The Brain Metastases Symptom Checklist as a novel tool for symptom measurement in patients with brain metastases undergoing whole-brain radiotherapy.

PURPOSE: We evaluated the feasibility, reliability, and validity of the Brain Metastases Symptom Checklist (bmsc), a novel self-report measure of common symptoms experienced by patients with brain metastases. METHODS: Patients with first-presentation symptomatic brain metastases (n = 137) referred for whole-brain radiotherapy (wbrt) completed the bmsc at time points before and after treatment. Their caregivers (n = 48) provided proxy ratings twice on the day of consultation to assess reliability, and at week 4 after wbrt to assess responsiveness to change. Correlations with 4 other validated assessment tools were evaluated. RESULTS: The symptoms reported on the bmsc were largely mild to moderate, with tiredness (71%) and difficulties with balance (61%) reported most commonly at baseline. Test-retest reliability for individual symptoms had a median intraclass correlation of 0.59 (range: 0.23-0.85). Caregiver proxy and patient responses had a median intraclass correlation of 0.52. Correlation of absolute scores on the bmsc and other symptom assessment tools was low, but consistency in the direction of symptom change was observed. At week 4, change in symptoms was variable, with improvements in weight gain and sleep of 42% and 41% respectively, and worsening of tiredness and drowsiness of 62% and 59% respectively. CONCLUSIONS: The bmsc captures a wide range of symptoms experienced by patients with brain metastases, and it is sensitive to change. It demonstrated adequate test-retest reliability and face validity in terms of its responsiveness to change. Future research is needed to determine whether modifications to the bmsc itself or correlation with more symptom-specific measures will enhance validity.

Expression of human amyloid precursor protein in Drosophila melanogaster nerve cells causes a decrease in presynaptic gene mRNA levels.

Amyloid precursor protein (APP) is a key player in Alzheimer's disease. The proteolytic cleavage of APP results in various short peptide fragments including the toxic amyloid-beta peptide, which is a main component of senile plaques. However, the functions of APP and its processed fragments are not yet well understood. Here, using real-time polymerase chain reaction, we demonstrate that exogenous expression of APP, its mutant form APP-Swedish, or two truncated forms in Drosophila melanogaster causes a significant (P ≤ 0.05) drop in the mRNA levels of the presynaptic proteins synaptotagmin-1 and neuronal synaptobrevin. The results obtained from this study suggest a potential role of APP or its fragments in the regulation of synaptic gene transcription.

Enhanced morphological transformation of human lung epithelial cells by continuous exposure to cellulose nanocrystals.

Cellulose nanocrystals (CNC), also known as nanowhiskers, have recently gained much attention due to their biodegradable nature, advantageous chemical and mechanical properties, economic value and renewability thus making them attractive for a wide range of applications. However, before these materials can be considered for potential uses, investigation of their toxicity is prudent. Although CNC exposures are associated with pulmonary inflammation and damage as well as oxidative stress responses and genotoxicity in vivo, studies evaluating cell transformation or tumorigenic potential of CNC's were not previously conducted. In this study, we aimed to assess the neoplastic-like transformation potential of two forms of CNC derived from wood (powder and gel) in human pulmonary epithelial cells (BEAS-2B) in comparison to fibrous tremolite (TF), known to induce lung cancer. Short-term exposure to CNC or TF induced intracellular ROS increase and DNA damage while long-term exposure resulted in neoplastic-like transformation demonstrated by increased cell proliferation, anchorage-independent growth, migration and invasion. The increased proliferative responses were also in-agreement with observed levels of pro-inflammatory cytokines. Based on the hierarchical clustering analysis (HCA) of the inflammatory cytokine responses, CNC powder was segregated from the control and CNC-gel samples. This suggests that CNC may have the ability to influence neoplastic-like transformation events in pulmonary epithelial cells and that such effects are dependent on the type/form of CNC. Further studies focusing on determining and understanding molecular mechanisms underlying potential CNC cell transformation events and their likelihood to induce tumorigenic effects in vivo are highly warranted.

Pregnancy outcomes in women with gestational diabetes treated with metformin or insulin: a case-control study.

