Thymic cysts in mediastinal Hodgkin disease

Three cases of proved thymic cysts associated with mediastinal Hodgkin disease are presented. Two illustrate regression of lymphoma with chemotherapy but persistence of thymic cysts. The third case demonstrates a thymic cyst in untreated Hodgkin disease. These cases suggest that such cysts are probably neither coincidental with nor a consequence of therapy but are probably related to initial thymic involvement by Hodgkin disease.     

Transcellular transfer of HRP in the amphibian visual system

Unilateral intraocular injections of horseradish peroxidase (HRP) were made in the green tree frog, Hyla cinerea. Survival times ranged from 1 to 28 days. Control injections were placed in the orbit, peritoneum, or third ventricle. By 1 day after ocular injection anterogradely transported HRP was observed in the optic nerve and tract and in thalamic and midbrain retinal recipient zones. Retrograde filling of motor neurons was also observed by 1 day. At 3 days, HRP-positive magnocellular preoptic neurons became apparent. Finally, at 3-5 days post-injection, ependymal cells radially adjacent to HRP-positive neuropils, but not retrogradely filled cells, contained a small amount of reaction product. By 7 days these ependymal cells were densely filled and processes could be seen extending toward the neuropils. There was never evidence of HRP uptake by neurons in or adjacent to these HRP-positive neuropils. Neither retinal fibers nor ependymal cells were HRP-positive after any control injection or after processing uninjected material by the HRP histochemistry protocols. In contrast, motor cells were filled following orbital and peritoneal, but not ventricular, injections, suggesting blood-borne HRP reaching motor endplates could account for some of the motor neuron filling. Preoptic cells were filled after all control injections, demonstrating that they too could take up circulating HRP. The specificity of ependymal cell filling, however, suggests that anterogradely transported HRP can be released at the axon terminals and taken up specifically by ependymoglial cells.     

Current trends in the structure-activity relationship studies of the endogenous agouti-related protein (AGRP) melanocortin receptor antagonist

Agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin-3 and -4 (MC3R and MC4) G-protein coupled receptors. The 87-132 amino acid C-terminal domain of hAGRP possesses five disulfide bridges and a well-defined three-dimensional structure that displays full biological activity as compared to the full-length protein. Based on the NMR structure of the C-terminal AGRP(87-132), a novel mini-protein, referred to as "Mini-AGRP" was designed that exhibited receptor binding affinity and antagonism similar to that of the parent hAGRP(87-132) protein. It was demonstrated that this new-engineered protein autonomously folds to the inhibitor cystine knot (ICK) motif. As this AGRP is a novel mammalian protein involved in energy homeostasis and possibly other physiological functions remaining to be identified, structure-function studies are starting to emerge toward the understanding of how this unique protein putatively interacts with the melanocortin receptors with the objective of designing potential therapeutic agents for in vivo physiological studies. This article summarizes the progress to date of AGRP-based structure-activity relationships and putative ligand-receptor interactions.     

Phase II trial of vinorelbine for relapsed ovarian cancer: a Southwest Oncology Group study

OBJECTIVES: To assess the activity of vinorelbine in women with recurrent or resistant epithelial ovarian cancer following treatment with platinum and paclitaxel in terms of survival rate at 6 months, objective response rate (in the subset of patients with bidimensionally measurable disease), and health-related quality of life. METHODS: Seventy-nine evaluable patients with progressive ovarian cancer following platinum and taxane therapy received vinorelbine 30 mg/m(2) days 1 and 8 of a 21-day treatment cycle. RESULTS: Six-month survival rate for the entire group was 65% (95% CI: 54-75%) and median survival was 10.1 months (95% CI: 7.7-13.6 months). In the 71 women with measurable disease, 0 complete and 2 partial responses were observed (RR = 3%) (95% CI: 0.3-10%). Patients reported substantial symptom-related distress at baseline, which persisted, but did not worsen, during treatment. Patients also had impaired physical functioning at baseline and this continued to decline during treatment. CONCLUSIONS: The 6-month survival rate achieved with salvage vinorelbine is comparable to the results obtained with other salvage therapies in patients with relapsed ovarian cancer. During the initial 10 weeks of treatment, vinorelbine did not appear to be effective in alleviating the symptom-related distress or progressive impairment of physical functioning associated with this disease.     

