Evaluation of estimated glomerular function (eGFR) versus creatinine clearance (CrCl) to predict acute kidney injury when using zoledronate for the treatment of osteoporosis.

Zoledronate could be contributing to the development of acute kidney injury in a small number of patients. Since estimated glomerular function (eGFR) is simpler to obtain and at least as good a predictor as creatinine clearance (CrCl), it should be used in everyday practice. INTRODUCTION: Zoledronate is widely used for the treatment of osteoporosis. A potential side effect is acute kidney injury (AKI). Advice from the UK Medicines and Healthcare products Regulatory Agency (MHRA) in 2019 stated that CrCl and not estimated glomerular filtration rate (eGFR) should be used and that treatment should not be given if CrCl < 35 ml/min. The objective of this study was to compare our current method of assessing renal function (eGFR) with the method proposed by the MHRA (CrCl) for predicting AKI after zoledronate infusions. METHODS: The evaluation was performed at the Metabolic Bone Centre in Sheffield Teaching Hospitals, UK. Data on all the patients who had zoledronate from 1/09/2015 to 1/10/2020 were included. RESULTS: Data on 4405 patients were retrieved (total number of infusions 7660). Creatinine in the 14 days post-infusion was available for a total of 969 infusions and AKI was observed within 14 days following 45 infusions (4.6%). One patient died due to pneumonia. One patient needed continued haemodialysis. Severe AKI (threefold in creatinine and/or eGFR < 15 ml/min/173 m2) was observed within 1 year following 24 infusions. If the MHRA recommendations had been followed, 996 infusions with baseline CrCl < 35 ml/min would not have been given. Of these, follow-up data on serum creatinine within 14 days were available for 142 infusions, showing AKI in only four (2.8%). Logistic regression showed that both CrCl and eGFR were significant factors in predicting AKI within 14 days, but that the current recommended cut-off of CrCl 35 ml/min had poor sensitivity. CONCLUSION: Since eGFR is at least as good a predictor of AKI as CrCl, and permits the treatment of more patients at high fracture risk, we recommend that eGFR is used to determine renal function for zoledronate treatment. We suggest that the infusion is given over 30 min in patients with eGFR < 50 ml/min/1.73 m2.

Acute kidney injury: prevention, detection, and management. Summary of updated NICE guidance for adults receiving iodine-based contrast media.

The National Institute for Health and Care Excellence (NICE) has recently updated the guideline for Acute kidney injury: prevention, detection and management (NG148), providing new recommendations on preventing acute kidney injury (AKI) in adults receiving intravenous iodine-based contrast media. The association between intravenous iodinated contrast media and AKI is controversial, particularly with widespread use of iso-osmolar agents. Associations between contrast media administration and AKI are largely based on observational studies, with inherent heterogeneity in patient populations, definitions applied, and timing of laboratory investigations. In an attempt to mitigate risk, kidney protection has typically been employed using intravenous volume expansion and/or oral acetylcysteine. Such interventions are in widespread use, despite lacking high-quality evidence of benefit. In the non-emergency setting, glomerular filtration rate (GFR) measurements should be obtained within the preceding 3 months before offering intravenous iodine-based contrast media. In the acute setting, adults should also have their risk of AKI assessed before offering intravenous iodine-based contrast media; however, this should not delay emergency imaging. Based on the evidence available from randomised controlled trials, the NICE committee recommends that oral hydration should be encouraged in adults at increased risk of AKI and that volume expansion with intravenous V fluids should only be considered for inpatients at particularly high risk.

Analysis of intraoperative radiation use in vascular surgery: Catalyst for quality improvement in patient and personnel safety.

