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Biomedical subjects

E J Lewis

Publications and source records attributed to E J Lewis.

At least 37 records · Page 2Linked to original sources
PubMed2000

Paired-like homeodomain proteins Phox2a/Arix and Phox2b/NBPhox have similar genetic organization and independently regulate dopamine beta-hydroxylase gene transcription.

The homeodomain transcription factors Arix/Phox2a and NBPhox/Phox2b play a role in the specification of the noradrenergic phenotype of central and peripheral neurons. To better understand the functions of these two factors, we have compared the genetic organization, chromosomal location, and transcriptional regulatory properties of Arix and NBPhox. The gene structure is very similar, with each gene containing three exons and two introns, extending a total of approximately 5 kb. Arix and NBPhox are unlinked in human and mouse genomes. NBPhox is located on human Chromosome 4p12 and mouse Chromosome 5, while Arix is located on human Chromosome 11q13 and mouse Chromosome 7. Both proteins bind to three sites in the promoter proximal region of the rat dopamine beta-hydroxylase gene (DBH). In vitro, Arix and NBPhox form DNA-independent multimers and exhibit cooperative binding to the DB1 regulatory element, which contains two homeodomain recognition sites. Both proteins regulate transcription from the rat DBH promoter, and transcription is synergistically increased in the presence of the protein kinase A catalytic subunit (PKA) plus either Arix or NBPhox. The transcription factors exhibit similar concentration-dependent efficacies, and when they are coexpressed, transcription is stimulated to a value approximately equal to that seen with either factor alone. The N-terminal segment of Arix is essential for transcriptional regulatory activity, and this region bears 50% identity with NBPhox, suggesting a similar mechanism of transcriptional activation of the DBH gene. We conclude from this study that Arix and NBPhox exhibit indistinguishable and independent transcriptional regulatory properties on the DBH promoter.

Amino Acid Sequence↗
PubMed2000

The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.

Adult↗
PubMed1999

Evaluation of the recovery of waterborne Giardia cysts by freshwater clams and cyst detection in clam tissue.

The Asian freshwater clam, Corbicula fluminea, inhabits environments recognized to be contaminated with waterborne Giardia cysts. Sixty-four tissue samples of Giardia-free clams were spiked with various numbers of Giardia duodenalis cysts within the range of 50-700 cysts. Regression analysis showed that paired numbers of spiked (x) versus recovered (y) cysts regressed significantly (P < 0.01) according to the equation y = 42.57 +/- 1.81x (+/- 64.3). The cyst detection threshold was 43 cysts/clam, the coefficient of determination was 77%, and the overall sensitivity of cyst detection was 42.9%. All 20 values of cyst numbers in clam tissue samples that were processed blind were located within the 95% prediction limits of the linear regression equation. The cyst retention rate of 160 clams kept in an aquarium with 38 l of water spiked with 1.00 x 10(5) G. duodenalis cysts was approximately 1.3 x 10(3) cysts/clam. No waterborne cysts were detected by the membrane filtration method 90 min after spiking the aquarium water. G. duodenalis cysts were detected in clam tissue up to 3 weeks post-exposure. Filtration of water by clams substantially depleted the aquarium water of its particulate matter. The sampling program demonstrated that the population of 160 clams examined during the study could be accurately assessed for exposure to waterborne Giardia cysts by random sampling of 86 (54%) clams. The results indicate that C. fluminea clams can be used for biological monitoring of contamination with Giardia.

Analysis of Variance↗
PubMed1999

Cryptosporidium oocysts in Bent mussels (Ischadium recurvum) in the Chesapeake Bay.

Filter-feeding molluscan shellfish can concentrate environmentally derived waterborne pathogens of humans, which can be utilized in the sanitary assessment of water quality. In the present study, oocysts of Cryptosporidium were detected in Bent mussels (Ischadium recurvum) at two Chesapeake Bay sites from which C. parvum-contaminated oysters had previously been collected. Spiking of Cryptosporidium-free blue mussel (Mytilus edulis) tissue with C. parvum oocysts showed a 51.1% recovery rate of oocysts, giving an oocyst detection limit of 19 oocysts/0.7 ml of mussel tissue homogenate. The results indicate that Bent mussels, which are common throughout the Chesapeake Bay region, may prove to be useful as biological indicators of water contamination with Cryptosporidium oocysts.

