Homozygous transcobalamin II deficiency maintained on oral hydroxocobalamin

A case of transcobalamin II (TCII) deficiency in which a total absence of TCII was demonstrated both functionally and immunologically is reported. Unlike previously described patients, this child has been maintained on oral hydroxocobalamin, 2 mg daily, without any parenteral supplementation for the last five years. At the age of six years her development is normal and her health is good. Plasma cobalamin levels are in the range of 3,000 ng/L and most of this appears to be bound to a molecule, which on gel filtration, elutes with albumin. In an extended family study, a clear separation of heterozygotes from both the propositus and from normal subjects suggests that the underlying defect in this condition is confined to a single gene.     

Effect of blood donation on iron stores as evaluated by serum ferritin

Serum ferritin was measured in 2982 blood donors. First-time male donors had a geometric mean of 127 microgram/liter and female donors 46 microgram/liter. While values were essentially constant in the women between the ages of 18 and 45, there was a rapid increase in the men between 18 and 30 years of age consistent with the establishment of iron stores during that time. Blood donation was associated with a decrease in serum ferritin. One unit per year, equivalent to an increased requirement of 0.65 mg/day, halved the serum ferritin level in the male. More frequent donations were associated with further decreases. From the data obtained it would appear that male donors, while depleting their iron stores, were able to donate 2-3 U/yr without an appreciable incidence of iron deficiency. Women could donate only about half that amount, and more frequent donations were associated with a high incidence of iron deficiency and donor dropout. These data have provided information on the effect of graded amounts of iron loss through bleeding on iron balance.     

Preparedness for treating victims of terrorist attacks in Australia: Learning from recent military experience

The Australian health system is generally well prepared for mass casualty events. Fortunately, there have been very few terrorist attacks and these have involved low numbers of casualties compared with events overseas. Nevertheless, Australian health professionals need to be prepared to treat mass casualties with blast and ballistic trauma. The US military and its allies including Australia have had extensive experience with mass casualty management in the Middle East and Afghanistan wars for more than a decade. To define their experience, they developed the Tactical Combat Casualty Care Guidelines that have saved many lives. It is now prudent to incorporate this knowledge and experience into civilian practice in Australia.     

Autonomic dysfunction in diabetes: a consequence of cardiovascular damage

In 1976, D.J. Ewing showed a clear survival disadvantage for diabetic patients that had 'diabetic autonomic neuropathy', as assessed by heart rate and blood pressure variations during a battery of bedside tests. However, these variations do not solely depend on autonomic nervous system function, but also and possibly to a more important extent on the integrity of cardiovascular autonomic reflex loops. Increased intima media thickness at the site of the baroreceptors, reduced vascular distensibility, endothelial dysfunction and impaired cardiac function contribute to the cardiovascular autonomic dysfunction. Interestingly, these abnormalities are closely associated with the presence of (micro-) albuminuria that is regarded as a reflection of endothelial dysfunction or vascular damage in diabetes mellitus. Modern techniques to assess cardiovascular autonomic, vascular and cardiac function have improved the ability to detect early abnormalities. Analysis of heart rate variability, baroreflex sensitivity, muscle sympathetic nervous activity, LNMAinfusions and advanced echocardiography have shown that it is the interplay between autonomic control and cardiac and vascular properties that determines cardiovascular autonomic function. Moreover, these modern techniques have improved power to predict survival in diabetic patients in comparison with the classical Ewing's bedside tests. In conclusion, cardiovascular damage may be more important in cardiovascular autonomic dysfunction than neural function.     

Efficacy of escalated imatinib combined with cytarabine in newly diagnosed patients with chronic myeloid leukemia

Background

In order to improve the molecular response rate and prevent resistance to treatment, combination therapy with different dosages of imatinib and cytarabine was studied in newly diagnosed patients with chronic myeloid leukemia in the HOVON-51 study.

Design and Methods

Having reported feasibility previously, we hereby report the efficacy of escalated imatinib (200 mg, 400 mg, 600 mg or 800 mg) in combination with two cycles of intravenous cytarabine (200 mg/m² or 1000 mg/m² days 1 to 7) in 162 patients with chronic myeloid leukemia.

Results

With a median follow-up of 55 months, the 5-year cumulative incidences of complete cytogenetic response, major molecular response, and complete molecular response were 89%, 71%, and 53%, respectively. A higher Sokal risk score was inversely associated with complete cytogenetic response (hazard ratio of 0.63; 95% confidence interval, 0.50–0.79, P<0.001). A higher dose of imatinib and a higher dose of cytarabine were associated with increased complete molecular response with hazard ratios of 1.60 (95% confidence interval, 0.96–2.68, P=0.07) and 1.66 (95% confidence interval, 1.02–2.72, P=0.04), respectively. Progression-free survival and overall survival rates at 5 years were 92% and 96%, respectively. Achieving a major molecular response at 1 year was associated with complete absence of progression and a probability of achieving a complete molecular response of 89%.

Conclusions

The addition of intravenous cytarabine to imatinib as upfront therapy for patients with chronic myeloid leukemia is associated with a high rate of complete molecular responses (Clinicaltrials.Gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00028847","term_id":"NCT00028847"}}NCT00028847).     

Epithelial-mesenchymal transition and senescence: two cancer-related processes are crossing paths

The epithelial-mesenchymal transition is involved in several physiological processes. However, it is also believed to contribute to cancer progression. Conversely, cellular senescence constitutes a failsafe program against cancer progression. Interestingly, EMT and senescence seem to cross paths, with several factors playing dominant roles in both settings. Here, we describe recent observations that link these important cellular processes.