Quinazoline sulfonamides as dual binders of the proteins B-cell lymphoma 2 and B-cell lymphoma extra long with potent proapoptotic cell-based activity

ABT-737 and ABT-263 are potent inhibitors of the BH3 antiapoptotic proteins, Bcl-x(L) and Bcl-2. This class of putative anticancer agents invariantly contains an acylsulfonamide core. We have designed and synthesized a series of novel quinazoline-based inhibitors of Bcl-2 and Bcl-x(L) that contain a heterocyclic alternative to the acylsulfonamide. These compounds exhibit submicromolar, mechanism-based activity in human small-cell lung carcinoma cell lines in the presence of 10% human serum. This comprises the first successful demonstration of a quinazoline sulfonamide core serving as an effective benzoylsulfonamide bioisostere. Additionally, these novel quinazolines comprise only the second known class of Bcl-2 family protein inhibitors to induce mechanism-based cell death.     

Ultrasound Guided Foam Sclerotherapy: Factors Associated with Outcomes and Complications

ObjectivesIn recent years ultrasound guided foam sclerotherapy (UGFS) has become an increasingly popular treatment for varicose veins. Although many published series detail the results of UGFS, little is known about the factors which are associated with outcomes and complications. The aim of this study was to identify these factors.DesignA review of a prospectively collected database of UGFS which commenced in July 2007.MethodsA successful outcome was defined as complete occlusion of the target vein on duplex scanning at follow-up. Eight factors were assessed to determine whether they were associated with outcomes and complications. These factors were age, gender, compliance with post-procedure compression hosiery, previous varicose vein surgery, single or multiple sites of injection, concentration of sclerosant, volume of sclerosant and pre-procedure severity score.ResultsBetween July 2007 and July 2009, a total of 126 patients (60 men, 66 women) attended follow-up visits and had a post-procedure duplex scan. Targets for UGFS included the great saphenous vein (n = 75), small saphenous vein (n = 13) and anterior accessory great saphenous vein (n = 8). The remainder of procedures involved other veins or more than a single target vein. The median timing of follow-up was 3 months (range 1.5–14 months) with duplex scans revealing complete occlusion of the target vein in 79% of patients. The only factor associated with a successful outcome was compliance with post-procedure compression hosiery (p < 0.05). The most frequently encountered complications following UGFS were skin staining (28%), superficial thrombophlebitis (18%) and pain (14%). The only factor associated with post-UGFS complications was female gender (p < 0.05). When complications were analysed in isolation female gender was also significantly associated with skin staining (p < 0.05), but no other complication.ConclusionsThese data suggest that compliance with post-procedure compression hosiery and gender are important factors associated with a successful outcome and reported complications following UGFS, respectively.     

Vacuum-assisted closure as a surgical assistant in life-threatening necrotizing fasciitis in children

Necrotizing fasciitis is a severe soft tissue infection that can involve skin, subcutaneous fat, fascia and muscle. It can result in devastating sequelae including tissue necrosis, sepsis, toxic shock syndrome, cardiopulmonary collapse and death. To control rapidly spreading necrosis, early diagnosis and aggressive surgical treatment with extensive radical debridement of the affected areas is necessary, as well as systemic administration of broad-spectrum antimicrobials and, very often, intensive care support.The subatmospheric negative pressure dressing has been previously used in acute and complex wounds management. The concept of using vacuum-assisted closure dressing as another management component is presented in the current article.     

Fear of childbirth and obstetrical events as predictors of postnatal symptoms of depression and post-traumatic stress disorder

This prospective study examined psychological and obstetrical predictors of enduring postpartum symptoms of depression and post-traumatic stress disorder. Contrary to prediction, prenatal fear of childbirth did not significantly predict symptoms of depression or post-traumatic stress disorder at one month postpartum, but anxiety sensitivity was an unexpected predictor that merits further investigation. Several obstetrical and neonatal variables significantly predicted symptoms of post-traumatic disorder, but not depression.     

Navitoclax (ABT-263) reduces Bcl-x(L)-mediated chemoresistance in ovarian cancer models

To examine the potential of combining Bcl-2 family inhibitors with chemotherapy in ovarian cancer, we evaluated a panel of 27 ovarian cancer cell lines for response to the combination of navitoclax (formerly ABT-263) and paclitaxel or gemcitabine. The majority of cell lines exhibited a greater than additive response to either combination, as determined by the Bliss independence model, and more than 50% of the ovarian cell lines exhibited strong synergy for the navitoclax/paclitaxel combination. To identify biomarkers for tumors likely to respond to this combination, we evaluated the protein levels of intrinsic apoptosis pathway components. Bcl-x(L) seems necessary, but not sufficient, for navitoclax/paclitaxel synergy in vitro, suggesting that exclusion of patients whose tumors have low or undetectable Bcl-x(L) would enrich for patients responsive to the combination. We evaluated Bcl-x(L) levels in ovarian cancer tumor tissue from 40 patients (20 taxane responsive and 20 with poor response to taxane) and found that patients with high Bcl-x(L) were less sensitive to taxane treatment (10 of 12) Bcl-x(L) positive patients, P = 0.014). These data support the use of navitoclax in combination with taxane-based therapy in ovarian cancer patients with high levels of Bcl-x(L).     

