A comparison of self-reported risk and protective factors and the death implicit association test in the prediction of future suicide attempts in adolescent emergency department patients.

BACKGROUND: Concerns have been raised about the utility of self-report assessments in predicting future suicide attempts. Clinicians in pediatric emergency departments (EDs) often are required to assess suicidal risk. The Death Implicit Association Test (IAT) is an alternative to self-report assessment of suicidal risk that may have utility in ED settings. METHODS: A total of 1679 adolescents recruited from 13 pediatric emergency rooms in the Pediatric Emergency Care Applied Research Network were assessed using a self-report survey of risk and protective factors for a suicide attempt, and the IAT, and then followed up 3 months later to determine if an attempt had occurred. The accuracy of prediction was compared between self-reports and the IAT using the area under the curve (AUC) with respect to receiver operator characteristics. RESULTS: A few self-report variables, namely, current and past suicide ideation, past suicidal behavior, total negative life events, and school or social connectedness, predicted an attempt at 3 months with an AUC of 0.87 [95% confidence interval (CI), 0.84-0.90] in the entire sample, and AUC = 0.91, (95% CI 0.85-0.95) for those who presented without reported suicidal ideation. The IAT did not add significantly to the predictive power of selected self-report variables. The IAT alone was modestly predictive of 3-month attempts in the overall sample ((AUC = 0.59, 95% CI 0.52-0.65) and was a better predictor in patients who were non-suicidal at baseline (AUC = 0.67, 95% CI 0.55-0.79). CONCLUSIONS: In pediatric EDs, a small set of self-reported items predicted suicide attempts within 3 months more accurately than did the IAT.

MGMT-inhibitor in combination with TGF-BRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells

Background Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-βRI inhibitor) seeking to overcome GB treatment resistance. Methods Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. Results Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-β–dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. Conclusion This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells (AU)

MGMT-inhibitor in combination with TGF-ßRI inhibitor or CDK 4/6 inhibitor increases temozolomide sensitivity in temozolomide-resistant glioblastoma cells.

BACKGROUND: Glioblastoma (GB) remains an incurable and deadly brain malignancy that often proves resistant to upfront treatment with temozolomide. Nevertheless, temozolomide remains the most commonly prescribed FDA-approved chemotherapy for GB. The DNA repair protein methylguanine-DNA methyl transferase (MGMT) confers resistance to temozolomide. Unsurprisingly temozolomide-resistant tumors tend to possess elevated MGMT protein levels or lack inhibitory MGMT promotor methylation. In this study, cultured human temozolomide resistance GB (43RG) cells were introduced to the MGMT inhibitor O6-benzylguanine combined with temozolomide and either LY2835219 (CDK 4/6 inhibitor) or LY2157299 (TGF-ßRI inhibitor) seeking to overcome GB treatment resistance. METHODS: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot, cell viability, and cell cycle progression. RESULTS: Our in vitro study demonstrated that sequential treatment of O6-Benzylguanine with either LY2385219 or LY2157299-enhanced temozolomide enhanced sensitivity in MGMT+ 43RG cells. Importantly, normal human neurons and astrocytes remained impervious to the drug therapies under these conditions. Furthermore, LY2835219 has additional anti-proliferative effects on cell cycling, including induction of an RB-associated G (1) arrest via suppression of cyclin D-CDK4/6-Rb pathway. LY2157299 enhances anti-tumor effect by disrupting TGF-ß-dependent HIF-1α signaling and by activating both Smad and PI3K-AKT pathways towards transcription of S/G2 checkpoints. CONCLUSION: This study establishes the groundwork for the development of a combinatorial pharmacologic approach by using either LY2385219 or LY2157299 inhibitor plus O6-Benzylguanine to augment temozolomide response in temozolomide-resistant GB cells.

Leukocyte-dependent effects of platelet-rich plasma on cartilage loss and thermal hyperalgesia in a mouse model of post-traumatic osteoarthritis.

