Cognitive Effects of Chemotherapy-Induced Menopause in Breast Cancer

This study examined whether chemotherapy-induced menopause affects cognitive functioning in women with early breast cancer. The neuropsychological performance of 121 breast cancer patients (age M?=?49.62, SD?=?8.11, range?=?25.25–67.92) treated with chemotherapy was assessed pre-chemotherapy, as well as 1, 6, and 18 months post-chemotherapy completion. Linear mixed modeling was used to evaluate the data. Type of menopause (pre, chemotherapy-induced, and post menopause) was found to significantly interact with cognitive performance on two cognitive variables. Specifically, chemotherapy-induced menopausal women did not show any significant changes in performance on an abstract reasoning task, while the pre-menopausal and post-menopausal groups significantly improved over time. A significant interaction on a test of finger dexterity and coordination was also found, although inspection of the results indicated that this was due to a significant improvement in the pre-menopausal groups at 6 months post chemotherapy. After chemotherapy most cognitive variables showed improvements over time, although two indicators of verbal memory showed significant declines immediately after chemotherapy, with improvement by 18 months post completion. The current study found little evidence to suggest that chemotherapy-induced menopause broadly affects cognitive functioning after treatment administration. However, longer follow-up assessments are warranted to assess the long-term effects of combined chemotherapy and endocrine treatment.     

Comparison of a Low,Fixed Dose and a High,Weight-Based Dose of Recombinant Factor VIIa in the Treatment of Warfarin-Associated Intracranial Hemorrhage

Background

Recombinant activated Factor VII (rFVIIa) can be used for rapid INR normalization in patients with warfarin-associated intracranial hemorrhage (WA-ICH); however, the optimal dose to normalize INR has not been established.

Methods

This is a retrospective review comparing two rFVIIa hospital protocols for WA-ICH [weight-based dose (80 mcg/kg) or fixed dose (2 mg)]. Primary endpoint was the percentage of patients with INR reversal (INR <1.3) at the next INR draw and the need for further doses of rFVIIa. Secondary endpoints included time to documented INR reversal and sustained INR normalization, morbidity, mortality, change in hematoma size, cost, and adverse drug reactions.

Results

Twenty-nine patients were included in each group. The weight-based group received a mean dose of 78.9 ± 21 mcg/kg versus 26.6 ± 8 mcg/kg in the fixed dose group. More patients in the fixed dose protocol achieved documented INR reversal than those in the weight-based group (92.6 vs 72.4 %, p = 0.19). The weight-based group achieved INR normalization in 229.5 [102, 331] minutes versus 165 [83, 447] minutes in the fixed dose group (p=0.02). Time to sustained INR normalization was similar in both groups. Four patients in the fixed dose group received an additional dose of 1 mg per hospital protocol. With the exception of medication acquisition cost savings of about $4,300 per patient who received fixed dose protocol, all other endpoints were similar between groups.

Conclusions

A low, fixed dose of rFVIIa appears to be as effective as a high, weight-based dose in achieving INR normalization in patients with WA-ICH.     

Smoking Habits of Black South African Patients with Diabetes Mellitus

Cigarette smoking is a major arteriosclerotic risk factor, and this is enhanced by the presence of diabetes mellitus. Although smoking rates are increasing in many African countries, they have been little studied. We have critically assessed smoking among black diabetic and general medical patients at Baragwanath Hospital in Soweto, South Africa. As well as direct questioning of patients, we also used urinary cotinine:creatinine ratio as an objective marker. The admitted smoking rate was 16 % in 118 diabetic patients, compared with 22 % in 105 medical patients. Using a validated biochemical index of smoking (urinary cotinine:creatinine >1.0 μg mg⁻¹) the rates were 37 % and 33 %, respectively. Most of the excess however was due to women who took snuff, and when excluded, the estimated real rates were 20 % (diabetic) and 24 % (medical). Amongst diabetic smokers mean cotinine:creatinine ratio was higher than in medical smokers (4.7 ± 6.0 v 1.8 ± 2.0 μg mg⁻¹) despite admitted similar smoking consumption. A separate control group of British smokers had a mean level of 3.6 ± 1.3 though their consumption was twice that of the South African groups. We conclude that smoking is common among South African black diabetic patients (20 %), though it is less than reported figures for the black general population (28 %), and British diabetic patients (35 %). Questionnaire studies may seriously underestimate smoking rates, though this effect is considerably less in African compared with British smokers. Urinary cotinine also allows quantification of the ‘smoking load’, which is rarely reflected by admitted cigarette consumption.     

