Ultrastructural tubular basement membrane lesions in adult polycystic kidney disease

The pathogenesis of adult polycystic kidney disease (PCKD) remains an enigma. In an attempt to find a defect that might explain the cyst formation, an ultrastructural study was performed on seven fresh bilateral nephrectomies of seven patients suffering from adult PCKD. Marked electron microscopic changes of the tubular basement membranes were detected, including thickening, splitting, fraying, and multilayering of the basement membranes. By contrast, glomerular basement membranes lacked these alterations. The kidneys from two control groups (five donor kidneys harvested for transplantation; 10 patients who suffered from end stage renal disease) showed none of the lesions detected in the polycystic kidneys. The lesions of the tubular basement membrane, the principal support of tubular wall, may be the primary phenotypic expression and cause of the inherited defect.     

Chromosome abnormalities in chronic lymphocytic leukemia revealed by TPA as a mitogen

Bone marrow and peripheral blood cultures of chronic lymphocytic leukemia patients were mitogenically stimulated with TPA (12-0-tetradecanylphorbol-13-acetate). Clonal cytogenetic abnormalities were detected in frequencies varying from 15% to 100%, in five of the six patients studied. Parallel studies with pokeweek mitogen showed a much lower level of stimulation and only two abnormal clones were detected. The chromosome abnormalities described in this study are similar to those reported in CLL by other authors, particularly with respect to trisomy 12 and deletion 11q. A significant frequency of hypodiploidy and chromosome deletion was also detected in this study, and further studies are underway to determine the significance of these findings.     

Seasonal variation of mixed and pure episodes of bipolar disorder

BACKGROUND: Although seasonal patterns of manic episodes have been reported, the seasonal variation of mixed states of bipolar disorder has received little attention. In the current report we address that concern as well as the overall seasonality of manic episodes. METHODS: The seasonal pattern of 304 psychiatric hospital admissions for treatment of mixed or manic bipolar episodes over a 3-year period were analyzed employing two definitions of mixed manic states: DSM-III-R and an ROC derived definition. RESULTS: The frequency of all manic episodes combined peaked in early spring, with a nadir in late fall. Pure manic admissions showed a similar pattern. Mixed manic admissions had a significantly different pattern, with a peak in late summer and a nadir in November. The differences between pure and mixed manic admissions were demonstrated with the use of the ROC definition for mixed states. LIMITATIONS: Effects of medications and medication non-compliance may dampen natural seasonal patterns of episodes. CONCLUSIONS: The different seasonal pattern of mixed and pure manic episodes support the separation of mixed episodes as a distinct clinical subtype.     

Expression of a novel combination of fast and slow troponin T isoforms in rabbit extraocular muscles

Summary The properties of extraocular muscles (EOMs) are quite different from those of the trunk and limb. Here we show that there is a novel pattern of troponin T (TnT) expression in EOMs which most likely contributes to the fine control of ocular movement and may reflect their innervation by cranial motoneurons. Three regions of the muscle were analysed to distinguish the TnT isoforms present in the fast singly-innervated fibres from those in the multiply-innervated fibres. More than 95% of the TnT in the singly-innervated fibres is TnT_3f, which exhibits the most graded response to changes in calcium concentration during activation (Schachatet al., J. molec. Biol. 198, 551–4). In multiply-innervated fibres, which exhibit tonic contractures, the slow troponin T TnT_2s is expressed. While neither TnT_3f nor TnT_2s is unique to EOM, this pattern is unusual in two respects: first, both TnT_3f and TnT_2s are minor components of the trunk and limb musculature, and second, most muscles express several fast and both slow TnT species. Although EOM occupies a highly specialized physiological niche, its unusual physiology is not reflected in the presence of new TnT isoforms but in the expression of a different ratio of the known species of TnT.     

Photodynamic therapy for the treatment of metastatic lesions in bone: studies in rat and porcine models

This study represents the first reported use of photodynamic therapy (PDT) for metastatic bone lesions and specifically, as a treatment for spinal metastases. A model of bone metastasis in rat confirmed the efficacy of benzoporphyrin derivative-monoacid-mediated PDT for treating lesions within the spine and appendicular bone. Fluorimetry confirmed the selective accumulation of drug into the tumor(s) at 3 h post-injection. 48 h post-light delivery into the vertebral body of the rat spine loss of bioluminescent signal and histological analyses of sectioned spine confirmed MT-1 tumor cell kill in vivo as previously confirmed in vitro using an established cell viability assay. Porcine vertebrae provided a model comparable to that of human for light propagation and PDT response. Histological examination of vertebrae 48 h post-PDT revealed a necrotic radius of 0.6 cm with an average fluence rate of 4.3 mW/cm2. Non-necrotic tissue damage was evident up to 2 cm out from the treatment fiber. Results support the application of PDT to the treatment of primary or metastatic lesions within bone.     

