Long-term metformin therapy and vitamin B12 deficiency: An association to bear in mind

To date, metformin remains the first-line oral glucose-lowering drug used for the treatment of type 2 diabetes thanks to its well-established long-term safety and efficacy profile. Indeed, metformin is the most widely used oral insulinsensitizing agent, being prescribed to more than 100 million people worldwide, including patients with prediabetes, insulin resistance, and polycystic ovary syndrome. However, over the last decades several observational studies and meta-analyses have reported a significant association between long-term metformin therapy and an increased prevalence of vitamin B12 deficiency. Of note, evidence suggests that long-term and high-dose metformin therapy impairs vitamin B12 status. Vitamin B12(also referred to as cobalamin) is a water-soluble vitamin that is mainly obtained from animal-sourced foods. At the cellular level, vitamin B12 acts as a cofactor for enzymes that play a critical role in DNA synthesis and neuroprotection. Thus, vitamin B12 deficiency can lead to a number of clinical consequences that include hematologic abnormalities(e.g., megaloblastic anemia and formation of hypersegmented neutrophils), progressive axonal demyelination and peripheral neuropathy. Nevertheless, no definite guidelines are currently available for vitamin B12 deficiency screening in patients on metformin therapy, and vitamin B12 deficiency remains frequently unrecognized in such individuals. Therefore, in this "field of vision" article we propose a list of criteria for a cost-effective vitamin B12 deficiency screening in metformin-treated patients, which could serve as a practical guide for identifying individuals at high risk for this condition. Moreover, we discuss additional relevant topics related to this field, including:(1) The lack of consensus about the exact definition of vitamin B12 deficiency;(2) The definition of reliable biomarkers of vitamin B12 status;(3) Causes of vitamin B12 deficiency other than metformin therapy that should be identified promptly in metformin-treated patients for a proper differential diagnosis; and(4) Potential pathophysiological mechanisms underlying metformin-induced vitamin B12 deficiency. Finally, we briefly review basic concepts related to vitamin B12 supplementation for the treatment of vitamin B12 deficiency, particularly when this condition is induced by metformin.     

The nuclear concentration of kin17, a mouse protein that binds to curved DNA, increases during cell proliferation and after UV irradiation

UV-irradiation induces, in mammalian cells, the expression of a set of genes known as the 'UV-response', which may be reminiscent of the bacterial response, called SOS system. The multifunctional protein RecA controls the expression of the SOS genes. We report the expression profile of a mouse gene conserved among mammals, called Kin17, that codes a DNA-binding protein of undetermined biochemical activity and which shares epitopes with the bacterial RecA protein. We demonstrate that the level of Kin17 RNA was 5-fold higher in mid-S phase of serum- stimulated BALB/c 3T3 fibroblasts than in quiescent cells. Cells in S- phase displayed a high level of kin17 protein with a marked nuclear localisation. The maximal level of Kin17 RNA was observed 18 h after serum stimulation, indicating that Kin17 gene is a new member of the late growth-related genes. The accumulation of kin17 protein during cell proliferation follows the increase in Kin17 RNA and correlates with DNA synthesis, which suggests a possible role of kin17 protein in a transaction related to DNA-replication. In quiescent fibroblasts, a 3- fold increase in Kin17 RNA was seen 13 h after UV irradiation. In parallel, kin17 protein accumulated in the nucleus, which suggests that it might be required after the stress produced by UV irradiation.      

Chronic daily headache with migrainous features due to papilledema-negative idiopathic intracranial hypertension

Patients with the syndrome of chronic daily headache often report migrainous symptoms and consequently are diagnosed as having a primary headache syndrome. We report two cases of idiopathic intracranial hypertension causing chronic daily headache with migrainous features in the absence of associated papilledema.     

Évaluation clinique des chimioradiothérapies concomitantes et recommandations pratiques

The efficacy of concurrent radiochemotherapy should be evaluated in term of therapeutic ratio. The aims of treatment are increasing local control and possibly overall survival. Acute toxicity should be reported using the WHO recommendations, while late toxicity is reported using the scales recommended by the EORTC and RTOC Radiotherapy Groups. Moreover, functional, esthetic and quality of life considerations should be introduced. The application of these treatments needs a well-designed multidisciplinary staff.     

Necrotizing leukoencephalopathy associated with nonconvulsive status epilepticus and periodic short-interval diffuse discharges: a clinicopathological study.

We describe the clinical, neuroimaging and neuropathological features of an immunocompromised patient diagnosed as having refractory nonconvulsive status epilepticus (NCSE), and whose consecutive electroencephalograms (EEGs) revealed persistent periodic short-interval diffuse discharges (PSIDDs). Prominent subcortical white matter lesions in keeping with the diagnosis of multifocal necrotizing leukoencephalopathy may be neuropathological substrate of NCSE with persistent PSIDDs.     

Latin American registry of dialysis and renal transplantation: 1993 annual dialysis data report

Background: The Latin America Registry of Dialysis and Transplantation was created in October 1991 and comprises the national Societies of Nephrology from 21 countries with a total population of 468.56 million inhabitants. Methods: This report includes data from 21 181 patients from Argentina, Brazil, Chile, El Salvador, Panama, Paraguay, Peru, Puerto Rico, Uruguay, and Venezuela who were receiving chronic dialysis treatment during 1993. Data was collected by individual patient questionnaire except from Chile and Brazil where the data was obtained from a local centre questionnaire. Results: The prevalence rate averaged 131.1 per million population. The mean age of the 8972 incident patients was 50.5 years, with 58.2% males. The more frequent causes of renal failure were glomerulopathies (22.6%), vascular nephropathy (20.9%) and diabetes (16.9%). Haemodialysis was the most used treatment (88.3%). Gross mortality was 21.1% and the more frequent causes of death were cardiac complications and infections. The analysis of mortality risk factors using a logistic regression model showed that diabetics patients older than 65 years had the highest probability of death (43.0%) and patients with glomerulonephritis, younger than 65 years had the lowest (8.0%). The adjusted mortality rate was 241 deaths/1000 patient-years at risk when the USRDS 1987-1989 white mortality rate by age groups and primary diseases was used as standard. Conclusion: In spite of the economic difficulties, very important efforts have been made to treat ESRD patients and gross mortality statistics in some countries are similar to those reported by other regional registries.     

Prospective study of lung volumes in young asthmatic children

In a 9-y prospective study, the occurrence and duration of lung volume abnormalities in 21 young asthmatic children (median age at recruitment 4y, range 3–8 y) was determined. The median functional residual capacity (FRC) at recruitment was 135% of that predicted for height (range 79–187%) and 13 children were hyperinflated. The median FRC decreased significantly after 3 y of follow-up and by 9 y only one child remained hyperinflated. We conclude that persistent elevation of lung volume in young asthmatic children appears to be uncommon.     

Clinical studies of valproate for migraine prophylaxis

Within the last decade our understanding of the pathophysiologic mechanisms which generate migraine has expanded considerably. Accompanying these advances in basic science, new agents designed to treat migraine acutely have exhibited unprecedented pharmacologic selectivity and clinical efficacy. While these abortive agents clearly can provide many migraine patients with a degree of headache control they previously have not enjoyed, such treatment typically will not provide lasting benefit to individuals whose headaches are more pervasive and may require stabilization through effective prophylactic therapy. Unfortunately, our arsenal of agents for migraine prophylaxis has not grown as rapidly as that of the abortive medications, and for the most part clinicians and patients are left to rely upon a small handful of "traditional" drugs for that purpose. One notable exception to this is divalproex sodium; the safety and efficacy of this new agent for migraine prevention have been documented consistently in a series of recent clinical trials.