CD40 expression by gingival fibroblasts: correlation of phenotype with function

CD40, a member of the tumor necrosis factor-alpha receptor family, is constitutively expressed by cells of hematopoietic and non- hematopoietic origin, including fibroblasts. Signaling through this receptor molecule regulates inflammatory cytokine secretion by many cell types. Based on the recently described cytokine secretory heterogeneity of fibroblast cell subsets, we hypothesized that secretion of inflammatory cytokines by gingival fibroblast cultures may be dictated by the existence of differential proportions of cytokine- secreting subpopulations which express high levels of CD40. After examining a large number of gingival fibroblast (GF) cultures we find that the frequency of IL-6- and IL-8-secreting cells mirrors the frequency of cells expressing high levels of CD40 in these cultures. In addition, we demonstrate a direct functional relationship between CD40 expression and IL-6 or IL-8 secretion by showing that ligation of this molecule on GF, and CD40+ fibroblast subsets in particular, up- regulates secretion of these cytokines in vitro.      

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Neurological deficits and glycosphingolipid accumulation in saposin B deficient mice

Saposin B derives from the multi-functional precursor, prosaposin, and functions as an activity enhancer for several glycosphingolipid (GSL) hydrolases. Mutations in saposin B present in humans with phenotypes resembling metachromatic leukodystrophy. To gain insight into saposin B's physiological functions, a specific deficiency was created in mice by a knock-in mutation of an essential cysteine in exon 7 of the prosaposin locus. No saposin B protein was detected in the homozygotes (B-/-) mice, whereas prosaposin, and saposins A, C and D were at normal levels. B-/- mice exhibited slowly progressive neuromotor deterioration and minor head tremor by 15 months. Excess hydroxy and non-hydroxy fatty acid sulfatide levels were present in brain and kidney. Alcian blue positive (sulfatide) storage cells were found in the brain, spinal cord and kidney. Ultrastructural analyses showed lamellar inclusion material in the kidney, sciatic nerve, brain and spinal cord tissues. Lactosylceramide (LacCer) and globotriaosylceramide (TriCer) were increased in various tissues of B-/- mice supporting the in vivo role of saposin B in the degradation of these lipids. CD68 positive microglial cells and activated GFAP positive astrocytes showed a proinflammatory response in the brains of B-/- mice. These findings delineate the roles of saposin B for the in vivo degradation of several GSLs and its primary function in maintenance of CNS function. B-/- provide a useful model for understanding the contributions of this saposin to GSL metabolism and homeostasis.     

Changes in left ventricular diastolic performance after aortic balloon valvuloplasty: acute and late effects

To evaluate acute and follow-up changes in left ventricular diastolic performance, simultaneous digital left ventriculography and micromanometry were performed in 49 patients undergoing aortic balloon valvuloplasty. All patients improved symptomatically after valvuloplasty, and 26 returned 6.3 +/- 1.5 months later for follow-up catheterization. Immediately after valvuloplasty, aortic valve area increased (before 0.5 +/- 0.2 versus after 0.8 +/- 0.2 cm2, p less than 0.01), cardiac output (before 4.3 +/- 1.2 versus after 4.4 +/- 1.3 liters/min) and ejection fraction (before 51 +/- 18% versus after 52 +/- 17%) did not change and diastolic indexes worsened, signified by a decrease in peak filling rate (before 247 +/- 80 versus after 226 +/- 78 ml/s, p less than 0.01) and increase in the time constant of isovolumetric relaxation (tau) (before 78 +/- 29 versus after 96 +/- 40 ms, p less than 0.01) and the modulus of chamber stiffness (before 0.107 +/- 0.071 versus after 0.141 +/- 0.083, p less than 0.01). At follow-up catheterization, 16 patients continued to have symptomatic improvement (group 1) and 10 had recurrence of symptoms (group 2). Aortic valve area, cardiac output and ejection fraction at follow-up catheterization in both groups were similar and unchanged from values before valvuloplasty.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in left ventricular systolic performance immediately after percutaneous aortic balloon valvuloplasty

To evaluate the acute changes in left ventricular (LV) performance before and immediately after percutaneous aortic valvuloplasty, 25 patients underwent first-pass radionuclide angiocardiography for construction of pressure-volume loops. Simultaneously, high-fidelity micromanometric aortic and LV pressures were recorded. Echocardiographic wall thickness was used to define wall stress. After valvuloplasty, no acute changes were observed in the heart rate, aortic systolic pressure, cardiac output or degree of aortic insufficiency. Valvuloplasty decreased the peak aortic valve gradient from 73 to 40 mm Hg (p less than 0.001) and the mean gradient from 61 to 30 mm Hg (p less than 0.001); aortic valve area increased from 0.55 to 0.80 cm2 (p less than 0.001). Meridional end-systolic wall stress decreased from 83 to 55 X 10(3) dynes/cm2 (p less than 0.01). LV ejection fraction increased from 0.41 to 0.48 (p less than 0.01). LV end-diastolic volume decreased from 186 to 160 ml (p less than 0.001), end-systolic volume decreased from 115 to 87 ml (p less than 0.001) and end-diastolic pressure decreased from 22 to 17 mm Hg (p less than 0.01). LV stroke work decreased from 16.0 to 14.0 X 10(6) erg (p less than 0.001). No change was observed in peak positive LV dP/dt or the end-systolic pressure-volume ratio. This study documents variable and complex changes in the measures of cardiac function after aortic valvuloplasty. A decrease in the amount of LV outflow obstruction with maintenance of the cardiac output at a decreased level of LV filling occurs.     

