Longitudinal variations and predictors of increased perceived impact of multiple sclerosis, a two-year study

OBJECTIVE: To explore variations and the capacity of selected factors - contextual factors, disease-related characteristics, cognition, fatigue, mood and time - to predict an increase in the perceived physical and psychological impact of multiple sclerosis (MS) over a two-year period. METHODS: At an MS specialist clinic, 219 outpatients were included in the study and data were collected every 6 months. The Multiple Sclerosis Impact Scale was used for assessment of the perceived physical and psychological impact of MS. For statistical analysis of changes in impact during the study period, Friedman ANOVA was used and predictors of increased impact were explored with Generalized Estimating Equations employing proportional odds models. RESULTS: The majority had changes in perceived physical impact of established important magnitude and the psychological impact varied significantly. A period of more than 10 years since diagnosis, cognitive disability, fatigue and signs of depression were independent predictors of increase in physical impact. Weak or moderate sense of coherence, absence of immunomodulatory treatment, fatigue and signs of depression were independent predictors of increase in psychological impact. CONCLUSION: The fluctuation in perceived impact should be taken into account in clinical decision-making and when designing studies and interpreting the results. This study identifies the predictors of increased perceived physical and psychological impact that health-related services should pay special attention to, in order to provide interventions aimed at minimizing the perceived impact of MS.     

Body mass index and prognostic markers at radical prostatectomy

OBJECTIVE: Obesity is increasing rapidly in Western countries. Approximately 40% of adult Danes are overweight and approximately 15% of these are obese. Epidemiological studies of obesity in relation to prostate cancer have provided conflicting results. Therefore, we examined correlations between body mass index (BMI) and clinicopathological prognostic markers, biochemical recurrence and operative morbidity in patients who had undergone radical prostatectomy. MATERIAL AND METHODS: The sample consisted of 293 Danish men treated with radical prostatectomy between 2000 and 2005 at Aarhus University Hospital. BMI was calculated as an indicator of obesity. Prospectively collected clinical and pathologic data from this population were used. RESULTS: The median BMI value was 26.2 kg/m(2) (range 19.6-41.7 kg/m(2)), which is slightly above the upper limit of normal. Currently accepted prognostic markers, such as prostate-specific antigen level, Gleason score and pT class, showed no statistically significant correlations with BMI. Patients with biochemical recurrence were evenly distributed among four different BMI quartiles and there was no difference in the length of hospitalization, indicating no differences in pre- or postoperative morbidity. Computations were repeated using only patients with the lowest (19.6-21.3 kg/m(2)) and highest (34.2-41.7 kg/m(2)) BMI values but statistically significant correlations were still not found. CONCLUSIONS: Several American studies have shown that obesity can lead to prostate cancer becoming more aggressive. The results of the present study involving a Danish prostate cancer population do not substantiate this or suggest any connection between BMI and operative morbidity. A possible explanation is that Danish obesity problems are not yet as severe as those in the USA.     

Post-marketing safety monitoring of a new group B meningococcal vaccine in New Zealand, 2004-2006

New Zealand introduced a new outer membrane vesicle vaccine in 2004 to combat an epidemic of group B meningococcal disease. An Independent Safety Monitoring Board oversaw intensive safety monitoring, which included hospital surveillance, health professional reporting (passive and active) and mortality monitoring. With over three million doses administered to individuals aged under 20 years, the monitoring results provide consistent evidence supporting the vaccine's safety.     

From bacterial genomes to novel antibacterial agents: discovery, characterization, and antibacterial activity of compounds that bind to HI0065 (YjeE) from Haemophilus influenzae

As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.     

Discovery of potent & selective inhibitors of activated thrombin-activatable fibrinolysis inhibitor for the treatment of thrombosis

Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans.     

Disassociation of bone resorption and formation by GLP-2: a 14-day study in healthy postmenopausal women

We have previously shown that a single subcutaneous injection of glucagon-like peptide-2 (GLP-2) at 10 p.m. in postmenopausal women results in a dose-dependent decrease in the nocturnal serum and urine concentrations of fragments derived from the degradation of the C-terminal telopeptide region of collagen type I (s-CTX and u-CTX) and u-DPD, markers of bone resorption. In contrast, bone formation, as assessed by serum osteocalcin and procollagen type I N-terminal propeptide (PINP), appeared to be unaffected by treatment with exogenous GLP-2. These effects were further investigated in a 14-day study. The aim was to demonstrate that a parenteral formulation of GLP-2 is safe and well tolerated after repeated dosing in healthy postmenopausal women for 14 days. It was further investigated whether the effects on bone turnover markers were sustained throughout the study period. The study was a double-blind placebo-controlled trial with 60 postmenopausal women and 2 different doses of GLP-2 (1.6 mg and 3.2 mg GLP-2) against a saline control. The data for bone resorption revealed a similar reduction on Day 1 and Day 14, both based on time course and AUC. There were no signs of tachyphylaxis and no serious adverse reaction. Both GLP-2 doses resulted in similar and significant (p<0.001) reduction in bone resorption indicating that the maximum efficacious dose has been approached. Osteocalcin and PINP levels were unaffected at Day 1 and Day 14, suggesting a disassociation between bone resorption and bone formation during GLP-2 treatment.     

