Systematic review with meta-analysis: the association between hepatitis E seroprevalence and haemodialysis.

BACKGROUND: Hepatitis E virus (HEV) infection appears to be more common than previously thought. HEV seroprevalence in patients on maintenance haemodialysis (HD) is unclear with a range from 0% to 44%. In addition, risk factors of transmission of HEV in patients on haemodialysis are unknown. AIM: To perform a systematic review and meta-analysis of HEV seroprevalence in HD patients compared with controls. METHODS: A systematic search of several databases identified all observational studies with comparative arms. Two reviewers extracted data and assessed the methodological quality. A random-effects model was used for pooled odds ratio (OR) and 95% confidence interval (CI) of positive anti-HEV IgG in both groups. Heterogeneity and publication bias were assessed with appropriate tests. RESULTS: We identified 31 studies from 17 countries between 1994 and 2016. Sixteen studies were judged to have adequate quality and 15 to have moderate limitations. HEV infection was more prevalent in patients on haemodialysis compared with controls (OR 2.47, 95% CI 1.79-3.40, I2 = 75.2%, P < .01). We conducted several subgroup analyses without difference in results. Egger regression test did not suggest publication bias (P = .83). Specific risk factors of HEV transmission in patients on haemodialysis were not clearly identified. CONCLUSIONS: Hepatitis E virus infection is more prevalent in patients on haemodialysis compared with non-haemodialysis control groups. Further studies are needed to determine risk factors of acquisition, impact on health, and risk for chronic HEV especially among those patients going to receive organ transplantation.

Thermoacoustic range verification using a clinical ultrasound array provides perfectly co-registered overlay of the Bragg peak onto an ultrasound image.

The potential of particle therapy due to focused dose deposition in the Bragg peak has not yet been fully realized due to inaccuracies in range verification. The purpose of this work was to correlate the Bragg peak location with target structure, by overlaying the location of the Bragg peak onto a standard ultrasound image. Pulsed delivery of 50 MeV protons was accomplished by a fast chopper installed between the ion source and the cyclotron inflector. The chopper limited the train of bunches so that 2 Gy were delivered in [Formula: see text]. The ion pulse generated thermoacoustic pulses that were detected by a cardiac ultrasound array, which also produced a grayscale ultrasound image. A filtered backprojection algorithm focused the received signal to the Bragg peak location with perfect co-registration to the ultrasound images. Data was collected in a room temperature water bath and gelatin phantom with a cavity designed to mimic the intestine, in which gas pockets can displace the Bragg peak. Phantom experiments performed with the cavity both empty and filled with olive oil confirmed that displacement of the Bragg peak due to anatomical change could be detected. Thermoacoustic range measurements in the waterbath agreed with Monte Carlo simulation within 1.2 mm. In the phantom, thermoacoustic range estimates and first-order range estimates from CT images agreed to within 1.5 mm.

Charcoal hemofiltration for hepatic veno-occlusive disease after hematopoietic stem cell transplantation.

Hepatic veno-occlusive disease (HVOD) after hematopoietic stem cell transplantation (HSCT) results in considerable morbidity and mortality. No therapy has been shown to be uniformly effective. Several studies have highlighted the pivotal role of endothelial injury and the hemostatic system in the pathogenesis of HVOD. Charcoal hemofiltration has been shown to be effective for adsorbing circulating bilirubin and other protein-bound toxins and for supporting patients in hepatic failure. We describe two adult patients with severe, biopsy-proven HVOD (peak bilirubin levels, more than 50 mg/dl in both cases) after HSCT who were successfully treated with charcoal hemofiltration after other treatments failed (including defibrotide in one patient). Both patients were heavily treated before they underwent either autologous (melphalan and total body irradiation conditioning) or allogeneic (cyclophosphamide and total body irradiation conditioning) HSCT. Additional studies are warranted to confirm this preliminary observation and investigate the mechanism of action.

Efficacy of chlorfenapyr (AC 303630) experimental pour-on and CyLence formulations against naturally acquired louse infestations on cattle in New York.

The four chlorfenapyr formulations examined provided 100% control of both the nymphal and adult stages of naturally acquired Bovicola bovis (L.) on cattle up to 35 days after application. Treatment with 6mg chlorfenapyr per kg BW in a 0.12ml per kg BW formulation was as effective as treatment with CyLence (cyfluthrin) in controlling naturally acquired Solenopotes capillatus (Enderlein) on cattle for 35 days. Percent reduction was never greater than 90% with any chlorfenapyr application against Linognathus vituli (L.). However, percent reduction was greater than 90% with CyLence from day 21 through 35. No adverse effects were noted on cattle from any of the chlorfenapyr dosages used.

