Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis.

PURPOSE: Evidence suggests anti-estrogen endocrine therapy (ET) is associated with adverse cognitive effects; however, findings are based on small samples and vary in the cognitive abilities affected. We conducted a meta-analysis to quantitatively synthesize the evidence. METHODS: Electronic databases were searched in November 2016. Fourteen studies totaling 911 BC patients on aromatase inhibitors (AIs) or tamoxifen (TAM) and 911 controls (i.e., non-cancer controls and BC controls not using ET) were included. Neuropsychological tests were categorized into six domains. Effect sizes were computed to compare (1) ET patients versus controls and (2) TAM patients versus AI patients. RESULTS: In cross-sectional comparisons, ET patients performed worse than control groups on verbal learning/memory, visual learning/memory, frontal executive function, and processing speed, but did not differ on psychomotor efficiency or visuospatial function. Subgroup analyses revealed that verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls. In other domains, ET patients and BC controls performed equivalently. Regarding change from pre-treatment performance, ET patients did not differ from controls on any domain. TAM and AI patients did not from one another differ overall; however, subgroup analyses indicated that TAM patients performed better than non-steroidal AI patients on several domains, but showed few performance differences relative to steroidal AI patients. CONCLUSIONS: Verbal learning/memory was the only domain where ET patients performed worse than both non-cancer and BC controls, suggesting specific adverse effects on this domain. Additional studies assessing change from pre-treatment performance and differences between steroidal and non-steroidal AIs are warranted.

Multiple pathologies are common in Alzheimer patients in clinical trials.

OBJECTIVE: To determine the frequency of multiple pathology [Alzheimer Disease (AD) plus Vascular Dementia and/or Dementia with Lewy Bodies] in patients enrolled in clinical trials of AD therapy, and to compare the cognitive and functional assessments between patients with pure AD and AD with multiple pathology. METHODS: We conducted a retrospective analysis of patients with a clinical diagnosis of AD who were enrolled in AD therapy clinical trials and subsequently received an autopsy for confirmation of their diagnosis from 2000 to 2009. Performance on cognitive screening tests, namely Modified Mini Mental state (3MS) exam, Mini Mental state Exam (MMSE) and Functional Rating Scale (FRS) were compared between patients with pure AD and multiple pathology. RESULTS: Autopsy reports were available for 16/47 (34%) of deceased patients. Of these 16 patients, 5 (31%) had pure AD pathology, 10 (63%) had AD with other pathology, and 1 (6%) had non-AD pathology. Compared to patients with pure AD, patients with AD mixed with other pathology had poorer baseline FRS in problem-solving (p<0.01) and community affairs (p<0.02). CONCLUSION: While the strict enrollment criteria for clinical trials identified the presence of AD pathology in the majority of cases (15/16), multiple pathology was more common than pure AD in our series of autopsied patients. Premortem biomarkers that can distinguish between pure AD and AD with multiple pathology will be beneficial in future clinical trials and dementia patient management.

DNA-based programming of quantum dot valency, self-assembly and luminescence.

The electronic and optical properties of colloidal quantum dots, including the wavelengths of light that they can absorb and emit, depend on the size of the quantum dots. These properties have been exploited in a number of applications including optical detection, solar energy harvesting and biological research. Here, we report the self-assembly of quantum dot complexes using cadmium telluride nanocrystals capped with specific sequences of DNA. Quantum dots with between one and five DNA-based binding sites are synthesized and then used as building blocks to create a variety of rationally designed assemblies, including cross-shaped complexes containing three different types of dots. The structure of the complexes is confirmed with transmission electron microscopy, and photophysical studies are used to quantify energy transfer among the constituent components. Through changes in pH, the conformation of the complexes can also be reversibly switched, turning on and off the transfer of energy between the constituent quantum dots.

Published randomized controlled trials of drug therapy for dementia often lack complete data on harm.