Structural characterization and pharmacology of a potent (Cys101-Cys119, Cys110-Cys117) bicyclic agouti-related protein (AGRP) melanocortin receptor antagonist

Agouti-related protein (AGRP) is one of two known naturally occurring antagonists of G-protein coupled receptors. AGRP is synthesized in the brain and is an antagonist of the melanocortin-3 and -4 receptors (MC3R, MC4R). These three proteins are involved in the regulation of energy homeostasis and obesity in both mice and humans. The human AGRP protein is 132 amino acids and contains five disulfide bridges in the C-terminal domain. Previous reports of the NMR structures of hAGRP(87-132) and a truncated 34 amino acid form consisting of four disulfide bridges identified that AGRP contains an inhibitor cystine knot (ICK) structural fold, and that is the first mammalian example. Herein, we report a bicyclic hAGRP analogue that, when compared to hAGRP(87-132), possesses equal binding affinity but is 80-fold less potent at the mouse MC4R. Using NMR, computer assisted molecular modeling (CAMM), and cluster analysis, we have identified five structural families, two of which are highly populated, of this bicyclic hAGRP analogue. Computational docking experiments of this bicyclic hAGRP derivative, using a three-dimensional homology molecular model of the mouse MC4R, identified that three of the five structural families could be docked into the MC4R without problems from steric hindrance. Those three docked mMC4R-bicyclic hAGRP family structures were compared with putative hAGRP(87-132) ligand-receptor interactions previously reported (Wilczynski et al. J. Med. Chem. 2004, 47, 2194) in attempts to identify a "bioactive" conformation of the bicyclic hAGRP peptide and account for the 80-fold decreased ligand potency compared to hAGRP(87-132).     

Bacteria-induced intestinal cancer in mice with disrupted Gpx1 and Gpx2 genes

Two glutathione peroxidase (GPX) isozymes, GPX-1 and GPX-2 (GPX-GI), are the major enzymes that reduce hydroperoxides in intestinal epithelium. We have previously demonstrated that targeted disruption of both the Gpx1 and Gpx2 genes (GPX-DKO) results in a high incidence of ileocolitis in mice raised under conventional conditions, which include the harboring of Helicobacter species [non-specific-pathogen-free (non-SPF) conditions]. In this study, we have characterized GPX-DKO mice that have microflora-associated intestinal cancers, which are correlated with increased intestinal pathology/inflammation. We found that GPX-DKO mice raised under germ-free conditions have virtually no pathology or tumors. After colonizing germ-free mice with commensal microflora without any known pathogens (SPF), <9% of GPX-DKO mice develop tumors in the ileum or the colon. However, about one-fourth of GPX-DKO mice raised under non-SPF conditions from birth or transferred from SPF conditions at weaning have predominantly ileal tumors. Nearly 30% of tumors are cancerous; most are invasive adenocarcinomas and a few signet-ring cell carcinomas. On the basis of these results, we conclude that GPX-DKO mice are highly susceptible to bacteria-associated inflammation and cancer. The sensitivity exhibited in these mice suggests that peroxidative stress plays an important role in ileal and colonic pathology and inflammation, which can lead to tumorigenesis.     

Hospitalization of children with acute immune thrombocytopenic purpura – is it necessary?

OBJECTIVE:

To identify a target group of children with acute immune thrombocytopenic purpura (ITP) that may not require hospitalization for management.

METHODS:

A retrospective chart review was conducted of all children admitted over a two-year period to a tertiary care paediatric hospital with the diagnosis of acute ITP. Patients were classified according to typical and atypical presentations. Typical patients were defined as those aged between one and 10 years, with no hepatomegaly or significant splenomegaly and who had typical laboratory features for ITP. Patients who did not meet these criteria were categorized as atypical. Outcome measures included length of stay (LOS) in hospital; frequency of bone marrow aspiration (BMA); type of treatment; incidence of intracranial hemorrhage (ICH) or severe bleeding; and admission and discharge platelet counts.

RESULTS:

There were 74 patients hospitalized for a mean of 3.6 days. No patients suffered an ICH or bleeding requiring transfusion. Patients with typical presentations (42) were compared with patients with atypical presentations (32) and were not significantly different for clinically important outcomes such as admission and discharge platelet counts, serious complications or type of therapy. Typical patients had significantly fewer BMAs than did atypical patients – 22 of 42 (52%) versus 25 of 32 (78%) (P=0.02), and a shorter LOS – 3.1 (±0.9) days versus 4.2 (±1.8) days (P=0.01).

CONCLUSIONS:

Children presenting with ITP have a low incidence of bleeding complications and many of these patients can be managed as outpatients. A multicentre study is needed to properly delineate a low risk group suited for outpatient medical management.     

