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D Witte

Publications and source records attributed to D Witte.

At least 19 recordsLinked to original sources
PubMed2006

Preoperative elevation of serum C--reactive protein is predictive for prognosis in myeloma bone disease after surgery.

We investigated whether preoperative levels of serum C-reactive protein (CRP) and its correlation with tumour clinicopathological findings adds prognostic information beyond the time of diagnosis in patients with myeloma bone disease (MM) to facilitate the surgical decision-making process. Six hundred and fifty-eight myeloma patients were evaluated retrospectively for surgery. Clinicopathological variables of patients who underwent surgery (n=71) were compared between patients with preoperative CRP>or=6 mg l-1 and those with CRP<6 mg l-1. Univariate and multivariate analyses were performed to identify prognostic factors after surgery. Patients with an increase of CRP prior to surgery showed inferior survival compared to patients with normal levels. Patients with normal CRP levels at diagnosis but elevations prior to surgery do seem to have a similar unfavourable overall survival (OS) than patients with an increase both, at diagnosis and at surgery. Conversely, patients with normal CRP levels prior to surgery still have the best OS, irrespective of their basic values. Multivariate analysis revealed preoperative CRP levels above 6 mg l-1 Lactate dehydrogenase (LDH) above normal, and osteolyses in long weight bearing bones as independent predictors of survival. These findings suggest that in patients with MM serum levels of CRP increase during disease activity and might be significantly correlated with specific disease characteristics including adverse prognostic features such as osteolyses in long weight bearing bones. Thus, preoperative elevated CRP serum levels might be considered as independent predictor of prognosis and could provide additional prognostic information for the risk stratification before surgical treatment in patients with myeloma bone disease.

Adult↗
PubMed2005

Acceptability of human papillomavirus self testing in female adolescents.

OBJECTIVES: To develop scales assessing acceptability of human papillomavirus (HPV) testing in adolescents, to compare acceptability of self to clinician testing, and to identify adolescent characteristics associated with acceptability. METHODS: Female adolescents 14-21 years of age attending a hospital based teen health centre self collected vaginal samples and a clinician, using a speculum, collected cervicovaginal samples for HPV DNA. Acceptability of and preferences for self and clinician testing were assessed at baseline and 2 week visits. RESULTS: The mean age of the 121 participants was 17.8 years and 82% were black. The acceptability scales demonstrated good internal consistency, reliability, test-retest reliability, and factorial validity. Scores were significantly lower for self testing than clinician testing on the acceptability scale and three subscales measuring trust of the test result, confidence in one's ability to collect a specimen, and perceived effects of testing (p < 0.01). Of those who reported a preference, 73% preferred clinician to self testing. Acceptability scores for both self and clinician testing increased significantly pre-examination to post-examination (p < 0.01). Multivariable analyses demonstrated that race was independently associated with pre-examination and post-examination acceptability of self testing, and that sexual behaviours and gynaecological experiences were associated with specific acceptability subscales. CONCLUSIONS: This sample of adolescents found clinician testing for HPV to be more acceptable than self testing and preferred clinician to self testing. If self testing for HPV is offered in the future, clinicians should not assume that adolescent patients will prefer self testing. Instead, they should educate adolescents about available testing options and discuss any concerns regarding self collection technique or accuracy of test results.

Adolescent↗
PubMed2002

C5a is important in the tubulointerstitial component of experimental immune complex glomerulonephritis.

