Left ventricular shape analysis from three-dimensional echocardiograms

Cystic fibrosis patients require pancreatic enzyme supplements to aid food digestion. It is suspected that incorrect delivery of this enzyme may result in both significant malabsorption and the development of strictures in the proximal colon caused by the high-dose supplement reaching this region before the food. Investigations into the drug's delivery were performed using dual-isotope imaging; a method was developed to directly label the enteric-coated enzyme pellets with 111In, re-applying the enteric coating afterwards, and this was then ingested with a pancake meal labelled with 99Tcm-tin colloid. Consecutive image data, acquired over a period of > or = 4 h using a dual-headed gamma camera, were analysed to assess intestinal transit. In-vitro stability checks on these labelling techniques were encouraging, showing < 2% 99Tcm and < 7% 111In elution over 90 min in hydrochloric acid. In 5 of the 12 patients studied to date, the pellets were seen to pass through significantly faster than the food, with a mean difference in 50% gastric emptying time of greater than 93 min. The mean absolute difference in emptying time for all 12 patients was > 67 min. Thus, a technique has been developed to effectively radiolabel pancreatic enzyme pellets, and analysis of dual-isotope images using this preparation, together with radiolabelled solid food, has demonstrated significant differences in the transit of these two substances through the gastrointestinal tract of some cystic fibrosis patients.     

FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord

The adult rat brain contains progenitor cells that can be induced to proliferate in vitro in response to FGF-2. In the present study we explored whether similar progenitor cells can be cultured from different levels (cervical, thoracic, lumbar, and sacral) of adult rat spinal cord and whether they give rise to neurons and glia as well as spinal cord-specific neurons (e.g., motoneurons). Cervical, thoracic, lumbar, and sacral areas of adult rat spinal cord (>3 months old) were microdissected and neural progenitors were isolated and cultured in serum-free medium containing FGF-2 (20 ng/ml) through multiple passages. Although all areas generated rapidly proliferating cells, the cultures were heterogeneous in nature and cell morphology varied within a given area as well as between areas. A percentage of cells from all areas of the spinal cord differentiate into cells displaying antigenic properties of neuronal, astroglial, and oligodendroglial lineages; however, the majority of cells from all regions expressed the immature proliferating progenitor marker vimentin. In established multipassage cultures, a few large, neuron-like cells expressed immunoreactivity for p75NGFr and did not express GFAP. These cells may be motoneurons. These results demonstrate that FGF-2 is mitogenic for progenitor cells from adult rat spinal cord that have the potential to give rise to glia and neurons including motoneurons.     

Limb swelling in patients who have fibrodysplasia ossificans progressiva

Fibrodysplasia ossificans progressiva is a rare heritable disorder of connective tissue characterized by progressive heterotopic ossification of soft tissues and by congenital malformation of the great toes. Limb swelling has also been noted, yet little is known about this complication of fibrodysplasia ossificans progressiva. To determine the prevalence of limb swelling in this condition, the authors reviewed detailed medical records on 74 patients (25 males, 49 females; age range, 1-49 years) who had a documented history of fibrodysplasia ossificans progressiva. The study population included more than 90% of all patients known to have fibrodysplasia ossificans progressiva in the United States. Acute swelling of the limbs occurred in association with flareups of the condition in nearly all cases. Acute swelling in the upper limbs was focal and nodular in contrast to acute swelling in the lower limbs, which was more diffuse. Acute swelling in the upper limbs occurred in all 74 patients whereas acute swelling in the lower limbs occurred in 47 of the 74 patients (64%). Two of the 74 patients who had acute swelling in the lower limbs (4%) had a documented episode of deep vein thrombophlebitis. Chronic swelling in the upper limbs occurred in 9 of the 74 patients (12%) and was not seen before the age of 12 years. Chronic swelling in the lower limbs occurred in 36 of the 74 patients (49%) and was not seen before the age of 9 years. The intense angiogenesis and edema seen on histopathologic evaluation of preosseous fibrodysplasia ossificans progressiva lesions may play a role in the pathogenesis of the limb swelling. The data show an age related prevalence of limb swelling in fibrodysplasia ossificans progressiva and suggest a model for understanding the complex pathways leading to limb swelling in this disorder.     

Failure of ketoprofen and interferon combination therapy to improve interferon-resistant chronic hepatitis C

Previous studies have documented the effectiveness of magnetic resonance imaging for evaluating and following up the development of avascular necrosis of the femoral head. One of the limitations of this technique, however, is the distortion that is encountered with ferromagnetic screws. A traumatic fracture to the femoral head is a risk factor for avascular necrosis. The addition of internal fixation, which is often required in Pipkin-type fractures of the femoral head, creates significant image distortion on magnetic resonance scans used for postoperative follow-up. The artifact and field distortion present in magnetic resonance imaging when ferromagnetic screw fixation is used has been avoided at our institution by the use of titanium hardware. The authors, therefore, recommend the use of titanium screws in the fixation of Pipkin-type fractures in the hip joint.     

