A comparison of vitamin D activity in paired non-malignant and malignant human breast tissues

Links between a low vitamin D status and an increased risk of breast cancer have been observed in epidemiological studies. These links have been investigated in human tissue homogenates and cultured cell lines. We have used non-malignant, malignant and normal reduction mammoplasty breast tissues to investigate the biological and metabolic consequences of the application of vitamin D to intact ex vivo human breast tissue. Tissues were exposed to 1α,25(OH)(2)D(3) (1,25D; active metabolite) and 25(OH)D (25D; pre-metabolite). Changes in mRNA expression and protein expression after vitamin D exposure were analysed. Results indicate that while responses in normal and non-malignant breast tissues are similar between individuals, different tumour tissues are highly variable with regards to their gene expression and biological response. Collectively, malignant breast tissue responds well to active 1,25D, but not to the inactive pre-metabolite 25D. This may have consequences for the recommendation of vitamin D supplementation in breast cancer patients.     

Low-Dose Rituximab Therapy for Antibody-Mediated Rejection in a Highly Sensitized Heart-Transplant Recipient

Antibody-mediated rejection is the B-cell–mediated production of immunoglobulin G antibody against the transplanted heart. The currently available therapies for antibody-mediated rejection have had marginal success, and chronic manifestations of rejection can result in an increased risk of graft vasculopathy and perhaps require repeat transplantation. Rituximab, a monoclonal antibody directed against the CD20 receptor of B-lymphocytes and approved as therapy for lymphoma, can be used in heart-transplant patients for the management of antibody-mediated rejection.We present the case of a 52-year-old woman with high allosensitization (pre-transplantation panel reactive antibody level, 72%) who underwent successful orthotopic heart transplantation. Postoperatively, her acute antibody-mediated rejection with concomitant cellular rejection was successfully treated with low-dose rituximab. The patient died 5 months later because of multiple other medical problems. The present case suggests a role for low-dose rituximab as therapy for antibody-mediated rejection in heart-transplant patients.Key words: Antibodies, monoclonal/therapeutic use; antigens, CD20/immunology; B-lymphocytes/immunology; graft rejection/drug therapy; heart transplantation/pathology; HLA antigens/immunology; immunity, humoral/physiology/therapy; immunoglobulins, intravenous/metabolism; plasmapheresis; rituximab; time factorsAntibody-mediated rejection (AMR) in heart-transplant recipients is mediated by donor-specific antibodies and is histologically defined by linear deposits of immunoglobulin (Ig) and complement in the myocardial capillaries.¹ Antibody-mediated rejection is often accompanied by hemodynamic compromise and is associated with diminished graft survival. Standard immunosuppressive therapy, designed to target T-cell immune function, is largely ineffective against this B-cell–driven process. Various therapies for AMR, although available, can be of marginal use secondary to patients'' comorbidities.^2,3 We present the case of a woman with a history of ventricular assist device (VAD) implantation, dialysis dependence, and severe thrombocytopenia who responded well to the addition of anti-CD20 monoclonal antibody therapy with rituximab after heart transplantation.     

A case of an atypically large proximal 15q deletion as cause for Prader–Willi syndrome arising from a de novo unbalanced translocation

We describe an 11 month old female with Prader–Willi syndrome (PWS) resulting from an atypically large deletion of proximal 15q due to a de novo 3;15 unbalanced translocation. The 10.6 Mb deletion extends from the chromosome 15 short arm and is not situated in a region previously reported as a common distal breakpoint for unbalanced translocations. There was no deletion of the reciprocal chromosome 3q subtelomeric region detected by either chromosomal microarray or FISH. The patient has hypotonia, failure to thrive, and typical dysmorphic facial features for PWS. The patient also has profound global developmental delay consistent with an expanded, more severe, phenotype.     

Increased risk of pneumonia among ventilated patients with traumatic brain injury: every day counts!

Background

Patients with traumatic brain injury (TBI) frequently require mechanical ventilation (MV). The objective of this study was to examine the association between time spent on MV and the development of pneumonia among patients with TBI.

Materials and methods

Patients older than 18 y with head abbreviated injury scale (AIS) scores coded 1–6 requiring MV in the National Trauma Data Bank 2007–2010 data set were included. The study was limited to hospitals reporting pneumonia cases. AIS scores were calculated using ICDMAP-90 software. Patients with injuries in any other region with AIS score >3, significant burns, or a hospital length of stay >30 d were excluded. A generalized linear model was used to determine the approximate relative risk of developing all-cause pneumonia (aspiration pneumonia, ventilator-associated pneumonia [VAP], and infectious pneumonia identified by the International Classification of Disease, Ninth Revision, diagnosis code) for each day of MV, controlling for age, gender, Glasgow coma scale motor score, comorbidity (Charlson comorbidity index) score, insurance status, and injury type and severity.

