11β-Hydroxysteroid dehydrogenase type 1, but not type 2, deficiency worsens acute inflammation and experimental arthritis in mice

Glucocorticoids profoundly influence immune responses, and synthetic glucocorticoids are widely used clinically for their potent antiinflammatory effects. Endogenous glucocorticoid action is modulated by the two isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). In vivo, 11β-HSD1 catalyzes the reduction of inactive cortisone or 11-dehydrocorticosterone into active cortisol or corticosterone, respectively, thereby increasing intracellular glucocorticoid levels. 11β-HSD2 catalyzes the reverse reaction, inactivating intracellular glucocorticoids. Both enzymes have been postulated to modulate inflammatory responses. In the K/BxN serum transfer model of arthritis, 11β-HSD1-deficient mice showed earlier onset and slower resolution of inflammation than wild-type controls, with greater exostoses in periarticular bone and, uniquely, ganglion cysts, consistent with greater inflammation. In contrast, K/BxN serum arthritis was unaffected by 11β-HSD2 deficiency. In a distinct model of inflammation, thioglycollate-induced sterile peritonitis, 11β-HSD1-deficient mice had more inflammatory cells in the peritoneum, but again 11β-HSD2-deficient mice did not differ from controls. Additionally, compared with control mice, 11β-HSD1-deficient mice showed greater numbers of inflammatory cells in pleural lavages in carrageenan-induced pleurisy with lung pathology consistent with slower resolution. These data suggest that 11β-HSD1 limits acute inflammation. In contrast, 11β-HSD2 plays no role in acute inflammatory responses in mice. Regulation of local 11β-HSD1 expression and/or delivery of substrate may afford a novel approach for antiinflammatory therapy.     

Prolonged lymphocytosis as the first manifestation of Hodgkin-like adult T-cell leukemia/lymphoma

Hodgkin-like ATLL is a rare variant of adult T-cell leukemia/lymphoma (ATLL), a disease caused by human T-cell lymphotropic virus type-1 (HTLV-1). At admission, a 46-year-old female presented with lymphadenomegaly, lymphocytosis, slight elevation of LDH blood level, and acid-alcohol resistant bacilli in sputum and was being treated for pulmonary tuberculosis (Tb). She had lymphocytosis in the previous 20 months. Serology for HTLV-1 was positive. Lymph node was infiltrated by medium-sized lymphocytes with scattered Hodgkin and Reed-Sternberg-like cells CD30+, CS1-4+, and CD79a+. Background cells were CD4+ and CD25+. A clinical diagnosis of favorable chronic ATLL was given. She was treated with chemotherapy but later progressed to acute ATLL and ultimately died. Hodgkin-like ATLL should be considered in the histological differential diagnosis with Hodgkin lymphoma since treatment and prognosis of these diseases are distinct. It is also important to search for HTLV-1 infection in patients with unexplained prolonged lymphocytosis.     

The role of low-molecular-weight heparins in the prevention and treatment of venous thromboembolism in cancer patients

Accumulating evidence suggests that low-molecular-weight heparins are the drug of choice for the prevention and treatment of venous thromboembolism in patients with cancer. For prophylaxis in the surgical setting, once-daily subcutaneous injections of low-molecular-weight heparin are as effective and safe as multiple doses of unfractionated heparin. Extending prophylaxis with low-molecular-weight heparins beyond hospitalization was recently found to reduce safely the risk of postoperative thrombosis after abdominal surgery for cancer. For the long-term treatment of deep vein thrombosis and in select patients with pulmonary embolism, recently completed clinical trials have shown that secondary prophylaxis with low-molecular-weight heparin is feasible and more effective than oral anticoagulant therapy in preventing recurrent venous thromboembolism in cancer patients. There is also evidence that low-molecular-weight heparins are effective in cancer patients who develop recurrent thrombosis while on warfarin therapy. Lastly, the potential antineoplastic effects of low-molecular-weight heparins make these agents an attractive option in patients with cancer. Although the management of cancer patients with venous thromboembolism remains challenging, low-molecular-weight heparins have simplified and improved the prevention and treatment of venous thromboembolism in these high-risk patients.     

