Temporal stability of MGMT promoter methylation in glioblastoma patients undergoing STUPP protocol.

Epigenetic silencing of O-6-methylguanine-DNA methyltransferase (MGMT) promoter via methylation in a glioblastoma (GBM), has been correlated with a more favourable response to alkylating chemotherapeutic agents such as temozolomide. The use of global methylation surrogates such as Long Interspersed Nucleotide Element 1 (LINE1) may also be valuable in order to fully understand these highly heterogeneous tumours. In this study, we analysed both original and recurrent GBMs in 22 patients (i.e. 44 tumours), for both MGMT and LINE1 methylation status. In the 22 patients: 14 (63.6%) displayed MGMT methylation stability in the recurrent GBM versus 8 (36.4%), with instability of methylation status. No significant differences in overall and progression free survival was evident between these two groups. LINE1 methylation status remained stable for 12 (54.5%) of recurrent GBM patients versus 9 (41%) of the patients with instability in LINE1 methylation status (p = 0.02), resulting in an increase in overall survival of the stable LINE1 group (p = 0.04). The results obtained demonstrated major epigenetic instability of GBMs treated with temozolomide as part of the STUPP protocol. GBMs appear to undergo selective evolution post-treatment, and have the ability to recur with a newly reprogrammed epigenetic status. Selective targeting of the altered epigenomes in recurrent GBMs may facilitate the future development of both prognostic biomarkers and enhanced therapeutic strategies.

Measurement of linear stark interference in 199Hg.

We present measurements of Stark interference in the (61)S(0)→6(3)P(1) transition in (199)Hg, a process whereby a static electric field E mixes magnetic dipole and electric quadrupole couplings into an electric dipole transition, leading to E-linear energy shifts similar to those produced by a permanent atomic electric dipole moment (EDM). The measured interference amplitude, a(SI) = (a(M1) + a(E2)) = (5.8 ± 1.5) × 10(-9) (kV / cm)(-1), agrees with relativistic, many-body predictions and confirms that earlier central-field estimates are a factor of 10 too large. More importantly, this study validates the capability of the (199)Hg EDM search apparatus to resolve nontrivial, controlled, and sub-nHz Larmor frequency shifts with EDM-like characteristics.

Is provision of contraception at discharge following delivery associated with postpartum visit attendance?

OBJECTIVES: We examined whether provision of contraception at discharge following delivery was associated with lower rates of postpartum visit (PPV) attendance. METHODS: We conducted a retrospective cohort study of women who received pregnancy care at a Midwestern medical center in 2013. Attendance at the postpartum visit was compared for women with sterilization, contraception initiated prior to discharge (depot medroxyprogesterone acetate or etonogestrel implant), hormonal contraception prescription, or no contraception provided at postpartum discharge. Poisson regression models with robust standard errors were used to estimate the relative risk of postpartum visit attendance controlling for age, race, and parity, insurance status, and histories of both depression and drug abuse. RESULTS: Of the 1015 women who met inclusion criteria, 55% had been prescribed contraception, had initiated contraception prior to discharge, or were sterilized at the time of discharge following delivery. After adjustment for confounders, there was no association between receiving contraception and PPV attendance (relative risk for prescribed contraception = 1.09 [95% CI 0.85, 1.39], for contraception initiated prior to discharge = 0.83 [95% CI 0.67, 1.03], for sterilization = 0.86 [95% CI 0.63, 1.17] compared to no contraception). CONCLUSIONS: We found no evidence that prescribing or administering contraception post-delivery was associated with lower rates of return for postpartum follow up. IMPLICATIONS: This single site study suggests that providing effective contraception at discharge following delivery does not appear to impact PPV attendance.

Cardiovascular death and progression to end-stage renal disease after major surgery in elderly patients.