AIMS: To compare maternal and neonatal outcomes in women with gestational diabetes mellitus (GDM) treated with either metformin or insulin. METHODS: One hundred and twenty-seven women with GDM not adequately controlled by dietary measures received metformin 500 mg twice daily initially. The dose was titrated to achieve target blood glucose values. Pregnancy outcomes in the 100 women who remained exclusively on metformin were compared with 100 women with GDM treated with insulin matched for age, weight and ethnicity. RESULTS: There were no significant differences in baseline maternal risk factors. Women treated with insulin had significantly greater mean (sem) weight gain from enrolment to term (2.72 +/- 0.4 vs. 0.94 +/- 0.3 kg; P < 0.001). There was no difference between the metformin and insulin groups, respectively, comparing gestational hypertension (6 vs. 7%, P = 0.9), pre-eclampsia (9 vs. 2%, P = 0.06) induction of labour (26 vs. 24%, P = 0.87) or rate of Caesarean section (48 vs. 52%, P = 0.67). No perinatal loss occurred in either group. Neonatal morbidity was improved in the metformin group; prematurity (0 vs. 10%, P < 0.01), neonatal jaundice (8 vs. 30%, P < 0.01) and admission to neonatal unit (6 vs. 19%, P < 0.01). The incidence of macrosomia (birthweight centile > 90) was not significantly different [metformin (14%) vs. insulin (25%); P = 0.07]. CONCLUSIONS: Women with GDM treated with metformin and with similar baseline risk factors for adverse pregnancy outcomes had less weight gain and improved neonatal outcomes compared with those treated with insulin. Diabet. Med. 26, 798-802 (2009).

[Studying pathogenesis of Alzheimer's disease in a Drosophila melanogaster model: human APP overexpression in the brain of transgenic flies leads to deficit of the synaptic protein synaptotagmin].

Alzheimer's disease (AD) is a progressive neurodegenerative disease whose main pathomorphological sign is synapse degeneration in the cortex and hippocampus. Abnormal synaptogenesis precedes amyloidosis and neurodegeneration and correlates with memory impairment during the early clinical phase. Mutations in the amyloid precursor protein (APP) gene cause familial AD and enhance the secretion of amyloid-beta-protein (Abeta). However, it remains unclear in what way APP and Abeta are involved in synaptic disorder in the absence of visible amyloid structures. In this study, the role of the human APP gene in synaptogenesis in transgenic lines of Drosophila melanogaster whose nerve cells express the human APP695 isoform, truncated APPs, and the presynaptic marker synaptotagmin driving the sequence of the green fluorescent protein. The expression of APP and its truncated forms caused a decrease in the synaptotagmin content of antennal lobes and mushroom lobes of the D. melanogaster brain, as well as neurodegeneration that progressed with age. The results suggest that that abnormal synaptogenesis and neurodegeneration occur in the Drosophila brain in the absence of Abeta. It is assumed that impaired cellular functions of APP and secretion of Abeta independently contribute to the pathogenesis of AD.

Global Collaborations for Cervical Cancer: Can the East-West Alliance Facilitate Treatment for all?

Despite the advances in the primary prevention of cervical cancer, there is an absolute increase in the incidence of cervical cancer as a result of an increase in world population. A vast majority of patients in low and low-middle income countries continue to present at a locally advanced stage, necessitating treatment with chemoradiation and brachytherapy. There is a dearth of equipment and trained professionals for the treatment of cervical cancer, especially in low and low-middle income countries. There is an urgent need to improve treatment availability and develop better treatments. Worldwide trends, however, reveal a low number of therapeutic and innovative research trials in cervical cancer. The present article elucidates the existing challenges and provides solutions to improve outcomes. The proposed strategies hinge on strengthening collaborations for global advocacy.

[Changes in physicochemical properties of proteins, caused by modification with alkylhydroxybenzenes].

Kinetic characteristics of model enzymes and physicochemical properties of globular proteins modified by chemical analogues of low-molecular-weight microbial autoregulators (alkylhydroxybenzenes, AHBs) have been studied. C7 and C12 AHB homologues were used, differing in the length of the alkyl radical and the capacity for weak physicochemical interactions. Both homologues affected the degree of protein swelling, viscosity, and the degree of hydrophobicity. The effects depended on the structure of AHBs, their concentration, and pH of the solution, which likely reflects changes in the charge of the protein globule and its solvate cover. Variations of hydrophobicity indices of AHB-modified enzymes (trypsin and lysozyme) were coupled to changes in the catalytic activity. The values of K(M), measured for the enzymes within both AHB complexes, did not change, whereas V(max) increased (in the case of C7 complexes) or decreased (C12 complexes). Possible molecular mechanisms of changes in the physicochemical and catalytic parameters of enzymatically active proteins, induced by modification with structurally distinct AHBs, are described, with emphasis on targeted regulation of functional activity.