Results

Among the 24,525 patients with TBI who required MV included in this study, 1593 (6.5%) developed all-cause pneumonia. After controlling for demographic and injury factors, each additional day on the ventilator was associated with a 7% increase in the risk of pneumonia (risk ratio 1.07, 95% confidence interval 1.07–1.08).

Conclusions

Patients who have sustained TBIs and require MV are at higher risk for VAP than individuals extubated earlier; therefore, shortening MV exposure will likely reduce the risk of VAP. As patients with TBI frequently require MV because of neurologic impairment, it is key to develop aggressive strategies to expedite ventilator independence.     

Periprosthetic joint infection: Current concept

Periprosthetic joint infection (PJI) is one of the most devastating and costly complications following total joint arthroplasty (TJA). Diagnosis and management of PJI is challenging for surgeons. There is no “gold standard” for diagnosis of PJI, making distinction between septic and aseptic failures difficult. Additionally, some of the greatest difficulties and controversies involve choosing the optimal method to treat the infected joint. Currently, there is significant debate as to the ideal treatment strategy for PJI, and this has led to considerable international variation in both surgical and nonsurgical management of PJI. In this review, we will discuss diagnosis and management of PJI following TJA and highlight some recent advances in this field.     

The relationship between circulating endothelin-1, soluble fms-like tyrosine kinase-1 and soluble endoglin in preeclampsia

Placental overproduction of anti-angiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng) has a key role in the development of preeclampsia (PE). Circulating endothelin-1 (ET-1) levels are also elevated in PE. In this study, we investigated the correlation between ET-1 and sFlt-1, placental growth factor (PlGF), sEng levels during uncomplicated normotensive pregnancy and PE. A total of 218 pregnant primigravid women were enrolled: 110 with PE and 108 uncomplicated normotensive pregnancies. PE was defined as new onset of elevated blood pressure (BP) >140/90?mm?Hg and ≥2+ proteinuria on two occasions after 20 weeks of gestation in previously normotensive pregnant women. Circulating ET-1, sFlt-1, sEng and PlGF levels were estimated using enzyme immunoassays, and correlation between variables was ascertained. Women with PE showed higher levels of sFlt-1 (41.5±15.7 vs 6.15±3.4?ng?ml(-1), P<0.001), sEng (84.9±38.8 vs 13.2±6.3?ng?ml(-1), P<0.001), ET-1 (1.52±0.55 vs 0.88±0.35 pg?ml(-1), P<0.001) and sFlt-1:PlGF ratio (591.1±468.4 vs 18.3±2.1, P<0.001); and lower levels of PlGF (96.3±47.2 vs 497.6±328.2 pg?ml(-1), P<0.001). BP levels showed an independent relationship with sFlt-1:PlGF ratio in normotensive pregnant women and with sFlt-1:PlGF ratio and ET-1 in PE. sFlt-1 and sFlt-1:PlGF ratio correlated with proteinuria. ET-1 correlated significantly with sFlt-1, sEng and sFlt-1:PlGF ratio in PE. Our results show an association between elevation of sFlt-1 and sEng and ET-1 in the maternal circulation in PE, and strengthen the possibility that ET-1 may be a mediator in genesis of PE syndrome secondary to anti-angiogenic factors released by the placenta.     

Utility of Sonoclot analysis and tranexamic acid in tetralogy of Fallot patients undergoing intracardiac repair

Sonoclot analysis is a point of care test to monitor the coagulation process, presenting a comprehensive evaluation of the clot formation and retraction as well as platelet function. This randomized double-blinded study was designed to investigate the utility of Sonoclot analysis in monitoring the coagulation profile as also the antifibrinolytic effects of tranexamic acid administered in patients with tetralogy of Fallot undergoing intracardiac repair. Eighty of a total 94 patients were randomly divided into two groups of 40 each. In the study group, TA was administered thrice at a dosage of 10 mg/kg, i.e. before CPB, on CPB and after CPB, whereas in the control group, placebo was administered at the same time intervals. Sonoclot analysis and D-dimer measurement were performed at baseline and following heparin neutralisation. An additional variable, DR?? (diminishing rate of clot strength at 15 min postmaximal clot strength), was calculated from the Sonoclot graph and was compared with d-dimer levels as a measure of fibrinolysis. The three Sonoclot variables, i.e. activated clotting time, clot rate and platelet function, were deranged at baseline in all the patients. Post-CPB, the change in these variables was not significant. ACT, clot rate and platelet function showed no significant (P > 0.05) difference in both the groups at both the time intervals. DR?? and d-dimer values were comparable at baseline in both the groups. However, a significant (P < 0.05) difference was seen in these variables in the control group as compared with the TA group following heparin neutralisation. To conclude, Sonoclot analysis is a useful, point of care method for the monitoring of coagulation and fibrinolysis in patients with tetralogy of Fallot undergoing intracardiac repair.