BACKGROUND: Reliable estimates for risk of cardiovascular-specific mortality and progression to end-stage renal disease (ESRD) among elderly patients undergoing major surgery are not available. This study aimed to develop simple risk scores to predict these events. METHODS: In a single-centre cohort of elderly patients undergoing major surgery requiring hospital stay longer than 24 h, progression to ESRD and long-term cardiovascular-specific mortality were modelled using multivariable subdistribution hazard models, adjusting for co-morbidity, frailty and type of surgery. RESULTS: Before surgery, 2·9 and 11·9 per cent of 16 655 patients had ESRD and chronic kidney disease (CKD) respectively. During the hospital stay, 46·9 per cent of patients developed acute kidney injury (AKI). Patients with kidney disease had a significantly higher risk of cardiovascular-specific (CV) mortality compared with patients without kidney disease (adjusted hazard ratio (HR) for CKD without AKI 1·60, 95 per cent c.i. 1·25 to 2·01; AKI without CKD 1·70, 1·52 to 1·87; AKI with CKD 2·80, 2·50 to 3·20; ESRD 5·21, 4·32 to 6·27), as well as increased progression to ESRD (AKI without CKD 5·40, 3·44 to 8·35; CKD without AKI 8·80, 4·60 to 17·00; AKI with CKD 31·60, 19·90 to 49·90). CV Death and ESRD Risk scores were developed to predict CV mortality and progression to ESRD. Calculated CV Death and ESRD Risk scores performed well with c-statistics: 0·77 (95 per cent c.i. 0·76 to 0·78) and 0·82 (0·78 to 0·86) respectively at 1 year. CONCLUSION: Kidney disease in elderly patients undergoing major surgery is associated with a high risk of CV mortality and progression to ESRD. Risk scores can augment the shared decision-making process of informed consent and identify patients requiring postoperative renal-protective strategies.

ANTECEDENTES: No se dispone de estimaciones fiables acerca del riesgo de mortalidad cardiovascular y de progresión a insuficiencia renal terminal (end-stage renal disease, ESRD) en pacientes longevos a los que se realiza cirugía mayor. Este estudio tiene como objetivo desarrollar un sistema de puntuación simple de riesgos para predecir estos eventos. MÉTODOS: En una cohorte de un solo centro de 16.655 pacientes longevos a los que se realizó cirugía mayor con hospitalización de más de 24 horas, se estimó la progresión a ESRD y la mortalidad cardiovascular a largo plazo utilizando modelos multivariables de subdistribucion de riesgos ajustados por comorbilidades, fragilidad y tipo de cirugía. RESULTADOS: Antes de la cirugía, presentaron ESRD y enfermedad renal crónica (chronic kidney Disease, CKD) un 2,9% y un 12,3% de los pacientes, respectivamente. Durante la hospitalización, el 46,9% de los pacientes desarrollaron insuficiencia renal aguda (acute kidney injury, AKI). Los pacientes con enfermedad renal tenían un riesgo significativamente mayor de mortalidad cardiovascular (CV) en comparación con los pacientes sin enfermedad renal para presentar AKI (cociente de riesgos instantáneos, hazard ratio, HR ajustado) 1,6 (i.c. del 95% 1,3-2,0), AKI sin CKD 1,7 (1,5-1,9), AKI en presencia de CKD 2,8 (2,5-3,2) y ESRD 5,2 (4,3-6,3), así como una mayor progresión a ESRD (AKI sin CKD 5,4 (3,4-8,4), CKD sin AKI 8,8 (4,6-17), y AKI en presencia de CKD 31,6 (19,9-49,9)). Se desarrollaron las escalas CV Death y ESRD Risk para predecir la mortalidad cardiovascular y la progresión a ESRD. Ambas escalas funcionaron bien a 1 año con un coeficiente de concordancia de 0,77 (i.c. del 95% 0,76-0,78) y 0,82 (0,78-0,86) respectivamente. CONCLUSIÓN: La enfermedad renal en pacientes longevos tras cirugía mayor se asocia con un elevado riesgo de mortalidad cardiovascular y de progresión a ESRD. Las escalas de riesgo pueden facilitar la toma de decisiones en el momento del consentimiento informado e identificar los pacientes que requieren estrategias de protección renal postoperatorias.

Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors.