Interstitial injury is the hallmark of glomerulonephritis which is progressing to end-stage renal disease (ESRD). In humans and experimental animals, we have shown that interstitial disease is accompanied by up-regulation of complement components in tubular epithelial cells. Glomerulonephritis was induced in mice by the intraperitoneal injection of horse spleen apoferritin (HSA) and lipopolysaccharide (LPS). In addition to wild-type C57/B6 mice, animals in which the C5a receptor had been deleted (C5aR KO) were used. Animals were killed after 3 or 6 weeks, and kidneys harvested. At three weeks, both groups had evidence of mild mesangial matrix expansion and increased cellularity; there were no crescents, sclerotic lesions, or interstitial disease. At six weeks, glomerular lesions were advanced, but identical in the two groups. Both groups had evidence of an identical pattern of C3 gene expression in the tubular epithelium by in situ hybridization. There was a marked difference, however, in the extent of interstitial injury. Wild-type animals had significantly greater numbers of infiltrating interstitial cells, greater expansion of the peritubular space, more tubular atrophy, and more apoptotic tubular cells than did C5aR KOs. The anaphylotoxic fragment of C5, C5a, is not likely to be important in the glomerular component of this model of progressive glomerulonephritis. On the other hand, the interstitial component is markedly attenuated in knockout animals. These data support a role for complement in the interstitial component of this glomerulonephritis model. They are consistent with our hypotheses of a role for complement in the progression of some forms of glomerulonephritis to ESRD.

Animals↗
PubMed2001

Estrogen receptor beta is expressed in human colorectal adenocarcinoma.

Estrogen receptor beta (ER-beta) has recently been detected in a human colon cancer cell line. The aim of this work was to determine whether ER-beta is expressed in human colorectal carcinoma (CRC) tissue and the extent of this expression. ER-beta expression in CRC was investigated by immunohistochemical staining of sections of formalin-fixed, paraffin-embedded tissue from 55 CRC. The percent of positive cells was recorded. ER-beta immunoreactivity was always present in normal epithelium and adenomas in the same sections of some CRC and was always nuclear. In CRC, nuclear ER-beta immunoreactivity was detected in >10% of the cancer cells in 67% of the cases and was almost always associated with cytoplasmic immunoreactivity. There were no statistically significant differences between the ER-beta-positive and -negative groups in regard to depth of invasion, nodal metastases, or survival, regardless of the cut-off value used. We conclude that (1) a significant number of CRCs are positive for ER-beta. (2) estrogen may play an important role in the proliferation of normal colonic epithelium, and (3) there is differential localization of ER-beta immunoreactivity between normal colon, adenomas, and CRCs. Whether different ER-beta isoforms are differentially expressed in CRCs, and whether human CRCs respond to treatment with antiestrogens, is the subject of studies currently in progress.

Adenocarcinoma↗
PubMed2000

Evidence of a role for local complement expression in a murine model of progressive glomerulonephritis.

C57/B6 mice received intraperitoneal horse spleen apoferritin (4 mg) with lipopolysaccharide (0.05 mg); control mice received 0.15 M NaCl. Control and treated animals were killed weekly for 6 wk; blood and urine specimens were obtained, and tissue samples were secured. Treated animals showed evidence of significant chronic disease, with proteinuria, hematuria, and uremia. A mild glomerulonephritis was present at 2 wk, with significant proliferative glomerulonephritis at 4 wk, progressing to chronic disease with tubulointerstitial changes at 6 wk. Changes at each time period were uniform between animals. C3 mRNA was first detected by in situ hybridization at 3 wk. Message was restricted to proximal tubular and periglomerular epithelial cells. Presence of C3 message preceded the development of interstitial inflammation and fibrosis by 1-2 wk, and its location and intensity paralleled the evolving interstitial disease. Although extensive mesangial C3 protein deposits appeared early, there was never C3 message in glomeruli or infiltrating cells. Before C3 message became apparent, two cytokines known to up-regulate C3 transcription in vitro, IL-1 and IL-6, were detected by immunohistochemistry. The temporal sequence in this model is consistent with our hypothesis that local synthesis and activation of C3 in tubular epithelium is important to the interstitial component of chronic glomerulonephritis. The process is independent of the deposition of circulating complement in the glomerulus, but may be triggered by glomerular cytokines.

Animals↗
PubMed1999

Interventional catheter magnetic resonance angiography with a conventional 1.5-T magnet: work in progress.