OBJECTIVES: There is paucity in the literature reporting radiation usage analysis in vascular surgery. In the era of endovascular surgeries, analyzing the surgeons' use of radiation in vascular procedures can help establish quality improvement initiatives. METHODS: A retrospective review was undertaken of intraoperative fluoroscopic-guided vascular surgery procedures at a single institution from 2010 to 2017. Mobile C-arms were utilized to gather the six radiation usage metrics and cases were categorized into 6 anatomic surgical fields and 10 surgical procedure types. RESULTS: Three hundred and eighteen vascular surgery cases were analyzed and notable trends in all radiation usage metrics were identified both across the surgical field location and type of surgical procedure. The highest cumulative dose was identified in embolization cases with a mean of 932.5 mGy. The highest fluoroscopic time was seen in atherectomies with a mean of 2629.6 s. In terms of surgical field, the highest cumulative does and fluoroscopic time was identified in abdomen/pelvis procedures with a mean of 352.1 mGy and 1186.8 s, respectively. Analysis of dose reduction techniques also demonstrated notable trends. CONCLUSIONS: There were notable trends in the analyzed radiation usage variables both across the surgical field location and type of surgical procedure. Specifically, cases that involve the abdomen/pelvis, embolization and atherectomy have the highest radiation use. These types of cases can be targeted for future improved dose reduction techniques or staged procedures. This data can serve as baseline information for future quality improvement initiatives for patient and personnel radiation exposure safety.

Seliciclib inhibits renal hypertrophy but not fibrosis in the rat following subtotal nephrectomy.

BACKGROUND: 5/6 subtotal nephrectomy (SNx) is a non-immune stimulus used to induce renal fibrosis. The ability of seliciclib, a cyclin-dependent kinase inhibitor, to reduce kidney hypertrophy and extracellular matrix (ECM) deposition has been examined in the SNx rat. METHODS: Wistar rats were subjected to SNx under isoflurane anaesthesia. The acute effect of seliciclib 28 mg/kg (5 days) on compensatory renal growth (CRG), kidney protein and DNA was determined. In chronic studies albuminuria, hypertension and GFR were monitored. Ki67, apoptag and α-smooth muscle actin were determined by immunohistochemistry together with Masson's trichrome staining. The effect of a maximum non-hypotensive dose of seliciclib 28 mg/kg (8 weeks) was determined. RESULTS: Acutely, the remnant kidney developed CRG. Seliciclib 28 mg/kg inhibited both CRG by 45% and increased kidney protein by 48% without affecting increased kidney DNA. Chronically, SNx rats developed albuminuria, hypertension, low GFR with increased tubulointerstitial cell proliferation, apoptosis, myofibroblast accumulation and enhanced ECM deposition. Seliciclib 28 mg/kg (8 weeks) had no effect on either renal function or renal pathology. Plasma concentrations of seliciclib exceeded 5 µM throughout the study. CONCLUSIONS: Despite inhibition of early renal hypertrophy, a maximum non-hypotensive dose of seliciclib 28 mg/kg had no impact on the progression of kidney fibrosis in the SNx rat.

Patterns of differentiated thyroid cancer in Baluchistan Province of Pakistan: some initial observations.

The incidence of thyroid cancer is increasing in several countries. The main objective of this retrospective study was to find and describe province-specific estimates of incidence in males and females by age groups for differentiated thyroid cancer (DTC). This study reports on 87 cases of DTC from Baluchistan province of Pakistan treated with post operative radioiodine at the Center for Nuclear Medicine and Radiotherapy (CENAR) Quetta from January 2003 to December 2009. The patient data has been collected from CENAR Quetta. Patients with DTC were confirmed by clinical examination, thyroid scintigraphy (Thyroid scan), blood tests (T3, T4, TSH) and histopathalogy tests and then treated with radioiodine. The Median age of the patients was 35.5 years (Range 12-70 years). The final histological diagnosis was papillary carcinoma in 71 (81.6 %) cases, follicular carcinoma in 6 (6.9%) cases while 10 (11.5%) cases presented with mixed papillary and follicular carcinoma. About 53 % cases were found in females with age 21-40 years. No strike predominance was observed in any age group for males. Four patients presented with recurrence while six patients showed metastasis in cervical lymph nodes. The small annual incidence did not follow any definite pattern. DTC has a small incidence in Baluchistan due to lack of education and health care facilities. The incidence of DTC is higher in females when compared with males as per this study. This preliminary study will provide an insight to incidence of DTC, its treatment facilities and future planning strategies in Baluchistan, Pakistan.

Scrub typhus-related hepatotoxicity: The Indian scenario.

In Scrunb Typhus, hepatotoxicity is an important, yet understudied, manifestation. We reviewed studies on scrub typhus, published in the last five years (2014-2019), which evaluated its clinico-epidemiological factors in India, and concentrated on its hepatic involvement. Nine studies were found, and no Indian study exclusively evaluated hepatic dysfunction. Thus, comments from a few international studies were also included. We conclude that liver dysfunction in the form of elevated serum transaminase levels is a common manifestation of scrub typhus, which may herald progress to fulminant hepatic failure.