OBJECTIVE: Platelet-rich plasma (PRP) is an emerging therapeutic strategy for treatment of osteoarthritis (OA); however, there is a lack of preclinical and clinical evidence for its efficacy and its mechanism of action is unclear. In the current study, we utilized leukocyte poor-PRP (LP-PRP) and leukocyte rich-PRP (LR-PRP) to mimic clinical point of care formulations and assessed their potential to alter disease progression in a mouse model of post-traumatic OA. METHOD: Three-month-old wild-type male FVB/N mice received destabilization of the medial meniscus (DMM) surgery to induce OA. To assess the efficacy of LP-PRP and LR-PRP, mice were given intraarticular injections at 2-, 7- and 28-days post-surgery. Mice were then assessed at 5-, 9-, and 13-weeks post-surgery for changes in chronic pain using the hot plate nociceptive assay. At 14-weeks, OA pathogenesis was evaluated using histology and phase-contrast µCT. RESULTS: Treatment with LP-PRP and to a lesser extent LR-PRP preserved cartilage volume and surface area compared to phosphate-buffered saline (PBS) as measured by phase-contrast µCT. However, both treatments had higher Osteoarthritis Research Society International (OARSI) and synovitis scores compared to sham, and neither substantially improved scores compared to PBS controls. With respect to thermal hyperalgesia, PBS-treated mice displayed reduced latency to response compared to sham, and LR-PRP but not LP-PRP improved latency to response at 5-, 9- and 13-weeks post-surgery compared to PBS. CONCLUSION: The results of this study suggest that effects of PRP therapy on OA progression and disease-induced hyperalgesia may be leukocyte-dependent. And while LP-PRP and to a lesser extent LR-PRP protect from volume and surface loss, significant pathology is still seen within OA joints. Future work is needed to understand how the different components of PRP effect OA pathogenesis and pain, and how these could be modified to achieve greater therapeutic efficacy.

Evaluating anti-tumor activity of palbociclib plus radiation in anaplastic and radiation-induced meningiomas: pre-clinical investigations.

PURPOSE: Meningiomas are common brain tumors, the majority of which are considered benign. Despite surgery and/or radiation therapy, recurrence rates are approximately 8-10%. One likely cause is the dysregulation of cyclin D-cyclin-dependent kinases 4 and 6 (CDK4/6)-retinoblastoma (Rb) pathway, which controls the cell cycle restriction point. This pathway is commonly dysregulated in anaplastic meningioma cell lines (AM) and radiation-induced meningioma cells (RIM), making it a rational target for anti-meningioma therapy. In this study, we investigate the effect of a CDK4/6 inhibitor, palbociclib, with radiation in relevant pre-clinical models. METHODS: In vitro cell culture, ex vivo slice culture and in vivo cell line-derived orthotopic xenograft animal models of AM/RIM were utilized to assess treatment efficacy with palbociclib plus radiation. Treatment effects were examined by immunoblot, cell viability, apoptosis, and cell cycle progression. RESULTS: The in vitro and ex vivo studies demonstrate that palbociclib plus radiation treatment reduced proliferation and has additional effects on cell cycling, including induction of an RB-associated G (1) arrest in Rb+ AM and RIM cells, but not in Rb- cells. Our results also demonstrated reduced CDK4 and CDK6 expression as well as reduced E2F target gene expression (CCNA2 and CCNE2) with the combination therapy. MRI results in vivo demonstrated reduced tumor size at 5 weeks when treated with 14 days palbociclib (10 mg/kg) plus 6 Gy radiation compared to saline-treated tumors. Finally, no hepatic toxicity was found after treatments. CONCLUSION: A pre-clinical murine model provides preclinical evidence for use of palbociclib plus radiation as a therapeutic agent for Rb+ meningiomas.

Ganoderic acid A/DM-induced NDRG2 over-expression suppresses high-grade meningioma growth.