With the escalation of obesity-related disease, there is great interest in defining the mechanisms that control appetite and body weight. We have identified a link between anabolic energy metabolism and appetite control. Both systemic and intracerebroventricular treatment of mice with fatty acid synthase (FAS) inhibitors (cerulenin and a synthetic compound C75) led to inhibition of feeding and dramatic weight loss. C75 inhibited expression of the prophagic signal neuropeptide Y in the hypothalamus and acted in a leptin-independent manner that appears to be mediated by malonyl-coenzyme A. Thus, FAS may represent an important link in feeding regulation and may be a potential therapeutic target.

Modulating the transcriptional control of adipogenesis.

Current evidence indicates that much of the regulation of adipocyte differentiation serves to modulate a common adipogenic transcriptional control pathway, comprising members of the C/EBP and PPAR families. Hormonal regulators have been found to control expression of these factors and to alter their activity through ligand binding, post-transcriptional modification, and protein-protein interactions.

Intravascular large B-cell lymphoma presenting clinically as rapidly progressive dementia.

BACKGROUND: In patients presenting with rapidly progressive dementia, prion disease may enter the differential diagnosis. The commonest malignancies masquerading as prion disease are primary CNS lymphoma and intravascular large B-cell lymphoma, both rare and difficult to diagnose without brain biopsy. CASE PRESENTATION: This 82-year-old lady with a past history of hypertension, presented with rapidly progressive cognitive impairment and ataxia. The possibility of sCJD was raised. Brain biopsy was carried out. Western blot for prion protein was negative. Brain biopsy showed intravascular large B-cell lymphoma. She died shortly afterwards. CONCLUSION: The clinical presentation of intravascular large B-cell lymphoma is diverse. Patients may present as in this case with dementia, seizures, and myoclonus leading to a clinical diagnosis of sCJD. The diagnosis here was made at biopsy but is made at autopsy in over 50% of cases.

Brain biopsies requiring Creutzfeldt-Jakob disease precautions in the Republic of Ireland 2005-2016.

AIMS: Creutzfeldt-Jakob disease (CJD) risk precautions are required when performing brain biopsies on patients with a dementing illness and in 'risk' groups. The impact on a diagnostic neuropathology service is considerable. We sought to determine if better case selection might reduce the necessity for application of CJD risk precautions. METHODS: We reviewed the clinical information, contributory investigations and final neuropathologic diagnosis in a cohort of patients (n = 21), referred to the National CJD Surveillance Centre between January 1, 2005, and December 31, 2016. RESULTS: Of this 21-patient cohort, five were positive for CJD, four belonged to the 'at risk of CJD' category requiring brain surgery, while the remaining 12 were referred to the National CJD Surveillance Unit with CJD as part of their differential diagnosis. CJD was confirmed in 5/21 (three sporadic [s]CJD, one variant [v]CJD and one iatrogenic [i] CJD). CJD was clinically probable in 4/5 proven CJD patients (80%). The patients (n = 4) in the 'at risk of CJD' group were diagnosed with tumour (n = 2), inflammation (n = 1) and non-specific changes (n = 1). Of the remaining 12 patients (in whom CJD was included in the differential diagnosis), the final neuropathologic diagnoses included tumour (n = 2), neurodegenerative (n = 2), inflammatory (n = 1), metabolic (n = 2), vascular (n = 2) and non-specific gliosis (n = 3). CONCLUSIONS: More often than not, the clinical suspicion of CJD was not borne out by the final neuropathological diagnosis. Failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel.

Morphological and biochemical status of the mammary gland as influenced by conjugated linoleic acid: implication for a reduction in mammary cancer risk.

