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To exploit large-scale biomedical data, the application of common data models and the establishment of data networks are being actively carried out worldwide. However, due to the privacy issues, it is difficult to share data distributed among institutions. In this study, we developed and evaluated weight-based integrated Cox model (WICOX) as a privacy-protecting method without sharing patient-level information across institutions. WICOX generates a weight for each institutional model and builds an integrated model of multi-institutional data based on these weights. WICOX does not require iterative communication until the centralized parameter converges. We performed experiments to show the weight characteristic of our algorithm based on 10 hospitals (2910 intensive care unit (ICU) stays in total) from the electronic intensive care unit Collaborative Research Database to predict time to ICU mortality with eight risk factors. Compared with the centralized Cox model, WICOX showed biases from 0 to 0.68E-2, from 0.00E-2 to 4.98E-2, and from 0.74E-2 to 1.7E-2 for time-dependent AUC, log hazard ratio, and survival rate, respectively. In addition, through simulation results using real 10 hospitals, WICOX showed robust results in accuracy under any composition of hospitals. The results of the experiments highlight that WICOX has robust characteristics and provides predictive performance and statistical inference results nearly the same as those of the centralized model. WICOX is a non-iterative method using the weight of institutional model for implementing the Cox model across multiple institutions in a privacy-preserving manner.

BACKGROUND This study was conducted to evaluate predictive factors of urinary continence recovery after radical prostatectomy (RP) for high-grade prostate cancer (PCa). METHODS A total of 241 patients with high-grade (Gleason Score 8 or 9) PCa who underwent RP in a single Korean center between January 2011 and May 2018 were retrospectively reviewed. Urinary continence was defined as no pads use. Urinary continence was evaluated at 1, 3, 6, and 12 months after RP. Univariate and multivariate analyses were performed to determine the predictive factors of urinary continence recovery after RP. RESULTS The mean age was 67.6±6.4 years, and the mean PSA was 18.7±21.1 ng/dL. A total of 197 (81.7%) patients underwent nerve-sparing RP, and 198 patients (82.2%) were continent 1 year after RP. Multivariate analysis showed that the age (odds ratio [OR]=1.091 [1.015-1.172], P=0.018), Body Mass Index (BMI) (OR=1.227 [1.057-1.424], P=0.007), and modified surgical technique (OR=0.109 [0.044-0.267], P

We report the optimization of detergent-mediated reconstitution of an integral membrane-bound protein, full-length influenza M2 protein, by direct insertion into detergent-saturated liposomes. Detergent-mediated reconstitution is an important method for preparing proteoliposomes for studying membrane proteins, and must be optimized for each combination of protein and membrane constituents used. The purpose of the reconstitution was to prepare samples for site-directed spin-labeling electron paramagnetic resonance (SDSL-EPR) studies. Our goals in optimizing the protocol were to minimize the amount of detergent used, reduce overall proteoliposome preparation time, and confirm the removal of all detergent. The liposomes were comprised of (1-palmitoyl-2-oleyl-sn-glycero-phosphocholine (POPC) and 1-palmitoyl-2-oleyl-sn-glycero-3-[phospho-rac-(1-glycerol)] (POPG), and the detergent octylglucoside (OG) was used for reconstitution. Rigorous physical characterization was applied to optimize each step of the reconstitution process. We used dynamic light scattering (DLS) to determine the amount of OG needed to saturate the preformed liposomes. During detergent removal by absorption with Bio-Beads, we quantified the detergent concentration by means of a colorimetric assay, thereby determining the number of Bio-Bead additions needed to remove all detergent from the final proteoliposomes. We found that the overnight Bio-Bead incubation used in previously published protocols can be omitted, reducing the time needed for reconstitution. We also monitored the size distribution of the proteoliposomes with DLS, confirming that the size distribution remains essentially constant throughout the reconstitution process.

The volatile compound 2,3-butanediol, which is produced by certain strains of root-associated bacteria, consists of three stereoisomers, namely, two enantiomers (2R,3R- and 2S,3S-butanediol) and one meso compound (2R,3S-butanediol). The ability of 2,3-butanediol to induce plant resistance against pathogenic fungi and bacteria has been investigated; however, little is known about its effects on induced resistance against viruses in plants. To investigate the effects of 2,3-butanediol on plant systemic defense against viruses, we evaluated the disease control capacity of each of its three stereoisomers in pepper. Specifically, we investigated the optimal concentration of 2,3-butanediol to use for disease control against Cucumber mosaic virus and Tobacco mosaic virus in the greenhouse and examined the effects of drench application of these compounds in the field. In the field trial, treatment with 2R,3R-butanediol and 2R,3S-butanediol significantly reduced the incidence of naturally occurring viruses compared with 2S,3S-butanediol and control treatments. In addition, 2R,3R-butanediol treatment induced the expression of plant defense marker genes in the salicylic acid, jasmonic acid, and ethylene signaling pathways to levels similar to those of the benzothiadiazole-treated positive control. This study reports the first field trial showing that specific stereoisomers of 2,3-butanediol trigger plant immunity against multiple viruses.

