Calcineurin Inhibitor Withdrawal from Sirolimus-Based Therapy in Kidney Transplantation: A Systematic Review of Randomized Trials

Calcineurin inhibitor (CNI) withdrawal has been used as a strategy to improve renal allograft function, however, it also carries risk of acute rejection. We conducted a systematic review of randomized trials that involved CNI withdrawal from a sirolimus-based immunosuppressive regimen. The search strategy yielded six trials (n = 1047 patients) reported in eight publications. CNI withdrawal from sirolimus-based therapy, was associated with an increased risk of acute rejection (risk difference, 6%; 95% CI 2-10%, p = 0.002) but a higher creatinine clearance (mean difference, 7.49 mL/min; 95% CI 5.08-9.89 mL/min, p < 0.00001) at 1 year compared to continued CNI and sirolimus therapy. Graft loss (relative risk, 0.87; 95% CI 0.46-1.64, p = 0.66) and death (relative risk, 0.88; CI 0.40-1.96, p = 0.76) were similar in both groups at 1 year. Hypertension was significantly reduced in the CNI withdrawal group (relative risk, 0.56; 95% CI 0.40-0.78, p = 0.0006). CNI withdrawal from sirolimus-based therapy is associated with an increased risk of acute rejection in the short term with a significant improvement in renal function and a reduction in hypertension. Longer follow-up is needed to determine if these changes will result in a significant improvement in patient and graft survival.     

Glucose-deprivation-induced [3H]D-aspartate release from isolated bovine and human retinae.

The glucose deprivation-induced release of [3H]D-aspartate was studied in bovine and human retinas in a superfusion apparatus. [3H]D-aspartate release was significantly increased upon omitting glucose in the superfusion buffer. This effect was dependent on external Ca2+ because L- and N-type Ca2+-channel blockers, such as diltiazem (1 microM), nitrendipine (1 microM), and omega-conotoxin (100 nM), significantly reduced the effect of glucose-deprivation induced release of [3H]D-aspartate. Furthermore, while glutamate receptor agonists (L-glutamate, N-methyl-D-aspartate, but not kainate) potentiated the effects of glucose deprivation, antagonists (MK-801, MCPG, ifenprodil, and L-AP3) at these receptors blocked the glucose deprivation-induced release process. Taken together, these studies have demonstrated that under conditions of glucose deprivation, as may happen during ischemic events in vivo, the retinal glutamatergic nerve endings and/or glial cells promote the efflux of [3H]D-aspartate into the extracellular environment. This process appears to be receptor-mediated and dependent on extracellular Ca2+ and is similar to previous reports pertaining to brain tissues.     

Prevalence, course, and risk factors for executive impairment in patients hospitalized on a general medicine service

The purpose of this study was to determine the prevalence, course, and risk factors for executive impairment in patients hospitalized on a general medicine service. One hundred patients were administered the Executive Interview (EXIT25), the Executive Clock Drawing Task (CLOX), and the Mini-Mental State Examination at admission and discharge. Fifty-two percent of the patients at admission and 56% at discharge had scores indicating impairment on at least one measure of executive function. Median scores on every measure improved during hospitalization. Older patients and those with a cardiac or gastrointestinal disorder were more likely to have executive impairment. The prevalence of executive impairment on general medicine services is high. Although improvement in executive function occurs during hospitalization, many patients remained impaired.     

Bounds in the Sensitivity of BioMEMS Devices for Cell Detection

This paper presents an ongoing effort to characterize performance and reliability of micro electromechanical systems used for biomedical diagnostics (BioMEMS). In order to study the interactions of human osteosarcoma (HOS) cells with BioMEMS devices, cultures were performed on silicon (Si) surfaces as well as silicon surfaces coated with 50 nm of titanium (Ti). Cell spreading on the surfaces was observed over time for up to 2 hours. It was seen that titanium coated silicon surfaces have the potential to provide a better interface for BioMEMS devices, due to enhanced adherence and spreading of the cells on these surfaces. Atomic force microscope (AFM) cantilevers were used as cell detection sensors. These cantilevers were coated with 50nm of titanium metal to provide a cell friendly surface. Theoretical models were then developed for the prediction of the vibrational responses of the AFM cantilevers before and after cell attachment. The models were used to relate the experimentally observed changes in frequency to the number of cells that are attached on the cantilever. The bounds in the possible frequency changes were determined within a theoretical framework. From experimentally calculated values for the mass of cells, random number simulations were carried out to determine the probability of cell attachment as a function of the change in resonance frequency of the cantilever sensor. The implications of the results are then discussed for the future reliability modeling of the sensor.     

