Arginine Deprivation Therapy: Putative Strategy to Eradicate Glioblastoma Cells by Radiosensitization.

Tumor cells-even if nonauxotrophic-are often highly sensitive to arginine deficiency. We hypothesized that arginine deprivation therapy (ADT) if combined with irradiation could be a new treatment strategy for glioblastoma (GBM) patients because systemic ADT is independent of local penetration and diffusion limitations. A proof-of-principle in vitro study was performed with ADT being mimicked by application of recombinant human arginase or arginine-free diets. ADT inhibited two-dimensional (2-D) growth and cell-cycle progression, and reduced growth recovery after completion of treatment in four different GBM cell line models. Cells were less susceptible to ADT alone in the presence of citrulline and in a three-dimensional (3-D) environment. Migration and 3-D invasion were not unfavorably affected. However, ADT caused a significant radiosensitization that was more pronounced in a GBM cell model with p53 loss of function as compared with its p53-wildtype counterpart. The synergistic effect was independent of basic and induced argininosuccinate synthase or argininosuccinate lyase protein expression and not abrogated by the presence of citrulline. The radiosensitizing potential was maintained or even more distinguishable in a 3-D environment as verified in p53-knockdown and p53-wildtype U87-MG cells via a 60-day spheroid control probability assay. Although the underlying mechanism is still ambiguous, the observation of ADT-induced radiosensitization is of great clinical interest, in particular for patients with GBM showing high radioresistance and/or p53 loss of function. Mol Cancer Ther; 17(2); 393-406. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."

Current characteristics and outcome of cytomegalovirus infections after kidney transplantation.

INTRODUCTION: The clinical course of cytomegalovirus (CMV) infections in the current era is poorly described. We characterized the symptoms and outcome of all CMV infections in a large cohort of kidney transplant recipients. Among 1129 kidney transplant recipients transplanted between 2004 and 2011 in Charité Universitätsmedizin Berlin and Helsinki University Hospital, 297 patients with CMV infection were characterized. RESULTS: CMV disease occurred in 217/1129 patients (19.2%), and CMV infection in 297/1129 (26.3%). Gastrointestinal symptoms were recorded in 58% and fever in 47% patients with primary CMV disease, compared to 46% and 27% patients with symptomatic CMV reactivation, whereas leukopenia or thrombocytopenia were seen in only 17-28% patients, and malaise in 9-10%. Tissue-invasive CMV gastroenteritis was confirmed in 11% and CMV pneumonia in only 1% of patients with CMV disease. Only 1 patient died because of CMV infection (mortality 0.3%). Virus-related factors or the use of secondary prophylaxis did not predict the risk of recurrence, which occurred in 33% patients. CONCLUSION: In conclusion, CMV disease remains a common problem after kidney transplantation. Gastrointestinal symptoms were common, especially in patients with primary CMV infection, whereas bone marrow suppression, hepatopathy, or malaise were seen less frequently.

Genotypic testing in clinically defined HHT: would Osler approve or turn in his grave?

Modern diagnostic possibilities pose a number of challenges. When is a precise genetic diagnosis justifiable in today's climate of cost-cutting? We would like to pose that question to Sir William Osler. Sir William was a keen observer, a master 'translator' of science into clinical medicine. Would he have required or supported genetic testing? We treated a patient whose case reminded us of Sir William's belief that clinical exactness was the ultimate aim, regardless of cost.

Treatment of PTLD with rituximab and CHOP reduces the risk of renal graft impairment after reduction of immunosuppression.

We addressed the effect of post-transplant lymphoproliferative disorder (PTLD) treatment with rituximab monotherapy or CHOP-based chemotherapy (+/- rituximab) after upfront immunosuppression reduction (IR) on renal graft function in a longitudinal analysis of 58 renal transplant recipients with PTLD and 610 renal transplant controls. Changes in the estimated glomerular filtration rate over time were calculated from a total of 6933 creatinine measurements over a period of >1 year using a linear mixed model with random and fixed effects. Renal graft function significantly improved with treatment of PTLD, especially in the chemotherapy subgroup. Patients treated with IR+chemotherapy +/- rituximab had a noninferior graft function compared with untreated controls suggesting that the negative impact of IR on the renal graft function can be fully compensated by the immunosuppressive effect of CHOP. The immunosuppressive effect of single agent rituximab may partially compensate the negative impact of IR on the graft function. Thus, it is possible to reduce immunosuppression when using chemotherapy to treat PTLD.

Pressure drop increase by biofilm accumulation in spiral wound RO and NF membrane systems: role of substrate concentration, flow velocity, substrate load and flow direction.