Background/Aims: The double-guidewire technique (DGT) and transpancreatic precut sphincterotomy (TPS) are introduced as alternative biliary cannulation techniques for difficult biliary cannulation. This study aimed to evaluate the sequential use of DGT and TPS compared with a needle-knife precut papillotomy (NK). Patients and Methods: Six hundred and thirty-five consecutive patients with naοve papilla and who underwent endoscopic retrograde cholangiopancreatography (ERCP) for biliary cannulation from March 2010 to April 2014 in a single institute were analyzed. When standard techniques were unsuccessful, DGT or NK was performed. TPS was sequentially performed if DGT failed. Results: DGT and NK were attempted in 65 and 58 patients, respectively. A sequential DGT-TPS was performed in 38 patients after a failed DGT. Biliary cannulations were successful in 42%, 74%, and 66% of the DGT, sequential DGT-TPS, and NK patients, respectively (P = 0.002). The cannulation rate was higher in the DGT ± TPS patients (85%) than in the NK patients (P = 0.014). Post-ERCP pancreatitis (PEP) developed in 26% of the successful DGT patients, 37% of the sequential DGT-TPS patients, and 10% of the NK patients (P = 0.008). Of the sequential DGT-TPS patients, the incidence of PEP was significantly reduced in patients with a pancreatic duct (PD) stent compared with patients without a PD stent (24% vs. 62%, P = 0.023). Conclusions: Sequential DGT-TPS is a useful alternative method compared with NK for patients in whom biliary cannulation is difficult. In the sequential DGT-TPS patients, the incidence of PEP was significantly reduced with the use of a PD stent.

To investigate the clinicopathologic and genetic correlations between double primary endometrial and colorectal cancer related to Lynch syndrome and to analyze germline mutations in mismatch repair genes in endometrial cancer patients in Korea.Thirteen patients diagnosed with pathologically endometrial and colorectal cancer between January 2005 and November 2016 in a single institution were enrolled in the study. The medical records were retrospectively analyzed. The genetic mutational information of endometrial cancer in Korea was retrieved from the literature review.Endometrial cancer was diagnosed first in eight (62%) patients, and one patient was diagnosed with colorectal cancer first. Endometrioid adenocarcinoma was reported in 10 of 13 (77%) endometrial cancer patients. Endometrial cancer was found at the low uterine segment in three patients. Three of four patients had high microsatellite instability. The loss of mismatch repair proteins was confirmed in 7 of 11 cases using immunohistochemistry. Four patients fulfilled clinical criteria based on a family history of cancer. Overall, the incidence of suspected Lynch syndrome was 77% (10/13). Four of them underwent genetic testing and three were found to have a pathogenic germline mutation. A possible founder mutation, c.1757_1758insC in MLH1, was observed in 21 germline mutation information from literature review.The present study describes the clinicopathologic data of double primary endometrial and colorectal cancer patients and supports that these patients should undergo closed approach for Lynch syndrome. Moreover, a possible founder mutation in Korean endometrial cancer patients was identified.

The Foot and Mouth Disease (hereinafter referred to as ‘FMD’) is a type of acute and febrile infectious disease which occurs when hoofed and even-toed animals (artiodacty) such as cows, pigs, sheep, goats and deer are infected by FMD viruses. FMD viruses have a huge host range and strong invasiveness, as well as wide infection routes. Sensitive individuals may be affected by the disease with a relatively small amount of the infectious virus, while their latent period is quite short. In addition, as the virus is excreted out of the body before the clinical symptoms become apparent, the virus discharged through the respiratory system may spread a fair distance to other individuals via air.(Timoney etc., 1988; Gamer, 2000). Thus, this study aims to analyze and predict the diffusion route of domestic animal contagious diseases to prevent it in consideration of the domestic geographical features such as topography as well as direction and speed of the wind and by means of GIS. Since FMD and the bird flu are contagious through the air, it is of great importance to refer to the wind direction and speed data. GIS was adopted to analyze and predict the diffusion route of FMD in Gyeongsangbukdo area. Based on the data from GIS, the diffusion of FMD would be readily grasped, which is expected to reduce damage to farm houses. In the future, it is thought that the range of analysis in 2010 should be expanded nationwide.

Azole antifungal agents are essential drugs in the treatment of fungal infections in renal transplant patients. As azoles, these antifungal agents are inhibitors of CYP3A4 and P-glycoprotein (P-gp); and thus therapeutic drug monitoring is important. We evaluated a patient with cutaneous and pulmonary aspergillosis who was successfully treated with voriconazole and a low cyclosporine trough level (3.2 - 27.9 ng/ml) for 3 months. During that period, the patient showed good allograft function with the co-administration of voriconazole and cyclosporine. We measured the patient's genotype of MDR1, CYP3A4, CYP3A5 and CYP2C19 enzymes in addition to the intracellular concentration of cyclosporine in peripheral blood mononuclear cells (PBMCs). The intracellular concentration of cyclosporine in PBMC is 3.2 times higher with no functionally defected alleles in MDR1, CYP3A4, CYP3A5 or CYP2C19 enzymes when cyclosporine is co-administered with voriconazole ex vivo. Although other confounding factors causing immunological modulation may exist, it is plausible that low serum and high intracellular cyclosporine concentrations, due to the inhibition of P-gp activity by voriconazole, also contribute to an immunosuppressive state.