Systemic stromal effects of estrogen promote the growth of estrogen receptor-negative cancers

Numerous hormonal factors contribute to the lifetime risk of breast cancer development. These include inherited genetic mutations, age of menarche, age of menopause, and parity. Inexplicably, there is evidence indicating that ovariectomy prevents the formation of both estrogen receptor (ER)-positive and ER-negative breast cancers, suggesting that ER-negative breast cancers are dependent on ovarian hormones for their formation. To examine the mechanism(s) by which this may be occurring, we investigated the hypothesis that steroid hormones promote the outgrowth of ER-negative cancers by influencing host cell types distinct from the mammary epithelial cells. We used a novel xenograft mouse model of parturition-induced breast carcinoma formation, in which the tumors that arise following pregnancy lack the expression of nuclear hormone receptors, thereby recapitulating many clinical cases of this disease. Despite lacking ER expression, the tumors arising following pregnancy in this model require circulating estrogens for their formation. Moreover, increasing the levels of circulating estrogens sufficed to promote the formation and progression of ER-negative cancers, which was accompanied by a systemic increase in host angiogenesis and was attendant with the recruitment of bone marrow-derived stromal cells. Furthermore, bone marrow cells from estrogen-treated mice were sufficient to promote tumor growth. These results reveal a novel mechanism by which estrogens promote the growth of ER-negative cancers.     

Endothelial Akt signaling is rate-limiting for rapamycin inhibition of mouse mammary tumor progression

Chronic activation of Akt signaling in the endothelium recapitulates the salient features of a tumor vasculature and can be inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. This led to the hypothesis that the antitumor efficacy of rapamycin may be partially dependent on its ability to inhibit endothelial Akt signaling, making rapamycin an antiangiogenic agent and endothelial Akt pathway inhibitor. Dose-response studies with rapamycin showed that primary human endothelial cells and fibroblasts had a bimodal Akt response with effective reductions in phosphorylated Akt (pAkt) achieved at 10 ng/mL. In contrast, rapamycin increased pAkt levels in tumor cell lines. When tumor-bearing mice were treated with rapamycin doses comparable to those used clinically in transplant patients, we observed strong inhibition of mammary tumor growth. To test whether Akt activation in the endothelium was rate-limiting for this antitumor response, we engineered mouse mammary tumor virus-polyoma virus middle T antigen mice with endothelial cell-specific expression of constitutively activated Akt. We observed that the antitumor efficacy of rapamycin was reduced in the presence of elevated endothelial Akt activation. Just as we observed in MCF7 cells in vitro, rapamycin doses that were antiangiogenic resulted in increased pAkt levels in total mouse mammary tumor virus-polyoma virus middle T antigen tumor lysates, suggesting that tumor cells had an opposite Akt response following mammalian target of rapamycin inhibition compared with tumor endothelial cells. Together, these data support the hypothesis that endothelial Akt signaling in the tumor vasculature is an important target of the novel anticancer drug rapamycin.     

Temozolomide and methotrexate for primary central nervous system lymphoma in the elderly

Background Treatment for primary CNS lymphoma (PCNSL) in the elderly is associated with lower response rates and higher risks of acute and late delayed toxicity as compared to younger patients. Temozolomide has emerged as a new alternative treatment for PCNSL and constitutes an attractive option for the elderly because of its favorable toxicity profile. In this study we report outcomes of a consecutive series of PCNSL elderly patients initially treated with an innovative regimen combining methotrexate and temozolomide without radiotherapy or intra-thecal chemotherapy. Methods Histologically confirmed newly-diagnosed PCNSL patients older than 60 years were included. An induction chemotherapy was initially given (methotrexate 3 g /m² on days 1, 10, and 20, and temozolomide 100 mg/m² on days 1–5). Patients achieving a partial or complete response proceeded to a maintenance phase (up to 5 monthly cycles of methotrexate 3 g/m² on day 1, and temozolomide 100 mg/m² days 1–5). Non-responders were treated on an individual basis. Results Among the 23 included patients, a complete response was observed in 55%, and disease progressed in the other 45%. Median event-free survival was 8 months, and median overall survival was 35 months. Grades 3 or 4 toxicities included nephrotoxicity in three patients, and hematotoxicity in five; no neurotoxicity has been observed to date. One patient died while on treatment from complications of intestinal obstruction. Conclusion Our efficacy results are comparable to other reported regimens, with the advantages of a favorable toxicity profile, and absence of intra-thecal chemotherapy. Prospective, controlled studies are warranted to confirm such results.     

Dual-isotope lymphoscintigraphy using albumin nanocolloid differentially labeled with 111In and 99mTc

The aim of this study was to develop and evaluate ¹¹¹In- and ^99mTc-labeled derivatives of albumin nanocolloid (NC) for dual-label lymphoscintigraphy to allow simultaneous comparison of lymphatic flow from different tissue planes draining a tumour bed for accurate identification of sentinel lymph nodes (SLN). Using the chelator, p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid (DOTA), ¹¹¹In-DOTA-NC and ^99mTc-DOTA-NC were compared in vitro with respect to stability of labeling, colloidal status and particle size, then in vivo by measuring their clearance rates from a subcutaneous injection depot. ¹¹¹In-DOTA-NC and ^99mTc-DOTA-NC were indistinguishable on the basis of in vitro criteria. Their in vivo clearance rates, however, were disparate (0.0015 to 0.075 min^-1 for ¹¹¹In and 0.0072 to 0.067 min^-1 for ^99mTc), ¹¹¹In being faster in three studies and markedly slower in three. This demonstrates that even when dual-labeled radiotracers behave identically in vitro, they will not necessarily do so in vivo. Further work is needed to develop dual-labeled NC.