Mir142 loss unlocks IDH2R140-dependent leukemogenesis through antagonistic regulation of HOX genes.

AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.

Lack of correlation between activation of Jun-NH2-terminal kinase and induction of apoptosis after detachment of epithelial cells.

Detachment of epithelial cells from the extracellular matrix leads to induction of programmed cell death, a process that has been termed "anoikis." It has been reported recently that detachment of MDCK cells from matrix results in activation of Jun-NH2-terminal kinases (JNKs) and speculated that these stress activated protein kinases play a causal role in the induction of anoikis (Frisch, S.M., K. Vuori, D. Kelaita, and S. Sicks. 1996. J. Cell Biol. 135:1377-1382). We report here that although JNK is activated by detachment of normal MDCK cells, study of cell lines expressing activated signaling proteins usually controlled by Ras shows that stimulation of JNK fails to correlate with induction of anoikis. Activated phosphoinositide 3-OH kinase and activated PKB/Akt protect MDCK cells from detachment-induced apoptosis without suppressing JNK activation. Conversely, activated Raf and dominant negative SEK1, a JNK kinase, attenuate detachment-induced JNK activation without protecting from apoptosis. zVAD-fmk, a peptide inhibitor of caspases, prevents MDCK cell anoikis without affecting JNK activation. p38, a related stress-activated kinase, is also stimulated by detachment from matrix, but inhibition of this kinase with SB 203580 does not protect from anoikis. It is therefore unlikely that either JNK or p38 play a direct role in detachment-induced programmed cell death in epithelial cells.

Direct contrast-enhanced magnetic resonance lymphangiography in the diagnosis of persistent occult chylous effusion leak after thoracic duct embolization.

Thoracic duct embolization (TDE) is currently the technique of choice for chylothorax refractory to medical management. Diagnosis and treatment of persistent lymphatic leakage after an initially successful TDE are complicated by inadequate imaging to localize the nidus of the lymphatic leak. Traditional imaging modalities including nuclear medicine lymphoscintigraphy, magnetic resonance lymphangiography, and fluoroscopic lymphangiography lack spatial resolution and dynamic physiologic real-time evaluation. We report a contemporary imaging technique using direct contrast-enhanced magnetic resonance lymphangiography to diagnose an occult chylous leak after TDE.

The unravelled Enterococcus faecalis zoonotic superbugs: Emerging multiple resistant and virulent lineages isolated from poultry environment.

This study aimed to investigate the zoonotic potential by virtue of phylogenetic analysis, virulence and resistance gene profiles of Enterococcus faecalis originating from poultry environment. The ERIC, BOX and RAPD PCR analysis showed the clustering of E. faecalis strains (n = 74) into five groups (G1-G5) and fifteen sub-clusters (B1-B15), which share 50%-80% similarities with ATCC E. faecalis and clinical strains of human infection. E. faecalis strains harboured seven enterocins genes including ent1097 (85%), entB (84%), enterolysinA (51%), entSEK4 (51%), entL50 (31%), entA (25.7%) and ent1071 (14.9%). The highest prevalence of gelE-sprE (90%), lip-fl (90%) followed by cylL (62%), hyl (60%), katA (16%) and cylA (5.4%) was observed in poultry isolates. The fsr operon and gelE-sprE was co-associated in 66.2% strains. E. faecalis also harboured biofilm and endocarditis-associated genes, including efaAfs (97%), ebp-pilli (ebpABC and srtC 69.9%-80%), asa1 (71%), agg (55%), ace (54%) and esp-Tim (3%). Despite all found sensitive to vancomycin, 98.6% strains were multi-drug resistant to five to twelve tested antimicrobials. An increased-level of resistance (≥32 µg/ml) was observed to ampicillin (8.1%), meropenem (21.6%), chloramphenicol (73.4%), erythromycin (90.5%), tetracycline (100%) and high-level resistance to kanamycin (79.7%) and gentamicin (52.7%). The multi-drug resistant E. faecalis (MDRe.f) were carried pbp4 (90%), tetL (90%), tetM (70%), ermB (81%), cat (52.7%), acc6-aph2 (58.1%), aaph(3)-III (49.9%), gyrA (97%) and parC (98%) genes. Moreover, these MDRe.f were also harboured, hospital-associated marker IS16 (58%) and pheromone responsive genes, that is ccf (88%), cpd (74%), cob (62%) and eep (66%). Thus, regardless of the distinct phylogenetic background of E. faecalis of poultry origin, ATCC E. faecalis and clinical strains of human origin, we found major similarities in virulence, resistance gene profiles and mobile genetic elements (IS16 and pheromone responsive plasmids), supporting the zoonotic/reverse zoonotic risk associated with this organism.