Please cite this paper as: Kim et al. (2012) Characteristics of respiratory viral infections during influenza season in Canadian Hutterite Communities. Influenza and Other Respiratory Viruses DOI:10.1111/irv.12021. Objectives: To determined the pathogen-specific incidence of respiratory virus infection in Hutterite communities occurring over the 2008–2009 influenza season and assess temporal characteristics of respiratory illness related to infection. Methods: 3273 participants community members enrolled in a cluster randomized trial of influenza vaccine were studied. Results: One hundred forty-nine participants had laboratory-confirmed influenza, and 595 had at least one episode of laboratory-confirmed respiratory viral infection other than influenza. Entero/rhinovirus had the highest incidence among children

This study was conducted to investigate the decomposition of three γ-irradiated antibiotics (e.g., tetracycline, sulfamethazine, and lincomycin) and to compare the toxic effects on Daphnia magna, Vibrio fischeri, and Pseudokirchneriella subcapitata. The median cell growth inhibition concentrations (IC50) of tetracycline, lincomycin, and sulfamethazine for P. subcapitata dramatically increased (e.g., toxicity decreased) after radiolysis. The results demonstrated that γ-radiation treatment was efficient to decompose antibiotics and thereby their toxicity on P. subcaptitata remarkably decreased due to reduced parent compounds.

The objective of our study was to introduce a safe and effective method for the treatment of cervical pregnancy. This was a case series and took place at the minimal invasive surgery clinic at Soonchunhyang University Bucheon Hospital, Bucheon, Korea. From April 2005 through October 2007, a total of 10 patients with cervical pregnancy underwent hysteroscopic surgery. An 18 F foley catheter was inserted through the cervical canal after dilation, and the uterine cavity was irrigated with 3.5% H 2 O 2 300 mL for prevention of unrelenting bleeding. Hysteroscopic removal of cervical gestation under ultrasonographic guidance was performed uneventfully. All patients had an unremarkable postoperative course. Serum β–human chorionic gonadotropin levels were monitored after surgery and exhibited optimal decrease. All cases had histologic confirmation of products of conception removed from the cervix. The estimated blood loss was less than 50 mL. All patients were discharged after the first or second postoperative day. Hysteroscopic removal of cervical pregnancy with H 2 O 2 is very useful and safe and preserves fertility.

Preoperative radiological identification of the Adamkiewicz artery and intraoperative neurologic monitoring are known to be helpful for preventing paraplegia after thoracoabdominal aorta replacement. To answer whether they should be used routinely, we investigated the incidence of spinal cord ischemia after extensive descending aortic repair without using such modalities.We retrospectively reviewed the outcome of 95 patients who underwent extensive descending thoracic (DTA) or thoracoabdominal aorta (TAA) repair without the Adamkiewicz artery identification or neurologic monitoring from 2006 through 2010. Spinal cord protection strategy consisted of distal aortic perfusion, cerebrospinal fluid drainage, mild hypothermia, and maintenance of hypertension (systolic≥120mmHg) through the second postoperative day. A few segmental arteries were empirically selected for reimplantation based on the size and the amount of backbleeding; overall 1.4 per patient, 0.3 for DTA, 1.4 for type I, 2.4 for type II, 0.9 for type III, and 0 for type IV TAA.Two patients died early after surgery. All the remaining patients awoke without paraplegia or paraparesis. Delayed deficit occurred in 7 patients (7.4%) after hypotensive events caused by sedation, bleeding, respiratory distress, or cardiac dysfunction. Three patients (3.2%) became permanently paraplegic and the other four recovered completely within 48 hours after cerebrospinal fluid drainage and elevation of systemic blood pressure.Even without the Adamkiewicz artery identification and neuromonitoring, the incidence of immediate paraplegia could be kept low by applying the strategy based on the modern concept of cord perfusion. The relatively high incidence of delayed deficit suggests the importance of postoperative hemodynamic management and prevention of cardiopulmonary complications.

This article argues that the territorial trap and the social amplification of risks associated with a porous border have led to an increased vulnerability for unauthorised migrants along the US-Mexico boundary. A contradiction of globalisation is discussed examining how goods and capital are given more guarantees and social protections than certain people. The concept of escrow is introduced as a mitigation measure to reduce human vulnerability. Examples of other comparable and contentious programs are discussed to support the need for such measures. The discussions and methods outlined in this article, attempt to bring about an increased awareness of the territorial trap and the role it plays in producing the hazardous conditions along the US-Mexico boundary.

