Effects of short daily hemodialysis and extended standard hemodialysis on blood pressure and cardiac hypertrophy: a comparative study

BACKGROUND: Causes of hypertension and cardiac hypertrophy in hemodialysis (HD) patients are multiple, but the role of fluid overload appears to be crucial. Short daily HD (sDHD = 2 hr x 6/week) seems to allow reductions in left ventricular mass (LVM) through the reduction of extracellular water (ECW). Better cardiovascular stability during HD can be obtained with short, but more frequent HD sessions, but also by increasing the session length accompanied with a reduction in ultrafiltration (UF)/hr. Regardless of the method, the adequate reduction in extracellular volume should permit better control of hypertension and left ventricular hypertrophy (LVH). This study aimed to compare sDHD with an extended form of standard HD (eSHD = 4.5-5 hr x 3/week) on the reduction of fluid overload, blood pressure (BP) and LVM index (LVMi). Patients and methods:Twenty-four HD patients with hypertension and LVH were enrolled in a prospective non-randomized study. After a 3-month run-in period they were divided in two comparable groups: 12 patients treated with sDHD, and 12 patients treated with eSHD for 6 months. LVMi, 24 hr BP monitoring, ECW, determined with electrical bio-impedance, biochemical correlates and spKT/V were studied at the beginning of the study and 6 months later. RESULTS: The weekly session length was increased in eSHD from 722.9 +/- 7.5 to 877.3 +/- 35.5 min. ECW% was reduced similarly in the two groups (Delta ECW: eSHD = 4.6 +/- 2.4 L; sDHD = 4.1 +/- 2.3 L); 24 hr BP decreased significantly from 157/81 to 137/75 mmHg in eSHD, and from 149/79 to 128/72 mmHg in sDHD. The reduction in systolic BP was similar in the two groups (eSHD = 20.1 +/- 15.3 mmHg, sDHD = 21.2 +/- 16.7 mmHg). Finally, LVMi was similarly reduced (eSHD = 55 +/- 30.3 g/m(2), sDHD = 54.4 +/- 21.3 g/m(2). The number of antihypertensive drugs decreased significantly after ECW% reduction: only 2/10 patients on eSHD and 4/12 patients on sDHD were maintained on therapy (p = ns). Intra-dialysis hypotension episodes did not differentiate between SHD and DHD. The reduction in LVMi was significantly correlated to fluid volume changes when these were measured as phase angle (PA) with bio-impedance (r = -0.43, p < 0.05). CONCLUSIONS: In hypertensive HD patients with LVH, fluid overload is invariably present and its reduction allows the decrease of BP and LVM. These results can be obtained by forcing UF with eSHD and sDHD, but patients maintained on x 3/week schedules need longer dialysis sessions to avoid intra-dialysis symptoms.     

Treatment of temporomandibular joint ankylosis in children: is it necessary to perform mandibular distraction simultaneously?

Temporomandibular joint (TMJ) ankylosis in children disturbs not only mandibular growth, but also facial skeletal development. Costochondral graft was used to ensure growth, but it had proven to be unpredictable. The authors evaluate retrospectively 41 patients who underwent temporomandibular joint reconstruction during the last 10 years. Twenty were treated by costochondral graft, 15 by arthroplasty, and 6 by other surgical procedures, and they were excluded. The etiology was septic in 54% of the cases. Follow-up was at least 12 months in all cases. Arthroplasty was a quicker and easier procedure than the costochondral graft, reducing operating time, risk of blood transfusion, and hospital stays and costs. It also was associated with less risk of reankylosis, 13%vs 25%. Furthermore, it was associated with a minor morbidity and secondary complications. Seventy-five percent of the patients treated with bone graft required additional secondary surgery. Radiographically, the authors observed a remodeled neocondyle at the level of proximal mandibular end in cases treated by arthroplasty. On clinical examination, patients showed variable degrees of facial deformity and an unknown potential of mandibular growth after TMJ arthroplasty. The authors also observed improved clinical and radiologic appearance after ankylosis correction. Is it reasonable to perform ankylosis release and mandibular distraction simultaneously without knowing which patients will be able to experience growth with time? In that case it would be necessary a predict growth to apply the exact amount of mandibular distraction for obtaining stable results. Timing of mandibular distraction, after TMJ arthroplasty is performed and mandibular function restored, must be specific to each patient's needs, assuring the best distraction conditions and planning. The authors present their treatment protocol, including TMJ joint arthroplasty with temporal muscle interposition, and mandibular distraction osteogenesis, as a second procedure, to correct residual asymmetry or retrognathism if necessary.     

