Determinants of mitotic catastrophe on abrogation of the G2 DNA damage checkpoint by UCN-01

Genotoxic stress such as ionizing radiation halts entry into mitosis by activation of the G(2) DNA damage checkpoint. The CHK1 inhibitor 7-hydroxystaurosporine (UCN-01) can bypass the checkpoint and induce unscheduled mitosis in irradiated cells. Precisely, how cells behave following checkpoint abrogation remains to be defined. In this study, we tracked the fates of individual cells after checkpoint abrogation, focusing in particular on whether they undergo mitotic catastrophe. Surprisingly, while a subset of UCN-01-treated cells were immediately eliminated during the first mitosis after checkpoint abrogation, about half remained viable and progressed into G(1). Both the delay of mitotic entry and the level of mitotic catastrophe were dependent on the dose of radiation. Although the level of mitotic catastrophe was specific for different cell lines, it could be promoted by extending the mitosis. In supporting this idea, weakening of the spindle-assembly checkpoint, by either depleting MAD2 or overexpressing the MAD2-binding protein p31(comet), suppressed mitotic catastrophe. Conversely, delaying of mitotic exit by depleting either p31(comet) or CDC20 tipped the balance toward mitotic catastrophe. These results underscore the interplay between the level of DNA damage and the effectiveness of the spindle-assembly checkpoint in determining whether checkpoint-abrogated cells are eliminated during mitosis.     

Glycaemic control in type 2 diabetes: the impact of body weight, beta-cell function and patient education

We examined the determinants of glycaemic control in a consecutive cohort of 562 newly-referred Chinese type 2 diabetic patients (57% women) during a 12-month period. All patients underwent a structured assessment with documentation of clinical and biochemical characteristics. Pancreatic beta-cell function was assessed by fasting plasma C-peptide concentration. Insulin deficiency was defined as fasting plasma C-peptide <0.2 pmol/ml. Insulin resistance (IR) was calculated using the homeostasis model assessment (HOMA) based on a product of fasting plasma glucose and insulin concentrations. Treatment was considered appropriate when insulin-deficient patients were treated with insulin and non-insulin-deficient patients were treated with oral agents or diet. Mean (+/-SD) age was 54.3+/-13.8 years (range 17-87 years) and disease duration was 5.0+/-5.9 years. At the time of referral, 70.5% (n=396) were on drug therapy (9% on insulin and 62.8% on oral agents), 20.6% (n=116) were on diet and 9% (n=50) had not received any form of treatment. The mean HbA(lc) was 8.4+/-2.3%. The geometric mean (x// antilog SD) of IR was 4.62x//2.51 (range 0. 63-162.7) and correlated only with waist : hip ratio (WHR, p=0.008). The geometric mean of plasma C peptide was 0.47x//2.89 nmol/l and correlated with BMI (p<0.001). Glycated haemoglobin was correlated positively with age (p=0.013), disease duration (p<0.001), IR (p<0. 001) and negatively with BMI (p<0.001). Glycated haemoglobin was lower in patients who had seen a dietitian (7.9% vs. 8.7%, p<0.001) or diabetes nurse (7.8% vs. 8.7%, p<0.001) or who performed self blood glucose monitoring (7.9% vs. 8.6%, p=0.001) and higher among smokers (8.9% vs. 8.2%, p=0.003). Compared to insulin-deficient patients (n=118), non-insulin-deficient patients (n=413) had features resembling that of the Metabolic Syndrome with increased WHR (p=0.005), blood pressure (p<0.001), BMI (p=0.001) and were older (p=0.04). Amongst the insulin-deficient patients, 27% were treated with oral agents or diet. Patients receiving appropriate therapy (n=362) had a lower HbA(lc) than those treated inappropriately (n=173) (8.2% vs. 8.7%, p=0.02). On multivariate analysis, short disease duration (p<0.001), low IR (p<0.001), high BMI (p=0.001), diabetes education (p<0.001), lack of smoking (p=0. 014) and choice of appropriate treatment (p=0.009) were the independent determinants of good glycaemic control.     

Once-monthly ibandronate for postmenopausal osteoporosis: review of a new dosing regimen