PURPOSE: N-myc downstream-regulated gene 2 (NDRG2) is down-regulated in grade-III meningioma [anaplastic meningioma (AM)] and associated with clinically aggressive behavior. Current therapies in the treatment of high-grade meningioma are lacking with limited success. This study aims to validate the effect of NDRG2-targeted therapy using structurally related bioactive triterpene compounds derived from the edible mushroom Ganoderma lucidum (ganoderic acid A:GA-A/ganoderic acid DM:GA-DM) in human AM in relevant pre-clinical models. METHODS: Tissue samples from the AM tumor regions of three human patients and control non-tumor samples were used to analyze the expression pattern of NDRG2. In vitro cell culture and in vivo cell-line-derived orthotopic xenograft animal models of AM were utilized to assess efficacy of treatment with GA-A/DM. RESULTS: Downregulation of NDRG2 expression was observed in surgically resected high-grade meningiomas compared to normal brain. These results prompt us to use NDRG2-targeting agents GA-A/DM. In vitro results showed that 72-h treatments of 25 µM GA-A/DM induced AM cell death, upregulate NDRG2 protein expression, downregulate NDRG2 promoter methylation in meningioma cells as compared to azacitidine and decitabine, the most commonly used demethylating agents. Our results also demonstrated that GA-A/DM does not have any detrimental effect on normal human neurons and arachnoid cells. GA-A/DM promoted apoptotic factors (Bax) while suppressing MMP-9, p-P13K, p-AKT, p-mTOR, and Wnt-2 protein expression. RNAi-mediated knockdown of NDRG2 protein expression increased tumor proliferation, while forced expression of wt-NDRG2 decreased proliferation in an in vitro model. Magnetic resonance (MR) imaging and Hematoxylin (H&E) staining demonstrated gross reduction of tumor volume in GA-A/DM treated mice at 5 weeks when compared with saline-treated orthotopic AM xenografted controls. There was an overall decrease in tumor cell proliferation with increased survival in GA-A/DM-treated animals. Enzyme assays showed that GA-A/DM did not negatively impact hepatic function. CONCLUSION: GA-A/DM may be a promising natural therapeutic reagent in the treatment of AM by suppressing growth via NDRG2 modulation and altering of intracellular signal pathways. We have shown it could potentially be an effective treatment for AM with decreased cellular proliferation in vitro, decreased tumor volume and increased survival in vivo.

The efficacy of unilateral laparoscopic nephrectomy in the pediatric hypertensive patient.

BACKGROUND: Secondary hypertension due to a poorly functioning or non-functional kidney may be refractory to medical management. In such cases, nephrectomy can improve or cure hypertension. With the routine use of laparoscopy, nephrectomy can be performed in a minimally invasive manner, but surgery still carries inherent risks and complications. OBJECTIVE: The objective of this study is to evaluate the outcomes of laparoscopic nephrectomy performed for secondary hypertension and identify potential predictors of postoperative hypertension resolution. METHODS: After obtaining approval from institutional review board, patients from January 2002 to March 2018 who underwent laparoscopic nephrectomy were identified using Current Procedural Technology codes. All charts were then manually reviewed to isolate those patients with secondary hypertension present preoperatively. Patient demographics, urologic history, and laboratory and imaging findings were recorded for all patients. Serial blood pressures were recorded at all renal visits along with any antihypertensive medication changes. Postoperative outcomes and complications were also noted for all patients. RESULTS: A total of 20 patients (7 girls, 13 boys) underwent laparoscopic nephrectomy to treat hypertension at an average age of 10.6 years (range 1.7-17.0 years). Etiology of a solitary non-functional kidney was vesicoureteral reflux in 10 of 20 patients, multicystic dysplastic kidney in 5 of 20, ureteropelvic junction obstruction in 2 of 20, ureteral obstruction in 1 of 20, and renal artery stenosis in 2 of 20 patients. At time of surgery, 3 of 20 patients were on two antihypertensives, 10 of 20 were on one antihypertensive, and 7 of 20 proceeded to surgery with no medical management. In the 30-day postoperative period, no complications were noted. Hypertension improved in 10 of 20 (50%) patients, all of whom were not on any antihypertensive medications after surgery. Hypertension persisted in 4 of 20 (20%) patients, requiring the same antihypertensive regimen and worsened in 6 of 20 (30%) patients, requiring increased doses and/or additional antihypertensives. Average follow-up time was 2.7 years. No significant predictors of postoperative hypertension result were identified when comparing the groups of responders and non-responders. DISCUSSION: While laparoscopic nephrectomy for a non-functioning kidney in the setting of hypertension is a safe procedure, the cure rate for hypertension in the cohort appears to be on the low side of what was previously reported. While the small sample size is a main limitation, it is among the largest sample sizes for pediatric hypertensive patients. Previously shown predictors were not predictive in the similar-sized cohort. CONCLUSIONS: Patients should be carefully counseled on the risks and benefits of nephrectomy to treat hypertension, the importance of continued follow-up after nephrectomy, and the possible need for chronic medical management with antihypertensives.

