.02). By multivariate analysis, the only risk factors for in-hospital mortality were age (P=0.003), prosthetic valve (P=0.002), and cerebral embolism (P=0.006). Conversely, surgical management was associated with a lower in-hospital mortality (P=0.03). CONCLUSIONS: In this largest series of elderly patients with IE, IE in elderly carries specific features when compared with younger patients, although the echographic characteristics and embolic risk are similar. The overall mortality rate in elderly patients is higher than in younger, but the mortality in operated patients is low and similar than that of younger patients.     

Erythrocyte folate levels: a clinical study

PURPOSE: 1) To determine if there are significant differences in laboratory parameters and patient characteristics between patients with low erythrocyte (RBC) folate levels and those with normal RBC folate levels; 2) to determine the correlation between serum and RBC folate levels; 3) to determine if the RBC folate level changed the diagnosis, treatment, and outcome of these patients if the serum folate level was available. PATIENTS AND METHODS: The study is a retrospective review of all inpatients and outpatients at a public teaching hospital who had an RBC folate level less than or equal to 175 ng/ml (N = 57) over the study period (69 months) and a blindly selected group of patients with RBC folate levels greater than 175 ng/ml (N = 53) during the same period. RESULTS: Patients with low RBC folate levels had higher mean corpuscular volume (MCV) and red cell distribution width (RDW) values and lower serum folate and B12 values than patients with normal RBC folate levels, but there was no difference in degree of anemia, presence of oval macrocytes and/or hypersegmented neutrophils on the peripheral blood smear, LDH, alcohol use, diet, or any other measured clinical parameter. Serum and RBC folate levels were highly correlated and a low RBC folate affected the clinical outcome of three patients (5% of the low RBC folate group). CONCLUSIONS: Based upon these retrospective data and a review of the literature, we cannot define significant differences between patients with low RBC folate and randomly selected patients with normal RBC folate that could not have been equally well defined using serum folate values. The sensitivity and specificity of a low RBC folate level in the diagnosis of ill or healthy individuals are undefined, and until prospective studies utilizing some of the newer, more specific biochemical indicators of tissue folate are completed, the interpretation of low RBC folate levels will remain problematic.     

Is there a role for folate determinations in current clinical practice in the USA?

Our objectives were to determine the likelihood of true folate deficiency among patients tested for this disorder, to identify whether there were differences between the clinical indications for folate testing in folate‐normal and folate‐deficient patients and to assess the impact of a diagnosis of folate deficiency on patient management. The results of all blood samples analyzed for serum and erythrocyte folate levels during the year 2001 at the Cleveland Clinic Foundation were retrieved. Folate deficient patients were identified and their medical charts were reviewed to determine the indications, patient characteristics, and impact of this diagnosis on patient management. For comparison, medical chart review was also conducted on a control group composed of an equal number of randomly selected patients with normal serum folate values. A total of 6024 (4689 serum and 1335 erythrocyte) samples from 4985 patients were collected. In the study, 77 (1.6%) of the serum folate levels, from 74 patients, were identified as low. When compared with the control group, patients with low serum folate levels had lower hemoglobin and a greater red cell distribution width. Mean corpuscular volume, however, did not differ between the two groups. No significant differences in the clinical indications for serum folate level determinations could be identified. Only 39 of the 74 patients with low serum folate levels were given folate replacement, representing only 0.9% of the clinically suspected and tested patients. We conclude that determination of serum folate level infrequently led to appropriate folate replacement therapy. Moreover, even when suspected, true folic acid deficiency is rare and clinical indications are not helpful in diagnosis.     

Serum cobalamin, folate, methylmalonic acid and total homocysteine as vitamin B12 and folate tissue deficiency markers amongst elderly Swedes--a population-based study

OBJECTIVES: The possibilities of detecting tissue cobalamin and folate deficiency are under debate. In this report the levels of serum cobalamin, folate, methylmalonic acid (MMA) and total homocysteine (tHcy) and their interrelations in a representative random population sample are presented. DESIGN: Cohort study. SETTING: A general mid-Swedish population. SUBJECTS: A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey. A total of 235 (85%) persons responded, out of whom 224 had no interfering diseases. MAIN OUTCOME MEASURES: Serum cobalamin, folate, MMA and tHcy. RESULTS: The serum levels of cobalamin, folate, MMA and tHcy were all correlated to cobalamin and folic acid treatment. They were also correlated to the intake of multivitamin preparations. In addition, serum cobalamin was higher in untreated women than in men but not correlated to age. Serum folate was correlated neither to sex nor age. Serum tHcy and MMA were both directly correlated to age but MMA not to sex. MMA was inversely correlated to serum cobalamin but not to serum folate, whereas serum tHcy was inversely correlated to serum cobalamin, folate and creatinine. Neither serum cobalamin, folate, MMA nor tHcy had any significant correlation to haemoglobin, erythrocyte volume fraction (EVF) or mean red cell volume. Half of the study population had abnormal MMA or tHcy levels, suggesting a latent or overt tissue deficiency of cobalamin or folate. CONCLUSIONS: A substantial proportion of the elderly general population had signs of low tissue levels of cobalamin or folate. Amongst those who took multivitamin preparations this proportion was much lower.     

Folate metabolism and chromosomal stability in the fragile X syndrome

Folate metabolism and the effects of folic acid on chromosome stability were studied in four related patients with the fragile X syndrome. In three adults, uptake and subsequent utilization of folate compounds for conversion of deoxyuridylate to thymidylate by marrow cells and stimulated lymphocytes, and the affinity and maximal transport velocity of erythrocyte membrane carriers, were normal. Numbers of sister chromatid exchanges and double-stranded DNA breaks were comparable in cells from patients and control subjects, but both were increased after incubation in folate-deficient media. In vitro expression of the fragile site was strikingly reduced by oral folate therapy. It is concluded that the folate-sensitive chromosomal defect in this syndrome is limited to a specific site, Xq28, and there is no generalized tendency to frequent DNA breaks or recombination. Although expression was modified by folic acid treatment in the patients, no consistent abnormality of folate metabolism could be identified.