Previous research showed that treatment with conjugated linoleic acid (CLA) during the period of active mammary gland morphogenesis was sufficient to confer a lasting protection against subsequent mammary tumorigenesis induced by methylnitrosourea. The present study was designed to characterize certain morphological and biochemical changes of the mammary gland that might potentially render it less susceptible to cancer induction. Female Sprague Dawley rats were fed a 1% CLA diet from weaning until about 50 days of age. The mammary gland parameters under investigation included (a) the deposition of neutral lipid, (b) the identification and quantification of CLA and its metabolites, (c) the density of the epithelium, and (d) the proliferative activity of various structural components. Our results showed that CLA treatment did not affect total fat deposition in the mammary tissue nor the extent of epithelial invasion into the surrounding fat pad but was able to cause a 20% reduction in the density of the ductal-lobular tree as determined by digitized image analysis of the whole mounts. This was accompanied by a suppression of bromodeoxyuridine labeling in the terminal end buds and lobuloalveolar buds. The recovery of desaturation and elongation products of CLA in the mammary gland confirmed our prior suggestion that the metabolism of CLA might be critical to risk modulation. The significance of the above findings was investigated in a mammary carcinogenesis bioassay with the use of the dimethylbenz[a]anthracene model. When CLA was started at weaning and continued for 6 months until the end of the experiment, this schedule of supplementation produced essentially the same magnitude of mammary tumor inhibition in the dimethylbenz[a]anthracene model as that produced by 1 month of CLA feeding from weaning. The observation is consistent with the hypothesis that exposure to CLA during the time of mammary gland maturation may modify the developmental potential of a subset of target cells that are normally susceptible to carcinogen-induced transformation.

Induction of apoptosis by conjugated linoleic acid in cultured mammary tumor cells and premalignant lesions of the rat mammary gland.

Conjugated linoleic acid (CLA) is an effective agent in preventing mammary cancer in rats treated with a carcinogen. The appearance of a tumor mass is the net result of cell proliferation minus cell death. Thus, apoptosis could be an important mechanism in controlling clonal expansion of the early premalignant lesions. The overall objective of this report was to determine whether CLA stimulated apoptosis. In the first part of the study, CLA was found to increase chromatin condensation (visualized through fluorescent 4',6-diamidino-2-phenylindole staining to DNA) and to induce DNA laddering, both evidence of apoptosis, in a rat mammary tumor cell line. The second part was to investigate the effect of CLA feeding on the development of histologically identifiable premalignant lesions in the rat mammary gland, as well as on the quantification of apoptosis (by terminal uridyltransferase nick end labeling assay) and the expression by immunohistochemistry of apoptosis regulatory proteins (bcl-2, bak, and bax) in normal versus premalignant mammary structures. CLA inhibited the formation of premalignant lesions by approximately 50%. It also significantly increased apoptosis and reduced the expression of bcl-2 in these lesions, but it did not modulate the levels of bak or bax. In contrast, neither apoptosis nor any of the apoptosis regulatory proteins was affected by CLA in normal mammary gland alveoli or terminal end buds. The data suggest that early pathological lesions may be particularly sensitive to CLA. In addition to providing a molecular basis for elucidating the mechanism of action of CLA in cancer prevention, the research on CLA-responsive biomarkers also has a practical side because these assays can be applied to biopsied human tissue samples in future CLA intervention trials.

Normal inhibition of mammary tumor metastasis in C3H/He mice.

The blood of normal C3H mice contains molecular factors that can rapidly lyse mammary carcinoma cells that enter the circulation. The cytotoxic effect of blood on tumor cells during incubation was most clearly demonstrated if fibrin formation was prevented. The conversion of the mammary carcinoma cells to ascites growth increased both the resistance to lysis in plasma and the ability to form lung colonies after intravenous injection. Mice that were surgically cured of numerous 9 mm tumors and survived for an average 10 months had a lower incidence (36%) of spontaneous metastases than mice that experienced one 30 mm tumor and survived for an average 8 weeks (65%). This is interpreted to mean that mice that retained their vitality by early surgical cures, could suppress the development of metastases by the action of normal serum factors that can destroy neoplastic cells that enter the circulation.

Prophylaxis and therapy of mouse mammary carcinomas with doxorubicin and vincristine encapsulated in sterically stabilised liposomes.

