Prediction of peak pressure from clinical and radiological measurements in patients with diabetes

Background

Various structural and functional factors of foot function have been associated with high local plantar pressures. The therapist focuses on these features which are thought to be responsible for plantar ulceration in patients with diabetes. Risk assessment of the diabetic foot would be made easier if locally elevated plantar pressure could be indicated with a minimum set of clinical measures.

Methods

Ninety three patients were evaluated through vascular, orthopaedic, neurological and radiological assessment. A pressure platform was used to quantify the barefoot peak pressure for six forefoot regions: big toe (BT) and metatarsals one (MT-1) to five (MT-5). Stepwise regression modelling was performed to determine which set of the clinical and radiological measures explained most variability in local barefoot plantar peak pressure in each of the six forefoot regions. Comprehensive models were computed with independent variables from the clinical and radiological measurements. The difference between the actual plantar pressure and the predicted value was examined through Bland-Altman analysis.

Results

Forefoot pressures were significant higher in patients with neuropathy, compared to patients without neuropathy for the whole forefoot, the MT-1 region and the MT-5 region (respectively 138 kPa, 173 kPa and 88 kPa higher: mean difference). The clinical models explained up to 39 percent of the variance in local peak pressures. Callus formation and toe deformity were identified as relevant clinical predictors for all forefoot regions. Regression models with radiological variables explained about 26 percent of the variance in local peak pressures. For most regions the combination of clinical and radiological variables resulted in a higher explained variance. The Bland and Altman analysis showed a major discrepancy between the predicted and the actual peak pressure values.

Conclusion

At best, clinical and radiological measurements could only explain about 34 percent of the variance in local barefoot peak pressure in this population of diabetic patients. The prediction models constructed with linear regression are not useful in clinical practice because of considerable underestimation of high plantar pressure values. Identification of elevated plantar pressure without equipment for quantification of plantar pressure is inadequate. The use of quantitative plantar pressure measurement for diabetic foot screening is therefore advocated.     

First clinical experience with the R Stent: a new highly flexible stainless steel tube intracoronary stent

BACKGROUND: Coronary stents have been used with increasing frequency and in increasingly complex coronary disease. A new 316 LVM stainless steel coronary stent, the R Stent, has been designed to provide maximum flexibility for tracking and high radial strength post-deployment. PURPOSE: To assess the clinical feasibility of the R Stent in a tertiary referral population of patients with coronary heart disease. Specific objectives are to assess the R Stent's deployment success, angiographic and procedural success (<20% residual stenosis and >TIMI 2 flow), safety (absence of complications), and 30-day clinical success (angiographic/procedural success plus no major adverse coronary events). METHODS: Between April and November 1998, stent deployment was attempted in 27 patients with stable (46%) or unstable (54%) angina pectoris who qualified for percutaneous transluminal coronary angioplasty. Eighty per cent of patients had a pre-existing history of myocardial infarction, coronary bypass surgery or percutaneous transluminal coronary angioplasty, and several of the lesions were anatomically complex (totally occluded, n 32; thrombus present, n 32; heavily calcified, n 33; ostial, n 31; >20 mm long, n 39; angulation >45 degrees, n 37). Lesions in aortocoronary saphenous vein grafts were excluded. Adjunctive medical management included intraprocedural aspirin and heparin and post-procedural aspirin and ticlopidine. After deployment, patients were followed up in the hospital and at 30 days post procedure. RESULTS: Stent deployment was achieved in 32 of 33 attempts (26 of 27 patients). There was one deployment failure in a long, calcified ostial and proximal left coronary lesion. In the 26 successful deployments, TIMI 3 flow was achieved. One other patient experienced a painless increase in creatine kinase to 375 (CK-MB of 59) at 12 h without ECG changes. At 30 days, there were no deaths, no myocardial infarctions, no subacute thromboses, no repeat interventions, no bypass surgeries and no bleeding complications. Only the patient with post-procedural CK-MB elevation experience recurrence of CCS class 2 angina within the 30 days. CONCLUSION: The R Stent is a promising new device for the treatment of complex coronary heart disease. A larger, more broadly-based study is warranted.     