Optimizing empiric therapy for Gram-negative bloodstream infections in children.

Antimicrobial stewardship can be challenging in children with bloodstream infections (BSIs) caused by Gram-negative bacilli (GNB). This retrospective cohort study explored how data elements in the electronic health record could potentially optimize empiric antibiotic therapy for BSIs caused by GNB, via the construction of customized antibiograms for categorical GNB infections and identification of opportunities to minimize organism-drug mismatch and decrease time to effective therapy. Our results suggest potential strategies that could be implemented at key decision points in prescribing at initiation, modification, and targeting of therapy.

Observation of a topologically non-trivial surface state in half-Heusler PtLuSb (001) thin films.

The discovery of topological insulators, materials with bulk band gaps and protected cross-gap surface states in compounds such as Bi2Se3, has generated much interest in identifying topological surface states (TSSs) in other classes of materials. In particular, recent theoretical calculations suggest that TSSs may be found in half-Heusler ternary compounds. If experimentally realizable, this would provide a materials platform for entirely new heterostructure spintronic devices that make use of the structurally identical but electronically varied nature of Heusler compounds. Here we show the presence of a TSS in epitaxially grown thin films of the half-Heusler compound PtLuSb. Spin- and angle-resolved photoemission spectroscopy, complemented by theoretical calculations, reveals a surface state with linear dispersion and a helical tangential spin texture consistent with previous predictions. This experimental verification of topological behaviour is a significant step forward in establishing half-Heusler compounds as a viable material system for future spintronic devices.

Combination Drug Products for HIV-A Word of Caution for the Transplant Clinician.

Modern-day treatment regimens for human immunodeficiency virus (HIV) are not only highly effective, but are now more often available as convenient fixed-dose combination products. Furthermore, as medication adherence is of utmost importance in this setting, national guidelines endorse the use of such products. Transplant providers of HIV-infected patients will undoubtedly encounter these products, some of which contain medications known to drastically alter the metabolism of certain immunosuppressants. Herein, we describe an instance of drug interaction-induced calcineurin inhibitor (CNI) nephrotoxicity in a renal transplant recipient being started on a cobicistat-containing combination product for HIV. CNI toxicity, in turn, was resolved with the aid of phenytoin as an inducer of drug metabolism. This case underscores the importance of familiarity with newer combination products on the market and constant communication with HIV-positive transplant recipients and their providers.

Efficacy of spinal additives neostigmine and magnesium sulfate on characteristics of subarachnoid block, hemodynamic stability and postoperative pain relief: A randomized clinical trial.

BACKGROUND: Intrathecal neostigmine and magnesium sulfate (MgSO4) produce substantial antinociception, potentiate analgesia of bupivacaine without neurotoxicity. AIMS: The aim was to investigate the effect of neostigmine and MgSO4 on characteristics of spinal anesthesia (SA), hemodynamic stability and postoperative analgesia when added to 0.5% hyperbaric bupivacaine for SA. SUBJECTS AND METHODS: In this prospective, randomized, double-blind study 75 American Society of Anesthesiologist status I and II adult females posted for major gynecological surgery were assigned to one of the three groups (n = 25). Group N received Neostigmine 25 µg, Group M received MgSO4 50 mg, Group C received 0.5 ml saline as an adjuvant to 17.5 mg hyperbaric bupivacaine. Onset, duration of block, heart rate, mean arterial pressure, postoperative analgesia, analgesic requirement, and adverse effects were recorded. Data expressed as mean (standard deviation) or number (%). P <0.05 were statistically significant. RESULTS: The three groups were comparable in characteristics of SA. The mean duration of analgesia was significantly longer in Group N (5.1 h) followed by Group M (4.2 h) and Group C (3.8 h) (P = 0.0134). Analgesic requirement was significantly less in Group N followed by Group M and Group C (P = 0.00232). The pain score was significantly less in Group M (P < 0.05). The incidence of hypotension and vasopressor requirement was lowest (48%) in Group N than in Group M (64%) and Group C 84% (P = 0.0276). The incidence of bradycardia and atropine requirement was the lowest in Group M (P = 0.0354). Sedation was observed in 56% patients in Group M compared to 20% in Group N and 8% in Group C (P = 0.0004). CONCLUSION: Intrathecal Neostigmine and MgSo4 does not affect characteristics of SA. Postoperative analgesia of neostigmine was better than MgSO4. Neostigmine provides some protection against hypotension of SA whereas MgSO4 protects against bradycardia.