This study tested the prophylactic efficacies of doxorubicin hydrochloride and vincristine sulphate, encapsulated in sterically stabilised long circulating liposomes, against the spontaneous development of mammary carcinomas in C3H/He mice. Monthly prophylactic intravenous (i.v.) injections of 6 mg/kg doses of liposome-encapsulated doxorubicin (DOX-SL) or 1 mg/kg doses of liposome-encapsulated vincristine (VIN-SL) were begun when retired breeding mice were 26 weeks old. Mice that developed a mammary carcinoma while on the monthly prophylactic protocols were then given weekly i.v. injections of 6 mg/kg DOX-SL or 1 mg/kg VIN-SL to test the therapeutic efficacies of the drugs, and to determine whether the tumours were susceptible or resistant to therapy. The monthly prophylactic injections reduced the incidence of first mammary carcinomas from 87/88 (99%) in untreated mice to 24/42 (57%) in DOX-SL-treated mice and to 26/32 (81%) in VIN-SL-treated mice. Of the mice that developed a mammary tumour while on the prophylactic protocols, 12 of 30 mice were cured by the weekly therapeutic use of DOX-SL, and the growth of 18 tumours was inhibited. The weekly therapeutic use of VIN-SL cured 3 of 8 mice, and inhibited the growth of five tumours. Weekly DOX-SL therapy cured 7 of 22 previously untreated mice. The mean survival of tumour-bearing mice was extended from 24 days in untreated mice to 87 days in DOX-SL-treated mice, which had not received prophylactic treatment. Metastases were found in 29 of 54 untreated mice, and in 3 of 72 mice treated with DOX-SL and VIN-SL. Toxic side effects were limited to a transient weight loss during the weekly treatments. Drug resistance as a result of treatments was not observed.

Correlation of anti-HIV activity with anion spacing in a series of cosalane analogues with extended polycarboxylate pharmacophores.

Cosalane and its synthetic derivatives inhibit the binding of gp120 to CD4 as well as the fusion of the viral envelope with the cell membrane. The binding of the cosalanes to CD4 is proposed to involve ionic interactions of the negatively charged carboxylates of the ligands with positively charged arginine and lysine amino acid side chains of the protein. To investigate the effect of anion spacing on anti-HIV activity in the cosalane system, a series of cosalane tetracarboxylates was synthesized in which the two proximal and two distal carboxylates are separated by 6--12 atoms. Maximum activity was observed when the proximal and distal carboxylates are separated by 8 atoms. In a series of cosalane amino acid derivatives containing glutamic acid, glycine, aspartic acid, beta-alanine, leucine, and phenylalanine residues, maximum activity was displayed by the di(glutamic acid) analogue. A hypothetical model has been devised for the binding of the cosalane di(glutamic acid) conjugate to CD4. In general, the compounds in this series are more potent against HIV-1(RF) in CEM-SS cells than they are vs HIV-1(IIIB) in MT-4 cells, and they are least potent vs HIV-2(ROD) in MT-4 cells.

Refractory abdominal-cutaneous fistulas or leaks: percutaneous management with a collagen plug.

BACKGROUND: We report the results of abdominal-cutaneous fistula tract occlusion with a collagen plug in a series of patients with fistulas or leaks refractory to conservative therapy. STUDY DESIGN: Seven patients were found to have persistent fistula or leak after percutaneous drainage of abdominal pelvic fluid collections. All patients but one were refractory to surgical or percutaneous drainage. Under fluoroscopic guidance, modified Vasoseal (Datascope Inc, Montvale, NJ) collagen plugs were deployed into the fistulas using catheter-directed techniques. The plugs were split longitudinally to fit into an 8F or 9F peel-away sheath, placed into the fistula, and deployed. Results were tabulated and patients were followed up. RESULTS: Six of seven patients undergoing fluoroscopically guided, catheter-directed tract occlusion had resolution of the fistula, with no evidence of fistula or abscess recurrence from 30 to 180 days after closure. There were no procedural complications. The technique was unsuccessful in dosing a gastrocutaneous fistula after removal of a large-bore gastrostomy tube; this failure was believed to be secondary to the short length and large caliber of the tract in a patient with hypercortisolemia. CONCLUSIONS: Closure of abdominal-cutaneous fistula tracts by occlusion with a modified Vasoseal collagen plug shows promise in the management of fistulas refractory to catheter drainage.