Magnetic resonance contrast enhancement depends on the relative timing of image acquisition. Limited human trials have demonstrated efficacy of intra-arterial gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) in delineating vascular anatomy with X-rays. The present study assessed the ability of dynamic MR during intra-arterial Gd-DTPA administration to demonstrate vascular anatomy compared to conventional angiography as the gold standard. As interventional MR techniques using dedicated magnets proliferate, the ability to perform invasive MR angiography with a conventional magnet would be of great utility at established sites. Four subjects referred for different types of angiography underwent dynamic MR studies, including one with iliac artery stenting (Palmaz P204, Johnson and Johnson). All were examined with conventional angiography, and again after dynamic intra-arterial (IA) Gd-DTPA infusion. Coronal MRI images of the body were acquired using a 1.5-T superconducting magnet (three with a GE Signa, one with Philips NT), fast spoiled gradient echo (FSPGR); echo time (TE) = 4.2 msec, repetition time (TR) = 68-150 msec, flip = 75 degrees, 0-600 s after dilute Gd-DTPA IA bolus injection during sequential breath-hold acquisitions of 13-32 s each. All arteries were detected with dynamic MR. The FSPGR MRI with IA Gd-DTPA administration can provide adequate time and spatial resolution to demonstrate arterial anatomy and arterial stent patency.

Carotid Artery Diseases↗
PubMed1999

Targeted overexpression of parathyroid hormone-related protein (PTHrP) to vascular smooth muscle in transgenic mice lowers blood pressure and alters vascular contractility.

PTH-related protein (PTHrP) and its receptor are expressed in vascular smooth muscle cells and are believed to participate in the local regulation of vascular tone. To explore the function of locally produced PTHrP in vascular smooth muscle in vivo, we developed transgenic mice that overexpress PTHrP in smooth muscle using a smooth muscle alpha-actin promoter to direct expression of the transgene. In the PTHrP-overexpressing mice, messenger RNA expression was mainly restricted to smooth muscle-containing tissues. Several founders also expressed the transgene in bone and heart and exhibited striking abnormalities in the development of these tissues. In PTHrP-overexpressing mice, blood pressure was significantly lower than that in wild-type controls (121 +/- 3 vs. 135 +/- 2 mm Hg; P < 0.01). Moreover, the magnitude of the vasorelaxant response to iv infusions of PTHrP-(1-34)NH2 was significantly attenuated in the transgenic animals. A similar desensitization to PTHrP was observed in aortic ring and portal vein preparations. Surprisingly, PTHrP-overexpressing mice were also significantly less responsive to the hypotensive action of infused acetylcholine in vivo and to the relaxant actions of acetylcholine on aortic vessel preparations in vitro. In summary, we have successfully targeted overexpression of PTHrP to the smooth muscle of transgenic mice. When expressed in its normal autocrine/paracrine setting, PTHrP lowers systemic blood pressure and decreases vascular responsiveness to further relaxation by PTHrP and other endothelium-dependent vasorelaxants such as acetylcholine. We postulate that the heterologous desensitization to acetylcholine-induced relaxation in PTHrP-overexpressing blood vessels involves desensitization of second messenger/effector signaling pathways common to PTHrP and acetylcholine.

Actins↗
PubMed1998

Biological effects of targeted inactivation of hepatocyte growth factor-like protein in mice.

Hepatocyte growth factor-like protein (HGFL) is a liver-derived serum glycoprotein involved in cell proliferation and differentiation, and is proposed to have a fundamental role in embryogenesis, fertility, hematopoiesis, macrophage activation, and tissue repair. To assess the in vivo effects of total loss of HGFL, we generated mice with targeted disruption of the gene resulting in loss of the protein. Disruption of the HGFL gene allowed for normal embryogenesis, and followed a Mendelian pattern of genetic transmission. Mice homozygous for the targeted allele (HGFL-/- mice) are fertile, and grow to adulthood without obvious phenotypic abnormalities in unchallenged animals, except for development of lipid-containing cytoplasmic vacuoles in hepatocytes throughout the liver lobules. These histologic changes are not accompanied by discernible changes in synthetic or excretory hepatic functions. Hematopoiesis appears unaltered, and although macrophage activation is delayed in the absence of HGFL, migration to the peritoneal cavity upon challenge with thioglycollate was similar in HGFL-/- and wild-type mice. Challenged with incision to skin, HGFL-/- mice display normal wound healing. These data demonstrate that HGFL is not essential for embryogenesis, fertility, or wound healing. HGFL-deficient mice will provide a valuable means to assess the role of HGFL in hepatic and systemic responses to inflammatory and infectious stimuli in vivo.