Parental psychopathology and migraine headaches among adolescent girls

Migraine headaches and depression often co-occur within individuals, and both syndromes run in families. However, knowledge about how these disorders relate across generations, as well as how migraine relates to other forms of psychopathology, is sparse. This study examined risk for migraine among female adolescent offspring of parents with different types of psychopathology. The sample was drawn from the Minnesota Twin Family Study, a community-based study of adolescents and their families ( n  = 674, 17-year-old female adolescents and their biological parents). Diagnoses of maternal, paternal and offspring major depression, antisocial behaviour, alcohol dependence and drug dependence were based on structured interviews. Migraine headaches in each family member were assessed via interviews with the mother. Parental depression, antisocial behaviour and drug dependence were associated with offspring migraine. These associations mostly remained significant even when parental migraine and the corresponding type of psychopathology in offspring were adjusted for. In contrast, there were no significant associations between parental psychopathology and offspring stomach problems, indicating that these associations did not extend to all offspring somatic symptoms. These results emphasize the need to look at antisocial behaviour and substance-related problems when examining associations between migraine and psychopathology, and indicate that more research on inter-generational links between migraine and psychopathology is needed.     

Withdrawing intra-aortic balloon pump support paradoxically improves microvascular flow

Introduction

The Intra-Aortic Balloon Pump (IABP) is frequently used to mechanically support the heart. There is evidence that IABP improves microvascular flow during cardiogenic shock but its influence on the human microcirculation in patients deemed ready for discontinuing IABP support has not yet been studied. Therefore we used sidestream dark field imaging (SDF) to test our hypothesis that human microcirculation remains unaltered with or without IABP support in patients clinically ready for discontinuation of mechanical support.

Methods

We studied 15 ICU patients on IABP therapy. Measurements were performed after the clinical decision was made to remove the balloon catheter. We recorded global hemodynamic parameters and performed venous oximetry during maximal IABP support (1:1) and 10 minutes after temporarily stopping the IABP therapy. At both time points, we also recorded video clips of the sublingual microcirculation. From these we determined indices of microvascular perfusion including perfused vessel density (PVD) and microvascular flow index (MFI).

Results

Ceasing IABP support lowered mean arterial pressure (74 ± 8 to 71 ± 10 mmHg; P = 0.048) and increased diastolic pressure (43 ± 10 to 53 ± 9 mmHg; P = 0.0002). However, at the level of the microcirculation we found an increase of PVD of small vessels <20 μm (5.47 ± 1.76 to 6.63 ± 1.90; P = 0.0039). PVD for vessels >20 μm and MFI for both small and large vessels were unaltered. During the procedure global oxygenation parameters (ScvO₂/SvO₂) remained unchanged.

Conclusions

In patients deemed ready for discontinuing IABP support according to current practice, SDF imaging showed an increase of microcirculatory flow of small vessels after ceasing IABP therapy. This observation may indicate that IABP impairs microvascular perfusion in recovered patients, although this warrants confirmation.     

Impact of financial incentives on documented immunization rates in the inner city: results of a randomized controlled trial.

OBJECTIVE: This study determined the effect of 2 financial incentives---bonus and enhanced fee-for-service---on documented immunization rates during a second period of observation. METHODS: Incentives were given to 57 randomly selected inner-city physicians 4 times at 4-month intervals based on the performance of 50 randomly selected children. Coverage from linked records from all sources was determined for a subsample of children within physician offices. RESULTS: Up-to-date coverage rates documented in the charts increased significantly for children in the bonus group (49.7% to 55.6%; P <.05) and the enhanced fee-for-service group (50.8% to 58.2%; P <.01) compared with the control group. The number of immunizations given by these physicians did not change significantly, although the number of immunizations given by others and documented by physicians in the bonus group did increase (P <.05). Up-to-date coverage for all groups increased from 20 to 40 percentage points when immunizations from physician charts were combined with other sources. CONCLUSIONS: Both financial incentives produced a significant increase in coverage levels. Increases were primarily due to better documentation not to better immunizing practices. The financial incentives appeared to provide motivation to physicians but were not sufficient to overcome entrenched behavior patterns. However, true immunization coverage was substantially higher than that documented in the charts.