Acute renal failure: a practical update.

Acute renal failure (ARF) affects almost all medical specialties. Its occurrence seems to be increasing in hospitalized patients. A structured approach to the evaluation and management of ARF would facilitate rapid diagnosis and treatment in most patients. Appreciation for the multiple drugs that affect renal function is especially important. Exclusion of urinary outflow obstruction and administration of therapies that improve renal perfusion should be given top priority with respect to managing ARF. Dialytic intervention for ARF is required when otherwise irreversible pathophysiologic derangements of electrolyte homeostasis, fluid balance, and uremic solute control are imminent. This article provides a brief review and update on the clinical evaluation and management of ARF.

Patient survival and renal recovery in acute renal failure: randomized comparison of cellulose acetate and polysulfone membrane dialyzers.

OBJECTIVE: To investigate survival and renal recovery after dialysis in patients with acute renal failure with use of synthetic membranes compared with substituted cellulose membranes. PATIENTS AND METHODS: We prospectively studied survival and recovery of renal function of 66 patients with acute renal failure who required intermittent hemodialysis. Patients were randomized to exclusive treatment with either cellulose acetate (CA) or polysulfone (PS) hemodialysis membranes. Additionally, markers of biocompatibility (complement, leukocyte counts, cytokine concentration) were measured at initiation and 1 hour after initiation of dialysis among 10 patients equally distributed between the CA and PS groups. RESULTS: The cohorts were indistinguishable with respect to age, sex, presence of diabetes mellitus, Acute Physiology and Chronic Health Evaluation II scores, percentage in the intensive care unit (ICU), and adequacy of dialysis. Survival (76% CA, 73% PS; P=.78) and recovery of renal function at 30 days (58% CA, 39% PS; P=.14) were not statistically different in the 2 groups. Among 26 CA patients and 27 PS patients treated in the ICU, survival was not statistically different (73% CA, 67% PS; P=.61); however, the proportion of patients recovering renal function suggested a benefit favoring CA membranes (65% CA, 37% PS; P=.04). Additionally, markers of biocompatibility were not significantly different between groups among the 10 patients equally distributed between the CA and PS groups. CONCLUSIONS: Overall clinical outcomes among patients with acute renal failure treated with CA hemodialysis membranes and those treated with PS membranes were not significantly different. The observed advantage favoring renal recovery among this ICU population treated with CA hemodialysis membranes warrants further investigation.

Treatment of lithium intoxication with continuous venovenous hemodiafiltration.

Lithium intoxication is an important complication of its frequent use and narrow therapeutic index. Intermittent hemodialysis has been the treatment of choice when emergent extracorporeal lithium clearance is indicated, but postdialysis rebound elevations in lithium concentration with recurrent toxicity have been documented. We report a case of intentional acute on chronic lithium intoxication in which continuous venovenous hemodiafiltration was successfully used. This modality offers the advantage of slow sustained removal of lithium without hemodynamic instability or rebound elevations in lithium concentration.

A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.

A randomized, multicentre, open-label, phase II study compared temozolomide (TMZ), an oral second-generation alkylating agent, and procarbazine (PCB) in 225 patients with glioblastoma multiforme at first relapse. Primary objectives were to determine progression-free survival (PFS) at 6 months and safety for TMZ and PCB in adult patients who failed conventional treatment. Secondary objectives were to assess overall survival and health-related quality of life (HRQL). TMZ was given orally at 200 mg/m(2)/day or 150 mg/m(2)/day (prior chemotherapy) for 5 days, repeated every 28 days. PCB was given orally at 150 mg/m(2)/day or 125 mg/m(2)/day (prior chemotherapy) for 28 days, repeated every 56 days. HRQL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30 [+3]) and the Brain Cancer Module 20 (BCM20). The 6-month PFS rate for patients who received TMZ was 21%, which met the protocol objective. The 6-month PFS rate for those who received PCB was 8% (P = 0.008, for the comparison). Overall PFS significantly improved with TMZ, with a median PFS of 12.4 weeks in the TMZ group and 8.32 weeks in the PCB group (P = 0.0063). The 6-month overall survival rate for TMZ patients was 60% vs. 44% for PCB patients (P = 0.019). Freedom from disease progression was associated with maintenance of HRQL, regardless of treatment received. TMZ had an acceptable safety profile; most adverse events were mild or moderate in severity.