Targeting acute myeloid leukemia by drug-induced c-MYB degradation.

Despite advances in our understanding of the molecular basis for particular subtypes of acute myeloid leukemia (AML), effective therapy remains a challenge for many individuals suffering from this disease. A significant proportion of both pediatric and adult AML patients cannot be cured and since the upper limits of chemotherapy intensification have been reached, there is an urgent need for novel therapeutic approaches. The transcription factor c-MYB has been shown to play a central role in the development and progression of AML driven by several different oncogenes, including mixed lineage leukemia (MLL)-fusion genes. Here, we have used a c-MYB gene expression signature from MLL-rearranged AML to probe the Connectivity Map database and identified mebendazole as a c-MYB targeting drug. Mebendazole induces c-MYB degradation via the proteasome by interfering with the heat shock protein 70 (HSP70) chaperone system. Transient exposure to mebendazole is sufficient to inhibit colony formation by AML cells, but not normal cord blood-derived cells. Furthermore, mebendazole is effective at impairing AML progression in vivo in mouse xenotransplantation experiments. In the context of widespread human use of mebendazole, our data indicate that mebendazole-induced c-MYB degradation represents a safe and novel therapeutic approach for AML.

A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16.

Current therapy for acute myeloid leukaemia (AML) is suboptimal with a high incidence of relapse. There is strong evidence that constitutive phosphoinositide 3-kinase (PI3K) activity plays a significant role in the pathophysiology of AML. PI3K products are derived from the activity of a number of PI3K catalytic isoforms (class I, II and III) but the relative contribution of these enzymes in AML remains unknown. As non-isoform-selective inhibitors of PI3K such as LY294002 may produce unwanted toxicity to normal tissues, we have investigated the role of the leukocyte-restricted p110delta PI3K isoform in 14 cases of AML. p110delta was detected in all cases whereas the expression levels of the other class I PI3Ks varied more widely, and were often undetectable. The p110delta-selective compound IC87114 inhibited constitutive phosphorylation of the PI3K target Akt/PKB and reduced cell number to a mean of 66+/-5% (range 14-88%). In eight cases, the combination of IC87114 and VP16 (a topoisomerase II inhibitor) was synergistic in reducing viable cell number, and was associated with a reduction in constitutive NF-kappaB activity. IC87114 did not have direct adverse effects or enhance the activity of VP16 on the proliferation and survival of normal haemopoietic progenitors. Overall, our results identify the p110delta isoform as a potential therapeutic target in AML and support a clinical approach to use isoform-selective over broad-spectrum PI3K inhibitors.

PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-kappaB, Mapkinase and p53 pathways.

The phosphoinositide 3-kinase (PI3-kinase) signalling pathway plays a key role in the regulation of cell survival and proliferation. We show that the PI3-kinase/Akt pathway is constitutively active in primary acute myeloid leukaemia (AML) cells and that blockade by the selective inhibitor LY294002 reduces survival of the total blast population (mean 52%). The ERK/MAPK module is also constitutively active and treatment with the MAPKK inhibitor U0126 reduces cell survival by 22%. In 10 of 18 samples, PI3-kinase contributes to MAPK activation as incubation with LY294002 leads to a marked reduction in its phosphorylation. PI3-kinase inhibition reduces survival of the CD34+38- AML progenitor subset by 44%, whereas MAPKK inhibition has little effect. Reporter assays in primary AML cells show that blocking PI3-kinase leads to a marked reduction of constitutive NF-kappaB activity and promotes p53-mediated transcription. This is associated with a synergistic interaction between LY294002 and Ara-C. An inducible activated form of Akt protects normal myeloid cells from Ara-C and etoposide-mediated apoptosis. These results show that blocking PI3-kinase has direct antileukaemic effects and potentiates the response to conventional cytotoxics via a number of targets including NF-kappaB, p53 and MAPK. Inhibitors of PI3-kinase and Akt may be useful in the treatment of AML.