Delayed activation of quiescent donor hematopoietic stem cells in the host marrow cavity by anti-host monoclonal antibody

To understand the mechanisms controlling hematopoietic engraftment in untreated, normal recipients, we investigated the fate of parental, donor hematopoietic stem cells after apparent graft failures in unconditioned F1 hybrid recipient mice. By administering an anti-host H- 2K monoclonal antibody, which targets host cells but spares the donor, we found that chimerism could be induced by delayed conditioning in animals with apparent graft failure. Engraftment kinetics in the host were followed by typing individual colony forming unit-- granulocyte/macrophage (CFU-GM) colonies for their origin and showed that parental cells, which were otherwise virtually absent, become promptly detectable within the marrow cavity after antibody administration. Marrow transfers to secondary hosts suggested that parental stem cells were present in the marrow of the untreated recipients. These findings establish that the elimination of all parental cells cannot account for the absence of peripheral blood chimerism in the unconditioned F1 hybrid recipient. Thus, viable and functional donor stem cells, which remain quiescent in the host marrow, can be activated by a selective conditioning regimen and can rescue an apparent graft failure. The selective activation in vivo of marked stem cells in an unirradiated microenvironment may be a useful system to study the regulation of cellular proliferation within the marrow cavity.     

Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts

The hammerhead ribozyme is a small catalytic RNA molecule. Potential hammerhead ribozymes that possess a catalytic domain and flanking sequence complementary to a target mRNA can cleave in trans at a putative cleavage site within the target molecule. We have investigated the potential of hammerhead ribozymes to down-regulate the product of the fibrillin-1 gene (FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of the elastin-associated microfibrils. Mutations in the FBN1 gene are responsible for Marfan syndrome (MFS), a common systemic disorder of the connective tissue. Many FBN1 mutations responsible for MFS appear to act in a dominant-negative fashion, raising the possibility that reduction of the amount of product from the mutant FBN1 allele might be a valid therapeutic approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to the 5' end of the human FBN1 mRNA has been designed and synthesized, and shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is magnesium dependent and efficient at both 37 and 50 degrees C. Delivery of the FBN1-RZ1 ribozyme into cultured dermal fibroblasts, by receptor- mediated endocytosis of a ribozyme-transferrin-polylysine complex, specifically reduces both cellular FBN1 mRNA and the deposition of fibrillin in the extracellular matrix. These results suggest that the use of hammerhead ribozymes is a valid approach to the study of fibrillin gene expression and possibly to the development of a therapeutic approach to MFS.      

Polarized immune responses modulated by layered double hydroxides nanoparticle conjugated with CpG

Modulation of the immune response is an important step in the induction of protective humoral and cellular immunity against pathogens. In this study, we investigated the possibility of using a nanomaterial conjugated with the toll-like receptor (TLR) ligand CpG to modulate the immune response towards the preferred polarity. MgAl-layered double hydroxide (LDH) nanomaterial has a very similar chemical composition to Alum, an FDA approved adjuvant for human vaccination. We used a model antigen, ovalbumin (OVA) to demonstrate that MgAl-LDH had comparable adjuvant activity to Alum, but much weaker inflammation. Conjugation of TLR9 ligand CpG to LDH nanoparticles significantly enhanced the antibody response and promoted a switch from Th2 toward Th1 response, demonstrated by a change in the IgG2a:IgG1 ratio. Moreover, immunization of mice with CpG-OVA-conjugated LDH before challenge with OVA-expressing B16/F10 tumor cells retarded tumor growth. Together, these data indicate that LDH nanomaterial can be used as an immune adjuvant to promote Th1 or Th2 dominant immune responses suitable for vaccination purposes.     

Autosomal glycogenosis of liver and muscle due to phosphorylase kinase deficiency is caused by mutations in the phosphorylase kinase beta subunit (PHKB)

Glycogen storage disease due to phosphorylase kinase deficiency occurs in several variants that differ in mode of inheritance and tissue- specificity. This heterogeneity is suspected to be largely due to mutations affecting different subunits and isoforms of phosphorylase kinase. The gene of the ubiquitously expressed beta subunit, PHKB, was a candidate for involvement in autosomally transmitted phosphorylase kinase deficiency of liver and muscle. To identify such mutations, the complete PHKB coding sequence was amplified by RT-PCR of RNA isolated from blood samples of patients and analyzed by direct sequencing of PCR products. The characterization of mutations was complemented by PCR of genomic DNA. In one female and four male patients, we identified five independent nonsense mutations (Y418ter; R428ter; Y974H+E975ter; Q656ter in two cases), one single-base insertion in codon N421, one splice-site mutation affecting exon 31, and a large deletion involving the loss of exon 8. Although these severe translation-disrupting mutations occur in constitutively expressed sequences of the only known beta subunit gene of phosphorylase kinase, PHKB, they are associated with a surprisingly mild clinical phenotype, affecting virtually only the liver, and relatively high residual enzyme activity of approximately 10%.