Postgraduate Global Health Competency Profile for Radiation Oncology.

AIMS: To identify core competencies for postgraduate radiation oncology trainees in global health and cancer that may inform revisions across radiation oncology residency specialty training curricula. MATERIALS AND METHODS: A review of the literature was conducted to identify all potential global health competency items. An international two-phase Delphi process was conducted with experts in oncology. In phase 1, all experts scored, on a nine-point Likert scale, the degree to which they agreed an item should be included in the competency profile. Items with a mean score ≥7 were included, those scoring 4-6 were reviewed in phase 2, and items scored ≤3 were excluded. In phase 2, items were discussed and subsequently ranked for inclusion or exclusion in the competency profile. Items with >75% voting for inclusion were included in the final competency profile. RESULTS: In total, 142 potential global health competency items were identified. Sixty-one items were removed as redundant or irrelevant, leaving 81 items for the Delphi process. Eighteen specialists were invited to participate, with 10 (56%) agreeing to participate in phase 1 of the Delphi process. Participants represented 10 centres in seven countries. Of the 81 items ranked in phase 1, 72 items (89%) had a mean score ≥7 and were automatically included in the final competency profile. The remaining nine items received a score of 4-6 and were discussed in phase 2 of the Delphi process, of which three received <75% agreement for inclusion and were excluded. The result was a final list of 78 enabling competency items. CONCLUSIONS: The radiation oncology global health competency profile represents an international consensus on the items that can inform radiation oncology training requirements.

[Transurethral endoscopic pyelolithotripsy in combined treatment of complex forms of nephrolithiasis].

The article presents results of retrograde endoscopic pyelolithotripsy (REP) in 75 patients with large and coral nephroliths. Retrograde contact pyelolithotripsy was made with application of Swiss Lithoclast unit, semirigid ureteroscopes R. Wolf with a cone 8-9 Ch and working channel 5.3 Ch. This enables maximal removal of the destroyed concrement by hydraulic litholapaxia with consequent insertion of the internal stent. Extracorporeal lithotripsy with low-energy shock-wave impulses was performed on demand (1-3 sessions). The stent was removed in 3-5 days in cases of complete one-stage sanation of the kidney and in 2-3 weeks in the presence of residual fragments of the nephrolith. One-stage complete sanation in coral nephrolithiasis (K1-K2) up to 5 cm3 and large concrements was achieved in 69.3% patients. Three months later residual fragments of the nephroliths were observed in 8% patients, 6 months later--in 5.3%. One year after treatment a complete sanation was achieved in 96%. Complications of the method consisted in exacerbation of chronic pyelonephritis observed in 12% cases. The control examination revealed improvement of renal function early and late after surgery. As shown by 6-year follow-up, recurrent nephroliths occurred in 6% patients. Endoscopic retrograde pyelolithotripsy can be used as a method of choice in the treatment of compound forms of nephrolithiasis in intrarenal type of the pelvis, the absence of marked extension of the caliceal-pelvic system of the kidney, in other stones resistant to extracorporeal lithotripsy.

Balancing Equity and Advancement: The Role of Health Technology Assessment in Radiotherapy Resource Allocation.

Radiotherapy is an essential modality for effective cancer control, yet enormous inequalities in access in low- and middle-income countries (LMICs) have created one of the largest global technology gaps in medicine today. The Global Task Force on Radiotherapy for Cancer Control quantified this gap and showed that over half of patients worldwide do not have access to treatment. Governments, policy makers and the global health community have ignored this crisis due to the complexity of radiotherapy technology and its seemingly high upfront costs. However, understanding the cost of treatment in the context of a dramatic clinical benefit could help to demonstrate the feasibility of radiotherapy in diverse income settings. When there are scarce resources, such analysis is essential in order to set priorities and provide high-value interventions to large populations. Here we explore the current status of economic evaluation tools in LMICs and some of the barriers to their use. We describe how the concepts of health technology assessment, value-based care and investment frameworks can be applied to the global crisis of radiotherapy availability to guide appropriate capacity building and resource utilisation. The development of local expertise in these health economic tools can be a powerful level to improve cancer care in LMICs and to build universal global access to radiotherapy.