Observations on the use of cidofovir for BK virus infection in renal transplantation.

BACKGROUND: In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir. METHODS: We evaluated kidney and kidney-pancreas recipients who received cidofovir combined with reduced IS for management of high-level BKV or BK virus nephropathy (BKVN). We examined the rate and timing of BKV clearance, and performed a multivariate analysis to identify risk factors associated with long-term (>6 months) viremia. RESULTS: In total, 75 patients received a median of 13 doses of cidofovir in conjunction with reduced IS; 32 patients (43%) had short-term BKV (≤6 months), and 43 (57%) had long-term BKV. Overall, 53 of 75 patients (71%) eventually cleared BKV at a median of 4.2 months (interquartile range 2.1-9.3 months). Independent factors associated with long-term BKV included older age (odds ratio [OR] 1.1, P = 0.02), delayed graft function (OR 31.4, P = 0.01), and higher peak BKV (OR 12.8, P = 0.02), while BKV reduction by at least 1 log(10) copies/mL at 1 month of treatment was associated with clearance within 6 months (OR 49.3, P < 0.01). Patients with earlier clearance maintained stable graft function and no graft losses, while long-term BKV was associated with a 15% decline in estimated glomerular filtration rate. CONCLUSIONS: Adjunct cidofovir resulted in preservation of renal function when viral clearance occurred within 6 months of initiation. This retrospective review defines factors predicting response to cidofovir in conjunction with reduced IS for BKVN or high-level BKV. Still, considering cost, frequency of administration, and treatment duration, a randomized trial is necessary to define the exact utility of cidofovir in the setting of BK virus infection.

Outcomes of living donor renal transplants with a negative cross-match and pretransplant donor-specific antibody.

INTRODUCTION: Management of renal transplant recipients with a negative complement-dependent cytotoxicity-antihuman globulin (CDC-AHG) cross-match and pretransplant donor-specific antibody (DSA) is controversial. We sought to compare outcomes of immunologically high-risk living donor (LD) renal transplant recipients with and without DSA. METHODS: We conducted a single-center, retrospective review of all high immune-risk LD renal transplant recipients with a negative CDC-AHG cross-match performed between January 2008 and December 2010. Pretransplant desensitization for DSA was not utilized. Immunosuppression consisted of thymoglobulin induction, followed by tacrolimus, myeophenolate mofetil, and prednisone. DSA was assessed pretransplant and at 1, 3, 6, 9, and 12 months, and every 6 months thereafter. RESULTS: Between January 2008 and December 2010, 44 LD renal transplants were performed in high immune-risk recipients with a negative CDC-AHG cross-match. Outcomes of 14 recipients with pretransplant DSA were compared with 30 recipients with no DSA. After a median follow-up of 26 months (range, 12-40), overall death-censored graft survival was 100%, with no acute rejection episodes in the DSA group and 1 antibody-mediated rejection in the non-DSA cohort. Mean serum creatinines of the DSA and non-DSA groups at 1 year post-transplant were 1.0 ± 0.4 and 1.2 ± 0.6 mg/dL (P = NS), respectively. Among the pretransplant DSA cohort, 5 of the 14 (36%) developed persistent post-transplant DSA at a median of 9 months (range, 3-24) versus 2 of 30 (7%; P = .025) at a median of 12 months post-transplant in the non-DSA cohort. All recipients in the pretransplant DSA group underwent renal biopsy for persistent post-transplant DSA. Three of 5 biopsies showed C4D deposition in peritubular capillaries without glomerulopathy or arteriopathy. CONCLUSIONS: Early post-transplant outcomes for LD recipients with a negative cross-match and pretransplant DSA were excellent. In recipients with good and stable renal function, the significance of persistent post-transplant DSA in combination with C4D deposition on biopsy is unclear at this time.