OBJECTIVE: The objective of the study was to determine the extent to which published randomized controlled trials (RCTs) report data on harm. STUDY DESIGN AND SETTING: A systematic search strategy was used to identify RCTs published between 1996 and 2005 on the use of cholinesterase inhibitors or atypical antipsychotics in patients with dementia. A structured abstraction form was used to determine if data on mortality or serious adverse events were reported and if the articles followed Consolidated Standards of Reporting Trials format for reporting harm. RESULTS: Thirty-three RCTs were identified (27 on cholinesterase inhibitors and 6 on atypical antipsychotics). Nineteen trials (58%) had explicit data on mortality and only four (12%) reported regulatory-agency-defined serious adverse events. Most abstracts (31, 94%) stated that harm was studied but few studies (9, 27%) provided a clear definition of the measures of harm. CONCLUSIONS: Although most published RCTs state that they examine harm, many failed to provide data on mortality and most lacked clear definitions or detailed analyses of harm. Better reporting of harm would provide timely and important information that could help physicians and the public to make more informed decisions.

Periurethral autologous fat injection as treatment for female stress urinary incontinence: a randomized double-blind controlled trial.

PURPOSE: We evaluated the effectiveness of periurethral autologous fat injection as treatment for female stress urinary incontinence. MATERIALS AND METHODS: Women with stress incontinence were randomized in a double-blind fashion to receive periurethral injections of autologous fat (treatment group) or saline (placebo group). After injection patients were evaluated monthly for 3 months by a validated standardized incontinence questionnaire, 1-hour pad test and cough test. Patients who remained incontinent were offered repeat injection using the same initial agent to a maximum of 3 injections. Every 3 months after injection patients were assessed by a standardized questionnaire, pad test, cough test and urodynamics. Those who did not qualify for repeat injection at 3 months were then followed 6, 9, 12, 18 and 24 months or until failure. RESULTS: Of the 68 women enrolled 35 received fat and 33 received saline injections. The groups were comparable in terms of baseline parameters. A total of 56 patients completed the study, including 27 in the fat and 29 in the placebo group, for a total of 189 injections (91 fat and 98 saline). At 3 months 6 of 27 (22.2%) and 6 of 29 (20.7%) women were cured or improved in the fat and saline groups, respectively. Complications included cystitis in 9 of 189 injections, urinary retention in 6 in the fat injection group, urge incontinence in 9 of 68 patients and pulmonary fat embolism resulting in death in 1 of 189 procedures. CONCLUSIONS: In this study periurethral fat injection did not appear to be more efficacious than placebo for treating stress incontinence.

The effect of octreotide on glucose and insulin levels in a patient with type 2 diabetes on glibenclamide.

We report the case of a 35 year-old woman with recurrent gastrointestinal bleeding in a type 2 diabetic patient well controlled with glibenclamide. After volume resuscitation and transfusion with packed blood cells an infusion of octreotide at 50 mcg/hr was started. It was decided to start a long term octreotide treatment and the potential effect on her glycemic control was studied. A 75 gram oral glucose tolerance test was performed in two consecutive days with and then without octreotide infusion. With octreotide blood glucose was higher and insulin levels were lower. As clinical indications expand, situations will arise where patients with diabetes on sulfonylureas may require octreotide with a conceivable dramatic worsening of glycemic control.

Molecular cloning, characterization, and expression of the Tipula iridescent virus capsid gene.