Animals↗
PubMed1999

Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy. Collaborative Study Group.

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m(2) at baseline and 54 mL/min/1.73 m(2) at the end of the study compared with a baseline of 64 mL/min/1.73 m(2) and final 58 mL/min/1.73 m(2) in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.

Adult↗
PubMed1999

Captopril-induced reduction of serum levels of transforming growth factor-beta1 correlates with long-term renoprotection in insulin-dependent diabetic patients.

The renoprotective effect of captopril on progression of diabetic nephropathy was demonstrated by the Collaborative Study Group Captopril Trial and might be independent of blood pressure. Because angiotensin II is known to stimulate the prosclerotic cytokine, transforming growth factor-beta (TGF-beta), we postulated that the renoprotective effect may be due to inhibition of TGF-beta1 production. TGF-beta1 levels were measured in serum at baseline and 6 months from patients in the captopril trial. TGF-beta1 analyses were performed on all available patient sera. Analysis was performed between the percent change in TGF-beta1 levels during the first 6 months versus the percent change in glomerular filtration rate (GFR) in the subsequent 2 years. TGF-beta1 levels increased by 11% (P = 0. 003) in the placebo group (n = 24), whereas there was a decrease of 14% (P = 0.01) in the captopril group (n = 34). There was an inverse correlation between the percent change in TGF-beta1 levels during the first 6 months and the percent change in GFR over the ensuing 2-year period in patients from both the placebo (r = -0.55, P = 0. 005) and captopril groups (r = -0.45, P = 0.008). In patients with initial GFR below 75 mL/min, there was an even stronger correlation in percent change in TGF-beta1 levels and percent change in GFR in both placebo (n = 9, r = -0.69, P = 0.03) and captopril groups (n = 21, r = -0.73, P = 0.0001). Our data suggest that captopril decreases TGF-beta1 levels in diabetic nephropathy and that changes in TGF-beta1 levels may predict the course of diabetic nephropathy.

Adult↗
PubMed1999

Remission of nephrotic syndrome in type 1 diabetes: long-term follow-up of patients in the Captopril Study.

In 1994, we reported a 3.4 +/- 0.8 year follow-up of the eight patients who experienced remission of nephrotic syndrome during the Collaborative Study Group-sponsored, multicenter trial of captopril therapy in patients with type 1 diabetes with nephropathy (Captopril Study). Of the 409 patients randomized to treatment on the Captopril Study, 108 had nephrotic syndrome (24-hour proteinuria >/= 3.5 g of protein) at baseline. Of these 108 patients, 8 experienced remission of nephrotic syndrome (proteinuria </= 1.0 g/24 h of protein). Remission was significantly associated with captopril therapy and control of systolic blood pressure. The present study describes the status of these eight patients during a follow-up of 7.7 +/- 0.3 years. Since our previous report, one patient has been lost to follow-up and one patient progressed to end-stage renal disease (ESRD) 3.7 years after completion of the Captopril Study. The remaining six patients remain in remission of nephrotic syndrome (mean 24-hour proteinuria, 1.03 +/- 0.3 g of protein) and have stable serum creatinine levels (mean, 1.58 +/- 0.3 mg/dL) and body weights (mean, 69.8 +/- 5.3 kg). Of the six patients, one has discontinued angiotensin-converting enzyme inhibitor (ACEi) therapy because of hypotension. Excluding the patient who progressed to ESRD, the current mean systolic blood pressure is 135 +/- 6 mm Hg and mean diastolic blood pressure is 78 +/- 4 mm Hg. We conclude that long-term remission of nephrotic syndrome and preservation of renal function is achievable in some patients with type 1 diabetes. Control of blood pressure and ACEi therapy appear to be important in achieving long-term remission.

Adult↗
PubMed1999

Giardia duodenalis cysts of genotype A recovered from clams in the Chesapeake Bay subestuary, Rhode River.