C-spine clearance in poly-trauma patients: A narrative review

The incidence of cervical spine injury in patients with polytrauma is 3.7%. Early identification and management of cervical spine injuries in these patients play a crucial role in preventing secondary cervical spine and cord injuries. C-spine clearance assumes a pivotal role in reducing the morbidity and mortality associated with cervical spine injury. Despite the availability of various validated management algorithms and protocols for C-spine clearance, there are several controversies regarding C-spine clearance, such as the ideal protocol and imaging modality, clearance of obtunded patients and management of patients that lie out of the described protocols and rules. The current article aims to provide a comprehensive review of the relevant literature and address the prevalent controversies.     

Management of Neglected Upper Cervical Spine Injuries

BackgroundInjuries involving upper cervical spine are serious and fatal injuries which are associated with alteration of normal occipital–cervical anatomy. These injuries may result in permanent neurologic deficits or neck deformity if not treated in a timely and appropriate manner.ObjectiveTo evaluate the outcomes of neglected upper cervical spine injuries treated by various methods.Study designRetrospective study.Materials and methodsTwelve patients attending ER or OPD with a history of neck trauma and who were diagnosed with fractures and fracture dislocations C1 and C2 were included in the study. Fresh injuries sustained within a week were excluded from study. The outcomes were measured in terms of improvement in VAS, ODI Scores and correction of the neck deformity. Surgical parameters like duration of surgery and blood loss were also observed.ResultsEleven males and one female. The mean age was 40.9 ± 16.9 (07–67 years). Eleven patients underwent posterior instrumentation, while one patient was treated anteriorly. The mean delay in presentation was 28 ± 8.67 days (15–42 days). The mean duration of surgery was 188.3 ± 34.35 min (120–240 min), average blood loss was 350 ± 111.8 ml (150–600 ml). The mean VAS improved from 8.45 ± 0.89 to 3.9 ± 0.51 (p < 0.05). The mean ODI Pre-operatively was 88.45 ± 5.89 which improved to 31.9 ± 4.01 (p < 0.05). The neck deformity/torticollis was corrected in all the patients.ConclusionsNeglected upper cervical spine injuries are difficult to treat and a posterior approach is helpful in reducing the subluxations indirectly and to obtain a posterior fusion.     

Podocyte loss involves MDM2‐driven mitotic catastrophe

Podocyte apoptosis as a pathway of podocyte loss is often suspected but rarely detected. To study podocyte apoptosis versus inflammatory forms of podocyte death in vivo, we targeted murine double minute (MDM)‐2 for three reasons. First, MDM2 inhibits p53‐dependent apoptosis; second, MDM2 facilitates NF‐κB signalling; and third, podocytes show strong MDM2 expression. We hypothesized that blocking MDM2 during glomerular injury may trigger p53‐mediated podocyte apoptosis, proteinuria, and glomerulosclerosis. Unexpectedly, MDM2 blockade in early adriamycin nephropathy of Balb/c mice had the opposite effect and reduced intra‐renal cytokine and chemokine expression, glomerular macrophage and T‐cell counts, and plasma creatinine and blood urea nitrogen levels. In cultured podocytes exposed to adriamycin, MDM2 blockade did not trigger podocyte death but induced G2/M arrest to prevent aberrant nuclear divisions and detachment of dying aneuploid podocytes, a feature of mitotic catastrophe in vitro and in vivo. Consistent with these observations, 12 of 164 consecutive human renal biopsies revealed features of podocyte mitotic catastrophe but only in glomerular disorders with proteinuria. Furthermore, delayed MDM2 blockade reduced plasma creatinine levels, blood urea nitrogen, tubular atrophy, interstitial leukocyte numbers, and cytokine expression as well as interstitial fibrosis. Together, MDM2‐mediated mitotic catastrophe is a previously unrecognized variant of podocyte loss where MDM2 forces podocytes to complete the cell cycle, which in the absence of cytokinesis leads to podocyte aneuploidy, mitotic catastrophe, and loss by detachment. MDM2 blockade with nutlin‐3a could be a novel therapeutic strategy to prevent renal inflammation, podocyte loss, glomerulosclerosis, proteinuria, and progressive kidney disease. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Neutrophil Extracellular Trap-Related Extracellular Histones Cause Vascular Necrosis in Severe GN