Ethanol induces oxidative stress and its exposure during early developmental age causes neuronal cell death which leads to several neurological disorders. We previously reported that vitamin C can protect against ethanol-induced apoptotic cell death in the developing rat brain. Here, we extended our study to understand the therapeutic efficacy of vitamin C against ethanol-induced oxidative stress, neuroinflammation mediated neurodegeneration in postnatal day 7 (PND7) rat. A single episode of ethanol (5g/kg) subcutaneous administration to postnatal day 7 rat significantly induced the production of reactive oxygen species (ROS), and activated both microglia and astrocytes followed by the induction of different apoptotic markers. On the other hand, due to its free radical scavenging properties, vitamin C treatment significantly reduced the production of reactive oxygen species, suppressed both activated microglia and astrocytes and reversed other changes including elevated level of Bax/Bcl-2 ratio, cytochrome c and different caspases such as caspase-9 and caspase-3 induced by ethanol in developing rat brain. Moreover, vitamin C treatment also reduced ethanol-induced activation of Poly [ADP-Ribose] Polymerase 1(PARP-1) and neurodegeneration as evident from Flouro-Jade-B and Nissl stainined neuronal cell death in PND7 rat brain. These findings suggest that vitamin C mitigated ethanol-induced oxidative stress, neuroinflammation and apoptotic neuronal loss and may be beneficial against ethanol damaging effects in brain development.

Parkinson disease is a neurodegenerative disease characterized by loss of midbrain dopaminergic neurons resulting in movement disorder. Neural stem cells (NSC) of the CNS have recently aroused a great deal of interest, not only because of their importance in basic research of neural development, but also for their therapeutic potential in neurological disorders. We have recently generated an immortalized human NSC cell line, HB1.F3, via retrovirus-mediated v-myc transfer. This line is capable of self-renewal, is multipotent, and expresses cell specific markers for NSC, ATP-binding cassettes transporter (ABCG2) and nestin. Next, we co-transduced the F3 NSC line with genes encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GTPCH1) in order to generate dopamine-producing NSC. The F3.TH.GTPCH human NSC line expresses TH and GTPCH phenotypes as determined by RT-PCR, western blotting and immunocytochemistry, and shows a 800 to 2000-fold increase in production of L-dihydroxyphenyl alanine in HPLC analysis. A marked improvement in amphetamine-induced turning behavior was observed in parkinsonian rats implanted with F3.TH.GTPCH cells, but not in control rats receiving F3 NSC. In the animals showing functional improvement, a large number of TH-positive F3.TH.GTPCH NSC were found at injection sites. These results indicate that human NSC, genetically transduced with TH and GTPCH1 genes, have great potential in clinical utility for cell replacement therapy in patients suffering from Parkinson disease.

This paper examines the timing of protective action recommendations in relationship to the distance of wildfire to a threatened community using exploratory map animation. The 2003 Southern California Wildfires were animated to assist in understanding the complex interaction between fire progression and warnings to threatened communities. Exploratory map animation provides a useful post-event analysis platform for hypothesis generation. A new method is introduced for interpolating the distance from a wildfire to a threatened community using geospatial data. The results are used to examine incident commander decision-making in regards to the estimated time of arrival of a wildfire at a community. The exploratory map animations were successful in generating an intriguing hypothesis concerning the timing of protective action recommendations and the proportional distance of a wildfire to a threatened community. Following a wildfire, emergency responders can use exploratory map animation as a training tool to evaluate protective action recommendations of wildfires.

Objectives: We wished to determine the feasibility and early safety of external beam radiation therapy (EBRT) used following balloon aortic valvuloplasty (BAV) to prevent restenosis. Background: BAV for calcific aortic stenosis (AS) has been largely abandoned because of high restenosis rates, i.e., > 80% at 1 year. Radiation therapy is useful in preventing restenosis following vascular interventions and treating other benign noncardiovascular disorders. Methods: We conducted a 20-patient, pilot study evaluating EBRT to prevent restenosis following BAV in elderly patients with calcific AS. Total doses ranging from 12–18 Gy were delivered in fractions over a 3–5 day post-op period to the aortic valve. Echocardiography was performed pre and 2 days post-op, 1, 6, and 12 months following BAV. Results: One-year follow-up is completed (age 89 ± 4). There were no complications related to EBRT. Eight patients died prior to 1 year; 5 of 10 (50%) in the low-dose (12 Gy) group and 3 of 10 (30%) in the high-dose (15–18 Gy) group. None of these 8 patients had restenosis, i.e., > 50% loss of the initial AVA gain, and only three deaths were cardiac in origin. One patient underwent aortic valve replacement and none repeated BAV. By 1 year, 3 of the initial 10 (30%) in the low-dose group and 1 of 9 (11%) in the high-dose group demonstrated restenosis (21% overall). Conclusions: EBRT following BAV in elderly patients with AS is feasible, free of early complications, and holds promise in reducing the 1 year restenosis rate in a dose-dependent fashion. © 2006 Wiley-Liss, Inc.