In an earlier study, it was shown that biofouling predominantly is a feed spacer channel problem. In this article, pressure drop development and biofilm accumulation in membrane fouling simulators have been studied without permeate production as a function of the process parameters substrate concentration, linear flow velocity, substrate load and flow direction. At the applied substrate concentration range, 100-400 microg l(-1) as acetate carbon, a higher concentration caused a faster and greater pressure drop increase and a greater accumulation of biomass. Within the range of linear flow velocities as applied in practice, a higher linear flow velocity resulted in a higher initial pressure drop in addition to a more rapid and greater pressure drop increase and biomass accumulation. Reduction of the linear flow velocity resulted in an instantaneous reduction of the pressure drop caused by the accumulated biomass, without changing the biofilm concentration. A higher substrate load (product of substrate concentration and flow velocity) was related to biomass accumulation. The effect of the same amount of accumulated biomass on the pressure drop increase was related to the linear flow velocity. A decrease of substrate load caused a gradual decline in time of both biomass concentration and pressure drop increase. It was concluded that the pressure drop increase over spiral wound reverse osmosis (RO) and nanofiltration (NF) membrane systems can be reduced by lowering both substrate load and linear flow velocity. There is a need for RO and NF systems with a low pressure drop increase irrespective of the biomass formation. Current efforts to control biofouling of spiral wound membranes focus in addition to pretreatment on membrane improvement. According to these authors, adaptation of the hydrodynamics, spacers and pressure vessel configuration offer promising alternatives. Additional approaches may be replacing heavily biofouled elements and flow direction reversal.

Evaluation of hybrid processes for nitrification by comparing MBBR/AS and IFAS configurations.

An integrated fixed-film activated sludge (IFAS) pilot plant and a moving bed biofilm reactor coupled with an activated sludge process (MBBR/AS) were operated under different temperatures, carbon loadings and solids retention times (SRTs). These two types of hybrid systems were compared, focusing on the nitrification capacity and the nitrifiers population of the media and suspended biomass alongside other process performances such as carbonaceous and total nitrogen (TN) removal rates. At high temperatures and loadings rates, both processes were fully nitrifying and achieved similarly high carbonaceous removal rates. However, under these conditions, the IFAS configuration performed better in terms of TN removal. Lower temperatures and carbon loadings led to lower carbonaceous removal rates for the MBBR/AS configuration, whereas the IFAS configuration was not affected. However, the nitrification capacity of the IFAS process decreased significantly under these conditions and the MBBR/AS process was more robust in terms of nitrification. Ammonia oxidising bacteria (AOB) and nitrite oxidising bacteria (NOB) population counts accurately reflected the changes in nitrification capacity. However, significantly less NOBs than AOBs were observed, without noticeable nitrite accumulation, suggesting that the characterisation method used was not as sensitive for NOBs and/or that the NOBs had a higher activity than the AOBs.

Radiologic manifestations of intraventricular and subarachnoid racemose neurocysticercosis.

Neurocysticercosis is a major cause of acquired epilepsy around the globe. The racemose form of this disease, which has a predilection for the subarachnoid space, is rare in the US. The patient described here had a combination of intraventricular and subarachnoid cysticercal cysts. In the following report, the CT and MR characteristics of this rare form of neurocysticercosis both before and after treatment are described, and the current issues surrounding management are briefly discussed.

Impact of a diagnostic workstation on workflow in the emergency department at a level I trauma center.

PURPOSE: When a computed tomography (CT) scan on a patient from the emergency department is completed at University of Medicine and Dentistry of New Jersey (UMDNJ)-University Hospital, a non-picture archiving and communication system (PACS) environment, formal diagnostic review cannot begin until the images are printed and transported to the on-call radiology resident. The time to reach a final diagnosis has been significantly reduced by the introduction of a single workstation in the on-call reading room. MATERIALS AND METHODS: Five radiology residents were studied. Each read 10 CT studies on film and 10 on a workstation. After a training period to familiarize the residents with the workstation, measurements were taken of the time required to read the examination and the time required for printing and transporting or networking the images. RESULTS: The average time required to transmit the images was reduced from approximately 40 minutes to 16 minutes. Interpretation times between the workstation and film were comparable. CONCLUSION: The addition of a single workstation significantly reduces the time required to reach a final diagnosis by obviating the need to print and transport the images to the on-call radiology resident. Such time savings can have a significant impact on the care of trauma patients.

[Evaluation of environmental medicine documentation in Schleswig-Holstein 1995-1999]. / Auswertung umweltmedizinischer Dokumentationsbogen in Schleswig-Holstein von 1995-1999.