BACKGROUND: Ibandronate, a nitrogen-containing bisphosphonate, was approved by the US Food and Drug Administration (FDA) in May 2003 as a daily oral regimen for the treatment and prevention of post-menopausal osteoporosis. In March 2005, the FDA approved once-monthly dosing with ibandronate for the same indications. OBJECTIVE: The purpose of this article was to review the efficacy and tolerability of ibandronate 150 mg once monthly in the treatment and prevention of post-menopausal osteoporosis. METHODS: A search of MEDLINE (1966-September 2005) and International Pharmaceutical Abstracts (1971-September 2005) for articles relating to the efficacy and tolerability of once-monthly ibandronate in the treatment of postmenopausal osteoporosis was conducted using the terms ibandronate and ibandronic acid. Additional searches were conducted to identify publications relevant to compliance and pharmacoeconomic considerations using the terms bispbospbonate, compliance, cost, and pharmacoeconomics. The reference lists of identified articles and presentations from recent scientific meetings also were reviewed. Selected safety information from the manufacturer was incorporated. RESULTS: Ibandronate 2.5 mg/d and intermittent ibandronate (20 mg QOD for 12 doses every 3 months) have been shown to effectively reduce the incidence of vertebral fractures; after 3 years of therapy in a placebo-controlled clinical trial, the relative risk reductions for new vertebral fractures with daily and intermittent ibandronate were 62% and 50%, respectively (both, P<0.001 vs placebo). Once-monthly ibandronate has been evaluated in 2 clinical trials: a Phase I dose-ranging trial in 144 healthy postmenopausal women and a Phase III noninferiority trial in 1609 women with postmenopausal osteoporosis who were randomized to receive ibandronate 2.5 mg/d or 1 of 3 monthly ibandronate regimens: 50/50 mg (50 mg given on 2 consecutive days) once monthly; 100 mg once monthly; and 150 mg once monthly. The primary end point of the Phase III trial was the change from baseline in lumbar spine bone mineral density (BMD). After 1 year of therapy, patients who received ibandronate 150 mg once monthly had a significantly greater increase from baseline in lumbar spine BMD compared with those who received ibandronate 2.5 mg/d (4.9% vs 3.9%, respectively; P=0.002). The overall adverse-event profile was similar between the daily and monthly regimens. Drug-related adverse events were reported in 32.4% of patients receiving ibandronate 2.5 mg/d and 36.9% of patients receiving ibandronate 150 mg monthly. Upper gastrointestinal adverse events occurred in a respective 22.8% and 22.5% of the 2 groups. After 1 year of therapy, patients receiving ibandronate 150 mg monthly reported more flulike symptoms (8.3%) compared with those receiving ibandronate 2.5 mg/d (2.8%). In a crossover study comparing preference for and convenience of monthly ibandronate and weekly alendronate in 342 ambulatory women with postmenopausal osteoporosis, significantly more patients preferred the monthly ibandronate regimen to the weekly alendronate regimen (71.4% vs 28.5%, respectively; P<0.001). CONCLUSION: Once-monthly ibandronate is an effective and well-tolerated treatment option for postmenopausal osteoporosis.     

Depression, automatic thoughts, alexithymia, and assertiveness in patients with tension-type headache

OBJECTIVE: The role of psychological factors related to headache has long been a focus of investigation. The aim of this study was to evaluate depression, automatic thoughts, alexithymia, and assertiveness in persons with tension-type headache and to compare the results with those from healthy controls. METHODS: One hundred five subjects with tension-type headache (according to the criteria of the International Headache Society classification) and 70 controls were studied. The Beck Depression Inventory, Automatic Thoughts Scale, Toronto Alexithymia Scale, and Rathus Assertiveness Schedule were administered to both groups. Sociodemographic variables and headache features were evaluated via a semistructured scale. RESULTS: Compared with healthy controls, the subjects with headache had significantly higher scores on measures of depression, automatic thoughts, and alexithymia and lower scores on assertiveness. Subjects with chronic tension-type headache had higher depression and automatic thoughts scores than those with episodic tension-type headache. CONCLUSIONS: These findings suggested that persons with tension-type headache have high depression scores and also may have difficulty with expression of their emotions. Headache frequency appears to influence the likelihood of coexisting depression.     

Elevated bradykinin and decreased carboxypeptidase R as a cause of hypotension during tryptophan column immunoabsorption therapy.

Tryptophan column immunoabsorption therapy is beneficial to the patient with a neuroimmunological disease, but some complications have been attributed to this treatment. There have been some instances of an abrupt shock state along with severe decreases in blood pressure. In regards to this shock state, it has been reported that plasma bradykinin levels increase during tryptophan column immunoabsorption therapy. In this study, we examined the correlation between plasma bradykinin levels and either blood pressure or the levels of its degrading enzymes, angiotensin converting enzyme (ACE) and carboxypeptidase R (CPR) in 6 patients. Increased concentrations of bradykinin were present in the latter half of the therapeutic interval, and plasma bradykinin levels were found to be inversely correlated to CPR activity. The decreased CPR level could augment the activities of bradykinin. We speculate that bradykinin could be responsible for the hypotension occurring in patients during tryptophan column immunoabsorption therapy and that the metabolism of bradykinin could be caused by the decreased activity of CPR.     

Classification of Giardia duodenalis parasites in Turkey into groups A and B using restriction fragment length polymorphism

PCR-RFLP (restriction fragment length polymorphism) analysis was used to determine the relation of Giardia duodenalis Groups A and B. Of these, 17 (85%) were found as Group A in symptomatic cases; 22 (92%) were Group B in asymptomatic cases by using PCR-RFLP (p < 0.001). Interestingly, 5 (83%) were Group A in examination of endoscopy aspirates of symptomatic cases, as 5 (83%) were Group B in asymptomatic cases.     

Case Report of Multiple Bilobar Hepatic Arterio-Portal Fistulas Post–Liver Transplantation Managed Conservatively

Multiple intrahepatic arterio-portal fistulas are rare. The majority are isolated and occur secondary to liver trauma including iatrogenic interventions such as liver biopsy. Post–liver transplantation 18 cases have been reported, all secondary to an interventional radiological procedure. We report multiple bi-lobar arterio-portal fistulas in a liver transplant recipient recognized 1 year after transplantation. The donor died due to intracerebral bleeding following blunt head and abdominal trauma. In the present case, the etiology is not very clear. The patient was managed conservatively and to date has not required intervention.