Differentiation of adult-type Leydig cells occurs in gonadotrophin-deficient mice

During mammalian testis development distinct generations of fetal and adult Leydig cells arise. Luteinising hormone (LH) is required for normal adult Leydig cell function and for the establishment of normal adult Leydig cell number but its role in the process of adult Leydig cell differentiation has remained uncertain. In this study we have examined adult Leydig cell differentiation in gonadotrophin-releasing hormone (GnRH)-null mice which are deficient in circulating gonadotrophins. Adult Leydig cell differentiation was assessed by measuring expression of mRNA species encoding four specific markers of adult Leydig cell differentiation in the mouse. Each of these markers (3β-hydroxysteroid dehydrogenase type VI (3βHSD VI), 17β-hydroxysteroid dehydrogenase type III (17βHSD III), prostaglandin D (PGD)-synthetase and oestrogen sulphotransferase (EST)) is expressed only in the adult Leydig cell lineage in the normal adult animal. Real-time PCR studies showed that all four markers are expressed in adult GnRH-null mice. Localisation of 3βHSD VI and PGD-synthetase expression by in situ hybridisation confirmed that these genes are expressed in the interstitial tissue of the GnRH-null mouse. Treatment of animals with human chorionic gonadotrophin increased expression of 3βHSD VI and 17βHSD III within 12 hours further indicating that differentiated, but unstimulated cells already exist in the GnRH-null mouse. Thus, while previous studies have shown that LH is required for adult Leydig cell proliferation and activity, results from the present study show that adult Leydig cell differentiation will take place in animals deficient in LH.     

A genetic study on C5-TRAF1 and progression of joint damage in rheumatoid arthritis

IntroductionThe severity of joint damage progression in rheumatoid arthritis (RA) is heritable. Several genetic variants have been identified, but together explain only part of the total genetic effect. Variants in Interleukin-6 (IL-6), Interleukin-10 (IL-10), C5-TRAF1, and Fc-receptor-like-3 (FCRL3) have been described to associate with radiographic progression, but results of different studies were incongruent. We aimed to clarify associations of these variants with radiographic progression by evaluating six independent cohorts.MethodsIn total 5,895 sets of radiographs of 2,493 RA-patients included in six different independent datasets from the Netherlands, Sweden, Spain and North-America were studied in relation to rs1800795 (IL-6), rs1800896 (IL-10), rs2900180 (C5-TRAF1) and rs7528684 (FCRL3). Associations were tested in the total RA-populations and in anti-citrullinated peptide antibodies (ACPA)-positive and ACPA-negative subgroups per cohort, followed by meta-analyses. Furthermore, the associated region C5-TRAF1 was fine-mapped in the ACPA-negative Dutch RA-patients.ResultsNo associations were found for rs1800795 (IL-6), rs1800896 (IL-10) and rs7528684 (FCRL3) in the total RA-population and after stratification for ACPA. Rs2900180 in C5-TRAF1 was associated with radiographic progression in the ACPA-negative population (P-value meta-analysis = 5.85 × 10⁻⁷); the minor allele was associated with more radiographic progression. Fine-mapping revealed a region of 66Kb that was associated; the lowest P-value was for rs7021880 in TRAF1. The P-value for rs7021880 in meta-analysis was 6.35 × 10⁻⁸. Previous studies indicate that the region of rs7021880 was associated with RNA expression of TRAF1 and C5.ConclusionVariants in IL-6, IL-10 and FCRL3 were not associated with radiographic progression. Rs2900180 in C5-TRAF1 and linked variants in a 66Kb region were associated with radiographic progression in ACPA-negative RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-014-0514-0) contains supplementary material, which is available to authorized users.     

Full Length Bid is sufficient to induce apoptosis of cultured rat hippocampal neurons

Background  

Bcl-2 homology domain (BH) 3-only proteins are pro-apoptotic proteins of the Bcl-2 family that couple stress signals to the mitochondrial cell death pathways. The BH3-only protein Bid can be activated in response to death receptor activation via caspase 8-mediated cleavage into a truncated protein (tBid), which subsequently translocates to mitochondria and induces the release of cytochrome-C. Using a single-cell imaging approach of Bid cleavage and translocation during apoptosis, we have recently demonstrated that, in contrast to death receptor-induced apoptosis, caspase-independent excitotoxic apoptosis involves a translocation of full length Bid (FL-Bid) from the cytosol to mitochondria. We induced a delayed excitotoxic cell death in cultured rat hippocampal neurons by a 5-min exposure to the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 300 μM).     