The capsid protein is the major structural component of the icosahedral Tipula iridescent virus (TIV) that replicates in cytoplasmic inclusion bodies of insect cells. TIV capsid protein purified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis was digested with trypsin and fractionated by reverse-phase high-pressure liquid chromatography. A mixed oligonucleotide constructed from the amino acid sequence of a capsid tryptic peptide was used for the identification and cloning of the corresponding gene. The single-copy capsid gene, located on a 2.47-kilobase-pair HindIII TIV genomic fragment, codes for a 464-amino-acid protein (50,831 daltons) with a predicted pI of 6.34. Analysis of total RNA from infected Estigmene acrea cells indicated that the 1.8-kilobase capsid transcript was maximally produced between 14 and 24 h after infection. Transcript mapping by primer extension indicated that the RNA start site was in the A+T-rich TGCTACTAAT sequence, 19 nucleotides upstream from the first ATG codon of the capsid open reading frame. Expression of the TIV capsid protein in infected E. acrea cells was demonstrated by in vivo labeling of total proteins with [35S]methionine, using anti-capsid antiserum as the probe. Capsid protein was also expressed in Escherichia coli cells by using a pUC19 plasmid containing a lacZ-capsid gene fusion.

Semipermissive replication of Tipula iridescent virus in Aedes albopictus C6/36 cells.

Comparative studies were carried out using two different insect cell lines, Aedes albopictus and Estigmene acrea, for Tipula iridescent virus (TIV) propagation. Light microscope autoradiography showed viral DNA present in viroplasmic centers (VCs) and an inhibition of nuclear DNA synthesis. These VCs appeared to be morphologically similar in both cell lines when examined by light and electron microscopy. Radiolabeled cDNA was synthesized from RNA samples obtained from infected cells at different times after infection and hybridized to TIV DNA digested with various restriction endonucleases. The results indicated that the pattern of transcription and the kinetics of TIV infection were qualitatively similar in both cell lines. The major TIV DNA components, L (greater than 174 kbp) and S1 (10.8 kbp) that are found in virions in approximately equivalent amounts, were made in both infected cell lines. However, the infected cell lines produced S1 DNA at higher levels relative to L than in virions. The cDNA hybridization studies also revealed that the S1 DNA has sequences that are transcribed and are TIV specific. While VC morphology, levels of L and S1 DNA synthesis, transcription, and capsid protein synthesis were similar in both cell lines, time course electron microscope studies revealed that progeny virions were detected only in the VCs of E. acrea cells and not in the VCs of A. albopictus cells, even by 96 hr p.i. These data suggest that the A. albopictus C6/36 cell line is semipermissive for TIV replication.

Formation and maintenance of viroplasmic centers in Tipula iridescent virus-infected mosquito cells with deranged cytoskeletons.

We have examined the role of cytoskeletal elements with respect to the formation and maintenance of viroplasmic centers (VCs) in Tipula iridescent virus (TIV)-infected mosquito Aedes albopictus (C6/36) cells. Filamentous systems consisting of microtubules and microfilaments were detected by immunofluorescence microscopy. Inoculation of cells with TIV resulted in an alteration of microtubule and microfilament organization whether or not VCs developed. The formation of short arrays of microtubules induced by taxol or the depolymerization of microtubules by colchicine, as observed by immunofluorescence microscopy, had no apparent effect upon the development of VCs as detected by Hoechst staining and electron microscopy. The dissolution of the actin-containing filamentous system by cytochalasin B also had no effect upon development. We conclude from these results that microtubules and microfilaments are not involved in the formation or maintenance of VCs in TIV-infected A. albopictus (C6/36) cells.

Association of nuclear matrix proteins with cytoplasmic assembly sites of Tipula iridescent virus.

Intact viroplasmic centers were isolated from Estigmene acres cells infected with Tipula iridescent virus (TIV) by homogenization, followed by differential and discontinuous sucrose gradient centrifugation. Labeling of in situ and isolated viral assembly sites by two monoclonal antibodies raised against lymphocyte nuclear matrix proteins indicated a possible involvement of highly conserved nuclear proteins in the assembly and maturation of virions, as well as in maintaining the integrity of membrane-free viroplasmic centres. Electron microscopy and immunofluorescence of intact and fractionated E. acrea cells at different times postinfection showed no evidence of cytoskeleton involvement in the formation and maintenance of TIV viroplasmic centers.