Prevalence and clinical significance of combined K-ras mutation and p53 aberration in pancreatic adenocarcinoma

CONCLUSION: This study could not attribute survival differences to the coincident acquisition of two common genetic alterations, K-ras mutation and p53 overexpression in pancreatic adenocarcinoma patients. Additionally, our data indicate the converse to be true: Those patients lacking both K-ras mutation and aberrant p53 expression showed the shortest survival when compared with cases showing either alteration or both. This study also showed the negative effect of K-ras mutation and p53 expression on pancreas cancer patients' survival after treatment with either radiation therapy or chemotherapy. BACKGROUND: Mutations of the oncogene K-ras at codon 12 are reported to be the most common genetic alteration in pancreatic carcinoma, whereas either overexpression or mutation of the tumor suppressor p53 gene is considered the most common genetic alteration in neoplasia of all types. p53 overexpression has been attributed to survival differences in pancreatic carcinoma, but such association is still controversial. No studies have fully documented the combined incidence of K-ras and p53 alterations in pancreatic adenocarcinoma, or their combined effect on patient survival in a large case series. The influence of radiation or chemotherapy in groups showing both, either, or neither mutation is also undocumented. METHODS: Paraffin-embedded tissue sections from 76 cases of pancreatic adenocarcinoma were cut for DNA extraction for K-ras analysis and immunohistochemical staining for aberrant p53 expression. K-ras mutation was determined by single-strand conformation polymorphism (SSCP) and slot-blot allele-specific oligonucleotide (ASO) hybridization of PCR-amplified DNA product p53 expression was scored on the basis of percent nuclear staining with the MAb DO7. RESULTS: Sixty-four of 76 cases (84%) showed K-ras mutation, p53 expression, or both, K-ras was mutated in 55 of 76 cases (72%). p53 was expressed in 33 of 76 cases (43%). Twenty-four of 76 cases (31%) showed both K-ras mutation and p53 expression. The presence of both alterations was not related to significant differences in tumor grade, stage, or survival compared to either alteration alone. A sizable subset (16% of cases) lacked either alteration, and surprisingly, this group showed the shortest median survival compared to those with K-ras mutation, p53 expression, or both (p = 0.024). Patients whose tumors were K-ras-negative showed the greatest difference in median survival with radiation therapy (median survival 30.8 mo vs 7.8 mo with no radiation, p = 0.005).     

Scintigraphic detection of infection and inflammation: new developments with special emphasis on receptor interaction

Various conventional radiopharmaceuticals are currently available for scintigraphic imaging of infection and inflammation. Although a wide variety of infectious and inflammatory foci can be detected with these agents, several disadvantages limit their application. These limitations have stimulated the search for new radiopharmaceuticals. In the past decade a new class of radiopharmaceuticals has emerged: radiolabelled receptor-specific small proteins and peptides. These proteins and peptides are naturally occurring inflammatory mediators which specifically bind to receptors abundantly present in the area of inflammation. In addition, owing to their small size, they rapidly clear from all non-target tissues. This paper provides an overview of these newly developed agents, focussing on imaging characteristics and in vivo uptake mechanisms.     

Identification of the vascular and avascular zones of the human meniscus using magnetic resonance imaging: correlation with histology

Since the initial employment of magnetic resonance imaging (MRI) to diagnose meniscal tears, a characteristic low-signal intensity, triangular-shaped structure has been interpreted as representing the entire meniscus. The difficulty in diagnosing meniscocapsular separations with MRI has brought attention to our lack of understanding of the appearance on MRI of the outer third of the meniscus and the meniscocapsular junction. We correlated MRIs of the meniscus in cadaver knees with histological sections and found that the low-signal, wedge-shaped structure corresponds only to the avascular (white) zone of the meniscus, whereas the high-signal zone peripheral to it corresponds to the vascularized (red) zone.     

Immunohistochemical analysis of intratumoral heterogeneity of [131I]cG250 antibody uptake in primary renal cell carcinomas

