Radiation dosimetry of <Superscript>131</Superscript>I-chlorotoxin for targeted radiotherapy in glioma-bearing mice

Chlorotoxin, or TM-601, is a peptide derived from the venom of the scorpionLeiurus Quinquestriatus that specifically binds to malignant brain tumors, but not to normal tissues. Targeted radiotherapy using ¹³¹I-Chlorotoxin is promising for post-surgery treatment of brain tumors. This study reports dosimetry results of ¹³¹I-Chlorotoxin in athymic nude mice with intracranially implanted human glioma xenografts and projected radiation doses in patients receiving 370 MBq of ¹³¹I-Chlorotoxin. ¹²⁵I/¹³¹I-Chlorotoxin were injected into the right brain where D54 MG xenografts were implanted. Mice were sacrificed 24–96 h later. The blood, normal organs, and tumors were weighed and counted to determine ¹³¹I-Chlorotoxin concentration. The radiation dose from ¹³¹I was calculated based on non-penetrating radiation in the mouse model. Assuming similar tissue uptake in mice and patients, radiation doses for patients were extrapolated. Distributions of ¹²⁵I/¹³¹I-Chlorotoxin were only significant in tumor, stomach, kidneys, and brain (injection site), reflecting non-specific uptake of Chlorotoxin in normal tissues. Mean radiation dose (cGy/37kBq) was 58.2 for tumor, 17.9 for brains, 1.8 for marrow, 27.1 for stomach, 16.0 for kidneys in mice. For intracranial injection of 370MBq ¹³¹I-Chlorotoxin in patients, extrapolated patient dose (cGy) was 70 for brains, 6 for marrow, 35 for stomach, 60 to kidneys, 227 to tumor, suggesting that 3.7GBq of ¹³¹I-Chlorotoxin can be safely administrated to patients. These promising results demonstrated potential in improving patient survival using this novel targeting agent.     

Lyn kinase activity is the predominant cellular SRC kinase activity in glioblastoma tumor cells

Cellular Src activity modulates cell migration, proliferation, and differentiation, and recent reports suggest that individual members of the Src family may play specific roles in these processes. As we have found that Lyn, but not Fyn, activity promotes migration of glioblastoma cells in response to the cooperative signal generated by platelet-derived growth factor receptor beta and integrin alpha(v)beta3, we compared the activity and expression of Lyn and Fyn in glioblastoma (grade IV) tumor biopsy samples with that in anaplastic astrocytoma (grade III) tumors, nonneoplastic brain, and normal autopsy brain samples. Lyn kinase activity was significantly elevated in glioblastoma tumor samples. Notably, the Lyn kinase activity accounted for >90% of pan-Src kinase activity in glioblastoma samples but only approximately 30% of pan-Src kinase activity in the other groups. The levels of phosphorylation of the autophosphorylation site were consistent with significantly higher Lyn activity in glioblastoma tumor tissue than nonneoplastic brain. Although the normalized levels of Lyn protein and the relative levels of Lyn message were significantly higher in glioblastoma samples than nonneoplastic brain, the normalized levels of Lyn protein did not correlate with Lyn activity in the glioblastoma samples. There was no significant difference in the normalized levels of c-Src and Fyn protein and message in the glioblastoma and nonneoplastic brain. Immunostaining revealed that Lyn is located primarily in the glioblastoma cells in the tumor biopsies. These data indicate that Lyn kinase activity is significantly elevated in glioblastoma tumors and suggest that it is the Lyn activity that promotes the malignant phenotype in these tumors.     