Polystyrene (PS)/organophilic montmorillonite (OMMT) clay nanocomposites were prepared by a solvent casting method using chloroform as a cosolvent. Intercalation of the OMMT in the PS matrix was achieved as revealed by X-ray diffraction. The IR spectra of the products indicated that the OMMT is homogeneously dispersed in the PS matrix. A thermogravimetric analysis (TGA) showed that the onset temperature increases linearly with the clay content. The glass-transition temperature of the PS, examined using differential scanning calorimetry, had a trend similar to that from the TGA. The rheological properties of the PS/OMMT nanocomposites were also investigated via a rotational rheometer with a parallel plate geometry, and they exhibited sharper shear thinning and increased storage and loss modulus with clay content. Furthermore, the shear viscosity obtained from the steady shear experiment was well correlated with the complex viscosity obtained from the oscillatory experiment via the Cox and Merz relation. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 87: 2106–2112, 2003

Polystyrene (PS)/clay nanocomposites were synthesized by the emulsion polymerization of styrene in the presence of sodium ion-exchanged montmorillonite (Na+-MMT), demonstrating that the strongly hydrophobic PS was intercalated into the hydrophilic silicate layers. The nanocomposites were examined by means of X-ray diffraction, transmission electron microscopy, thermogravimetric analysis. The rheological properties of the PS/Na+-MMT nanocomposites were also studied to exhibit more pronounced shear thinning behavior with increasing clay content.

Prothrombin, a protein involved in blood coagulation, is a plasma glycoprotein composed of the Gla domain, two adjacent kringle domains, and a serine protease domain. Kringles are triple-disulfide-loop folding domains, which are found in several other blood proteins. In this study, we showed that recombinant human prothrombin kringle-1, -2. and -1-2 (rk-1, -2, -1-2) all have potent anti-angiogenic activities, which inhibit Lewis lung carcinoma (LLC) tumor growth and metastases. Recombinant human prothrombin kringles were expressed by an E. coli expression system and purified to apparent homogeneity from crude E. coli extracts. Purified rk-1, -2, -1-2 migrated with a molecular mass of 14, 19, and 31 kDa, respectively, on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing conditions. rk-1, -2, -1-2 exhibited potent inhibitory effects on bFGF-stimulated bovine capillary endothelial cell growth with half-maximal concentrations (ED50) of approximately 41, 55, and 156 nM, respectively. All of the recombinant human prothrombin kringles also inhibited angiogenesis in the chorioallantoic membrane (CAM) of chick embryos at a dose of 20 microg. Systemic administration of rk-1, -2, -1-2 at a dose of 0.5 mg/kg/day suppressed the growth of primary LLC and at dose of 0.5 and 1.0 mg/kg/day inhibited LLC metastases in C57BL6/J mice lungs through their anti-angiogenic effects.

Background. Lamivudine has been reported to be able to stabilize liver enzyme and hepatitis B virus (HBV) replication with recurrent hepatitis that has been regarded as a frequent and major risk factor for hepatic dysfunction and chronic liver disease in renal transplant recipients. Because large number of hepatitis antigenemia patients among renal transplant patients experience recurrent hepatic dysfunction with HBV recurrence and permanent histological deterioration, preemptive or primary prophylactic use of lamivudine before transplantation may be more beneficial than a trial for the treatment of advanced hepatic dysfunction. Methods. We conducted a double arm study to compare the efficacy of lamivudine between the preemptive (HBV DNA positive) or prophylactic (HBV DNA negative) trial for the maintenance of stable liver function (n=10) and the trial for the salvage of advanced hepatic dysfunction developed after renal transplantation (n=6) in hepatitis B viremia carrier renal transplant recipients. Results. Hepatic dysfunction with recurrent HBV antigenemia developed in 11 of 36 (30.6%) hepatitis antigenemia patients with a mean duration of 8.4 months (range 5-19.4 months). In six patients treated with lamivudine after hepatic dysfunction from recurrent hepatitis B viremia, serum AST and ALT level normalized within 1 month and HBV-DNA disappeared in all cases. HBV-DNA, however, reappeared in three (50%) without any discontinuation of lamivudine. Liver biopsy revealed recurrent chronic active hepatitis with severe activity of fibrosis in four cases, cholestatic fibrosing hepatitis in one, and permanent cirrhotic change in one. In seven patients who had preemptive lamivudine treatment at 9, 6, 2, 2, 1, 0, 0 month before the transplantation, HBV-DNA had converted to negative with a mean follow up of 1.2 months (range 1-2 month) in all case. Three patients who had prophylactic trials with lamivudine have all remained HBV-DNA negative. The recurrence rate of HBV viremia in the preemptive or prophylactic lamivudine treated group is 10.0% (1/10), which is significantly lower than that (42.3%, 11/25) in the nonlamivudinetreated group. The re-recurrence rate of HBV viremia was significantly higher (3/6, 50.0%) in the reactive lamivudine treated group than in prophylactic or preemptive group (1/10, 10%). Conclusion. Although lamivudine treatment after hepatic dysfunction can be a sound conventional treatment modality, this preliminary study may suggest that preemptive or prophylactic trial of lamivudine before hepatic dysfunction might be a more effective strategy for prevention of permanent histological deterioration and recurrence of hepatitis B viremia.