Psychosocial, educational, and somatic factors in chronic nonspecific low back pain

Analysis of the effect of psychosocial factors and co-morbidities on the health status of patients with chronic nonspecific low back pain and patients with surgical intervention because of disk herniation was performed. One hundred and two nonselected consecutive inpatients with chronic nonspecific low back pain were included in the study. Their average age was 56.7 (SD = 10.9) years. The control group consisted of 199 subjects matched according to age and sex, chosen from the database of the national representative health survey Hungarostudy 2006, which involved 4,527 subjects. We measured quality of life including mental health with the SF-36 questionnaire validated for use in Hungary, the short 9-item version of the Beck Depression Inventory, the WHO-Five Well-Being Index, and the Hospital Anxiety-Depression Scale. We characterized the socio-demographic status with variables on age, sex, marital status, and education. Data on symptoms and signs of low back pain, other musculoskeletal diseases, and their treatments including spinal surgery were recorded. Co-morbidity and body mass index were considered as independent indicators of health. Depression as measured by Beck Depression Inventory and severity of depression did not vary significantly according to marital status, education, hypertension, diabetes, and gastrointestinal disease. Only half of the patients (52 %) were in the normal range of the scale; 22 % suffered from mild, 16 % from moderate, and 12 % from severe depression. Average values for anxiety and depression as measured by Hospital Anxiety-Depression Scale and Beck Depression Inventory were both significantly higher in the patient than in the control group (Hospital Anxiety Scale: p = 0.0001; Beck Depression Inventory: p = 0.0001). According to the WHO Well-Being Index-5 scale, the difference between patients and the control group was significant (p = 0.0001). Furthermore, correlation was found between the incidence of depression and surgery. Depression was demonstrated in 47.4 % of those patients who had no surgery, in 50 % of patients who had one round of surgery, and in 62.5 % of those who had undergone surgery more than once; the contingence coefficient was 0.211. According to different measurements, the psychological state of patients with chronic nonspecific low back pain was significantly altered as compared to the matched Hungarian population. Higher anxiety and depression markers occurred in 48 % of the patients. There was no correlation between the depression of patients with low back pain and variables such as marital status, education, and co-morbidities. Our study is the first to demonstrate that depression runs parallel with the number of surgical procedures. Therefore, if there is a relative indication for surgery, depression and severity of depression should be assessed and considered when deciding on the intervention.     

Blood haemoglobin concentrations are higher in smokers and heavy alcohol consumers than in non-smokers and abstainers—should we adjust the reference range?

The blood haemoglobin concentration is one of the most frequently used laboratory parameters in clinical practice. There is evidence that haemoglobin levels are influenced by tobacco smoking. The objective of this study was to evaluate the impact of smoking and alcohol consumption on haemoglobin concentrations in apparently healthy subjects living at sea level. A retrospective, epidemiological cohort study was performed in 1984. Participants were 1,503 men and 1,437 non-pregnant women evenly distributed in age cohorts of 30, 40, 50, and 60 years. Information of smoking habits and alcohol consumption were obtained by a questionnaire. Haemoglobin was measured in the fasting state on Coulter-S. Men displayed no difference in mean haemoglobin levels in the four age groups. In women, mean haemoglobin increased gradually with age (p = 0.001). Fifty-nine percent of men and 50% of women were daily smokers. Female smokers displayed a significant positive correlation between number of cigarettes/day and haemoglobin concentrations (r = 0.12, p = 0.002). Heavy smokers (more than ten cigarettes/day) had significantly higher mean haemoglobin (1.4% higher in men, on average 3.5% higher in women) than non-smokers (p < 0.01). Smokers demonstrated a significant correlation between cigarettes/day and drinks/week in men (r = 0.24, p < 0.001) and women (r = 0.16, p < 0.001). Non-smokers displayed a significant positive correlation between drinks/week and haemoglobin concentrations in men (r = 0.14, p = 0.001) and women (r = 0.08, p = 0.05). In non-smokers, alcohol consumption >14 drinks/week and more than seven drinks/week for men and women, respectively, increased mean haemoglobin by 1.3% in men and by average 1.9% in women compared with those consuming ≤14 and less than or equal to seven drinks/week. Smokers displayed similar results. Body mass index per se had no direct influence on haemoglobin levels but had indirect positive influence in men through its correlation with tobacco smoking and alcohol consumption. Tobacco smoking has an increasing effect on haemoglobin concentrations in both genders, which is proportional to the amount of tobacco smoked. The effect appears to be more pronounced in women. Likewise, high alcohol consumption has an increasing effect on haemoglobin in both genders, being most pronounced in women. However, in clinical biochemistry, the relatively small changes in haemoglobin do not justify the use of separate reference ranges in smokers and alcohol consumers.     