Mobilising Expertise and Resources to Close the Radiotherapy Gap in Cancer Care.

Closing the gap in cancer care within low- and middle-income countries and in indigenous and geographically isolated populations in high-income countries requires investment and innovation. This is particularly true for radiotherapy, for which the global disparity is one of the largest in healthcare today. New models and paradigms and non-traditional collaborations have been proposed to improve global equity in cancer control. We describe recent initiatives from within the radiation oncology community to increase access to treatment, build the low- and middle-income countries' radiation oncology workforce, mobilise more professionals from within high-income countries and raise awareness of the global need for equitable cancer care.

Gonadotropin-releasing hormone regulates follicle-stimulating hormone beta-subunit gene expression in the male rat.

Since the role of GnRH in the control of FSH release and synthesis is controversial, we have examined the effect of elimination of GnRH action on gonadotropes on FSH beta gene expression, FSH release, and synthesis. GnRH stimulation of the pituitary was abolished by continuous infusion of either a GnRH antagonist or a GnRH antiserum. We also examined the effects of gonadotrope desensitization, using a continuous infusion of GnRH or GnRH agonist analog. FSH beta mRNA levels were determined by dot blot hybridization using rat FSH beta cDNA, and changes were related to pituitary and serum FSH concentrations. FSH beta mRNA levels increased after orchidectomy and correlated well with serum FSH concentrations. Overall FSH synthesis was increased after castration, as judged by elevated serum FSH and unchanged pituitary FSH content. In orchidectomized rats, continuous GnRH antagonist infusion prevented the postcastration rise in FSH beta mRNA levels and serum FSH. Pituitary FSH content was reduced at 7 days, but not at 14 days. In intact rats, GnRH antagonist infusion for 7 days had no effect on FSH beta mRNA levels, but after 14 days, there was a 33% reduction, and serum FSH was suppressed. Pituitary FSH content was decreased after GnRH antagonist treatment for 7 or 14 days. Daily injection of GnRH antiserum for 6 days abolished the increases in FSH beta mRNA levels and serum FSH in orchidectomized rats, but pituitary FSH content was unaffected. In intact rats, GnRH antiserum treatment reduced FSH beta mRNA levels by 38%, suppressed serum FSH, and decreased pituitary FSH content. When gonadotropes were desensitized by a continuous infusion of GnRH for 14 days or GnRH agonist analog for 28 days, FSH beta mRNA levels and pituitary FSH content were markedly reduced, and serum FSH was suppressed to undetectable levels. We concluded that 1) endogenous GnRH is required for the maintenance of FSH beta mRNA levels in both intact and orchidectomized rats; 2) FSH beta mRNA levels are coupled to the level of FSH biosynthesis, indicating the physiological importance of this pretranslational regulation; 3) desensitization is more effective at inhibiting FSH beta gene expression and FSH synthesis than preventing gonadotrope stimulation using the GnRH antagonist or antiserum; and 4) the actions of GnRH on FSH beta mRNA levels are paralleled by its effects on LH beta mRNA levels, suggesting that GnRH provides a common primary stimulus for the induction of both beta-subunit genes in vivo. These data provide further evidence for the crucial stimulatory role of GnRH in the control of FSH synthesis.

Expression of the chimeric IgE gene in cell culture and in various mouse tissues.

Transient expression of recombinant gene constructs is now more widely used in gene therapy as well as in DNA vaccination. In this study, the ability of one and the same genetic construct to drive gene expression both in cell culture and in tissues of the whole organism was demonstrated. Chinese hamster ovarian cells (CHO) were transfected in vitro with plasmids bearing the genes for chimeric IgE (mouse/human) antibodies under control of the human cytomegalovirus (hCMV) promoter. Secretion of recombinant IgE antibodies by transfected cells reached 60% of the intracellular concentration of antibodies. The same gene constructs were introduced into various mouse tissues using ballistic transfection in vivo. The IgE content in blood after transfection of cartilage was found to be several times lower than after transfection of the liver, spleen, or foot pad. At the same time, the content of antibodies to the xenogenous determinants of IgE was essentially independent of the tissue type. These data can be employed in selecting conditions for genetic immunization and gene therapy.

Comparison of the pretranslational regulation of FSH synthesis by gonadal steroids in rats and mice.