Multiple human papillomavirus infections and HIV seropositivity as risk factors for abnormal cervical cytology among female sex workers in Nairobi.

We estimated type-specific prevalence of human papillomavirus (HPV) and examined risk factors for abnormal cervical cytology among 296 female sex workers from Nairobi, Kenya. Over half (54%) were infected with a high-risk (HR) HPV type, of which HPV16 and 52 were the most common types. HIV-1 prevalence was 23% and HIV-1 sero-positivity was associated with high-grade cervical lesions, particularly among women with CD4 count less than 500 cells/mm(3) (odds ratio [OR] = 6.9; 95% confidence interval [CI]: 1.7-24.9). Among women who had normal cytology at the time of entry into the study, the risk of having an abnormal Pap smear within one year was significantly elevated for women with multiple HPV types at study entry (adjusted odds ratio [aOR] = 6.0; 95% CI: 2.3-15.7) and with a subset of HR HPV types (aOR = 4.2; 95% CI: 1.6-11.2). Detection of multiple concurrent HPV infections may be a useful marker to identify women at risk of developing precancerous lesions in populations of high HPV prevalence.

De novo donor specific antibodies and patient outcomes in renal transplantation.

Single antigen identification of HLA antibodies is used to detect donor specific antibodies (DSAs). However, the impact of DSA elements such as class, relative strength, duration, and longitudinal effect on graft function and survival, remains unclear. Routine DSAs (LabScreen, One Lambda, Inc., Canoga Park, CA) and metabolic studies were performed at 1, 3, 6, 9, and 12 months post-transplant, and every 6 months for renal transplant recipients from 7/2007-7/2010 (n = 389). Biopsies were evaluated by updated Banff 2005 guidelines after two consecutive positive DSAs. Based on these tests, 25% of recipients developed de novo DSA. Those with DSA had increased acute rejection episodes (AR), higher creatinine (Scr), and worse graft survival. Three subgroups of these patients were identified based on duration: persistent DSA (> 1), isolated DSA, or no DSA. Persistent DSA patients were more likely to be African American, and have higher mean fluorescence intensity (MFI) and AR rates. Persistent DSA patients, with or without AR, had elevated Scr. Recipients with DQ-only DSA had higher rates of antibody mediated rejection (AMR). From this, we conclude that routine posttransplant DSA monitoring identifies recipients at risk for graft damage or loss. Persistent de novo DSAs correlated with inferior graft outcomes and AMR. With or without AR, DSA persistence was associated with worse outcomes, possibly warranting intervention. De novo DQ-DSA may be a biomarker for chronic damage and/or AMR, while an isolated DSA determination appears clinically insignificant.

Simultaneous kidney-pancreas transplantation for end-stage renal disease patients with insulin-dependent diabetes and detectable C-peptide.

INTRODUCTION: There is controversy regarding the place of simultaneous pancreas-kidney (SPK) transplantation in end-stage renal disease (ESRD) patients with insulin-dependent diabetes mellitus (IDDM) and detectable c-peptide. We sought to compare outcomes of recipients with and without pretransplantation c-peptide. METHODS: This retrospective single-center review included consecutive primary SPK transplantations performed between September 2007 and May 2010. Demographic characteristics and outcomes were compared between recipients with and without pretransplantation c-peptide. RESULTS: Seven of 25 (28%) consecutive SPK transplant recipients with a diagnosis of IDDM and ESRD had detectable c-peptide prior to transplantation. The mean c-peptide level was 6.3 ± 6.1 ng/mL. For those recipients with and without c-peptide, mean age at diagnosis of IDDM (12.4 ± 7.8 vs 17.1 ± 6.6 years; P = not significant [NS]), duration of IDDM prior to transplantation (30 ± 10 vs 23 ± 9 years; P = NS), and body mass index (25.9 ± 4.5 vs 26.7 ± 4.5 kg/m(2); P = NS) were equivalent between the groups. With a median follow-up of 17 months (range, 3-35 months) there was 1 graft loss (due to cardiovascular death) among the 25 patients. At the most recent follow-up, for recipients with and without c-peptide, both the mean serum creatinine (1.3 ± 0.6 vs 1.0 ± 0.2 ng/mL; P = NS) and the mean HbA1c level (5.3 ± 0.4 vs 5.3 ± 0.5; P = NS) were equivalent between the groups. CONCLUSION: For nonobese ESRD patients diagnosed with IDDM at a young age, the presence of detectable c-peptide should not influence the decision to proceed with SPK transplantation.