Physicians qualified in environmentally related disorders due to their participation in special training courses in the Federal State of Schleswig-Holstein (Germany) used a standardised questionnaire to report on their environmental medicine related cases. The course of the illness, if known, has been documented on a separate data sheet. During the period from 1995-1999 916 cases and 508 courses of illness were assessed. The environmental factors/toxicants of exposure most frequently documented by the 85 participating physicians and found to be related to symptoms of illness were biocides (mainly insecticides used indoors for pest control (32%), moulds (27%), dental amalgam (22%), solvents/volatile organic compounds (21%) and formaldehyde (16%), respectively. In 42% of the documented cases an exposure to more than one environmental factor/toxicant was registered. Age distribution, gender, location of exposure as well as the symptoms of illness of the patients were found to be dependent on the type of exposure. Cessation of exposure to harmful substances/environments was achieved in 54% of those cases where information regarding the course of the illness was given. In 65% of these cases recovery was reported and 30% recovered partially. In those cases where a cessation of exposure could not be achieved or was not complete, no or only partial recovery was mostly reported. From these results it may be concluded that research work on environmentally related disorders should be enforced in order to prevent unnecessary illness and to lower the public health system expenditure.

[Kinetics of arsenic in human blood after a fish meal]. / Kinetik von Arsen im Blut des Menschen nach einer Fischmahlzeit.

It is well known that fish contains high amounts of arsenic (As) compounds (mean values per wet weight [mg x kg-1] Ballin [1]: 41; Falconer et al. [2]: 14; Staveland et al. [3]: 5.2), which are mainly represented by organic As compounds, especially by arsenobetaine. It is generally assumed that arsenobetaine is rapidly eliminated via the urine and therefore seems to be non-toxic for humans. However, the kinetics of arsenobetaine in human blood are unknown to date. Therefore, the following experiments were performed: 14 women of 24 to 32 years of age voluntarily ingested 179 to 292 g of cooked plaice fillet containing 44 (minimum) to 276 (maximum) mg As x kg-1 dry weight. Hence, the volunteers ingested 2.5 (minimum) to 20 (maximum) mg As per person, equivalent to 0.04 to 0.35 mg As x kg-1 body weight. The element As was measured by atomic absorption spectrometry using the graphite furnace technique in order to detect the total amount of As including that of the stable arsenobetaine. In the blood, the highest As values of 55 +/- 5.8 micrograms x L-1 (median) were found 2 hours after fish ingestion. Subsequently the As concentrations declined reaching 16 +/- 0.69 micrograms x L-1 (median) 48 hours after fish ingestion. In respect of the As values in blood recorded between 2 and 10 hours after fish ingestion, rapid elimination could be observed leading to a half-life of 7.1 hours (first value) recorded by linear regression analysis. With regard to the As values in blood between 10 and 48 hours after fish ingestion, a lower elimination rate was estimated with a longer half-life of 63 hours (second value). The reason for this delayed elimination of As is not known. The results indicate that As mainly absorbed as arsenonetaine due to ingestion of fish is not eliminated as fast as had been expected on the basis of published data. As long as it is not known what happens to arsenobetaine remaining for longer periods in the blood with a half-life of 63 hours, caution is advised regarding the general opinion that arsenobetaine is rapidly eliminated and non-toxic for human consumption.

Sickle cell crisis in the adult: chest radiographic findings and comparison with pediatric sickle cell disease.

With the advent of improved therapy, an increasing proportion of individuals suffering from sickle cell disease (SCD) are surviving into adulthood. In contrast to children, little has been documented concerning the typical radiographic findings in adults presenting with sickle cell crises (SCC). We describe the chest radiographic (CXR) manifestations of adults with SCD presenting in SSC, correlated to hemoglobin (Hb) values, and compare them to those of the pediatric sickle cell population. The chest radiographs of 66 consecutive adults presenting to our emergency department complaining of symptoms consistent with acute SCC were retrospectively reviewed over a 12-month period. The radiographic findings were correlated with admission Hb values and compared with those of 50 children with known SCD presenting with SCC. Chi square analysis revealed no significant difference between the cardiovascular and bony findings in the adults and in those of the pediatric controls (p > 0.08-p > 1.0). However, one important difference in the two cohorts was that upper lobe infiltrates occurred exclusively in the pediatric group (p = 0.06). There was a statistically significant (p < 0.05) difference in cardiovascular and skeletal abnormalities between adults with Hb above and below the mean (8.2 g/dL). The radiographic features of adults presenting in acute SCCs are similar to those of children. Although the chest radiograph is often normal, in decreasing frequency, cardiovascular abnormalities, pneumonia sparing the upper lobes, and aseptic osteonecrosis of the shoulders and spine are not uncommon. There is a significant relationship, however, between cardiovascular abnormalities and Hb levels.

[Environmental pollution--assessment of environmental medicine questionnaires and data in Schleswig-Holstein from 1995-1997]. / Umweltmedizinische Belastung. Auswertungvon Dokumentations- und Verlaufsbögen in Schleswig-Holstein von 1995 bis 1997.