A 3-year-old girl received conventional-dose external beam posterior fossa irradiation (5400 cGy in 30 fractions over 40 days) for good-risk medulloblastoma. Soon thereafter, she experienced an extraneural (occipital scar, cervical lymph nodes) and central nervous system (CNS) recurrence. Intensive cisplatin and cyclophosphamide chemotherapy led to rapid disappearance of the extraneural disease. Methotrexate was administered via a ventricular reservoir. After 2 months of chemotherapy, CNS toxicity progressed rapidly from ataxia to paraplegia to quadriplegia to central respiratory failure. Radiographic scans and autopsy material revealed brain stem necrosis. This unusual toxicity raises concern about the safety of aggressive systemic chemotherapy and intrathecal therapy, when given after conventional radiotherapy.

Patients undergoing bone marrow transplantation often receive total body or total lymphoid irradiation as part of the conditioning regimen prior to marrow infusion. The cytogenetic effects of this therapy on skin fibroblasts were studied. Fibroblast cultures from eight skin biopsies were harvested in early passages for G-banded chromosome analysis. Four biopsies were from three patients who had high-dose cyclophosphamide and total body radiotherapy; one was from within and one was from outside the radiation field of a patient who had high-dose cyclophosphamide and lymphoid radiotherapy, one was from a patient who had combination chemotherapy alone, and one was from a normal control. No abnormal mitoses were found in the control or the patient who had chemotherapy alone, and only two of 30 mitoses from skin outside the lymphoid radiotherapy field were abnormal. However, most cells (49-88%) from five biopsies within radiotherapy fields were abnormal. Typically, abnormal karyotypes were pseudodiploid and contained multiple balanced rearrangements, of which reciprocal translocations were most common. The data indicate that the radiotherapy used for bone marrow transplantation induces extensive, sustained chromosome abnormalities in vivo in skin fibroblasts.

Field border separations for adjacent orthogonal fields can be calculated geometrically, given the validity of some important assumptions such as beam alignment and field uniformity. Thermoluminescent dosimetry (TLD) measurements were used to investigate dose uniformity across field junctions as a function of field separation and, in particular, to review the CCSG recommendation for the treatment of medulloblastoma with separate head and spine fields.

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976–June 1983) were prepared with cyclophosphamide sibling donors. The first 36 patients fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983–December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median follow-up of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapse-free survival, survival, and relapse rates at 3 years are 56, 58, and 19% in Group I and 69 ( p = 0.22), 77 ( p = 0.07), and 10% ( p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival.

The Children's Cancer Study Group instituted a pilot study to investigate the use of high doses of cytosine arabinoside (AraC) in the intensification phase of treatment for acute nonlymphocytic leukemia (ANLL). Patients achieving remission and not eligible for allogeneic bone marrow transplantation were treated with four doses of high-dose AraC and L-asparaginase. These drugs were repeated either on or after 28 days (q28 days), after recovery of hematologic parameters (for the first 49 patients entered onto this trial); or after 7 days (q7 days), despite dropping blood counts (for the last 53 patients enrolled). After completing an additional 3 months of intensification therapy, patients were then allocated by physician choice to either discontinue therapy or receive 18 28-day cycles of maintenance therapy, including the daily administration of 6-thioguanine. Despite three deaths associated with the toxicity of the aggressive (q7 days) AraC timing, patients receiving this approach demonstrated equal or better disease-free survival from the end of induction (55% versus 42% actuarially at 3 years [P = 0.52]). Maintenance therapy appeared to play no role in improving outcome for people who received the aggressive timing of AraC cycles. Fifty-nine percent were alive disease free actuarially at 3 years from the decision to not give maintenance therapy (n = 27) compared with 62% for those receiving maintenance therapy (n = 16; P = 0.49). On the other hand, patients who received the less aggressive AraC intensification timing (q28 days) had an improved survival rate if maintenance therapy was administered (n = 17) (65% versus 39% for patients not receiving maintenance therapy [n = 24] at 3 years [P = 0.07]). Maintenance therapy therefore may not improve outcome in patients receiving aggressive timing of high-dose AraC but may be important in less intensive postremission regimens in childhood ANLL.

This report is a 20-year follow-up of 14 patients treated with external beam craniospinal irradiation and intrathecal gold (10-45 mCi) for medulloblastoma. Six of the patients died within 2 years of treatment from persistent disease. No patients are alive without complications. Six of eight surviving patients developed arachnoiditis and cauda equina syndrome within 5 to 10 years of treatment. Seven of eight survivors developed aneurysms and/or cerebrovascular accidents 9 to 20 years after treatment. Four of the cerebrovascular events were fatal. Intrathecal gold pools in the basal cisterns and cauda equina delivering an extremely inhomogeneous dose throughout the neuroaxis. Its use is discouraged.