The effect of statin pretreatment on infarct volume in ischemic stroke.

BACKGROUND: Treatment with statins reduces infarct volume in animal models of ischemic stroke, independently of the effect on cholesterol. This study examined this effect in humans by testing whether patients taking statins at onset of ischemic stroke had smaller infarct volumes than those not taking statins. METHODS: The study design was a retrospective cohort analysis of all verified ischemic stroke patients admitted to the Medical University of South Carolina Hospital, in 2002-2006, with magnetic resonance diffusion-weighted imaging (DWI). Patients were grouped according to statin status at admission and compared relative to infarct volume, calculated (blinded to statin status) from DWI. RESULTS: A smaller than median infarct volume following ischemic stroke was associated with the interaction of statin pretreatment and positive diabetes status. This association remained significant (p = 0.01) in multivariable analysis even after controlling for factors related to demographics, comorbidities and risk factors, clinical features on admission, use of other medications and stroke features. CONCLUSIONS: Among ischemic stroke patients in this study, infarct volume below the median was significantly associated with statin pretreatment among those with diabetes.

Characterization of a familial small supernumerary marker chromosome in a patient with adult-onset tongue cancer.

Cytogenetic analysis in peripheral blood lymphocytes of a 50-year-old female with tongue cancer showed the presence of one to three copies of a small supernumerary marker chromosome (sSMC) in a mosaic state. Family studies also revealed the marker in mosaic form in four (age <29 years) of eleven clinically normal individuals studied from her family of 16 individuals spanning three generations. Due to the extremely small size of the marker chromosome, identification by classical cytogenetics was not informative. Multicolor FISH followed by whole chromosome painting identified the marker as a derivative of chromosome 21. This is the first report of sSMC21 in an adult-onset tongue cancer patient and some of her family members with no clinical symptoms.

Activation of multiple molecular mechanisms for apoptosis in human malignant glioblastoma T98G and U87MG cells treated with sulforaphane.

Glioblastoma is the most malignant and prevalent brain tumor that still remains incurable. Recent studies reported anti-cancer effect of the broccoli-derived compound sulforaphane. We explored the mechanisms of sulforaphane-mediated apoptosis in human glioblastoma T98G and U87MG cells. Wright staining and ApopTag assay confirmed apoptosis in glioblastoma cells treated with sulforaphane. Increase in intracellular free Ca2+ was detected by fura-2 assay, suggesting activation of Ca2+-dependent pathways for apoptosis. Western blotting was used to detect changes in expression of Bax and Bcl-2 proteins resulting in increased Bax:Bcl-2 ratio that indicated a commitment of glioblastoma cells to apoptosis. Upregulation of calpain, a Ca2+-dependent cysteine protease, activated caspase-12 that in turn caused activation of caspase-9. With the increased Bax:Bcl-2 ratio, cytochrome c was released from mitochondria to cytosol for sequential activation of caspase-9 and caspase-3. Increased calpain and caspase-3 activities generated 145 kD spectrin breakdown product and 120 kD spectrin breakdown product, respectively. Activation of caspase-3 also cleaved the inhibitor-of-caspase-activated-DNase. Accumulation of apoptosis-inducing-factor in cytosol suggested caspase-independent pathway of apoptosis as well. Two of the inhibitor-of-apoptosis proteins were downregulated because of an increase in 'second mitochondrial activator of caspases/Direct inhibitor-of-apoptosis protein binding protein with low pI.' Decrease in nuclear factor kappa B and increase in inhibitor of nuclear factor kappa B alpha expression favored the process of apoptosis. Collectively, our results indicated activation of multiple molecular mechanisms for apoptosis in glioblastoma cells following treatment with sulforaphane.