Outcomes evaluation for operative and nonoperative management of the abnormal mammogram.

BACKGROUND: This study reviewed the outcome of women with an abnormal mammogram and no mass (n = 194). METHODS: Patients were immediately biopsied (34%) or followed up mammographically (66%). Information was collected prospectively over a 13-year period. RESULTS: Eight of those initially biopsied (12%) proved to be cancer. Of the remaining 129 patients, 20 were lost to follow-up, leaving 109 for further review. Thirty of these patients ultimately came to biopsy, with 5 (17%) proving to be cancer. Of those followed up mammographically and not biopsied, the majority (92%) of lesions either remained unchanged or resolved. The average follow-up time is 53 months. Biopsy was avoided in 51%. Of the 179 patients with follow-up information, 40 (23%) developed new lesions. Fourteen of these lesions have been biopsied, and 36% were cancer. CONCLUSIONS: Most mammographic lesions resolve or remain unchanged. Women who have a lesion on mammography are at increased risk for further mammographic abnormalities.

Characterization of complexes of oligonucleotides with polyamidoamine starburst dendrimers and effects on intracellular delivery.

This study evaluates polyamidoamine PAMAM "starburst" dendrimers (generation 3, Mr 6909) as a potential delivery vehicle for oligonucleotides. Complexes between dendrimer and phosphorothioate oligonucleotides were observed by agarose gel electrophoresis and were positive, negative, or neutral in charge depending on stoichiometry. Complexes were stable in 50% serum to variations in pH (3, 5, and 10) and ionic strength (0-500 mM). Ultrafiltration and gel filtration characterization indicated that the dendrimer:oligonucleotide complexes were primarily < 100 kD, although some larger complexes were formed at oligonucleotide excess. Use of dendrimers resulted in a 50-fold enhancement in cell uptake of oligonucleotide as determined by flow cytometry, and enhanced cytosolic and nuclear availability, as shown by confocal microscopy. These data support the further evaluation of dendrimers for oligonucleotide delivery in cell culture and in vivo.

Treasure of the Past IX: Exposure Standardization of Iodine-125 Seeds Used for Brachytherapy.

A method for calibrating iodine-125 seeds in terms of exposure has been established. The standard free-air ionization chamber, used for measuring soft x rays, was chosen for the measurements. Arrays of four to six seeds were used to enhance the ionization-current-to-background-current ratio. Seeds from an array were measured individually in a re-entrant chamber. The quotient of the exposure rate for the array by the sum of the ionization currents in the re-entrant chamber is the calibration factor for the re-entrant chamber. Calibration factors were established for three types of iodine-125 seeds. The overall uncertainty for the seed exposure calibrations is less than 6%.

The isolation, localization and characterization of the QM homolog in Drosophila melanogaster.

A fragment of 443 bp was amplified from a lambda ZAPII Drosophila central nervous system (CNS) cDNA library using minimally degenerate primers to very conserved regions of the QM gene. This fragment was used as a probe to screen the lambda ZAPII Drosophila CNS cDNA library. Two clones of the Drosophila QM homolog (pDQM-7A1 and pDQM-2B1), each containing the complete coding region, were isolated. The 5'-UTR of this gene was obtained by RACE PCR and ligated to the coding sequence to produce a the full-length copy of the Drosophila QM homolog (DQM) cDNA. The DQM cDNA measures 746 nucleotides in length and encodes a polypeptide of 218 residues. The amino acid sequence shows 76.1 percent identity with human QM and 69.1 percent identity with QSR1, the yeast homolog of QM. Unlike the human or mouse genome which contains multiple copies of the QM gene, the Drosophila genome has only a single copy as indicated by genomic Southern blot analysis. In situ hybridization confirms the presence of a single copy of DQM in the Drosophila genome and localizes it to the left arm of the third chromosome at the end of region 80A (80A-4).