Monocarboxylate transporter antagonism reveals metabolic vulnerabilities of viral-driven lymphomas

Epstein–Barr virus (EBV) is a ubiquitous herpesvirus that typically causes asymptomatic infection but can promote B lymphoid tumors in the immune suppressed. In vitro, EBV infection of primary B cells stimulates glycolysis during immortalization into lymphoblastoid cell lines (LCLs). Lactate export during glycolysis is crucial for continued proliferation of many cancer cells—part of a phenomenon known as the “Warburg effect”— and is mediated by monocarboxylate transporters (MCTs). However, the role of MCTs has yet to be studied in EBV-associated malignancies, which display Warburg-like metabolism in vitro. Here, we show that EBV infection of B lymphocytes directly promotes temporal induction of MCT1 and MCT4 through the viral proteins EBNA2 and LMP1, respectively. Functionally, MCT1 was required for early B cell proliferation, and MCT4 up-regulation promoted acquired resistance to MCT1 antagonism in LCLs. However, dual MCT1/4 inhibition led to LCL growth arrest and lactate buildup. Metabolic profiling in LCLs revealed significantly reduced oxygen consumption rates (OCRs) and NAD+/NADH ratios, contrary to previous observations of increased OCR and unaltered NAD+/NADH ratios in MCT1/4-inhibited cancer cells. Furthermore, U-¹³C₆–glucose labeling of MCT1/4-inhibited LCLs revealed depleted glutathione pools that correlated with elevated reactive oxygen species. Finally, we found that dual MCT1/4 inhibition also sensitized LCLs to killing by the electron transport chain complex I inhibitors phenformin and metformin. These findings were extended to viral lymphomas associated with EBV and the related gammaherpesvirus KSHV, pointing at a therapeutic approach for targeting both viral lymphomas.

Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus transmitted through saliva, with more than 95% of the world being infected by adulthood. Primary EBV infection is typically asymptomatic and surmounts to latency establishment in quiescent memory B cells in the peripheral blood (1). However, in immunocompromised persons, EBV reactivation can cause uncontrolled B cell proliferation, leading to various lymphoproliferative disorders and frank lymphoma. Recent evidence suggests that host responses such as the DNA damage response (DDR) and metabolic stress play a significant cell-intrinsic role in preventing EBV-driven B cell transformation (2, 3).EBV infection of primary human peripheral blood B cells in vitro produces indefinitely proliferating lymphoblastoid cell lines (LCLs). LCLs express the Latency III growth program, where all six EBV nuclear antigens, or EBNAs, (EBNA-LP, 1, 2, 3A, 3B, and 3C) and two latent membrane proteins, or LMPs, (LMP1 and LMP2A/B) are present. This gene expression program mimics that of many EBV-associated B lymphoid cancers, making LCLs a suitable model for studying mechanisms underlying tumorigenesis (4). Prior to Latency III establishment in LCLs and shortly after EBV infection of B cells, a transient period of hyperproliferation, called Latency IIb, is induced, where only the viral EBNAs are expressed in the absence of the LMPs (5, 6). This culminates in an irreversible growth arrest in most cells caused by a persistent DDR (7). However, a very small subset (<10%) of hyperproliferating cells evade host barriers like the DDR and transition into Latency III–expressing LCLs within weeks (2).During EBV immortalization of B cells into LCLs, increased energetic demands for continued proliferation drive an up-regulation of glycolysis and extracellular acidification rates (ECAR) (3, 8–10). While the ECAR is largely a reflection of lactate export into the extracellular environment, the magnitude and role of lactate export during EBV-driven B cell immortalization remains poorly characterized. Besides being a glycolytic waste product, lactate has recently emerged to play a key role in tumor development, growth, and metastasis (11, 12). Furthermore, intracellular lactate buildup can have dire consequences on cell homeostasis due to acidification by lactic acid, highlighting the importance of lactate export for sustained cell growth and survival (13).Proton-coupled lactate export is driven by the plasma membrane–expressed solute carrier (SLC) family proteins monocarboxylate transporters (MCTs) 1 and 4 (SLC16A1/MCT1 and SLC16A3/MCT4). MCT1 has a much higher affinity for lactate than MCT4, making it the primary lactate transporter under normal physiological conditions (14–16). MCT4, however, is typically expressed in highly glycolytic tissues or when intracellular lactate concentrations are high, such as during aerobic glycolysis (17–19). MCT1 and MCT4 have the ability to transport other monocarboxylates such as pyruvate and ketone bodies like acetoacetate and β-hydroxybutyrate (15, 19, 20). However, these transporters are most commonly associated with their role in lactate transport across the plasma membrane, especially during tumor development, growth, and metastasis (21–23). As such, MCT1 and MCT4 act as essential buffers at the intersection of the intracellular and extracellular environments, sensing monocarboxylate concentrations and facilitating rapid transport based on the needs of the cell (24–26). Not surprisingly, MCT1 and MCT4 are commonly expressed in a wide variety of tumors, exporting lactate from glycolytic cancer cells, which can later be recycled by oxidative cells in the tumor microenvironment (27, 28).Targeting MCT1- and MCT4-mediated lactate export has become a highly attractive therapeutic strategy in recent years as blocking lactate export can lead to cell cycle arrest and sensitize tumor cells to killing by other metabolic inhibitors (20, 22, 29, 30). MCT1 inhibitors are currently in Phase I clinical trials for a number of solid tumors and lymphomas (31). While these inhibitors have proven to effectively reduce tumor burden in preclinical models of MCT1-overexpressing cancers, they are unfortunately ineffective in MCT1/MCT4-coexpressing cancers due to the redundant role of MCT4 as a lactate exporter (32). This highlights the need for MCT4-specific inhibitors, which are unfortunately not commercially available to date. Furthermore, while inhibition of MCT1 and MCT4 universally leads to a buildup of intracellular lactate in tumor cells, the mechanisms underlying growth arrest and cell death are not fully understood. Thus, studying how MCT1 and MCT4 are regulated in diverse contexts is critical for expanding our understanding of their role not only in tumorigenesis but in cell biology and homeostasis at large.Given their established roles in tumor development both in vitro and in vivo, we reasoned that MCT1- and MCT4-mediated lactate export might contribute to EBV-mediated B cell tumorigenesis and virus-associated lymphoma cell growth more broadly. To address this, we measured changes in lactate concentration and MCT expression through EBV-mediated B cell outgrowth and perturbed MCT1 and MCT4 function with small molecule antagonists and reverse genetic approaches. Our data identify metabolic vulnerabilities that we propose could be exploited for the treatment of viral-associated cancers.     

Psychological distress of patients with advanced cancer: influence and contribution of pain severity and pain interference