This paper describes a digital system which detects the configuration of any RS-232C cable that has 25 pin connectors at both ends. The system uses a single chip microcomputer as the system controller for flexibility and cost effectiveness. The system controller sends the configuration information to a PC to be displayed on the CRT screen. A software program which controls the overall operation of the system is also described. The system can be further expanded to a universal configuration detector by adding programmability on the number of pins.

The study of protein folding requires a method to drive unfolding, which is typically accomplished by altering solution conditions to favor the denatured state. This has the undesirable consequence that the molecular forces responsible for configuring the polypeptide chain are also changed. It would therefore be useful to develop methods that can drive unfolding without the need for destabilizing solvent conditions. Here we introduce a new method to accomplish this goal, which we call steric trapping. In the steric trap method, the target protein is labeled with two biotin tags placed close in space so that both biotin tags can only be bound by streptavidin when the protein unfolds. Thus, binding of the second streptavidin is energetically coupled to unfolding of the target protein. Testing the method on a model protein, dihydrofolate reductase (DHFR), we find that streptavidin binding can drive unfolding and that the apparent binding affinity reports on changes in DHFR stability. Finally, by employing the slow off-rate of wild-type streptavidin, we find that DHFR can be locked in the unfolded state. The steric trap method provides a simple method for studying aspects of protein folding and stability in native solvent conditions, could be used to specifically unfold selected domains, and could be applicable to membrane proteins.

M2 is a membrane protein critical to the life cycle of influenza A. We have capitalized on the expanding body of high-resolution structural data available for the 97 amino acid M2 protein to design and interpret site-directed spin labeling electron paramagnetic resonance spectroscopy (SDSL-EPR) experiments on the conformation and dynamics of the homotetrameric M2 protein embedded in lipid bilayers. We have obtained data for three different M2 constructs (M2TM 22-46, M2TMC 23-60 and full length M2 protein) spin-labeled at multiple sites within the transmembrane and C-terminal domains. CW and pulsed EPR spectra show evidence that M2 adopts multiple conformational states in bilayers, and that cholesterol content dictates the relative populations of the states.

Effective forms of treatment for acute lymphoblastic leukemia (ALL) in childhood now result in survival rates above 70 percent at five years, but the treatments are potentially carcinogenic. To determine the magnitude of this risk and identify possible risk factors for the development of second neoplasms, we studied a large cohort of children treated for ALL. METHODS AND RESULTS. We undertook a retrospective cohort study of 9720 children who had been given a diagnosis of ALL between June 1972 and August 1988 and had been treated according to the therapeutic protocols of the Children's Cancer Study Group. The median follow-up was 4.7 years (range, 2 months to 16 years). We found that 43 second neoplasms occurred among the children in the cohort, including 24 neoplasms of the central nervous system, 10 new leukemias and lymphomas, and 9 other neoplasms. This represented a 7-fold excess of all cancers and a 22-fold excess of neoplasms of the central nervous system. The estimated cumulative proportion of children in whom a second neoplasm developed was 2.53 percent 15 years after diagnosis (95 percent confidence limits, 1.74 percent and 3.38 percent). An even higher risk, particularly of central nervous system tumors, was evident in children five years of age or less at the time of the diagnosis of ALL (P = 0.012). All central nervous system neoplasms developed in children who had previously undergone irradiation. There was no association with exposure to cyclophosphamide or anthracyclines.There is a substantial excess of second neoplasms, especially of the central nervous system, among children treated for ALL. Children five years old or younger and those receiving radiation are at higher risk, especially for second tumors arising in the central nervous system.

✓ In a randomized postoperative trial, adjuvant post-irradiation chemotherapy, consisting of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP), was tested versus radiation therapy alone for newly diagnosed medulloblastoma in patients between 1 and 21 years of age. Patients treated with irradiation plus MOPP had a statistically significant increase in overall survival rate at 5 years posttreatment compared to patients treated with radiation therapy alone (74% vs. 56%; p = 0.06, adjusted for race and gender). Although the overall study failed to show a statistically significant advantage for irradiation plus MOPP in event-free survival (p = 0.18), statistical significance was attained in children 5 years of age or older (p = 0.05). More severe hematological toxicities occurred in the group with irradiation plus MOPP; however, this hematotoxicity appeared to be tolerable and acceptable. These results suggest that patients may benefit from combined irradiation and chemotherapy following surgery for medulloblastoma.