Alleles↗
PubMed1998

Targeted disruption of the mouse lysosomal acid lipase gene: long-term survival with massive cholesteryl ester and triglyceride storage.

Lysosomal acid lipase (LAL) is essential for the hydrolysis of the triglycerides and cholesteryl esters in lysosomes. Its deficiency produces two phenotypes, a severe infantile-onset variant, Wolman disease (WD), and a later onset variant, cholesteryl ester storage disease (CESD). A mouse model with a LAL null mutation was produced by targeting disruption of the mouse gene. Homozygote knockout mice (lal -/lal-) produce no LAL mRNA, protein or enzyme activity. The lal-/lal- mice are born in Mendelian ratios, are normal appearing at birth, and follow normal development into adulthood. However, massive accumulation of triglycerides and cholesteryl esters occurs in several organs. By 21 days, the liver develops a yellow-orange color and is approximately 1.5-2.0x larger than normal. The accumulated cholesteryl esters and triglycerides are approximately 30-fold greater than normal. The lal+/lal- mice have approximately 50% of normal LAL activity and do not show lipid accumulation. Male and female lal-/lal- mice are fertile and can be bred to produce progeny. This mouse model is a phenotypic model of human CESD, and a biochemical and histopathologic mimic of human WD. The lal-/lal- mice provide a model to determine the role of LAL in lipid metabolism and the pathogenesis of its deficiency states.

Animals↗
PubMed1998

Dynamic gadolinium DTPA-enhanced magnetic resonance of intravascular stents.

RATIONALE AND OBJECTIVES: Magnetic resonance contrast enhancement depends on the timing of image acquisition. Human trials have demonstrated efficacy of renal artery stents on salvage of renal function. This study assessed the ability of dynamic gadolinium (Gd)-DTPA administration to demonstrate renal and iliac artery stent patency compared to conventional angiography as the gold standard. METHODS: Seven subjects with eight stents referred for angiography underwent dynamic magnetic resonance studies, all with renal artery stenting. All were examined with conventional angiography and after dynamic Gd-DTPA infusion. Coronal magnetic resonance images were acquired using a GE Signa 1.5 T magnet (fast spoiled gradient echo; echo time = 4.2 ms; repetition time = 68-150 ms; flip angle = 75 degrees) 0 to 600 seconds after 0.1 mmol/Kg Gd-DTPA intravenous bolus injection during sequential breath-hold acquisitions 13 to 32 seconds each. RESULTS: All eight stents were visualized with 100% accurate patency documentation. CONCLUSIONS: Fast spoiled gradient echo magnetic resonance imaging with bolus Gd-DTPA administration can provide adequate time and spatial resolution to demonstrate arterial stent patency.

Aged↗
PubMed1997

Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic mice.

Smooth muscle cells (SMC) of the vascular wall, bladder, myometrium, and gastrointestinal and respiratory tracts retain the ability to proliferate postnatally, which enables adaptive responses to injury, hormonal, or mechanical stimulation. SMC growth is regulated by a number of mesenchymal growth factors, including insulin-like growth factor I (IGF-I). To explore the function of IGF-I on SMC in vivo, the mouse SMC alpha-actin promoter fragment SMP8 (-1074 bp, 63 bp of 5'UT and 2.5 kb of intron 1) was cloned upstream of rat IGF-I cDNA, and the fusion gene microinjected to fertilized eggs of the FVB-N mouse strain. Mating of hemizygous mice with controls produced about 50% transgenic offspring, with equal sex distribution. Transgenic IGF-I mRNA expression was confined to SMC-containing tissues, with the following hierarchy: bladder > stomach > aorta = uterus > intestine. There was no transgene expression in skeletal muscle, heart, or liver. Radioimmunoassayable IGF-I content was increased by 3.5- to 4-fold in aorta, and by almost 10-fold in bladder of transgenic mice at 5 and 10 wk, with no change in plasma IGF-I levels. Wet weight of bladder, stomach, intestine, uterus, and aorta was selectively increased, with no change in total body or carcass weight of transgenic animals. In situ hybridization showed that transgene expression was exquisitely targeted to the smooth muscle layers of the arteries, veins, bladder, ureter, stomach, intestine, and uterus. Paracrine overproduction of IGF-I resulted in hyperplasia of the muscular layers of these tissues, manifesting in remarkably different phenotypes in the various SMC beds. Whereas the muscular layer of the bladder and stomach exhibited a concentric thickening, the SMC of the intestine and uterus grew in a longitudinal fashion, resulting in a marked lengthening of the small bowel and of the uterine horns. This report describes the first successful targeting of expression of any functional protein capable of modifying the phenotype of SMC in transgenic mice. IGF-I stimulates SMC hyperplasia, leading to distinct patterns of organ remodeling in the different tissue environments.