Filter-feeding molluscan shellfish can concentrate zoonotic and anthroponotic waterborne pathogens. Cysts of Giardia sp. were detected by immunofluorescent antibodies in tissues of the clams Macoma balthica and M. mitchelli from Rhode River, a Chesapeake Bay (Maryland) subestuary. Molecular tests identified the cysts as Giardia duodenalis Genotype A, the most common genotype recovered from humans. Macoma clams are burrowers in mud or sandy-mud substrata and preferentially feed on the surface sediment layer. Waterborne Giardia cysts settle rapidly to the bottom in slow-moving waters and contaminate the sediment. Macoma clams do not have economic value, but can serve as biologic indicators of sediment contamination with Giardia sp. cysts of public health importance. These clams can be used for sanitary assessment of water quality.

Animals↗
PubMed1999

Report of an association between discoid lupus erythematosus and smoking.

Smoking has been shown to be associated with many medical disorders, including many involving the skin. While preliminary studies suggest a modest association between smoking and systemic lupus erythematosus, epidemiologic data on discoid lupus erythematosus (DLE) and smoking are lacking. To study this relationship, we examined current smoking habits in two unique patient populations with DLE. One group was compared with matched dermatology patients while the second group was compared with the corresponding statewide population. For both groups, the current smoking prevalence was much higher than that of the comparison population. For the control-matched group of DLE patients, smoking prevalence was found to be significantly greater than that of controls (odds ratio 12.2; p = 0.001). We therefore propose that smoking is a risk factor for development of DLE.

Adult↗
PubMed1999

A case of bullous frostbite following recreational snowmobiling.

Frostbite is the occurrence of localized tissue freezing and injury. It results following cold exposure of sufficient magnitude or duration to cause acute tissue damage. Although there are several conditions that predispose to frostbite, all are at risk if subject to sufficient cold exposure. We discuss a case of frostbite presenting with bullae localized to the neck resulting from extreme cold encountered while snowmobiling at night in Minnesota, an entity known by some local practitioners as "polaris vulgaris."

Anti-Infective Agents, Local↗
PubMed1998

AP1 proteins mediate the cAMP response of the dopamine beta-hydroxylase gene.

Neurotransmitter biosynthesis is regulated by environmental stimuli, which transmit intracellular signals via second messengers and protein kinase pathways. For the catecholamine biosynthetic enzymes, dopamine beta-hydroxylase and tyrosine hydroxylase, regulation of gene expression by cyclic AMP, diacyl glycerol, and Ca2+ leads to increased neurotransmitter biosynthesis. In this report, we demonstrate that the cAMP-mediated regulation of transcription from the dopamine beta-hydroxylase promoter is mediated by the AP1 proteins c-Fos, c-Jun, and JunD. Following treatment of cultured cells with cAMP, protein complexes bound to the dopamine beta-hydroxylase AP1/cAMP response element element change from consisting of c-Jun and JunD to include c-Fos, c-Jun, and JunD. The homeodomain protein Arix is also a component of this DNA-protein complex, binding to the adjacent homeodomain recognition sites. Transfection of a dominant negative JunD expression plasmid inhibits cAMP-mediated expression of the dopamine beta-hydroxylase promoter construct in PC12 and CATH.a cells. In addition to the role of c-Fos in regulating dopamine beta-hydroxylase gene expression in response to cAMP, a second pathway, involving Rap1/B-Raf is involved. These experiments illustrate an unusual divergence of cAMP-dependent protein kinase signaling through multiple pathways that then reconverge on a single element in the dopamine beta-hydroxylase promoter to elicit activation of gene expression.

Animals↗
PubMed1998

Ro 32-3555, an orally active collagenase selective inhibitor, prevents structural damage in the STR/ORT mouse model of osteoarthritis.

OBJECTIVE: To determine the efficacy of a selective inhibitor of collagenases in an animal model of osteoarthritis (OA). METHODS: Ro 32-3555, an orally active collagenase selective inhibitor, was administered to STR/ORT mice. Microfocal x-ray-generated images of the hind limbs were visually scored for joint space narrowing, osteophyte formation, and calcification of tendons. Histologic sections of the knees were scored for cartilage changes including loss of surface matrix, fibrillation, and eburnation. RESULTS: Significant inhibition of joint space narrowing and osteophyte formation was achieved in groups of animals treated with 10-50 mg/kg(-1) of Ro 32-3555. These effects were confirmed histologically in the same groups of animals: histologic analysis revealed that Ro 32-3555 protected cartilage from degradative changes. CONCLUSION: Ro 32-3555, a collagenase selective inhibitor, inhibits both the cartilage and bone changes in this mouse model of OA, and thus shows great potential as a treatment of OA in humans.

