Structural basis for mammalian vitamin B12 transport by transcobalamin

Cobalamin (Cbl, vitamin B(12)) serves for two essential cofactors in mammals. The pathway for its intestinal absorption, plasma transport, and cellular uptake uses cell surface receptors and three Cbl-transporting proteins, haptocorrin, intrinsic factor, and transcobalamin (TC). We present the structure determination of a member of the mammalian Cbl-transporter family. The crystal structures of recombinant human and bovine holo-TCs reveal a two-domain architecture, with an N-terminal alpha(6)-alpha(6) barrel and a smaller C-terminal domain. One Cbl molecule in base-on conformation is buried inside the domain interface. Structural data combined with previous binding assays indicate a domain motion in the first step of Cbl binding. In a second step, the weakly coordinated ligand H(2)O at the upper axial side of added H(2)O-Cbl is displaced by a histidine residue of the alpha(6)-alpha(6) barrel. Analysis of amino acid conservation on TC's surface in orthologous proteins suggests the location of the TC-receptor-recognition site in an extended region on the alpha(6)-alpha(6) barrel. The TC structure allows for the mapping of sites of amino acid variation due to polymorphisms of the human TC gene. Structural information is used to predict the overall fold of haptocorrin and intrinsic factor and permits a rational approach to the design of new Cbl-based bioconjugates for diagnostic or therapeutic drug delivery.     

How clean is the toothbrush that cleans your tooth?

Abstract:  Until recently, little attention has been directed towards the role the toothbrush may play in human health, even though a report of toothbrush as a significant factor in the infection appeared in 1920. It is common knowledge that the human mouth harbours a wide variety of microorganisms, some of which, at any given time, can be assumed to be potential pathogens. This was not known when toothbrushes were originally designed, yet the common toothbrush has been used in basically the same form for about 200 years. In today's world of organ transplantation and alteration of the immune system, it is important to consider the toothbrush as a source of potential pathogens. Given the fact that very often people will traumatize themselves with their toothbrush, this trauma may become a potential portal of entry for organisms. In this article, we have attempted to demonstrate the importance of toothbrush disinfection, given tips on home toothbrush care and hope to motivate the dentists to educate the patients on the importance of toothbrush disinfection.     

The value of inflammatory markers to diagnose and monitor diabetic foot osteomyelitis

In this study, we assessed the effectiveness of inflammatory markers to diagnose and monitor the treatment of osteomyelitis in the diabetic foot. We evaluated 35 consecutive patients admitted to our hospital with infected foot ulcers. Patients were divided in two groups based on the results of bone culture and histopathology: osteomyelitis and no osteomyelitis. The erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), procalcitonin (PCT), interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), tumor necrosis factor alpha (TNFα), monocyte chemotactic protein‐1 (MCP‐1) and macrophage inflammatory protein‐1 alpha (MIP1α) were measured at baseline after 3 and 6 weeks of standard therapy. PCT levels in the osteomyelitis group were significantly higher at baseline than in the group with no osteomyelitis (P = 0·049). There were no significant differences between the two groups in the levels of the other markers. CRP, ESR, PCT and IL‐6 levels significantly declined in the group with osteomyelitis after starting therapy, while MCP‐1 increased (P = 0·002). TNFα and MIP1α levels were below range in 80 out of 97 samples and therefore not reported. Our results suggest that PCT might be useful to distinguish osteomyelitis in infected foot ulcers. CRP, ESR, PCT and IL‐6 are valuable when monitoring the effect of therapy.     

