Combination versus sequential doxorubicin and docetaxel as primary chemotherapy for breast cancer: A randomized pilot trial of the Hoosier Oncology Group.

PURPOSE: To evaluate the efficacy and toxicity of combination and sequential dose-dense chemotherapy with doxorubicin and docetaxel (Taxotere; Rh?ne-Poulenc Rorer, Collegeville, PA) as primary chemotherapy of breast cancer. PATIENTS AND METHODS: Patients with newly diagnosed stage II or noninflammatory stage III breast cancer were randomly assigned to receive the same total doses of doxorubicin and docetaxel over a 12-week period before definitive surgery. Patients in arm A received sequential therapy with doxorubicin 75 mg/m(2) every 2 weeks for three cycles followed by docetaxel 100 mg/m(2) every 2 weeks for three cycles. Patients in arm B received combination therapy with doxorubicin 56 mg/m(2) plus docetaxel 75 mg/m(2) every 3 weeks for four cycles. Granulocyte colony-stimulating factor was administered on days 2 to 12 of each cycle in both groups. RESULTS: Forty patients were entered onto the trial. Pretreatment tumor size averaged 5.7 cm with clinically positive axillary lymph nodes in 23 patients (57%). As expected, myelosuppression was severe in both groups; however, >/= 80% of planned dose-intensity was delivered. Hand-foot syndrome was more common after sequential therapy. Clinical responses were similar in both groups, with an overall response rate of 87%, including 20% clinical complete remissions. Pathologic complete remission or residual in situ disease only was confirmed in five patients (12.8%). Patients who received sequential therapy had fewer positive lymph nodes (mean, 2.17 v 4.81; P <.037) at definitive surgery. CONCLUSION: Primary chemotherapy with doxorubicin and docetaxel is well tolerated and highly active. A sequential treatment schedule increases toxicity but may result in more substantial lymph node clearance than combination therapy.     

Enteric nerves in diabetic rats: Electron microscopic evidence for neuropathy of vasoactive intestinal polypeptide-containing fibres

Summary Enteric nerves in the ileum of rats 8 weeks after streptozotocin-induction of diabetes were examined under the electron microscope before and after immunolabeling for vasoactive intestinal polypeptide (VIP). These studies have provided evidence of degenerative changes in the myenteric nerve fibres of diabetic rats, many of which were shown to contain VIP. It is suggested that VIP-ergic nerves in the gut may play a role in the developent of gastrointestinal dysfunction in diabetes.Supported by grant from the Wellcome Trust Foundation (A. Loesch), World University Service, UK (A. Belai), and British Diabetic Association     

Application of the anthropometric discriminant functions in estimation of carrier probabilities in Martin-Bell syndrome

A method of estimating the likelihood ratio and the risk of an individual being affected with Martin Bell syndrome (MBS) from anthropometric measurements is described. The procedure is based on the discriminant functions (one for each sex), generated in our previous study in order to separate the individuals with MBS from the normal individuals. The procedure is illustrated by the examples of estimating the likelihood and the likelihood ratio in four individuals of either sex, belonging to MBS families, where the discriminant score value obtained from each individual is compared with the empirical (normalized) distribution of discriminant scores from the known MBS and normal subjects of a corresponding sex. The ways in which the risk of an individual being MBS is estimated in the general population or in members of the MBS families are indicated. The limitations of the discriminant diagnosis based on body measurements, as well as its particular applications in studies of the Martin-Bell syndrome, are discussed.     

Progress in laparoscopic anatomy research: A review of the Chinese literature

The development of laparoscopic surgery has generated the new field of study, laparoscopic anatomy. This article reviews the reported literature on laparoscopic anatomy and explores how it has evolved along with advances in abdominal surgery. In addition, the principal concerns in current laparoscopic anatomy research are discussed, including: (1) types of special adjacent anatomical structures; and (2) special surgical planes and anatomical landmarks. Understanding of systematic laparoscopic anatomy can pr...     

Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X

The distributions of scores for autistic behaviours obtained from the Autism Diagnostic Observation Scale-Generic (ADOS-G) were investigated in 147 males and females affected with the full mutation in the fragile X mental retardation 1 (FMR1) gene, in 59 individuals with the premutation, and in 42 non-fragile X relatives, aged 4-70 years. The scores representing communication and social interaction were continuously distributed across the two fragile X groups, and they were significantly elevated compared with the non-fragile X controls. Strong relationships were found between both these scores and FMRP deficits, but they became insignificant for social interaction, and the sum of social interaction and communication scores, when FSIQ was included as another predictor of autism scores. Other significant predictors of these scores in both sexes were those executive skills which related to verbal fluency, and to the regulation and control of motor behaviour. Overall, our data have shown that cognitive impairment, especially of verbal skills, best explains the comorbidity of autism and fragile X. This implies some more fundamental perturbations of specific neural connections which are essential for both specific behaviours and cognition. We also emphasize that FXS offers a unique molecular model for autism since FMRP regulates the translation of many other genes involved in synaptic formation and plasticity which should be natural targets for further exploration.     

Janus kinase 2 influences growth hormone receptor metalloproteolysis

GH signals through the GH receptor (GHR), a cytokine receptor superfamily member that couples to the cytoplasmic tyrosine kinase, Janus kinase 2 (JAK2). In addition to its role in signaling, we recently implicated JAK2 in the regulation of cell surface GHR abundance by modulation of GHR trafficking and mature GHR stability. GHR is a target for constitutive and inducible metalloprotease-mediated cleavage that alters surface GHR levels and can modulate GH signaling. We previously found that metalloprotease cleavage of GHR is dramatically lessened in fibroblasts derived from mice with targeted deletion of the zinc-binding domain of TNF-alpha-cleaving enzyme [TACE; ADAM17 (a disintegrin and metalloprotease)], implicating this transmembrane ectoenzyme as a GHR metalloprotease. In this study we used a human fibrosarcoma reconstitution system to compare the effects of RNA interference-mediated knockdown of TACE vs. a related metalloprotease, ADAM10. We found that TACE knockdown dramatically reduced both the pace and the degree of inducible GHR proteolysis and augmented the abundance of mature GHR, suggesting a role for TACE in constitutive receptor proteolysis in this system as well. Notably, ADAM10 knockdown also reduced inducible GHR proteolysis, although to a lesser degree than TACE knockdown, suggesting a contribution from this metalloprotease also. To determine whether JAK2 affects GHR proteolysis, we compared JAK2-deficient vs. JAK2-replete cells and found that phorbol 12-methyl 13-acetate-induced GHR proteolysis was significantly diminished in cells that lacked JAK2. Reconstitution with a GHR mutant that lacks the box 1 region (which mediates JAK2 association) resulted in phorbol 12-methyl 13-acetate-induced proteolysis similar in degree to that of the wild-type GHR in JAK2-deficient cells. Introduction of JAK2 did not affect the proteolysis of this box 1-deleted GHR, suggesting GHR-JAK2 association is required for JAK2 to affect GHR proteolysis. Additionally, the inhibitory effect of anti-GHRext-mAb, a conformation-sensitive GHR antibody, on receptor proteolysis was lost in cells that lacked JAK2. Our data indicate that the susceptibility of GHR to proteolysis is substantially affected by JAK2, suggesting yet another role for this kinase in determining GH sensitivity.     

Use of robust statistical methods to determine the effect of fragile X on means and variance components of a quantitative trait

Owing to the presence of outliers, an estimated 3.5% in the ridge breadth data and 1.7% in the height data, the effect of fragile X on height and ridge breadth was examined using robust statistical techniques for data collected from 54 families afflicted with this disorder. It is shown that fragile X affects ridge breadth and height in a different manner. Fragile X women had a greater mean ridge breadth than normal women, whereas there was a similar trend, but no significant difference, between normal and fragile X men. Fragile X men were shorter than normal men, but no significant difference between the mean height of normal and fragile X women was observed. However, fragile X girls were shown to grow more quickly and to stop growing earlier than normal girls. An examination of the covariance between relatives classified according to fragile X status showed that for both traits the effect of fragile X was to reduce the covariance between parents and offspring, which produced the effect of departure from an additive polygenic model of inheritance. ©1995 Wiley-Liss, Inc.     

Hypothesis: a potential role for the vasa vasorum in the maintenance of vein graft patency

Autologous saphenous vein is the most commonly used conduit for coronary artery bypass surgery with more than 50% grafts occluding within 10 years. In conventional preparation the vein undergoes considerable surgical trauma with damage to the outer layers during harvesting. Within these regions are situated the vasa vasorum and small vessels providing oxygen and nutrients to the vessel wall. Certain vasa vasorum terminate in the vessel lumen where it is suggested that they have a physiological role. Preservation of the vasa vasorum of saphenous veins used as bypass conduits may play an important role in the maintenance of graft patency.