Imaging of the articular cartilage in osteoarthritis of the knee joint: 3D spatial-spectral spoiled gradient-echo vs. fat-suppressed 3D spoiled gradient-echo MR imaging

PURPOSE: To compare three-dimensional (3D) spatial-spectral (SS) spoiled gradient-recalled acquisition in the steady state (SPGR) imaging with fat-suppressed 3D SPGR sequences in MR imaging of articular cartilage of the knee joint in patients with osteoarthritis. MATERIALS AND METHODS: MR images of six patients with osteoarthritis of the knee were prospectively examined with a 1.5T MR scanner. For quantitative analyses, the signal-to-noise ratios, contrast-to-noise ratios, and contrast of cartilage and adjacent structures including meniscus, synovial fluid, muscle, fat tissue, and bone marrow were measured. RESULTS: In patients with osteoarthritis, 3DSS-SPGR images demonstrated higher spatial resolution and higher mean signal-to-noise (S/N) ratios (cartilage, 24.9; synovial fluid, 12.3; muscle, 20.7; meniscus, 21.6), with shorter acquisition times (7 minutes 20 seconds), when compared to fat-suppressed 3D SPGR images (cartilage, 22.3; synovial fluid, 10.8; muscle, 16.7; meniscus, 13.4). CONCLUSION: 3DSS-SPGR imaging is a promising method for evaluating cartilage pathology in patients with osteoarthritis of the knee and has the potential to replace fat-suppressed 3D SPGR imaging.     

Detection and quantification of breast tumor necrosis with MR imaging: value of the necrosis-avid contrast agent Gadophrin-3

RATIONALE AND OBJECTIVES: The authors evaluated the use of T1-weighted magnetic resonance (MR) imaging with Gadophrin-3 enhancement and of plain T2-weighted MR imaging to detect and quantify breast tumor necrosis. MATERIALS AND METHODS: Twenty EMT-6 tumors (mouse mammary sarcoma), implanted into the mammary fat pad of BALB/c-AnNCrl mice, underwent MR imaging with plain T2-weighted and T1-weighted fast field echo sequences before and 24 hours after injection of Gadophrin-3, a new necrosis-avid contrast agent. Tumor necrosis on MR images was quantified by means of a dedicated segmentation program and was correlated with histologic findings. RESULTS: In all tumors a central necrosis was revealed by histopathologic analysis, and central enhancement was seen with Gadophrin-3 on T1-weighted images. Small tumors (diameter, < 1 cm) showed an inhomogeneous central enhancement, whereas larger tumors (diameter, > 1 cm) enhanced mainly in the periphery of necrotic tissue. Plain T2-weighted images showed a hyperintense central area in only three of 20 cases with a large central necrosis. CONCLUSION: Gadophrin-3-enhanced T1-weighted images are superior to plain T2-weighted images for the detection of necrosis in a murine tumor xenograft model.     

Role of radiotherapy in the treatment of neurosarcoidosis

Neurosarcoidosis is usually managed with steroids, immunosuppressives, and other medications. Several small series suggest that radiotherapy might be useful in patients whose disease is refractory to conventional treatment. The purpose of this article is to report the outcome of 4 patients with neurosarcoidosis who were treated at the University of Florida. With long-term follow up, partial regression of disease was observed in 2 patients, stabilization of disease in 1 patient, and disease progression in 1 patient. Our experience and review of the related literature suggest the following conclusions: (1) radiotherapy is often effective in preventing the progression of local symptoms from neurosarcoidosis, but has limited application in reversing established neurologic deficits; (2) sarcoid meningitis is responsive to radiotherapy; and (3) radiation dose for the palliation of symptoms related to neurosarcoidosis is 20 to 25 Gy.     

Hypoxia attenuates the p53 response to cellular damage

The tumour suppressor activity of p53 in vivo can be subject to pressure from the physiological stress of hypoxia and we report on the development of a cell system to define the p53-dependent stages in the adaptation of cells to hypoxia. p53(+/+) cells exposed to hypoxia exhibited a transient arrest in G2/M, but escaped from this checkpoint and entered a long-term G(0)/G(1) arrest. By contrast, isogenic p53-null cells exposed to hypoxic conditions exhibited a 6-10-fold higher level of apoptosis, suggesting that p53 acts as a survival factor under limiting oxygen concentrations. Surprisingly, hypoxia-dependent growth arrest in p53(+/+) cells did not result in either p21(WAF1) or HIF-1 protein stabilization, but rather promoted a significant decrease in Ser(392)-site phosphorylation at the CK2/FACT site. However, chemically induced anoxia induced Ser(392)-site phosphorylation as well as stabilization of both p53 and HIF-1 proteins. In contrast to hypoxia, 5-flourouracil (5-FU)-induced p53-dependent cell death correlated with enhanced Ser(392) phosphorylation of p53 and elevated p21(WAF1) protein levels. Hypoxia inhibited 5-FU-induced p53-dependent cell death and attenuated p53 phosphorylation at the ATM and CK2/FACT phosphorylation sites. Although anoxia activates the p53 response, hypoxia silences the p53 transactivation pathway and identifies a physiological signalling model to study mechanisms of p53 inactivation under hypoxic conditions.     

Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo

Deletion of the INK4a/ARF locus at 9p21 is detected with high frequency in human melanoma. Within a short genomic distance, this locus encodes several proteins with established tumor-suppressor roles in a broad spectrum of cancer types. Several lines of evidence support the view that p16INK4a and p19ARF exert the tumor-suppressor activities of this locus, although their relative importance in specific cancer types such as melanoma has been less rigorously documented on the genetic level. Here, we exploit a well-defined mouse model of RAS-induced melanomas to examine the impact of germline p16INK4a or p19ARF nullizygosity on melanoma formation. We demonstrate that loss of either Ink4a/Arf product can cooperate with RAS activation to produce clinically indistinguishable melanomas. In line with the common phenotypic end point, we further show that RAS+ p16INK4a-/- melanomas sustain somatic inactivation of p19ARF-p53 and, correspondingly, that RAS+ p19ARF-/- melanomas experience high-frequency loss of p16INK4a. These genetic studies provide definitive proof that p16INK4a and p19ARF cooperate to suppress the development of melanoma in vivo.     

Influence of tumor-associated E-cadherin mutations on tumorigenicity and metastasis

In this study, we investigated whether tumor-associated E-cadherin mutations impair the tumor-suppressive function of the cell adhesion molecule and influence metastasis formation in a severe combined immunodeficiency mouse model. The investigated E-cadherin mutations were in frame deletions of exons 8 (del 8) or 9 (del 9) and a point mutation in exon 8 (p8). Transfected human MDA-MB-435S carcinoma cells stably expressing wild-type (wt) or mutant E-cadherin were injected into the mouse mammary fat pad. Mice transplanted with wt E-cadherin transfectants developed significantly smaller tumors than animals transplanted with the E-cadherin-negative parental cell line. Animals transplanted with del 9 or p8 E-cadherin transfectants produced medium size tumors, indicating that these mutations impair the tumor-suppressive function of E-cadherin. In contrast, mice transplanted with del 8 E-cadherin transfectants developed tumors of approximately the same sizes as animals transplanted with wt E-cadherin expressing cells. Lung metastases were induced by all cell lines without significant differences. Immunohistochemical analysis of E-cadherin expression in the tumors revealed a heterogeneous staining pattern, indicating loss or down-regulation of E-cadherin in some tumor cells. Metastases were completely negative for E-cadherin. Our data suggest that the type of mutation determines whether the tumor-suppressive function of E-cadherin is impaired.     

Effect of oral administration ofHypericum perforatum extract (St. John's Wort) on skin erythema and pigmentation induced by UVB,UVA, visible light and solar simulated radiation

Hypericin from St John's wort (Hypericum perforatum L.) is a photosensitizing agent that may cause a severe photodermatitis when higher amounts of St John's wort are ingested by animals. Although Hypericum extracts are widely used in the treatment of depressive disorders, only a little information on the photosensitizing capacity of St John's wort in humans is available. In the present prospective randomized study we investigated the effect of the Hypericum extract LI 160 on skin sensitivity to ultraviolet B (UVB), ultraviolet A (UVA), visible light (VIS) and solar simulated radiation (SIM). Seventy two volunteers of skin types II and III were included and were divided into six groups, each consisting of 12 volunteers. In the single-dose study the volunteers (n = 48) received 6 or 12 coated tablets (5400 or 10 800 microgram hypericin). In the steady-state study the volunteers (n = 24) received an initial dose of 6 tablets (5400 microgram hypericin), and subsequently 3 x 1 tablets (2700 microgram hypericin) per day for 7 days. Phototesting was performed on the volar forearms prior to medication and 6 h after the last administration of Hypericum extract. The erythema-index and melanin-index were evaluated photometrically using a mexameter. After both single-dose and steady-state administration, no significant influence on the erythema-index or melanin-index could be detected, with the exception of a marginal influence on UVB induced pigmentation (p = 0.0471) in the single-dose study. The results do not provide evidence for a phototoxic potential of the Hypericum extract LI 160 in humans when administered orally in typical clinical doses up to 1800 mg daily. This is in accordance with previous pharmacokinetic studies that found hypericin serum and skin levels after oral ingestion of Hypericum extract always to be lower than the assumed phototoxic hypericin threshold level of 1000 ng/mL.     

The role of reflective practice in pharmacy

CONTEXT: There has been a considerable paradigm shift from a product-centred focus towards a patient-centered focus in pharmacy. Pharmaceutical care practice (Cipolle et al., 1998) can be seen as the latest proposal to transform the profession as mandated by most major professional associations in pharmacy. Pharmaceutical care is an innovative way of practicing pharmacy that has the potential to make drug-therapy safer, more effective, and more convenient for the patient. Even though pharmacists' time spent on customer communication has increased over time (Savage, 1999), this alone will not be sufficient to bring about a paradigm shift in view of what the pharmacist actually does to provide quality patient care. It appears equally important to reflect on how pharmacists practice pharmacy. METHODS/OBJECTIVES: It is the aim of this discussion paper to argue for the importance of linking education and practice as a core part of the teaching of pharmaceutical care. CONCLUSION: In order for pharmacists to partake in truly interdisciplinary health care teams and the profession of pharmacy to demonstrate its unique and indispensable contribution to quality health care, pharmacy curricula would teach toward reflective practice, be problem-based, be positioned in collaborative teams, and have an outside (authentic) focus.