Pharmacological Management of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease.

Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease (CKD) and is part of the CKD-mineral bone disorder (CKD-MBD). SHPT is associated with increased risk of fracture and mortality; thus, SHPT control is recommended as kidney function declines. Effective SHPT management becomes more difficult once skeletal and cardiovascular adverse effects associated with severe SHPT have become established. However, interventional studies to lower parathyroid hormone (PTH) have so far shown inconsistent results in improving patient-centred outcomes such as mortality, cardiovascular events and fracture. Pharmacological treatment effect on PTH level is also inconsistent between pre-dialysis CKD and dialysis patients, which adds to the complexity of SHPT management. This review aims to give an overview on the pathophysiology, pharmacological and non-pharmacological treatment for SHPT in CKD including some of the limitations of current therapeutic options.

Networks of interaction of p120cbl and p130cas with Crk and Grb2 adaptor proteins.

P120cbl, the product of the c-cbl proto-oncogene, has previously been shown to become tyrosine phosphorylated following EGF stimulation of cells, and to bind constitutively to the SH3 domain of the adaptor protein Grb2. Here we show that another adaptor protein, Crk, binds through its SH2 domain to tyrosine phosphorylated p120cbl. In addition, Crk becomes phosphorylated on tyrosine and serine following EGF treatment of PC12 and other cell lines. In unstimulated cells, while Grb2 is not bound to any tyrosine phosphoprotein, Crk is bound via its SH2 domain to tyrosine phosphorylated p130cas, the Crk-associated v-Src substrate. Following EGF treatment, Crk dissociates from p130cas, possibly due to a higher affinity of Crk SH2 for p120cbl compared with p130cas. Interaction between Grb2 and p120cbl increases threefold following EGF treatment of cells; in vitro, this induction of Grb2 association with unphosphorylated p120cbl can be mimicked by the addition of tyrosine phosphorylated Shc, suggesting a transfer of information between the SH2 and SH3 domains of Grb2. These data indicate that adaptor proteins can exchange binding partners in response to stimuli, and that different adaptor proteins can bind to the same partners by different mechanisms.

Development of a simplified single-apheresis approach for peripheral-blood progenitor-cell transplantation in previously treated patients with lymphoma.

PURPOSE: The aims of this study were to develop a simplified, safe, and cost-effective peripheral-blood progenitor-cell (PBPC) mobilization protocol. PATIENTS AND METHODS: Twenty-six patients with relapsed or resistant lymphomas were entered onto a sequential cohort study in which schedules of various granulocyte colony-stimulating factor (G-CSF) were administered after cyclophosphamide 1.5 g/m2. Hematologic recovery after high-dose carmustine (BCNU) etoposide, cytarabine, and melphalan (BEAM) chemotherapy was compared with that of 46 patients who received autologous bone marrow transplantation (ABMT) without growth factors and 28 patients who received ABMT followed by G-CSF. RESULTS: When G-CSF (10 micrograms/kg/d) was administered from the day after the cyclophosphamide, neutropenia developed on day 8 followed by an abrupt increase in the WBC count. The optimal time for PBPC harvesting was the day on which the postnadir WBC count was greater than 8.0 x 10(9)/L, as shown by CD34+ cell counts and granulocytic-macrophage colony-forming cell (GM-CFC) assays. The reproducibility of the response was such that routine monitoring of CD34+ cell counts and GM-CFC was not necessary. A single leukapheresis on this day was adequate for prompt hematologic engraftment, and posttransplant G-CSF made little further impact on the rapid recovery. Compared with both control groups, the use of PBPC led to more rapid neutrophil recovery, markedly accelerated platelet recovery, less use of antimicrobial agents and parenteral nutrition, and more than 10 days earlier discharge from hospital. All of these differences were highly significant (P < .01). CONCLUSION: A simplified mobilization protocol is described that requires only one apheresis to achieve rapid hematologic engraftment.