Animals↗
PubMed1997

Minor structural differences in Boc-CCK-4 derivatives dictate affinity and selectivity for CCK-A and CCK-B receptors.

We previously reported novel Boc-CCK-4 (Boc-Trp-Met-Asp-Phe-NH2) derivatives possessing the general structure Boc-Trp-Lys[N epsilon-CO-NH-(R-Ph)]-Asp-Phe-NH2 (Shiosaki et al. J. Med. Chem. 1991, 34, 2837-2842). In contrast to Boc-CCK-4, which is 70-fold selective for the CCK-B receptor, the modified lysine-bearing tetrapeptides were highly potent and selective full agonists at the CCK-A receptor. Further investigation of the structure-activity profile following modification of the substituted phenylurea moiety appended off the lysine revealed that moving certain substituents, e.g. nitro or acetyl, from the 2- or 3-position on the phenyl ring to the 4-position, a relatively minor and subtle structural modification within the tetrapeptide, resulted in loss of CCK-A receptor selectivity and development of a trend toward CCK-B selectivity. These tetrapeptides, e.g. Boc-Trp-Lys[N epsilon-CO-NH-(4-NO2-Ph)]-Asp-Phe-NH2 and Boc-Trp-Lys[N epsilon-CO-NH-(4-Ac-Ph)]-Asp-Phe-NH2, were full agonists relative to CCK-8 in stimulating intracellular calcium mobilization in a cell line that expresses the CCK-B receptor.

Cell Line↗
PubMed1997

Fibrolipomatous hamartoma: MR imaging findings.

OBJECTIVE: To analyze the MR imaging features of fibrolipomatous hamartoma (FLH) of nerves. DESIGN AND PATIENTS: MR imaging studies from six patients (three men and three women) were retrospectively reviewed by three musculoskeletal radiologists. In four patients, a biopsy of the nerve lesion was performed. In two patients, biopsy data were unavailable and the diagnosis was based on the clinical history combined with the MR imaging findings. RESULTS AND CONCLUSION: MR imaging demonstrated fusiform nerve enlargement that was caused by fatty proliferation and thickening of nerve bundles. Nerve bundles appeared as serpentine tubular structures, hypointense on both T1- and T2-weighted images. The degree of fatty proliferation varied among patients. In addition, significant variation in the distribution of fat along the course of the nerves was noted. In three patients, FLH followed the branching pattern of the nerves, a characteristic pathologic finding. In two patients, intramuscular fat deposition (biceps and tibialis posterior muscles) was present. MR imaging findings of FLH are typical, allowing a confident diagnosis. The variation of fatty proliferation among patients and involved nerves as well as the tendency of the abnormalities to follow the branching pattern of the nerves is well demonstrated with MR imaging. FLH may present as an isolated nerve lesion, may be associated with intramuscular fat deposition, or may occur as a feature of macrodystrophia lipomatosa (MDL).

Adult↗
PubMed1997

A submicroscopic deletion in Xq26 associated with familial situs ambiguus.

