IFN-alpha1,8 inhibits tumor-induced angiogenesis in murine angiosarcomas.

Interferon-alpha (IFN-alpha) has proved effective in the treatment of hemangiomas, hemangioblastomas, and Kaposi's sarcoma. To investigate the ability of IFNs to inhibit angiosarcoma, we used two transformed murine endothelial cell lines that form angiosarcomas in vivo. SVR and MS1-VEGF cell lines express oncogenic H-ras or vascular endothelial growth factor (VEGF), respectively. IFN-alpha1,8, which is active against murine and human cells, inhibited SVR and MS1-VEGF proliferation in vitro by 40% at 10(3) U/mL (p = 0.028). In vivo, IFN-alpha1,8 inhibited SVR tumor volume by 71% (p = 0.047) and MS1-VEGF volume by 79% (p = 0.003). Tumor-induced angiogenesis was decreased in SVR tumors by 52% (p = 0.005) and in MS1-VEGF tumors by 58% (p = 0.001). Sera from IFN-alpha1,8-treated mice bearing either SVR or MS1-VEGF tumors demonstrated a 5-fold increase in IP-10/CXCL10 (p = 0.001), an IFN-induced antiangiogenic protein. Both recombinant IP-10 and IFN-alpha1,8 inhibited human umbilical vein endothelial cell (HUVEC) vessel formation in the fibrin gel assay, a three-dimensional culture model of angiogenesis, by 56% at 25 ng/mL and 50% at 1.2 ng/mL, respectively (p < 0.001). An IP-10 blocking antibody restored vessel formation to 80% of untreated controls (p = 0.001). Given the magnitude of the in vivo response, these data suggested that the antitumor effects of IFN-alpha1,8 were likely mediated through angiogenesis inhibition rather than solely by direct inhibition of tumor cell proliferation.     

Immunocryosurgery for basal cell carcinoma: results of a pilot, prospective, open-label study of cryosurgery during continued imiquimod application

Background/aim  Theoretical considerations support the combination of cryosurgery and topical imiquimod to treat basal cell carcinomas (BCC). The aim of the present study was to test the feasibility and efficacy of 'cryosurgery during continued imiquimod application' ('immunocryosurgery') to treat 'high-risk-for-recurrence' BCCs.
Methods  Thirteen patients with 21 biopsy-proven tumours (4 of 21 relapses after prior surgery) were included. After 2–5 weeks (median, 3) of daily 5% imiquimod cream application, the tumours were treated by liquid N₂ cryosurgery (spray, two cycles, 10–20 s) and imiquimod was continued for additional 2–12 weeks (median, 4). The outcome after at least 18 months of follow-up (18–24 months) is currently reported.
Results  Nineteen of 21 tumours responded promptly to immunocryosurgery; two tumours required additional treatment cycles to clear. Thus, the clinical clearance rate was 100%. Only 1 of 21(5%) tumour relapsed after at least 18 months of follow-up (cumulative efficacy: 95%).
Conclusions  'Immunocryosurgery' is a promising non-surgical combination modality to treat 'high-risk-for-recurrence BCCs'. Initial evidence is suggestive of an at least additive effect of the two combined modalities. Further studies comparing immunocryosurgery directly with cryosurgery and imiquimod monotherapies will confirm the reported results.     

Increased salt retention and hypertension from non-steroidal agents in the elderly

We studied blood pressure and natriuretic responses to acute salt loading, and the effect of non-steroidal anti-inflammatory agents on these responses, in five healthy normotensive women aged 65 to 71 years. Five women aged 25 to 31 years acted as controls. Intravenous saline loading, with and without prior ingestion of ibuprofen, was 15 ml/kg/h for 3 h. Baseline blood pressures were higher in the elderly. Saline infusion without ibuprofen raised systolic blood pressure (SBP) by about 25 mmHg in the older group only. Ibuprofen increased baseline SBP in the elderly (129 +/- 6 vs. 116 +/- 5 mmHg, p < 0.05). Saline loading after ibuprofen again raised blood pressure by about 25 mmHg in the elderly only. The elderly group showed markedly increased sodium excretion during saline loading, but this was reduced by ibuprofen. Ibuprofen had no effect on SBP or sodium excretion in controls. Ageing appears to increase susceptibility to salt retention and hypertension from non-steroidal anti-inflammatory agents.      