There are significant differences between rats and mice in the gonadal regulation of several aspects of gonadotroph function. To investigate whether these extend to the pretranslational regulation of FSH synthesis by gonadal steroids, we have measured FSH-beta mRNA levels following gonadectomy and sex-steroid replacement and have related these to serum and pituitary FSH as a reflection of overall hormone synthesis. In ovariectomized rats, FSH-beta mRNA levels increased by 8 h, decreased, and then rose progressively over the next 28 days. A similar pattern of response was observed in orchidectomized rats. In mice, there were progressive increases in FSH-beta mRNA levels in both males and females following gonadectomy, without evidence of the early peaks observed in rats. In both species, the change in FSH-beta mRNA levels after gonadectomy was greater in females than in males. These changes in FSH-beta mRNA following gonadectomy were paralleled by changes in the serum FSH concentration. In ovariectomized female rats and mice, pituitary FSH stores increased by 8 h and 3 days respectively, whereas in male rats, pituitary FSH content did not rise until 10 days after orchidectomy. The most striking species difference was the marked and prolonged reduction of pituitary FSH after orchidectomy of mice. Treatment of rats and mice from the time of ovariectomy, with a dose of oestradiol that prevents increases in serum LH, only partially attenuated the rises in FSH-beta mRNA and serum FSH and did not prevent the increase in pituitary FSH content. Treatment of intact or orchidectomized rats with testosterone suppressed FSH-beta mRNA levels to 50% below intact control values without affecting pituitary FSH content.(ABSTRACT TRUNCATED AT 250 WORDS)

The quantitative characteristics of efficiency of ballistic transfection of chimeric antibody genes.

A quantitative approach was applied to the study of in vivo expression of foreign genes introduced into mice by ballistic transfection. Because in some cases one must take into account both the level of synthesized protein and that of antibodies to it, we derived the equation which allows to calculate the exact quantity of both proteins. This formula was applied to in vivo expression of a chimeric (human/mice) immunoglobulin E gene. The immunochemical analysis using this equation showed that the Ig concentration succeeded 4, 6, 12 IU/ml and undetectable level, respectively, upon transfection in mouse liver, spleen, foot pad and ear cartilage.

Cycle abnormalities in infertile women with regular menstrual cycles: effects of clomiphene citrate treatment.

OBJECTIVE: To investigate the incidence and nature of cycle abnormalities and the effect of clomiphene citrate (CC) treatment in women with apparently ovulatory cycles and unexplained infertility. DESIGN: Nonrandomized, open study of patients before and during treatment. SETTING: The Reproductive Medicine Clinic of a District General Hospital. PATIENTS: Thirty-five women with regular, apparently ovulatory menstrual cycles and unexplained infertility. INTERVENTIONS: Detailed ultrasound and hormonal cycle tracking was performed before and during treatment with CC. MAIN OUTCOME MEASURES: Serial ultrasound scans and measurements of serum LH, FSH, E2, and P. RESULTS: Before treatment, 54% of cycles were uniovulatory, 40% were characterized by cyst formation, and 6% were characterized by poor follicular growth. Fifty-one percent of pretreatment cycles had normal hormone profiles, 31% had defective luteal phases, 14% had increased early follicular phase serum FSH levels, and 9% had increased early follicular phase serum LH levels. Treatment with CC reduced the incidence of cyst formation to 9% and the incidence of luteal phase defects to 3%. However, 28% of CC-treated cycles showed ultrasound features of overstimulation and 51% had high follicular phase E2 peaks so that only 34% of CC-treated cycles had normal hormone profiles. CONCLUSIONS: Cycle abnormalities are common in unexplained infertility. The incidence of cyst formation and luteal phase defects, the most common abnormalities in this group, is reduced by CC treatment.

[Blood transfusion support in rendering medical care in extreme conditions]. / Problema transfuziologicheskogo obespecheniia pri okazanii meditsinskoi pomoshchi v ékstremal'nykh usloviiakh.

About 20% of accident and disaster victims need the hemotransfusion therapy. At present the method of erythrocyte long-term storage in the blood banks with glycerin high concentration is the most acceptable one. There are special medical teams (SMT) in the districts. They include the transfusiologic group with appropriate reserve of hemotransfusion materials. Most of them must be stored as untouchable reserve in the institutions of blood service and large hospitals on which the SMTs are based.