Acute onset of neutrophilic dermatosis in patients after therapy with a COX-2-specific inhibitor

Case 1 A 31‐year‐old black woman with an 8‐year history of Crohn's disease (CD) presented with multiple, erythematous, tender, leg nodules. She had started to develop these areas approximately 2 weeks earlier. About 1 week prior to the development of these areas, the patient had gone to her primary care physician because of increasing joint pains. She was given rofecoxib, 50 mg/day. A few months earlier, the patient had stopped taking the medication that had been prescribed for CD: sulfasalazine and prednisone. Since stopping sulfasalazine and prednisone, her gastrointestinal symptoms had increased. After starting rofecoxib, the patient did not notice any significant change in her gastrointestinal symptoms, although her arthritic symptoms improved. Earlier on the day of presentation, the patient's gastroenterologist had instructed her to stop rofecoxib, and to re‐start sulfasalazine and prednisone. On physical examination, the patient had multiple erythematous nodules on both legs, predominantly on the lower legs anteriorly and posteriorly ( Fig. 1a ). Some of the nodules showed central pustules and some showed superficial epidermal ulceration ( Fig. 1b ). A biopsy was performed on an indurated lesion that had not yet ulcerated.

Figure 1 Open in figure viewer PowerPoint Multiple, erythematous nodules on the legs of a patient with Crohn's disease (Case 1). Biopsy specimens from some lesions showed subepidermal pustule formation with or without epidermal ulceration     

Thrombosis at venous insertion sites after inferior vena caval filter placement

Color Doppler flow imaging or compression ultrasound (US) was used to prospectively determine frequency of thrombosis at 54 venous insertion sites (47 in common femoral veins, seven in right internal jugular veins) after percutaneous placement of Greenfield filters for interruption of the inferior vena cava. Fifty-one filters were successfully placed in 51 patients with a dilator set or a balloon angioplasty catheter. Nine focal thrombi were detected in the common femoral vein (19%) and one in the right internal jugular vein (14%). Use of dilators induced eight thrombi (24%), compared with two (10%) from balloon catheters. The left common femoral vein had a high frequency of thrombosis, regardless of dilation technique (five of nine). Of nine patients with acute common femoral vein thrombosis, four became symptomatic within 10 days after the procedure. Patients may remain asymptomatic or have delayed symptoms; thus, US is valuable for determining patients at risk of thrombosis of the common femoral vein.     

FM sonography in diffuse liver disease: prospective assessment and blinded analysis

FM sonography - a signal-processing technique that uses frequency and phase information as well as amplitude data - shows promise in evaluation of patients with diffuse liver disease. In a prospective blinded review of 37 patients with biopsy-proved liver disease and 42 healthy volunteers, FM sonography was clearly superior to traditional amplitude-based (AM) sonography in distinguishing healthy from diseased subjects. Statistically significant differences were seen in accuracy (FM, 98.7%; AM, 84.8%), sensitivity (FM, 97.3%; AM, 70.3%), and negative predictive value (FM, 97.7%; AM, 78.8%). Our data also suggest that current FM sonographic techniques cannot differentiate among histologic findings associated with different hepatic parenchymal abnormalities. It is unclear, therefore, whether FM imaging can reduce the numbers of patients who require biopsy for diagnosis or the frequency of biopsy procedures in patients with known disease.     

Pneumothorax and other lung diseases: effect of altered resolution and edge enhancement on diagnosis with digitized radiographs

Prior studies have shown that pneumothorax is one of the more difficult entities to diagnose with digitized radiography. This study was designed to test whether increasing resolution from 1.25 to 2.5 line pairs per millimeter (lp/mm) and image processing (edge enhancement from unsharp masking) would increase accuracy and confidence in the diagnosis of pneumothorax, as well as normal cases and other forms of lung disease. Conventional radiographs were digitized with use of a laser reader and then reformatted as film hard copy. Eleven observers read 35 cases reformatted in three different ways (1.25 lp/mm, 2.5 lp/mm, 1.25 lp/mm unsharp mask). The images with finer resolution (2.5 lp/mm) and unsharp mask images were superior to those with coarser resolution (1.25 lp/mm) for the diagnosis of pneumothorax. There was no difference in diagnostic accuracy for normal patients. For abnormalities other than pneumothorax, the unsharp mask images were significantly worse. Confidence in the diagnosis of pneumothorax and other abnormalities was highest with the finest resolution (2.5 lp/mm).