Estrogen and progesterone receptor expression in uterine and extrauterine leiomyosarcomas: an immunohistochemical study.

The authors have noted anecdotal cases of extrauterine leiomyosarcomas (LMS) with estrogen receptor (ER) and progester-one receptor (PR) immunoreactivity. However, there are few studies that have compared ER and PR immunoexpression in LMS of uterine and extrauterine origin. The authors obtained a representative formalin-fixed, paraffin-embedded tissue block from cases of uterine LMS (n = 15) and extrauterine LMS (n = 16) from the archives of the Cleveland Clinic Foundation and performed immunohistochemical staining for ER and PR. Staining was evaluated by 2 observers in a semiquantitative manner using the following scale: 0, no nuclear staining; 1+, 1 to 25% of nuclei stained; 2+, 26 to 50% of nuclei stained; 3+, 51 to 75% of nuclei stained; 4+, 76 to 100% of nuclei stained. The majority of uterine LMS stained for ER (13 of 15, 87%), PR (12 of 15, 80%), or both ER and PR (12 of 15, 80%), with most cases showing 3+ or 4+ positive staining. For the extrauterine LMS cases, staining for ER was seen in 4 of 16 cases (25%), staining for PR was observed in 2 of 16 cases (13%), and staining for both ER and PR was seen in 2 of 16 cases (13%). One extrauterine LMS showed 4+ coexpression of ER and PR, but the remaining extrauterine cases showed only 1+ ER and/or PR immunoreactivity. These data suggest that most uterine LMS coexpress ER and PR, and most extrauterine LMS do not stain for these antigens. However, a subset of extrauterine LMS are ER and/or PR immunoreactive. This raises the possibility that hormonal manipulation may be beneficial in the treatment of these therapeutically recalcitrant tumors.     

Facilitated percutaneous coronary intervention.

The goal of the initial treatment for ST-segment elevation myocardial infarction is rapid and effective reperfusion. Randomized trials have demonstrated that primary angioplasty is preferred over thrombolysis if done in a timely manner and by an experienced team. However, due to many factors, performance of primary angioplasty within the goal of 90 min is often not possible. A combined strategy of immediate thrombolysis in the emergency room or in the ambulance followed by angioplasty theoretically could provide early reperfusion with subsequent angioplasty to insure complete reperfusion. Over 17 clinical trials have been reported. Compared with thrombolysis, facilitated angioplasty in the most recent trials has been shown to have a more favorable long-term outcome. Trials comparing facilitated angioplasty with full- or half-dose thrombolysis versus primary angioplasty have been far less favorable with the largest trial to date, the ASSENT (Assessment of the Safety and Efficacy of a New Treatment Strategy with Percutaneous Coronary Intervention)-4 trial, demonstrating a worse outcome in the primary end point of death, congestive heart failure, or shock at 90 days. Pending the results of the FINESSE (Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events) trial, current data suggest that facilitated angioplasty does not offer any advantage over primary angioplasty and may be harmful.     

Sociometric status and academic, behavioral, and psychological adjustment: a five-year longitudinal study.

Six hundred fourth-graders rated how much they liked to play with each of their classmates and then nominated their three best friends; 296 of the 600 children were assigned sociometric classifications of popular, neglected, average, controversial, or rejected status (the remaining 304 children failed to meet inclusion criteria). Five years later, 267 of the 296 classified children (90.2%) were evaluated on measures of academic performance, social behavior, and psychological adjustment. The number and type of contacts with the juvenile justice system were also determined. In general, children classified as rejected or controversial tended to fare more poorly on indices of long-term adjustment than did children classified as popular, neglected, or average. Results are discussed in terms of the predictive validity of sociometric rating and nomination procedures and their utility in identifying children at risk for later maladjustment.     