Adenosine inhibits PDGF-induced growth of human glomerular mesangial cells via A(2B) receptors

The objectives of the present study were to determine whether adenosine attenuates proliferation of glomerular mesangial cells (GMCs), which adenosine receptor (AR) mediates the antimitogeneic actions of adenosine, and the cellular mechanisms by which adenosine inhibits growth of GMCs. Studies were conducted in both human and rat GMCs. Platelet-derived growth factor (PDGF)-BB (25 ng/mL) increased DNA synthesis ([3H]thymidine incorporation), cellular proliferation (cell number), collagen synthesis ([3H]proline incorporation), and mitogen-activated protein kinase (MAPK) activity, and these effects were attenuated by 2-chloroadenosine (nonselective AR agonist) and 5'-N-methylcarboxamidoadenosine (MECA; nonselective AR agonist), but not by N6-cyclopentyladenosine (selective A1 AR agonist), AB-N-MECA (selective A3 AR agonist), or CGS21680 (selective A(2A) AR agonist). KF17837 (selective A(2A/B) AR antagonist) and 1,3-dipropyl-8-p-sulfophenylxanthine (nonselective AR antagonist), but not 8-cyclopentyl-1,3-dipropylxanthine (selective A1 AR antagonist), blocked the growth-inhibitory effects of 2-chloroadenosine and 5'-N-MECA. Antisense, but not sense or scrambled, oligonucleotides to the A(2B) receptor increased both basal and PDGF-induced DNA synthesis, cell proliferation, and collagen synthesis, and the growth-inhibitory effects of 2-chloroadenosine, 5'-N-MECA, and erythro-9-(2-hydroxy-3-nonyl)adenine (inhibitor of adenosine deaminase) plus iodotubercidin (inhibitor of adenosine kinase) were abolished by antisense, but not scrambled or sense, oligonucleotides to the A(2B) receptor. We conclude that adenosine causes inhibition of GMC growth by activating A(2B) receptors coupled to inhibition of MAPK activity. A(2B) receptors may play an important role in regulating glomerular remodeling associated with GMC proliferation. Pharmacological or molecular biologic activation of A(2B) receptors may prevent glomerular remodeling associated with glomerulosclerosis, renal disease, and abnormal growth associated with hypertension and diabetes.     

In vitro testing of xylitol as an anticariogenic agent

A number of studies involving xylitol chewing gum have demonstrated that xylitol is both noncariogenic and anticariogenic. The ability of xylitol to act as an anticariogenic agent most likely is due to its ability to be transported into caries-causing oral bacteria and inhibiting fermentation either by depleting the cell of high-energy phosphate or by poisoning the glycolytic system. In vitro tests were conducted to determine the concentration of xylitol required to inhibit the growth of three strains of oral streptococcus (S. mutans, S. salivarius, and S. sanguis). All three strains were inhibited significantly at xylitol concentrations of 12.5% and higher; however, only S. mutans was inhibited significantly at a xylitol concentration of 1.56%.     

Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery.

PURPOSE: To report interim outcome data, using all available follow-up through 5 years after treatment initiation, in the Collaborative Initial Glaucoma Treatment Study (CIGTS). DESIGN: Randomized clinical trial. PARTICIPANTS: Six hundred seven newly diagnosed glaucoma patients. METHODS: In a randomized clinical trial, 607 patients with newly diagnosed open-angle glaucoma were initially treated with either medication or trabeculectomy (with or without 5-fluorouracil). After treatment onset and early follow-up, patients were evaluated clinically at 6-month intervals. In addition, quality of life telephone interviews were conducted at similar frequency to the clinical visits. Patients in both arms of CIGTS were treated aggressively in an effort to reduce intraocular pressure (IOP) to a level at or below a predetermined target pressure specific for each individual eye. Visual field (VF) scores were analyzed by time-specific comparisons and by repeated measures models. MAIN OUTCOME MEASURES: VF loss was the primary outcome variable in CIGTS. Secondary outcomes of visual acuity (VA), IOP, and cataract were also studied. RESULTS: On the basis of completed follow-up through 4 years and partially completed through 5 years, VF loss did not differ significantly by initial treatment. Over the entire period of follow-up, surgical patients had a greater risk of substantial VA loss compared with medical patients. However, by 4 years after treatment, the average VA in the two groups was about equal. Over the course of follow-up, IOP in the medicine group has averaged 17 to 18 mmHg, whereas that in the surgery group averaged 14 to 15 mmHg. The rate of cataract requiring removal was greater in the surgically treated group. CONCLUSIONS: Both initial medical or initial surgical therapy result in about the same VF outcome after up to 5 years of follow-up. VA loss was greater in the surgery group, but the differences between groups seem to be converging as follow-up continues. When aggressive treatment aimed at substantial reduction in IOP from baseline is used, loss of VF can be seen to be minimal in general. Because 4 to 5 years of follow-up in a chronic disease is not adequate to draw treatment conclusions, these interim CIGTS outcomes do not support altering current treatment approaches to open-angle glaucoma.     