The use of computer-assisted diagnosis in cardiac perfusion nuclear medicine studies: A review (part 3)

Computer-assisted diagnosis (CAID) is commonly used to evaluate cardiac nuclear medicine studies such as thallium perfusion scans. Part 1 of this series (Journal of Digital Imaging, 5:209–222, 1992) reviewed the basic theory underlying CAID in nuclear medicine and its use in planar thallium imaging. Part 2 discussed the application of CAID to SPECT perfusion studies (Journal of Digital Imaging, 6:1–15, 1993). This article reviews new variations of CAID programs for SPECT imaging and the application of expert systems and neural networks to CAID of nuclear medicine perfusion studies.     

Bedside to bench and back again: how animal models are guiding the development of new immunotherapies for cancer

Immunotherapy using adoptive cell transfer is a promising approach that can result in the regression of bulky, invasive cancer in some patients. However, currently available therapies remain less successful than desired. To study the mechanisms of action and possible improvements in cell-transfer therapies, we use a murine model system with analogous components to the treatment of patients. T cell receptor transgenic CD8+ T cells (pmel-1) specifically recognizing the melanocyte differentiation antigen gp100 are adoptively transferred into lympho-depleted mice bearing large, established, 14-day subcutaneous B16 melanoma (0.5-1 cm in diameter) on the day of treatment. Adoptive cell transfer in combination with interleukin interleukin-2 or interleukin-15 cytokine administration and vaccination using an altered form of the target antigen, gp100, can result in the complete and durable regression of large tumor burdens. Complete responders frequently develop autoimmunity with vitiligo at the former tumor site that often spreads to involve the whole coat. These findings have important implications for the design of immunotherapy trials in humans.     

Repeated measurement of nasal lavage fluid chemokines in school-age children with asthma.

BACKGROUND: Inflammatory processes at the mucosal surface may play a role in maintenance of asthma pathophysiology. Cross-sectional studies in asthmatic patients suggest that chemokines such as interleukin 8 (IL-8) are overproduced by respiratory epithelium. OBJECTIVE: To test the hypothesis that chemokine levels are persistently elevated in the respiratory secretions of asthmatic children at a stable baseline. METHODS: We measured nasal lavage fluid (NLF) levels of chemokines and other mediators at 3- to 4-month intervals in a longitudinal study of asthmatic children, with nonasthmatic siblings as controls. RESULTS: In a linear mixed-model analysis, both family and day of visit had significant effects on nasal mediators. Thus, data for 12 asthmatic-nonasthmatic sibling pairs who had 3 or more same-day visits were analyzed separately. For sibling pairs, median eosinophil cationic protein levels derived from serial measurements in NLF were elevated in asthmatic patients compared with nonasthmatic patients, with a near-significant tendency for elevation of total protein and eotaxin levels as well. However, no significant differences were found for IL-8 or several other chemokines. Ratios of IL-13 or IL-5 to interferon-gamma released by house dust mite antigen-stimulated peripheral blood mononuclear cells, tested on a single occasion, were significantly increased for asthmatic patients. CONCLUSIONS: Substantial temporal and family-related variability exists in nasal inflammation in asthmatic children. Although higher levels of eosinophil cationic protein are usually present in NLF of patients with stable asthma compared with patients without asthma, chemokines other than eotaxin are not consistently increased. Eosinophil activation at the mucosal surface is a more consistent predictor of asthmatic symptoms than nonspecific elevation of epithelium-derived inflammatory chemokine levels.     

Antimicrobial use and outcomes in patients with multidrug-resistant and pansusceptible Salmonella Newport infections, 2002-2003

Multidrug-resistant Salmonella Newport with decreased susceptibility to ceftriaxone (MDR-AmpC) is becoming increasingly common in its food animal reservoirs and in humans. Few data exist on rates of antimicrobial use or differences in clinical outcomes in persons infected with MDR-AmpC or other Salmonella strains. We conducted a case-comparison analysis of data from a multistate population-based case-control study to identify antimicrobial treatment choices and differences in clinical outcomes in those infected with MDRAmpC compared to pansusceptible S. Newport. Of isolates from 215 laboratory-confirmed S. Newport cases, 54 (25%) were MDR-AmpC, 146 (68%) were pansusceptible, and 15 (7%) had other resistance patterns; 146 (68%) patients with S. Newport were treated with antimicrobial agents and 66 (33%) were hospitalized. Over two-thirds of cases at low-risk for serious complications received antimicrobial therapy, most commonly with fluoroquinolones, to which this strain was susceptible. There were no significant differences in symptoms, hospitalization, duration of illness, or other outcomes between the persons infected with MDR-AmpC and pansusceptible S. Newport. Although currently prevalent MDR-AmpC S. Newport strains remains susceptible to the antimicrobial most commonly prescribed for it, continued efforts to reduce unnecessary use of antimicrobial agents in food animals and humans are critical to prevent further development of resistance to quinolones and cephalosporins, which is likely to lead to substantial adverse outcomes.