Permanent iodine-125 interstitial implants for the treatment of recurrent glioblastoma multiforme.

OBJECTIVE: Brachytherapy with temporary implants may prolong survival in patients with recurrent glioblastoma multiforme (GBM), but it is associated with relatively high costs and morbidity. This study reports the time to progression and survival after permanent implantation of iodine-125 seeds for recurrent GBM and examines factors predictive of outcome. METHODS: Forty patients with recurrent GBM were treated with maximal resection plus permanent placement of iodine-125 seeds into the tumor bed. A total dose of 120 to 160 Gy was administered, and patients were followed up with magnetic resonance imaging scans every 2 to 3 months. RESULTS: Actuarial survival from the time of implantation was 47 weeks, with 7 of 40 patients still alive at a median of 59 weeks after implantation. Survival was significantly better for patients younger than 60 years, and a trend for longer survival was demonstrated with gross total resection and tumors with a low MIB-1 (a nuclear antigen present in all cell cycles of proliferating cells) staining index. Median time to progression was 25 weeks and, on multivariate analysis, was favorably influenced by gross total resection and patient age younger than 60 years. After implantation, 27 of 30 patients with failure had a local component to the failure. No patient developed symptoms attributable to radiation necrosis or injury. CONCLUSION: Permanent iodine-125 implants for recurrent GBM result in survival comparable with that described in previous reports on temporary implants, but with less morbidity. Results are most favorable for patients who are younger than 60 years, and who undergo gross total resection. Despite this aggressive treatment, most patients die as a consequence of locally recurrent disease.

Preoperative anaplastic glioma tumor volume effects on patient survival.

BACKGROUND AND OBJECTIVES: The relationship between preoperative tumor volume and patient survival has long been studied, but the results have been inconsistent. Since geometric measurement of tumor volume was used in these studies, the aim of this study was to ascertain whether the inconsistency of the study results is due to less accurate geometric measurement. METHODS: Prognostic tumor volume effects were compared between the planimetry method and the geometric method using survival analysis, performed for 99 patients diagnosed with anaplastic glioma tumor. RESULTS: A significant correlation was found between planimetry tumor volume and patient survival, but there was no correlation between geometric tumor volume and patient survival. The larger planimetry tumor volume was significantly associated with shorter survival. CONCLUSIONS: The study indicated that in brain tumor research the preoperative tumor volume measured by the geometric method may not be prognostically important. The more accurate measurement, i.e., the planimetry method (based on either computed tomography or magnetic resonance imaging), is needed in brain tumor clinical research and prognostic diagnosis.

Microcomputer-based technique for 3-D reconstruction and volume measurement of computed tomographic images. Comparison of geometric and planimetry post-operative tumor volume effects on patient survival.

The relationship between brain tumor size and survival has been studied since the advent of CT and magnetic resonance imaging (MRI), however, all published studies are based on tumor sizes measured by the less accurate geometric method, with results that are inconsistent. For example, the influence of the extent of tumor resection on patient survival has been debated. Jelsma and Bucy advocated extensive resection based on their analysis of patients with glioblastoma multiforme, however, Green et al. produced conflicting results, showing that the extent of resection was not statistically significant when all variables were considered simultaneously. The present study investigates whether or not the study inconsistency is largely due to the use of the less accurate geometric tumor volume measurement. The study demonstrates that the geometric tumor volume and the planimetry tumor volume have significantly different prognostic effects.

Multicenter phase II trial of temozolomide in patients with anaplastic astrocytoma or anaplastic oligoastrocytoma at first relapse. Temodal Brain Tumor Group.

PURPOSE: To determine the antitumor efficacy and safety profile of temozolomide in patients with malignant astrocytoma at first relapse. PATIENTS AND METHODS: This open-label, multicenter, phase II trial enrolled 162 patients (intent-to-treat [ITT] population). After central histologic review, 111 patients were confirmed to have had an anaplastic astrocytoma (AA) or anaplastic mixed oligoastrocytoma. Chemotherapy-naive patients were treated with temozolomide 200 mg/m(2)/d. Patients previously treated with chemotherapy received temozolomide 150 mg/m(2)/d; the dose could be increased to 200 mg/m(2)/d in the absence of grade 3/4 toxicity. Therapy was administered orally on the first 5 days of a 28-day cycle. RESULTS: Progression-free survival (PFS) at 6 months, the primary protocol end point, was 46% (95% confidence interval, 38% to 54%). The median PFS was 5.4 months, and PFS at 12 months was 24%. The median overall survival was 13.6 months, and the 6- and 12-month survival rates were 75% and 56%, respectively. The objective response rate determined by independent central review of gadolinium-enhanced magnetic resonance imaging scans of the ITT population was 35% (8% complete response [CR], 27% partial response [PR]), with an additional 26% of patients with stable disease (SD). The median PFS for patients with SD was 4.4 months, with 33% progression-free at 6 months. Maintenance of progression-free status and objectively assessed response (CR/PR/SD) were both associated with health-related quality-of-life (HQL) benefits. Adverse events were mild to moderate, with hematologic side effects occurring in less than 10% of patients. CONCLUSION: Temozolomide demonstrated good single-agent activity, an acceptable safety profile, and documented HQL benefits in patients with recurrent AA.