Computational Biorheology of Human Blood Flow in Health and Disease

Hematologic disorders arising from infectious diseases, hereditary factors and environmental influences can lead to, and can be influenced by, significant changes in the shape, mechanical and physical properties of red blood cells (RBCs), and the biorheology of blood flow. Hence, modeling of hematologic disorders should take into account the multiphase nature of blood flow, especially in arterioles and capillaries. We present here an overview of a general computational framework based on dissipative particle dynamics (DPD) which has broad applicability in cell biophysics with implications for diagnostics, therapeutics and drug efficacy assessments for a wide variety of human diseases. This computational approach, validated by independent experimental results, is capable of modeling the biorheology of whole blood and its individual components during blood flow so as to investigate cell mechanistic processes in health and disease. DPD is a Lagrangian method that can be derived from systematic coarse-graining of molecular dynamics but can scale efficiently up to arterioles and can also be used to model RBCs down to the spectrin level. We start from experimental measurements of a single RBC to extract the relevant biophysical parameters, using single-cell measurements involving such methods as optical tweezers, atomic force microscopy and micropipette aspiration, and cell-population experiments involving microfluidic devices. We then use these validated RBC models to predict the biorheological behavior of whole blood in healthy or pathological states, and compare the simulations with experimental results involving apparent viscosity and other relevant parameters. While the approach discussed here is sufficiently general to address a broad spectrum of hematologic disorders including certain types of cancer, this paper specifically deals with results obtained using this computational framework for blood flow in malaria and sickle cell anemia.     

The first international intercomparison of EPR-dosimetry with teeth: First results

Intercomparison of EPR-dosimetric techniques using tooth enamel had been performed in order to check whether the results produced by different laboratories are consistent and accurate. Participants were supposed to evaluate doses applied to pulverized enamel samples, using routine techniques from their laboratories. The intercomparison has demonstrated a great variety of methods used for dose reconstruction. Peculiarities of experimental approaches are discussed systematically in terms of procedure for recording the EPR-spectra, determination of the amplitude of the radiation induced signal, determination of the dose, and error propagation.     

Morphological changes in the placenta in late pregnancy toxemias]

The article presents results of morphological, morphometric and cytochemical investigations of 100 placentae obtained in women who suffered from nephropathy of various degrees, and of placentae of mice with induced "graft versus host" reaction during pregnancy, and also of organs of two fetuses born to mothers who suffered from nephropathy of the III degree. In severe forms of late toxemia placentae, regularly showed infiltration of its structural elements with cells of the type of microlymphocytes with lytic properties. These changes occurred against the background of the placental metabolism turning into anaerobic respiration and they revealed a considerable degree of similarity to the changes in placentae of mice following the induction of the reaction "graft versus host". The morphological picture in lymphoid and other organs of the two investigated fetuses resembled very much that in "runt" disease.     

Cancer fear and fatalism among ethnic minority women in the United Kingdom

Background:

Cancer fear and fatalism are believed to be higher in ethnic minorities and may contribute to lower engagement with cancer prevention and early detection. We explored the levels of cancer fear and fatalism in six ethnic groups in the United Kingdom and examined the contribution of acculturation and general fatalism.

Methods:

A cross-sectional survey of 720 White British, Caribbean, African, Indian, Pakistani, and Bangladeshi women (120 of each) was conducted. Three items assessed cancer fear and two cancer fatalism. Acculturation was assessed using (self-reported) migration status, ability to speak English, and understanding of health leaflets; general fatalism with a standard measure.

Results:

Relative to White British women, African and Indian women were more fearful of cancer, Bangladeshi women less fearful, and Pakistani and Caribbean women were similar to White British women. Cancer fatalism was higher in all the ethnic minority groups compared with White British women. Less acculturated women were less likely to worry (ORs 0.21–0.45, all P<0.05) or feel particularly afraid (ORs 0.11–0.31, all P<0.05) but more likely to feel uncomfortable about cancer (ORs 1.97–3.03, all P<0.05). Lower acculturation (ORs 4.30–17.27, P<0.05) and general fatalism (OR 2.29, P<0.05) were associated with the belief that cancer is predetermined.

Conclusions:

In general, cancer fear and fatalism are more prevalent among ethnic minority than White British women and even more so in less acculturated ethnic minorities. This may affect their participation in cancer prevention and early detection.