Burden of diabetic foot disorders,guidelines for management and disparities in implementation in Europe: a systematic literature review

The study aimed to assess the economic and quality of life burden of diabetic foot disorders and to identify disparities in the recommendations from guidelines and the current clinical practice across the EU5 (Spain, Italy, France, UK and Germany) countries. Literature search of electronic databases (MEDLINE^®, Embase^® and Cochrane Database of Systematic Reviews) was undertaken. English language studies investigating economic and resource burden, quality of life and management of diabetic foot disease in the EU5 countries were included. Additionally, websites were screened for guidelines and current management practices in diabetic foot complication in EU5. Diabetic foot complications accounted for a total annual cost of €509m in the UK and €430 per diabetic patient in Germany, during 2001. The cost of diabetic foot complications increased with disease severity, with hospitalizations (41%) and amputation (9%) incurring 50% of the cost. Medical devices (orthopaedic shoes, shoe lifts and walking aids) were the most frequently utilized resources. Patients with diabetic foot complications experienced worsened quality of life, especially in those undergoing amputations and with non‐healed ulcers or recurrent ulcers. Although guidelines advocate the use of multidisciplinary foot care teams, the utilization of multidisciplinary foot care teams was suboptimal. We conclude that diabetic foot disorders demonstrated substantial economic burden and have detrimental effect on quality of life, with more impairment in physical domain. Implementation of the guidelines and set‐up of multidisciplinary clinics for holistic management of the diabetic foot disorders varies across Europe and remains suboptimal. Hence, guidelines need to be reinforced to prevent diabetic foot complications and to achieve limb salvage if complications are unpreventable. Copyright © 2014 John Wiley & Sons, Ltd.     

Human induced pluripotent stem cell derived erythroblasts can undergo definitive erythropoiesis and co‐express gamma and beta globins

Human induced pluripotent stem cells (hiPSCs), like embryonic stem cells, are under intense investigation for novel approaches to model disease and for regenerative therapies. Here, we describe the derivation and characterization of hiPSCs from a variety of sources and show that, irrespective of origin or method of reprogramming, hiPSCs can be differentiated on OP9 stroma towards a multi‐lineage haemo‐endothelial progenitor that can contribute to CD144⁺ endothelium, CD235a⁺ erythrocytes (myeloid lineage) and CD19⁺ B lymphocytes (lymphoid lineage). Within the erythroblast lineage, we were able to demonstrate by single cell analysis (flow cytometry), that hiPSC‐derived erythroblasts express alpha globin as previously described, and that a sub‐population of these erythroblasts also express haemoglobin F (HbF), indicative of fetal definitive erythropoiesis. More notably however, we were able to demonstrate that a small sub‐fraction of HbF positive erythroblasts co‐expressed HbA in a highly heterogeneous manner, but analogous to cord blood‐derived erythroblasts when cultured using similar methods. Moreover, the HbA expressing erythroblast population could be greatly enhanced (44·0 ± 6·04%) when a defined serum‐free approach was employed to isolate a CD31⁺ CD45⁺ erythro‐myeloid progenitor. These findings demonstrate that hiPSCs may represent a useful alternative to standard sources of erythrocytes (RBCs) for future applications in transfusion medicine.     

Local carotid atherosclerotic plaque proteins for the identification of circulating biomarkers in coronary patients

Objective

To identify circulating biomarkers that originate from atherosclerotic vulnerable plaques and that could predict future cardiovascular events.

Methods

After a protein enrichment step (combinatorial peptide ligand library approach), we performed a two-dimensional electrophoresis comparative analysis on human carotid plaque protein extracts (fibrotic and hemorrhagic atherosclerotic plaques). In silico analysis of the biological processes was applied on proteomic data. Luminex xMAP assays were used to quantify inflammatory components in carotid plaques. The systemic quantification of proteins originating from vulnerable plaques in blood samples from patients with stable and unstable coronary disease was evaluated.

Results

A total of 118 proteins are differentially expressed in fibrotic and hemorrhagic plaques, and allowed the identification of three biological processes related to atherosclerosis (platelet degranulation, vascular autophagy and negative regulation of fibrinolysis). The multiplex assays revealed an increasing expression of VEGF, IL-6, IL-8, IP-10 and RANTES in hemorrhagic as compared to fibrotic plaques (p < 0.05). Measurement of protein expressions in plasmas from patients with stable and unstable coronary disease identified a combination of biomarkers, including proteins of the smooth muscle cell integrity (Calponin-1), oxidative stress (DJ-1) and inflammation (IL-8), that allows the accurate classification of patients at risk (p = 0.0006).

Conclusion

Using tissue protein enrichment technology, we validated proteins that are differentially expressed in hemorrhagic plaques as potential circulating biomarkers of coronary patients. Combinations of such circulating biomarkers could be used to stratify coronary patients.     

Unrecognised tuberculosis at antiretroviral therapy initiation is associated with lower CD4+ T cell recovery

Objectives To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. Methods In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Results Included were 511 patients with a median baseline CD4 count of 57 cells/mm³ (interquartile range: 22–130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: ?22.3 cells/mm³ (95% confidence interval ?43.2 to ?1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine‐based regimen. Conclusions Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART‐associated TB and sub‐optimal immune reconstitution.