Crystal structure of an engineered Cro monomer bound nonspecifically to DNA: possible implications for nonspecific binding by the wild-type protein.

The structure has been determined at 3.0 A resolution of a complex of engineered monomeric Cro repressor with a seven-base pair DNA fragment. Although the sequence of the DNA corresponds to the consensus half-operator that is recognized by each subunit of the wild-type Cro dimer, the complex that is formed in the crystals by the isolated monomer appears to correspond to a sequence-independent mode of association. The overall orientation of the protein relative to the DNA is markedly different from that observed for Cro dimer bound to a consensus operator. The recognition helix is rotated 48 degrees further out of the major groove, while the turn region of the helix-turn-helix remains in contact with the DNA backbone. All of the direct base-specific interactions seen in the wild-type Cro-operator complex are lost. Virtually all of the ionic interactions with the DNA backbone, however, are maintained, as is the subset of contacts between the DNA backbone and a channel on the protein surface. Overall, 25% less surface area is buried at the protein DNA interface than for half of the wild-type Cro-operator complex, and the contacts are more ionic in character due to a reduction of hydrogen bonding and van der Waals interactions. Based on this crystal structure, model building was used to develop a possible model for the sequence-nonspecific interaction of the wild-type Cro dimer with DNA. In the sequence-specific complex, the DNA is bent, the protein dimer undergoes a large hinge-bending motion relative to the uncomplexed form, and the complex is twofold symmetric. In contrast, in the proposed nonspecific complex the DNA is straight, the protein retains a conformation similar to the apo form, and the complex lacks twofold symmetry. The model is consistent with thermodynamic, chemical, and mutagenic studies, and suggests that hinge bending of the Cro dimer may be critical in permitting the transition from the binding of protein at generic sites on the DNA to binding at high affinity operator sites.

Crystal structure of lambda-Cro bound to a consensus operator at 3.0 A resolution.

The structure of the Cro protein from bacteriophage lambda in complex with a 19 base-pair DNA duplex that includes the 17 base-pair consensus operator has been determined at 3.0 A resolution. The structure confirms the large changes in the protein and DNA seen previously in a crystallographically distinct low-resolution structure of the complex and, for the first time, reveals the detailed interactions between the side-chains of the protein and the base-pairs of the operator. Relative to the crystal structure of the free protein, the subunits of Cro rotate 53 degrees with respect to each other on binding DNA. At the same time the DNA is bent by 40 degrees through the 19 base-pairs. The intersubunit connection includes a region within the protein core that is structurally reminiscent of the "ball and socket" motif seen in the immunoglobulins and T-cell receptors. The crystal structure of the Cro complex is consistent with virtually all available biochemical and related data. Some of the interactions between Cro and DNA proposed on the basis of model-building are now seen to be correct, but many are different. Tests of the original model by mutagenesis and biochemical analysis corrected some but not all of the errors. Within the limitations of the crystallographic resolution it appears that operator recognition is achieved almost entirely by direct hydrogen-bonding and van der Waals contacts between the protein and the exposed bases within the major groove of the DNA. The discrimination of Cro between the operators OR3 and OR1, which differ in sequence at just three positions, is inferred to result from a combination of small differences, both favorable and unfavorable. A van der Waals contact at one of the positions is of primary importance, while the other two provide smaller, indirect effects. Direct hydrogen bonding is not utilized in this distinction.

How Cro and lambda-repressor distinguish between operators: the structural basis underlying a genetic switch.