Five cases of relapsing acute lymphocytic leukemia (ALL) presenting as an ovarian tumor have been treated at this institution, representing the largest reported series. In a review of the literature we identified 18 additional cases of ovarian leukemic relapse. Together, these 23 patients form the basis for this report. Abdominal pain is the most common presenting symptom of ovarian leukemia. An abdominal mass is usually palpable, and at least four patients had hydronephrosis. Nine patients had documented bilateral ovarian involvement; however, bilateral disease was not a poor prognostic sign. Most ovarian relapses occurred more than 36 months after the original diagnosis of ALL, with these "late" relapsers responding more favorably to treatment than "early" relapsers. Definitive statements can not be made from a retrospective review of 23 case reports; however, salpingooophorectomy had no obvious advantage over simple biopsy, and there was no obvious advantage to the routine use of radiation therapy. Most fallures in treating ovarian leukemia occurred within 2 years. Most failures were systemic rather than local, illustrating the need for aggressive multiagent systemic chemotherapy. Survival after ovarian leukemic relapse is possible, with eight of the 23 patients alive and in complete continuous remission following the ovarian relapse (median follow-up since relapse, 42 months; range, 2 to 135+ months). With the use of more intensive chemotherapy in recent protocols, the frequency of ovarian leukemic relapses appears to be decreasing. At this institution, no child with ALL diagnosed in the 1980s has subsequently developed an ovarian relapse.

We have read with great interest the paper by van Os et al. regarding the dose-fractionation and dose-rate relationships for the sterilization of bone marrow stem cells by totalbody irradiation (TBI) (1). Using an ingenious syngeneic murine chimera model, the authors unequivocally demonstrated that fractionated or single-dose TBI at a low dose rate was less effective than single-dose TBI at a high dose rate in depleting subsets of bone marrow stem cells in mice. This observation is consistent with the belief that bone marrow stem cells are capable of repairing sublethal radiation damage, but it is at variance with the general notion that the hemopoietic stem cells are characteristic of limited radiation repair capacity. While we are in total agreement with Dr. van Os and his colleagues regarding the radiosensitivity of bone marrow stem cells, we would like to note that we reported essentially the same conclusion more than 10 years ago. Based on our LD50/30 study using a murine model (2), and also on numerous experimental data reported by other investigators on the response of bone marrow stem cells to single-dose irradiation at different dose rates or to fractionated irradiations, we concluded that bone marrow stem cells possess a considerable capacity to repair sublethal radiation damage (3, 4). Our conclusion was based mostly on studies on the radiation repair capacity of bone marrow progenitor cells in vitro. Note that in vitro culture conditions are likely to result in an underestimation of the repair capacity of normal bone marrow progenitor cells. In recent studies, we reported that several cytokines, which are found at high concentrations within the bone marrow microenvironment, are able to enhance the ability of normal hemopoietic progenitor cell subpopulations CFU-GEMM, CFU-GM, CFU-E and BFU-E to repair sublethal radiation damage (5). Indications are that the radiation response of leukemic progenitor cells is not different from that of normal bone marrow progenitor cells. Fractionated or low-dose-rate TBI may allow leukemic progenitor cells to repair sublethal radiation damage. We have demonstrated that HL-60 cells, an established human acute promyelocytic eukemic cell line (6), as well as many of the primary clonogenic blasts from acute lymphoblastic leukemia patients (7), indeed possess a considerable capacity to repair sublethal radiation damage, and some of these are extremely radioresist nt (8). In this connection, we would like to point out that t e long-term survival among high-risk acute lymphoblastic leukemia (ALL) patients who receive bone marrow transplantation after TBI is only 5-15% because of recurrence of the leukemia. We also found that the number of residual

Several techniques for the treatment of the total skin of the patient using electron beams have been described in the literature. However, most techniques presuppose that the patient is capable of maintaining a standing position for the duration of the treatment. For patients either weakened by disease or those suffering from a loss of limbs, this is often an unrealistic expectation. We will describe a total skin electron irradiation technique that allows the patient to remain in a reclined position without sacrificing dose uniformity. This technique uses two symmetric +/- 48 degrees arc electron beams to provide a field uniformity of +/- 5% over a range of approximately 250 cm X 45 cm. Six patient positions are used to provide a uniform dose around the periphery of the patient. A description of the treatment technique along with details of the dosimetry are given.

Tumors originating in horseshoe kidneys are rare; only 21 cases of Wilms tumor reported in horseshoe kidneys. A seven-month-old girl with Wilms tumor arising from the isthmus of a horseshoe kidney is reported. The literature is reviewed, and surgical considerations are discussed.

Ovarian function was followed serially in a group of six postmenarcheal females after successful bone marrow transplantation (BMT). The patients were between 13 9/12 and 22 6/12 (median 16 5/12) years of age at the time of BMT and were followed a median of 20 months (range 17-45 months) posttransplantation. Two subjects received short-term high-dose cyclophosphamide combined with single-dose total lymphoid irradiation (Group I), whereas the remaining four were treated with short-term, high-dose chemotherapy plus single-dose total body irradiation (Group II). Group II subjects also received combination chemotherapy prior to BMT. One subject from Group I continues to have regular menses and normal gonadotropin levels, 36 months post-BMT. The remaining five patients have demonstrated persistently elevated plasma concentrations of LH and FSH over a 17- to 45-month period of time. None of the four patients in Group II has menstruated since undergoing BMT. We conclude that single-dose radiation combined with short-term, high-dose chemotherapy results in profound ovarian damage in the majority of young women undergoing BMT.