The growing interest in the psychological distress and the multidimensionality of pain in patients with cancer has been the major reason for the conduction of this study. The aims were to evaluate psychological distress and pain in patients with advanced cancer and the impact of pain severity and pain interference dimensions on the anxiety and depression. One hundred twenty patients with advanced cancer were surveyed at a palliative care unit in Athens, Greece. Greek versions of the Hospital Anxiety and Depression (G-HAD) scale and the Brief Pain Inventory were administered. Information concerning patients' treatment received was acquired from the medical records, whereas physicians recorded their clinical condition. The analysis showed that significant associations were found between pain interference to "mood" and HAD-A (anxiety) (r = 0.252, P = .005) and between pain interference to "relations with other people" and HAD-A (r = 0.474, P < .0005). Multiple regression analyses showed that "average pain" (P < .05), pain interference to "walking ability" (P < .05), "normal work" (P < .05, and "relations with other people" are significant predictors of HAD-anxiety (HAD-A) (P < .0005), explaining 46.2% of total variance. For depression (HAD-D), the Greek version of the Brief Pain Inventory dimension that serve as predictor is "enjoyment of life," as well as the demographic variables of "age," and "gender" (P < .05), explaining 22.2% of variance. Moreover, a further analysis of the pain severity and pain interference scales showed that they differentiate the anxiety of the patients with cancer. In this patient sample, pain interference and, to a lesser extent, pain severity was significantly associated with psychological distress (anxiety and pain), whereas pain interference to "walking ability," "normal work," and "relations with other people" was found to be more prominent and troublesome to patients' anxiety than that to patients' depression.     

Accumulation of vitamin E metabolites in the blood of renal failure patients

BACKGROUND & AIMS: Carboxyethyl-hydroxychromans (CEHC) are hydrosoluble vitamin E metabolites excreted through the renal filter. In this study we investigated the effect of the kidney damage on the blood levels of CEHC. METHODS: Plasma levels of alpha-CEHC, gamma-CEHC and their precursors (namely, alpha-tocopherol and gamma-tocopherol) were measured by HPLC with electrochemical detection in chronic (CRF) and end-stage renal failure patients on regular hemodialysis (HD) before and after dialysis. CRF patients (n = 26) were divided into three subgroups with different extent of kidney damage as measured by the intervals of creatinine clearance (CrCl, in ml/min): (a) 2-10, (b) 10-20, and (c) 20-45. HD patients (n = 8) did not show residual renal function. In all the subjects the intake of vitamin E (as alpha-tocopherol) was assessed using a food frequency questionnaire. In the HD group, the plasma concentrations of ascorbic and uric acid (AA and UA, respectively), total thiols, the total antioxidant status (TAS) and reactive carbonyls were also measured. RESULTS: The progressive deterioration of the kidney function in the different groups of patients produced an exponential increase of both alpha-CEHC and gamma-CEHC in plasma. Compared with healthy controls (alpha-CEHC = 20.1+/-13.4 and gamma-CEHC = 230.6+/-83.0 nmol/l) the levels of CEHC approximately doubled in patients with CrCl < or = 20ml/min (42.4+/-20.2 and 424.5.5+/-174.4; P <0.05 or higher in both) and reached a 3-fold maximum increase in HD patients (77.3+/-45.7 and 636.6+/-219.3). The hemodialysis provided a significant, but only a transient, correction of CEHC accumulation (44.8+/-23.5, 364.2+/-189.9). The HD patients showed lower intake and levels of vitamin E (alpha-tocopherol = 5.1+/-1.0 and gamma-tocopherol =0.32+/-0.11 micromol/mmol cholesterol; P <0.05) compared to healthy controls (5.8+/-0.8 and 0.43+/-0.14), but in the CRF patients tocopherol levels were normal or only slightly decreased even though approximately half of the subject had lowered vitamin E intake. When the entire patient population was considered, the blood concentrations of parental tocopherols and CEHC did not correlate. The HD patients before dialysis showed a marked decrease of TAS/UA, AA and thiols levels, while UA and free carbonyls significantly increased. After dialysis, the depletion of AA and thiols further worsened and also UA and TAS/UA decreased, but free carbonyls slightly increased. CONCLUSIONS: The results other than to confirm the key importance of the renal route for the excretion of CEHC, demonstrate that CEHC cannot be reliably used to investigate vitamin E biokinetics and transformation without a careful examination of the renal function. CEHC accumulation does not seem to influence the antioxidant status in the plasma of HD patients. Further studies are requested to establish whether such an increase in blood CEHC concentrations might be harmful or could contribute to the biological functions of the vitamin E in uremia and dialysis patients.     

Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy

Introduction: Angiogenesis is fundamental for tumor development and progression. Hence, anti-angiogenic drugs have been developed to target VEGF and its receptors (VEGFRs). Several tyrosine kinase inhibitors (TKIs) have been developed over the years and others are still under investigation, each anti-VEGFR TKI showing a different cardiotoxic profile. Knowledge of the cardiac side-effects of each drug and the magnitude of their expression and frequency can lead to a specific approach.

Areas covered: This work reviews the mechanism of action of anti-VEGFR TKIs and the pathophysiological mechanisms leading to cardiotoxicity, followed by close examination of the most important drugs individually. A literature search was conducted on PubMed selecting review articles, original studies and clinical trials, with a focus on Phase III studies.

Expert opinion: Side-effects on the cardiovascular system could lead both to the worsening of general health status of cancer patients and to the discontinuation of the cancer treatment affecting its efficacy. Cardiologists often have to face new triggers of heart disease in these patients. They need a specific approach, which must be carried out in cooperation with oncologists. It must start before cancer treatment, continue during it and extend after its completion.     

Implant of autologous mesothelial cells in animals and a peritoneal dialysis patient

Success in culturing human and animal peritoneal mesothelial cells for the purpose of study, led us to determine whether these cells could be autoimplanted in animals and man during peritoneal dialysis in cases of acute and extensive loss of mesothelial surface area. Using an original biopsy technique, we were able to cultivate and characterize from the structural and caryological point of view, human and rabbit peritoneal mesothelial cells. Staphylococcal peritonitis was provoked in 12 rabbits with in-dwelling peritoneal catheters and after 4 days of antibiotic therapy, 6 of them were autoimplanted with cultured mesothelial cells. In the animals sacrificed on the third and sixth days, direct morphological observation and autoradiographic techniques showed that the transplanted cells had taken and revealed a different picture from that in the non-transplanted rabbits. In a 56 year old female diabetic patient, upon insertion of the first peritoneal catheter, a specimen of mesothelial cells was cultured and then frozen. Seven months later after an episode of peritonitis from candida which dictated removal of the peritoneal catheter, since there was a sufficient number of cultured mesothelial cells and the patient consented, the implant was performed. Peritoneal biopsy by laparoscopy three and six days later showed that the cells had taken. The purpose of the study was merely to show that autoimplant of mesothelium in man and animals is possible.     

Single versus multiple drug therapy in the combined treatment of malignant gliomas. A multicenter study

The best treatment of malignant gliomas has been considered to be surgery followed by irradiation and chemotherapy with nitrosourea compounds. Our controlled and randomized trial was designed in 1982 to analyze the effectiveness of multiple-drug versus single-drug therapy in patients bearing malignant gliomas. After 3 weeks from surgery and histopathological diagnosis 173 patients were randomly assigned to receive one of the three chemotherapy regimens: CCNU alone, CCNU plus VM-26 or CCNU plus VM-26 plus 5-FU. Radiotherapy was administered whole-brain (40-45 Gy) and coned-down focal (15-20 Gy) irradiation for a total of 60 Gy (1700 rets) in conjunction with the first course of chemotherapy. 150/173 patients are evaluable. Statistical analysis of results shows a better quality of life and survival for patients treated with polychemotherapy using a three drug combination than two drug or single drug therapy (13.8 vs 14.7 vs 18.2 months MST; P less than 0.01) but with a higher incidence of toxicity problems. An analysis of prognostic factors and their distribution in each arm of the protocol will be made in the near future.     

Measuring total health inequality: adding individual variation to group-level differences

Background  

Studies have revealed large variations in average health status across social, economic, and other groups. No study exists on the distribution of the risk of ill-health across individuals, either within groups or across all people in a society, and as such a crucial piece of total health inequality has been overlooked. Some of the reason for this neglect has been that the risk of death, which forms the basis for most measures, is impossible to observe directly and difficult to estimate.