Abnormal left-right-axis formation results in heterotaxy, a multiple-malformation syndrome often characterized by severe heart defects, splenic abnormalities, and gastrointestinal malrotation. Previously we had studied a large family in which a gene for heterotaxy, HTX1, was mapped to a 19-cM region in Xq24-q27.1. Further analysis of this family has revealed two recombinations that place HTX1 between DXS300 and DXS1062, an interval spanning approximately 1.3 Mb in Xq26.2. In order to provide independent confirmation of HTX1 localization, a PCR-based search for submicroscopic deletions in this region was performed in unrelated males with sporadic or familial heterotaxy. A cluster of sequence-tagged sites failed to amplify in an individual who also had a deceased, affected brother. FISH identified the mother as a carrier of the deletion, which arose as a new mutation from the maternal grandfather. The deletion interval spans 600-1,100 kb and lies wholly within the 1.3-Mb region identified by recombination. Discovery of this deletion supports localization of HTX1 to Xq26.2 and reveals the first molecular-genetic abnormality associated with human left-right-asymmetry defects.

Abnormalities, Multiple↗
PubMed1997

Hereditary hemochromatosis. Preventing chronic effects of this underdiagnosed disorder.

Hereditary hemochromatosis, once thought to be rare, is the most common genetic disorder in the United States. Nonetheless, the condition often goes undetected and untreated until its severe effects have become apparent. What clues can lead you to the diagnosis, and how can you spot them in your patients, before significant morbidity has occurred? In this article, Drs McDonnell and Witte discuss the diagnosis and management of this underrecognized problem as well as the various issues involved in screening. An illustrative case of hemochromatosis is also included.

Hemochromatosis↗
PubMed1996

[Results after coronary bypass operation].

OBJECTIVE: To determine the influence of various risk factors on 30-day postoperative mortality rate of aortocoronary bypass operation at different centres. PATIENTS AND METHODS: Data on 227 patients (179 men, mean age 63 [40-87] years; 48 women, mean age 68 [44-81] years), 219 first operations, 8 second operations) were retrospectively analysed. In all patients the indications for aortocoronary bypass surgery had been established in the last 3 months of 1993. The operations had been performed at six cardiac centres in Germany (five in Hessen [H1-H5]) and in three hospitals elsewhere in Europe outside of Germany (E1-E3). RESULTS: The operative mortality was relatively high (5.3%), 152 patients (67%) presenting with one or more risk factors accounting for an increased perioperative mortality. The mortality rate was significantly higher for: clearly impaired left ventricular function (ejection fraction < 40%): 20 vs 3% with an ejection fraction > or = 40% (P < 0.001); emergency operation: 16.6 vs 2.7% for elective operation (P < 0.001); advanced age (> or = 70 years): 10.9 vs 3.1% for younger patients (P < 0.025); and unstable angina: 9.2 vs 2.9% with stable angina (P < 0.05). Most of the bypasses were done with the internal mammary artery (63.9%, usually combined with venous bypasses (exclusive use of venous bypasses in 35.2%), but the proportion of arterial bypasses differed greatly between centres (96% in H3, 19% in H4). CONCLUSIONS: (1) Aortocoronary bypass operations are done on many patients with important risk factors, resulting in a relatively high 30-day postoperative mortality rate. (2) The proportion of internal mammary artery bypasses markedly differs between centres in Hessen.

Adult↗
PubMed1996

Regulated expression of complement factor B in the human kidney.

We have previously demonstrated regulated expression of C3 in the proximal renal tubular epithelial cells of humans. To test the hypothesis that local alternative pathway complement activation could contribute to the tubulointerstitial component of chronic renal disease, we examined factor B gene expression in human kidneys. 35S riboprobes were generated from a human factor B cDNA. By in situ hybridization, proximal tubular factor B message was seen in 17 kidneys with various nephropathies. The expression was most intense in organs with evidence of interstitial inflammation, and its localization paralleled the inflammation. As was the case with C3 and C4, there was never any evidence of glomerular factor B message, nor was any seen in infiltrating inflammatory cells. In eight normal kidney tissues, factor B expression was either absent or restricted to rare foci of interstitial infiltration. The proximal renal tubular epithelium of humans appears to express the genes for both components of the alternative pathway convertase, C3 and factor B. These locally produced components may be important mediators of the interstitial inflammation that is common to all progressive nephritides.

Base Sequence↗