Paracrine control of tissue regeneration and cell proliferation by Caspase-3

Executioner caspases such as Caspase-3 and Caspase-7 have long been recognised as the key proteases involved in cell demolition during apoptosis. Caspase activation also modulates signal transduction inside cells, through activation or inactivation of kinases, phosphatases and other signalling molecules. Interestingly, a series of recent studies have demonstrated that caspase activation may also influence signal transduction and gene expression changes in neighbouring cells that themselves did not activate caspases. This review describes the physiological relevance of paracrine Caspase-3 signalling for developmental processes, tissue homeostasis and tissue regeneration, and discusses the role of soluble factors and microparticles in mediating these paracrine activities. While non-cell autonomous control of tissue regeneration by Caspase-3 may represent an important process for maintaining tissue homeostasis, it may limit the efficiency of current cancer therapy by promoting cell proliferation in those cancer cells resistant to radio- or chemotherapy. We discuss recent evidence in support of such a role for Caspase-3, and discuss its therapeutic implication.     

Identification of novel DNA methylation inhibitors via a two-component reporter gene system

Background

The extracellular calcium-sensing receptor (CaSR) belongs to family C of the G protein coupled receptors. Whether the CaSR is expressed in the pulmonary artery (PA) is unknown.

Methods

The expression and distribution of CaSR were detected by RT-PCR, Western blotting and immunofluorescence. PA tension was detected by the pulmonary arterial ring technique, and the intracellular calcium concentration ([Ca²⁺]_i) was detected by a laser-scanning confocal microscope.

Results

The expressions of CaSR mRNA and protein were found in both rat pulmonary artery smooth muscle cells (PASMCs) and PAs. Increased levels of [Ca²⁺]_o (extracellular calcium concentration) or Gd³⁺ (an agonist of CaSR) induced an increase of [Ca²⁺]_i and PAs constriction in a concentration-dependent manner_. In addition, the above-mentioned effects of Ca²⁺ and Gd³⁺ were inhibited by U73122 (specific inhibitor of PLC), 2-APB (specific antagonist of IP₃ receptor), and thapsigargin (blocker of sarcoplasmic reticulum calcium ATPase).

Conclusions

CaSR is expressed in rat PASMCs, and is involved in regulation of PA tension by increasing [Ca²⁺]_i through G-PLC-IP₃ pathway.     

Seropositivity for CMV and IL-6 levels are associated with grip strength and muscle size in the elderly

Background

Sarcopenia is an important cause of morbidity and mortality in older adults, with immunosenescence and inflammation being possible underlying mechanisms. We investigated the relationship between latent cytomegalovirus (CMV) infection, Interleukin 6 (IL-6) levels, muscle size and strength in a group of healthy older community-dwelling people.

Methods

Participants were healthy volunteers from the Lothian Birth Cohort 1936 study. Participants had IL-6 level and CMV antibody titre measured at age 70 years and grip strength and a volumetric T1-weighted MRI brain scan (allowing measurement of neck muscle cross-sectional area (CSA)) at age 73. Markers of childhood deprivation were adjusted for in the analysis due to correlations between childhood deprivation and latent CMV infection.

Results

866 participants were studied; 448 men (mean age 72.48 years, sd 0.70) and 418 women (mean age 72.51 years, sd 0.72). In men, CMV seropositivity was associated with smaller neck muscle CSA (p = 0.03, partial eta squared = 0.01), even after adjustment for IL-6 levels. Neck muscle CSA was not associated with CMV seropositivity in women, or CMV antibody titre or IL-6 level in either sex. Grip strength associated negatively with IL-6 level (right grip strength p<0.00001, partial eta squared 0.032 and left grip strength p<0.00001, partial eta squared 0.027) with or without adjustment for CMV serostatus or antibody titre. CMV status and antibody titre were not significantly associated with grip strength in either hand.

Conclusion

These findings support the hypothesis that there is a relationship between markers of immunosenescence (i.e. CMV serostatus and IL6 level) and low muscle mass and strength and longitudinal studies in older cohorts are now required to investigate these relationships further.