HPV infection and number of lifetime sexual partners are strong predictors for 'natural' regression of CIN 2 and 3

The aim of this paper was to evaluate the factors that predict regression of untreated CIN 2 and 3. A total of 93 patients with colposcopic persistent CIN 2 and 3 lesions after biopsy were followed for 6 months. Human papillomavirus (HPV) types were determined by polymerase chain reaction at enrolment. We analysed the biologic and demographic predictors of natural regression using univariate and multivariate methods. The overall regression rate was 52% (48 out of 93), including 58% (22 out of 38) of CIN 2 and 47% (26 out of 55) of CIN 3 lesions (P=0.31 for difference). Human papillomavirus was detected in 84% (78 out of 93) of patients. In univariate analysis, 80% (12 out of 15) of lesions without HPV regressed compared to 46% (36 out of 78) of lesions with HPV infection (P=0.016). Women without HPV and those who had a resolution of HPV had a four-fold higher chance of regression than those with persistent HPV (relative odds=3.5, 95% CI=1.4-8.6). Women with five or fewer lifetime sexual partners had higher rates of regression than women with more than five partners (P=0.003). In multivariate analysis, HPV status and number of sexual partners remained as significant independent predictors of regression. In conclusion, HPV status and number of lifetime sexual partners were strongly predictive of regression of untreated CIN 2 and 3.     

The prevalence of human papillomavirus genotypes in nonmelanoma skin cancers of nonimmunosuppressed individuals identifies high-risk genital types as possible risk factors

Nonmelanoma skin cancer is the most commonly diagnosed malignant disease in Caucasians. Known risk factors include fair skin, sun exposure, male gender, advancing age, and the presence of solar keratosis. No viral risk factors have been established thus far. To examine the association between nonmelanoma skin cancer and infection with human papilloma virus (HPV) types, we performed a retrospective study in which skin biopsies were collected from 496 nonimmunosuppressed patients attending dermatologic clinics during a defined period and for whom a biopsy or resection of a tumor was indicated for medical reasons. A total of 390 patients with histologically confirmed diagnosis of warts (n = 209), solar keratosis or Bowen's disease (n = 91), squamous cell carcinoma (n = 72), or basal cell carcinoma (n = 18), as well as 106 control patients with normal skin was analyzed for infection with HPV and, if positive, HPV typed by sequencing. Logistic regression was performed to separately investigate association of certain HPV types with the occurrence of warts, precancerous lesions, and skin cancer compared with normal skin. For all three histological groups, both crude risk and risk adjusted for age, sex, and sun exposure were calculated. HPV DNA was detected in only 4.7% of controls, in 90.9% of benign warts, in 60.4% of precancerous lesions, in 59.7% of squamous cell carcinoma, and in 27.8% of basal cell carcinoma, which demonstrates that viral infection is specifically linked to skin disorders. The distribution of viral types found is distinctly different between warts and precancers or cancers, supporting an etiologic role of specific HPV types. This is supported by statistical analysis, where after adjusting for age, gender, and sun exposure, the odds ratio for nonmelanoma skin cancer in patients who were DNA positive for the high-risk mucosal HPV types, 16, 31, 35, and 51 was 59 (95% confidence interval, 5.4-645) with normal skin as controls. These findings suggest that persistent infections of the skin with high risk genital HPV types recently identified as significant risk factors for cervical cancer may also represent a risk factor for nonmelanoma skin cancer in a nonimmunosuppressed population.     

Calorie restriction in nonhuman primates: mechanisms of reduced morbidity and mortality

Long term chronic calorie restriction (CR) of adult nonhuman primates significantly reduces morbidity and increases median age of death. The present review is focused upon an ongoing study of sustained adult- onset calorie restriction, which has been underway for 15 years. Monkeys, initially calorie restricted at about 10 years of age, are now approximately 25 years old. The median life span of these restricted monkeys is increasing, now exceeding that of ad libitum (AL)-fed monkeys. In our laboratory, maximum life span for AL-fed monkeys appears to be about 40 years. Thus, whether CR can also increase maximal life span, as it does in rodents, cannot be determined for at least another 15 years. The earliest detectable positive benefit on morbidity in these monkeys was previously reported as the prevention of obesity. Current evidence, as reviewed here, suggests that much obesity- associated morbidity is also mitigated by sustained calorie restraint in nonhuman primates. Furthermore, probably because of the prevention of obesity, diabetes has also been prevented. Recent findings include the identification of extraordinary changes in the glycogen synthesis pathway, and on the phosphorylation of glycogen synthase in response to insulin. This calorie restriction-induced prevention of morbidity does not require excessive leanness, but is clearly present when body fat is within the normal range of 10 to 22%, and this is likely to be true in humans as well.