Physicians qualified in environmental medicine due to their participation in special training courses in the federal state Schleswig-Holstein (Germany) may use a standardized questionnaire to report on their environmental medicine-related cases. The course of the illness and recovery, respectively, if known, is to be documented on a separate data sheet. During a three year period from 1995 to 1997 716 cases and 216 courses of illness and recovery, respectively, have been reported. The relevant environmental factors/toxicants of exposure most frequently documented by these physicians and found to be related to symptoms of illness were biocides (mainly insecticides used indoors for pest control, 31%) molds (30%), dental amalgam (28%), solvents or volatile organic compounds (VOC, 23%) and formaldehyde (17%), respectively. In 47% of the documented cases an exposure to more than one environmental factor/toxicant was registered. Age distribution as well as the symptoms of illness of the patients were found to be dependent on the type of exposure. After the physicians diagnosis of an environmental medicine-related illness the exposure was stopped completely in 57% of those cases of whom the course of the illness was known. Recovery was reported in 62% of these patients, and additional 30% had improved but had not recovered completely at the time of data-assessment. From these results it may be concluded that research work in the field of environmental medicine should be enforced in order to prevent unnecessary illness and to lower the costs of the public health system.

Masseter reflex latencies and amplitudes are not influenced by supratentorial and cerebellar lesions.

The aim of this study was to investigate possible influences of suprasegmental lesions on the masseter reflex. The masseter reflex was elicited in 54 patients with supratentorial (37 patients) or cerebellar (17 patients) lesions 3-11 days after the acute onset of clinical disease. Patients showing lesions within the pons and midbrain on thin-slice magnetic resonance imaging were excluded from evaluation. The testing procedure included an additional facilitating maneuver (opening and closing the jaw before tapping). Masseter reflex latencies, interside differences, and amplitudes were within the normal range in all patients. Latencies were not different with and without the facilitating maneuver. Amplitudes were significantly higher with the maneuver, but interside differences of amplitudes were unchanged. Masseter reflex abnormality can be taken as a reliable measure of direct involvement of the reflex arc.

[A cancer mortality atlas on a small geographic scale: procedure, validity and possibilities for its use]. / Erstellung eines kleinräumigen Krebsatlanten: Vorgehensweise, Validität und Nutzungsmöglichkeiten.

Cancer mortality in two counties (Dithmarschen and Nordfriesland) of the Federal State of Schleswig-Holstein (Germany) was assessed by analysing the death certificates for the period from 1980 to 1991. Age-adjusted cancer mortality rates were calculated for the more common cancers for counties as well as for smaller sub-scales. The procedure in respect of data base, data protection, data flow, calculation of rates and mapping of cancer mortality rates on small geographic scales is described and discussed. The data collected by us was compared with the data provided by the offices of statistic affairs on a county scale (only for the more common cancers). The comparison was done for each gender and each county, respectively. The agreement was high (> 95%) for 16 of 22 compared items, and below 90% for two items only. The validity of the data, therefore, was considered sufficient for epidemiological studies. As an example, results regarding female breast cancer rates are shown. The possibilities for the utilization of cancer registries on small geographic scales are discussed: Depending on the incidence of the occurrence of different cancers, cancer registries should provide data on multiple regional scales. A more flexible use of the possibilities of the assessment of regional cancer rates is imperative to utilise the very expensive and time-consuming instruments of analytical epidemiological studies of the causes of cancer more effectively.

Technical and surgical aspects of continuous vascular access in freely moving small animals.

Many systems and techniques for continuous vascular access in small animals have been described. Problems with these systems have included (1) insufficient free movement, (2) sepsis, (3) high cost, (4) complicated construction, (4) thrombosis, and (5) dislocations of the intravenous catheter. The described operative techniques and a new experimental setup overcome these complications. The apparatus involves a swivel that is connected with an intravenously placed polyurethane catheter. A leather harness on the back of the animal is connected with the end of the swivel joint via a silicone tube in which the intravenous catheter runs to the swivel. The swivel, a modified conventional glass syringe, is positioned in ball bearings and a Johnson joint. The swivel, ball bearings, and Johnson joint are counterbalanced and can move up and down. When this system was used, the catheters functioned well for as long as 28 days, with a mean duration of 24.4 +/- 1.8 days (n = 420). Five catheter dislocations resulted from harness failure, and three dislocations were caused by animals twisting. All animals gained weight (3.53 +/- 0.37 gm/day (mean +/- SEM)). The rotary portion of the swivel and the Johnson joint secure stressless movement of the animal, avoiding twisting and dislocation of the catheter, which overcomes typical problems of existing methods. The low thrombogenicity of the polyurethane catheter also reduces complications. A further advantage is low cost, because prefabricated, reusable materials are used.