Uroscopy in the 21st century: high-field NMR spectroscopy

From the experiments described, it can be seen that there are different research approaches that can be taken and these are summarized in Table 1. Whereas much scientific research is principally hypothesis led, there remains, nevertheless, an important place for exploratory research. High resolution NMR can measure, directly and simultaneously, a wide range of endogenous metabolites in biological fluids and has the unique capability of providing structural information on the metabolites detected. It has proved to be a powerful research tool with which to study inherited metabolic diseases, renal disease, drug metabolism, and toxicity, and can be used to monitor the effects of drug therapy. For instance, by using a library of experimental toxins one can map the metabolic profile of site-specific nephron injury. With this approach in man one could eventually take an unknown disease such as Balkan nephropathy and predict the initial site of tubular injury, the mode of injury and therefore the kind of toxin capable of producing that injury. NMR spectroscopic techniques are still advancing rapidly, with ever increasing sensitivity and sophistication of NMR pulse sequences to enhance structural elucidation in complex mixtures. Given the advances in directly coupled HPLC-NMR and even HPLC-NMR-mass spectroscopy it is likely that these technologies in conjunction with pattern recognition will make major contribution to our understanding of renal processes and provide new diagnostic insights in the 21st century.      

Spinocerebellar ataxia type 7 (SCA7): a neurodegenerative disorder with neuronal intranuclear inclusions

Autosomal dominant cerebellar ataxia with progressive macular degeneration is caused by a CAG/glutamine repeat expansion in the SCA7 gene/protein. Neuronal intranuclear inclusions were detected in the brain of an early onset SCA7 case with the 1C2 antibody directed against an expanded polyglutamine domain. Nuclear inclusions were most frequent in the inferior olivary complex, a site of severe neuronal loss in SCA7. They were also observed in other brain regions, including the cerebral cortex, not considered to be affected in the disease. Using confocal microscopy we showed that some inclusions were ubiquitinated, but to varying degrees, ranging from <1% in the cerebral cortex to 60% in the inferior olive. In addition, we also observed cytoplasmic staining using the 1C2 antibody, particularly in the supramarginal gyrus, the hippocampus, the thalamus, the lateral geniculate body and the pontine nuclei. These data confirm that the presence of intranuclear inclusions in neurons is a common characteristic of disorders caused by CAG/polyglutamine expansions, but unlike what has been reported for Huntington's disease, SCA1 and SCA3/MJD, in SCA7 the inclusions were not restricted to the sites of severe neuronal loss.      

A formalism for independent checking of Gamma Knife dose calculations

For stereotactic radiosurgery using the Leksell Gamma Knife system, it is important to perform a pre-treatment verification of the maximum dose calculated with the Leksell GammaPlan (DLGP) stereotactic radiosurgery system. This verification can be incorporated as part of a routine quality assurance (QA) procedure to minimize the chance of a hazardous overdose. To implement this procedure, a formalism has been developed to calculate the dose DCAL(X,Y,Z,dav,t) using the following parameters: average target depth (dav), coordinates (X,Y,Z) of the maximum dose location or any other dose point(s) to be verified, 3-dimensional (3-dim) beam profiles or off-centerratios (OCR) of the four helmets, helmet size i, output factor Oi, plug factor Pi, each shot j coordinates (x,y,z)i,j, and shot treatment time (ti,j). The average depth of the target dav was obtained either from MRI/CT images or ruler measurements of the Gamma Knife Bubble Head Frame. DCAL and DLGP were then compared to evaluate the accuracy of this independent calculation. The proposed calculation for an independent check of DLGP has been demonstrated to be accurate and reliable, and thus serves as a QA tool for Gamma Knife stereotactic radiosurgery.