Severe GN involves local neutrophil extracellular trap (NET) formation. We hypothesized a local cytotoxic effect of NET-related histone release in necrotizing GN. In vitro, histones from calf thymus or histones released by neutrophils undergoing NETosis killed glomerular endothelial cells, podocytes, and parietal epithelial cells in a dose-dependent manner. Histone-neutralizing agents such as antihistone IgG, activated protein C, or heparin prevented this effect. Histone toxicity on glomeruli ex vivo was Toll-like receptor 2/4 dependent, and lack of TLR2/4 attenuated histone-induced renal thrombotic microangiopathy and glomerular necrosis in mice. Anti–glomerular basement membrane GN involved NET formation and vascular necrosis, whereas blocking NET formation by peptidylarginine inhibition or preemptive anti-histone IgG injection significantly reduced all aspects of GN (i.e., vascular necrosis, podocyte loss, albuminuria, cytokine induction, recruitment or activation of glomerular leukocytes, and glomerular crescent formation). To evaluate histones as a therapeutic target, mice with established GN were treated with three different histone-neutralizing agents. Anti-histone IgG, recombinant activated protein C, and heparin were equally effective in abrogating severe GN, whereas combination therapy had no additive effects. Together, these results indicate that NET-related histone release during GN elicits cytotoxic and immunostimulatory effects. Furthermore, neutralizing extracellular histones is still therapeutic when initiated in established GN.     

An evaluation of wear of human enamel opposed by ceramics of different surface finishes

Statement of Problem:

Surface of porcelain restoration is a matter of clinical concern because of its abrasive action on the opposing enamel.

Purpose:

This study comparatively evaluated wear of enamel when opposed by three different surface finishes of ceramic.

Materials and Methods:

A total of 60 metal-ceramic discs (10 mm × 2 mm) with different surface finishes were fabricated. They were divided into four groups of autoglazed ceramic surface, over glazed ceramic surface, ceramic surface polished with Shofu polishing kit and ceramic surface polished with DFS polishing wheels and paste. Each group comprised of 15 discs. Sixty human teeth samples were prepared from freshly extracted, unrestored, caries free, nonattrited maxillary first premolars. Each tooth sample was weighed before wear testing using AT200 Mettler Toledo electronic analytical balance of 0.0001 g accuracy. Occlusal surfaces of these teeth were then abraded against the substrates in a wear machine for a total of 10,000 cycles. Each tooth sample was weighed after 5000 cycles and after the total of 10,000 cycles, respectively, using the same balance. Differences in weight of tooth samples before and after wear testing were evaluated statistically using one-way analysis of variance and Bonferroni''s correction for multiple group comparisons.

Results:

The values obtained for percentage weight loss after 10,000 cycles for over glazed ceramic surface were marginally higher than values obtained for autoglazed surface. It was observed that values obtained for percentage weight loss by polished ceramic after 10,000 cycles were statistically less as compared to the values obtained with autoglazed and over glazed ceramic surface (P < 0.001). There was no statistically significant difference between the values obtained by polished ceramic surfaces of two different groups.

Conclusion:

Enamel wear produced by polished porcelain is substantially less than autoglazed and over glazed porcelain. No significant difference was found in enamel wear when opposed by ceramic surfaces polished by two different methods. This study indicates the potential damage porcelain can inflict upon enamel and suggests that porcelain should be polished instead of over glazed.     

Acute kidney injury in critically ill children: Risk factors and outcomes

Background:

Acute kidney injury (AKI) is common in patients in the pediatric intensive care unit (PICU) and is associated with poor outcome. We conducted the present study to determine the incidence, risk factors and outcomes of AKI in the PICU.

Materials and Methods:

We collected data retrospectively from case records of children admitted to the PICU during one year. We defined and classified AKI according to modified pRIFLE criteria. We used multivariate logistic regression to determine risk factors of AKI and association of AKI with mortality and morbidity.

Results:

Of the 252 children included in the study, 103 (40.9%) children developed AKI. Of these 103 patients with AKI, 39 (37.9%) patients reached pRIFLE max of Risk, 37 (35.9%) patients reached Injury, and 27 (26.2%) had Failure. Mean Pediatric Risk of Mortality (PRISM III) score at admission was higher in patients with AKI than in controls (P < 0.001).