Animals↗
PubMed1998

A simple inflammation model that distinguishes between the actions of anti-inflammatory and anti-rheumatic drugs.

OBJECTIVE AND DESIGN: To determine the effects of anti-inflammatory and anti-rheumatic drugs on paw swelling and changes in plasma levels of acute phase proteins (APPs) during acute inflammation in the rat. MATERIALS AND METHODS: Inflammation was induced in rats by the injection of adjuvant and the animals were bled five days later and plasma levels of seromucoid, haptoglobin, caeruloplasmin and albumin were determined spectrophotometrically using a Cobas-bio centrifugal analyzer. The effects of daily administration of a variety of drugs used to treat arthritis were determined on paw swelling and APP levels. RESULTS: Injection of the adjuvant induced a pronounced change in APP levels which correlated with the increase in paw swelling. In general, the NSAIDs tested significantly reduced paw swelling and significantly increased levels of haptoglobin and caeruloplasmin in a dose-related manner. Two dose-levels of steroids were administered, the higher dose reduced swelling, and reduced levels of seromucoid, haptoglobin and caeruloplasmin, but raised albumin levels; the lower dose also reduced paw swelling, but the only change in APPs was increased albumin levels. Anti-rheumatic drugs such as gold salts reduced levels of some APPs (seromucoid, haptoglobin and caeruloplasmin) without reducing paw swelling. Immunomodulators had a variety of effects on inflammation and APPs depending on mechanism of action. CONCLUSIONS: The different classes of anti-inflammatory/anti-rheumatic drug tested show distinct profiles of activity against APPs and paw swelling. These differential effects may result from modulation of cytokine activity.

Acute-Phase Proteins↗
PubMed1998

Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy. The Collaborative Study Group.

BACKGROUND: The glomerular and retinal vessels are both affected in patients with type I and type II diabetes mellitus. However, the prevalence of the nodular form of diabetic glomerular sclerosis (Kimmelstiel Wilson lesion) and other forms of glomerular pathology including diffuse mesangial sclerosis and their clinical correlates in type II diabetes are less well known. In addition, although recent studies have suggested that non-diabetic glomerular disease was a common cause of proteinuria in type II diabetes, the prevalence of other diseases is unknown. The literature on this subject is clouded by clinical bias regarding patients with diabetes who undergo renal biopsy. METHODS: Glomerular and retinal pathology and clinical correlates were studied in 36 patients enrolled in a prospective clinical trial of patients with type II diabetes mellitus, proteinuria, renal insufficiency, and hypertension. RESULTS: Seventeen biopsies had diabetic glomerular sclerosis with Kimmelstiel Wilson nodules; 15 biopsies had glomerular changes characteristic of the diabetic state including enlarged glomeruli and an increase in mesangial matrix without Kimmelstiel Wilson nodules (mesangial sclerosis lesion); and two had other primary glomerular diseases (IgA and membranous nephropathy). Patients with Kimmelstiel-Wilson nodules had elevated serum creatinines compared to patients with mesangial sclerosis lesions, but there were no other significant differences. Patients with Kimmelstiel Wilson nodules had more severe overall retinopathy than those with mesangial sclerosis lesions (P = 0.0043): six of seven with proliferative retinopathy had Kimmelstiel Wilson nodules, and seven of the eight patients without retinopathy had mesangial sclerosis lesions. CONCLUSIONS: The two discrete patterns of glomerular pathology and the correlation between diabetic retinopathy and the Kimmelstiel-Wilson lesion but not the mesangial sclerosis lesion suggest that the Kimmelstiel Wilson and mesangial sclerosis lesions of diabetic glomerulosclerosis are caused by different pathogenetic mechanisms. In this study, diabetic glomerulosclerosis was responsible for the clinical renal abnormalities in 94%, of patients with type II diabetes mellitus.

Adult↗