Knowledge of the three-dimensional structures of the lambda-Cro and lambda-repressor proteins in complex with DNA has made it possible to evaluate how these proteins discriminate between different operators in phage lambda. As anticipated in previous studies, the helix-turn-helix units of the respective proteins bind in very different alignments. In Cro the recognition helices are 29 A apart and are tilted by 55 degrees with respect to each other, but bind parallel to the major groove of the DNA. In lambda-repressor [Beamer, L. J. & Pabo, C. O. (1992) J. Mol. Biol. 227, 177-196] the helices are 34 A apart and are essentially parallel to each other, but are inclined to the major grooves. The DNA is much more bent when bound by Cro than in the case with lambda-repressor. The first two amino acids of the recognition helices of the two proteins, Gln-27 and Ser-28 in Cro, and Gln-44 and Ser-45 in lambda-repressor, make very similar interactions with the invariant bps 2 and 4. There are also analogous contacts between the thymine of bp 5 and, respectively, the backbone of Ala-29 of Cro and the backbone of Gly-46 of lambda-repressor. Otherwise, however, unrelated parts of the two proteins are used in sequence-specific recognition. It appears that similar contacts to the invariant or almost invariant bps (especially 2 and 4) are used by both Cro and lambda-repressor to differentiate the operator sites as a group from other sites on the DNA. The discrimination of Cro and lambda-repressor between their different operators is more subtle and seems to be achieved primarily through differences in van der Waals contacts at bp 3', together with weaker, less direct effects at bps 5' and 8', all in the nonconsensus half of the operators. The results provide further support for the idea that there is no simple code for DNA-protein recognition.

Prediction of mandibular third molar impaction in the orthodontic patient from a panoramic radiograph.

In this study we explored the predictability of mandibular third molar impactions. Serial panoramic radiographs from 50 non-extraction and 15 extraction patients were traced for various angular and linear measurements. A linear discriminant function analysis was performed for each stage of third molar development. The results indicate that the earliest stages of development have very little predictive value. Accordingly, a justification for the oft-practiced enucleation procedure cannot be made. Although the more the tooth is developed, the higher is the accuracy of prediction, two earlier stages where the crown is fully formed or the roots 1/3 formed possess high predictive values. Based on our data, impaction of third molars in the mandible is a predictable event both in extraction and non-extraction patients.

Stereotactic radiosurgery for the treatment of brain metastases. Results of a single institution series.

BACKGROUND: Stereotactic radiosurgery is being used with increasing frequency for the treatment of brain metastases. Optimal patient selection and treatment factors continue to be defined. This study provides outcome data from a single institutional experience with radiosurgery and identifies parameters that may be useful for the proper selection and treatment of patients. METHODS: Eighty-four patients underwent stereotactic radiosurgery for brain metastases between September 1989 and November 1995. Seventy-nine patients (93%) were treated at recurrence after previous whole brain radiotherapy. Patients had between 1 and 6 lesions treated with a median minimum tumor dose of 1600 centigrays (cGy). Thirty-eight patients (45%) had active extracranial disease at the time of radiosurgery. RESULTS: Median survival for the entire group was 43 weeks from the date of radiosurgery and 71 weeks from the original diagnosis of brain metastases. Patients with 1 or 2 metastases had significantly improved survival compared with patients with > or = 3 metastases (P = 0.02), and patients without active extracranial tumor survived longer than those with extracranial disease (P = 0.03). Median time to failure for 145 evaluable lesions was 35 weeks. Local control was significantly improved for radiosurgery doses of > 1800 cGy, and for melanoma histology. CONCLUSIONS: These results are comparable to reports of patients treated with resection and significantly superior to results observed after whole brain radiotherapy. The authors conclude that stereotactic radiosurgery is an effective, low risk treatment for extending the survival of patients with recurrent brain metastasis. Although survival is best for patients with < or = two lesions and no active extracranial disease, selected patients with > two lesions or active extracranial tumor may benefit as well.

High-resolution structure of an engineered Cro monomer shows changes in conformation relative to the native dimer.

A rationally designed, genetically engineered, monomeric form of the Cro protein from bacteriophage lambda has been crystallized and its structure determined by isomorphous replacement and refined to a resolution of 1.54 A. The structure confirms the rationale of the design but, at the same time, reveals 1-2 A shifts throughout the monomer structure relative to the previously determined structure of the dimeric wild-type protein. These changes include a 1.6 A main-chain shift in part of the beta-sheet region of the molecule relative to the alpha-helical region and a 1.1 A shift of a buried phenylalanine within the core as well as a correlated 2.2 A shift in a solvent-exposed beta-hairpin. The conformational adjustments appear to reflect an inherent flexibility of the protein that is associated with its DNA-binding function.