In previous studies, highly heterogeneous uptake of 131I-labelled chimeric monoclonal antibody G250 ([131I]cG250) in primary renal cell carcinomas has been observed (intratumoral differences > factor 100). In this study, we investigated a possible correlation between intratumoral antibody uptake and four immunohistochemically determined parameters: G250 antigen expression, blood vessel density, neovascularization and percentage of viable tumour cells. Whole tumour slices of four different tumours were cut into 1-cm3 cubes, and in each cube the [131I]cG250 uptake was determined. The correlation between [131I]cG250 uptake and each individual parameter was determined in a multiple regression analysis. Additionally, the data were reanalysed after introducing arbitrary cut-off values for each parameter. If a sample showed expression of a parameter above the introduced threshold value, this sample fulfilled one condition. Subsequently, the Pearson correlation coefficients were calculated from [131I]cG250 uptake and the number of fulfilled conditions (0-3). All tumour samples with high [131I]cG250 uptake [> 0.1% of the injected dose per gram (ID g(-1))] showed high antigen expression (> 50%). However, not all samples with high antigen expression displayed high uptake. A statistically significant correlation between [131I]cG250 uptake and antigen expression was found (beta = 0.44, 0.69 and 0.74) in three out of four tumours analysed. Of the other determined parameters, no consistent correlation with [131I]cG250 uptake was found; only the percentage of viable tumour cells correlated significantly in two out of four tumours (beta = 0.80 and 0.26). Calculation of the Pearson correlation coefficients showed a statistically significant correlation between [131I]cG250 uptake and an increased number of fulfilled conditions in all tumours, indicating that each of the individual parameters contribute to the uptake of [131I]cG250. These observations indicate that high antigen expression is a prerequisite for high antibody uptake. However, regional differences in antibody uptake within a tumour cannot be explained by antigen expression alone.     

Therapeutic efficiency and safety of a second-generation replication-conditional HSV1 vector for brain tumor gene therapy

A second-generation replication-conditional herpes simplex virus type 1 (HSV) vector defective for both ribonucleotide reductase (RR) and the neurovirulence factor gamma34.5 was generated and tested for therapeutic safety and efficiency in two different experimental brain tumor models. In culture, cytotoxic activity of this double mutant HSV vector, MGH-1, for 9L gliosarcoma cells was similar to that of the HSV mutant, R3616, which is defective only for gamma34.5, but was significantly weaker than that of the HSV mutant hrR3, which is defective only for RR. The diminished tumoricidal effect of the gamma34.5 mutants could be accounted for by their reduced ability to replicate in 9L cells. The MGH-1 vector did not achieve significant prolongation of survival in vivo in the syngeneic 9L rat gliosarcoma model for either single brain tumor focus or multiple intracerebral and leptomeningeal tumors, when the vector was applied intratumorally or intrathecally, respectively, and with or without subsequent ganciclovir (GCV) treatment. In identical 9L brain tumor models with single and multiple foci, application of hrR3 with or without GCV was previously shown to result in marked long-term survival. Contrary to the findings with intrathecal injection of hrR3, no vector-related mortality was observed in any animals treated with MGH-1. Thus, in these rat brain tumor models, the double mutant, replication-conditional HSV vector MGH-1 showed a higher therapeutic safety than the RR-minus vector, hrR3, but had clearly decreased therapeutic efficiency compared to hrR3. The development of new HSV vectors for brain tumor gene therapy will require a balance between maximizing therapeutic efficacy and minimizing toxicity to the brain. Standardized application in brain tumor models as presented here will help to screen new HSV vectors for these requirements.     

Neurotrophic ACTH4-9 analogue therapy normalizes electroencephalographic alterations in chronic experimental allergic encephalomyelitis

Chronic experimental allergic encephalomyelitis (CEAE) is an established experimental model for multiple sclerosis (MS). The demyelinating lesions in the white matter of the central nervous system observed in CEAE and in MS are accompanied by various neurophysiological alterations. Among the best defined electrophysiological abnormalities are the changes in event-related potentials, in particular evoked potentials involving the spinal cord, i.e. motor and sensory evoked potentials. Less familiar are the changes observed in the electroencephalogram of CEAE-affected animals, which are also encountered in the human equivalent, MS. In the present experiment we evaluated the therapeutic value of a neurotrophic peptide treatment [H-Met(O2)-Glu-His-Phe-D-Lys-Phe-OH, an ACTH4-9 analogue] and its effect on the delayed flash visual evoked potentials (VEP) and power spectra of the electroencephalogram, during a 17-week follow-up of CEAE. CEAE animals treated with the neurotrophic peptide were protected against the development of neurological symptoms during the course of the demyelinating syndrome. VEPs of animals suffering from CEAE showed a delay of the latencies of the late components which was significantly counteracted by peptide treatment. The peak-to-peak amplitude of the VEP afterdischarge recorded from CEAE animals was significantly increased during the course of CEAE and correlated closely with the progression of the myelinopathy. Furthermore, CEAE animals showed an increase of electroencephalogram (EEG) beta activity of up to 500% as compared with the age-matched control group. This increase in beta power mainly consisted of a prevailing 20-21 Hz peak, a frequency that normally is not dominant in control EEG recordings of the rat during passive wakefulness. All these electrophysiological phenomena were absent in ACTH4-9 analogue-treated animals. The present findings underscore the potential importance of a neurotrophic peptide treatment in the pharmacotherapy of central demyelinating syndromes, and possibly of MS.