Beverage choices affect adequacy of children's nutrient intakes

OBJECTIVE: To assess the relationship between beverage choices and the adequacy of nutrient intakes among children and adolescents. DESIGN: Beverages reported in 24-hour recall records were classified as milk, 100% juice, fruit-flavored drinks, or carbonated sodas. Recommended intakes were based on Recommended Dietary Allowances or Dietary Reference Intakes. PARTICIPANTS: Four thousand seventy children aged 2 to 5, 6 to 11, and 12 to 17 years participating in the 1994-96 Continuing Survey of Food Intakes by Individuals. STATISTICAL ANALYSIS: The likelihood of achieving recommended intakes of selected nutrients on the day of recall was assessed with multiple logistic regression including ounces of milk, juice, fruit-flavored drinks, and carbonated sodas in the model while controlling for sex, age in years, race/ethnic group, household income, and total energy intake. RESULTS: Milk consumption was positively (P<.0001) associated with the likelihood of achieving recommended vitamin A, folate, vitamin B(12), calcium, and magnesium intakes in all age strata. Juice consumption was positively (P< or =. 001) associated with achieving recommended vitamin C and folate intakes in all age strata and magnesium intakes among children aged 6 years and older. Carbonated soda consumption was negatively (P< or =. 01) associated with achieving vitamin A intake in all age strata, calcium in children younger than 12 years, and magnesium in children aged 6 years and older. CONCLUSION: Beverage choice can have a significant effect on the nutrient adequacy of the diets of children and adolescents.     

Psychosocial and sexual functioning in women with vulvodynia and chronic pelvic pain. A comparative evaluation

OBJECTIVE: To determine whether women with vulvodynia differ from women with chronic pelvic pain and normal controls in their psychological functioning, somatic preoccupation, pain experience and sexual functioning. STUDY DESIGN: Cross-sectional, self-report study of women presenting to University of Michigan specialty and general clinics for the treatment of vulvodynia or chronic pelvic pain or seeking a routine gynecologic examination. All subjects completed questionnaires assessing demographic characteristics, pain, depressive symptoms, general affective state, marital adjustment, functional activity, somatic complaints, exposures, and medical and sexual history. Univariate analyses, chi 2 tests, analyses of variance and logistic regression were used to assess associations between these variables and the diagnostic category. RESULTS: Women with vulvodynia (n = 31) were similar to asymptomatic control women (n = 23) in demographic characteristics, sexual relationship variables, sexual behaviors, current and past depression, somatic sensitivity, and history of sexual or physical abuse. Women with chronic pelvic pain (n = 18) were younger and less educated than the other two groups and were more likely to have a history of physical and sexual abuse, to report recent depression and to screen positive for current depression, to have more work absences and to have more somatic complaints. CONCLUSION: Women with vulvodynia are psychologically similar to control women but differ significantly from women with chronic pelvic pain. A primary psychological cause of vulvodynia is not supported.     

Multi-cultural health provision

It has almost become a cliché now that the changes the NHS is currently undergoing are the most far reaching since its inception in 1948. Some say that the NHS and Community Care Act represents the greatest opportunity for improvement: Rosemary Gillespie looks at the means to better the NHS's poor record on provision for ethnic minorities.