Biomedical subjects
Andrew Muir
Publications and source records attributed to Andrew Muir.
The influence of prosthesis size and design on exercise dynamics after aortic valve replacement.
BACKGROUND AND AIM OF THE STUDY: Residual gradient following aortic valve replacement (AVR) may adversely affect clinical outcome. The size and design of the valve may influence these characteristics. The study aim was to determine the influence of prosthesis physical size and leaflet design on hemodynamic performance after mechanical AVR. METHODS: After AVR, two patient groups with a range of valve sizes were studied. Group 1 patients (n=19) each received a monoleaflet valve; group 2 patients (n=18) each received a bileaflet valve. Transthoracic echocardiography was performed at rest and after graded bicycle ergometry to assess prosthetic valve parameters, including mean and peak transvalvular gradient and effective orifice area (EOA). RESULTS: Transprosthetic gradients (mean and peak) measured at rest, maximum exercise and 3-min recovery were related to indexed geometric orifice area (IGOA) by an exponential decay function, with no significant advantage for either valve design. However, in valve sizes < or =25 mm the bileaflet valves demonstrated lower gradients, both at rest and under exercise conditions (mean gradient during exercise, bileaflet versus monoleaflet 19.9 +/- 7.2 mmHg versus 25.6 +/- 6.3 mmHg, p = 0.01). Similarly, EOAs were larger in the bileaflet group when equivalent GOAs < or =2.5 cm2 were compared (EOA: bileaflet versus monoleaflet 1.51 +/- 0.33 cm2 versus 1.14 +/- 0.26 cm2, p = 0.018). The total work performed correlated with prosthesis diameter (r2 = 0.81, p = 0.037) and was not influenced by valve design. CONCLUSION: The hemodynamic performance of mechanical aortic valves, including transprosthetic gradient and maximum exercise work performed, related principally to the prosthesis physical size. However, within the smaller valve sizes, the bileaflet design appeared to offer hemodynamic advantages.
Gastrointestinal hemorrhage due to complicated gastroduodenal ulcer disease in liver transplant patients taking sirolimus.
Sirolimus is emerging as a popular immunosuppressive agent for patients undergoing solid organ and pancreatic cell transplantation. Here, we report the clinical courses of three patients receiving sirolimus who developed aggressive gastroduodenal ulcer disease. One patient died from massive gastrointestinal bleeding, and ulcers in the other two patients healed only after discontinuation of sirolimus. We propose that the mechanism underlying this severe ulcer diathesis, and poor ulcer healing, was linked to the well-known inhibitory effects of sirolimus on wound healing. We propose that sirolimus should be used carefully (or even withheld) in patients with known or previous ulcer disease, and further that it should be used prudently and/or in conjunction with aggressive prophylaxis therapy in those at risk for ulcer disease.
Chronic inflammatory demyelinating polyradiculoneuropathy in two children with type 1 diabetes mellitus.
An association between chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and type 1 diabetes has been described in adults, but not previously in children. Two adolescents with both CIDP and type 1 diabetes are reported here. In order to raise the awareness of CIDP among pediatricians, a description of the clinical and laboratory features, treatment, and prognosis of the condition is provided. A preliminary study was undertaken to determine whether responses to autoantigens in peri-islet Schwann cells and Schwann cells may account for the association between type 1 diabetes and CIDP. Lymphocyte proliferation in response to these autoantigens was abnormal in one of the two patients, but was also abnormal in one control subject.
A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes.
Previous studies have suggested more than 20 genetic intervals that are associated with susceptibility to type 1 diabetes (T1D), but identification of specific genes has been challenging and largely limited to known candidate genes. Here, we report evidence for an association between T1D and multiple single-nucleotide polymorphisms in 197 kb of genomic DNA in the IDDM5 interval. We cloned a new gene (SUMO4), encoding small ubiquitin-like modifier 4 protein, in the interval. A substitution (M55V) at an evolutionarily conserved residue of the crucial CUE domain of SUMO4 was strongly associated with T1D (P = 1.9 x 10(-7)). SUMO4 conjugates to I kappa B alpha and negatively regulates NF kappa B transcriptional activity. The M55V substitution resulted in 5.5 times greater NF kappa B transcriptional activity and approximately 2 times greater expression of IL12B, an NF kappa B-dependent gene. These findings suggest a new pathway that may be implicated in the pathogenesis of T1D.
Tinkering and tailoring with HCV therapy: can we get away with less?
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Preservation of C-peptide secretion in subjects at high risk of developing type 1 diabetes mellitus--a new surrogate measure of non-progression?
Individuals at high risk of developing type 1 diabetes mellitus can be identified using immunologic, genetic, and metabolic parameters. In the Diabetes Prevention Trial-1 (DPT-1), annual intravenous infusions of low doses of regular insulin, together with daily subcutaneous injection of a single low dose of Ultralente insulin at nighttime, failed to prevent or delay the onset of type 1 diabetes in high-risk non-diabetic relatives. In our study, we attempted to achieve beta-cell rest by administering higher doses of neutral protamine Hagedorn (NPH) insulin twice daily to high-risk non-diabetic subjects in an effort to prevent or delay the onset of the disease. The maximum tolerable dose was given with the dose reduced for any hypoglycemia (mean dose 0.33 +/- 0.15; range 0.09-0.66 units/kg/d). We treated 26 subjects who were confirmed to have islet cell antibodies (ICAs) and a low first-phase insulin response (FPIR) to intravenous glucose. Fourteen had normal glucose tolerance and 12 impaired glucose tolerance (IGT). The median duration of follow-up was 5.5 yr. Diabetes occurred in 10 of 12 subjects with IGT and five of 14 subjects with normal glucose tolerance. The cumulative incidence of diabetes was the same as with that seen in a matched, observation group (subjects followed prospectively as part of the University of Florida natural history studies) (age, sex, ICA, insulin autoantibodies, duration of ICA prior to enrollment, FPIR, and glucose intolerance; p = 0.39), as was the rate of progression (p = 0.79). There was a higher rate of progression to diabetes in the group with abnormal glucose tolerance at baseline than in those with normal baseline glucose tolerance (p = 0.003). Interestingly, in non-progressors, as opposed to progressors, there was no fall in C-peptide (peak and area under the curve) production regardless of the type of tolerance testing (mixed meal, oral or intravenous) over time (p < 0.001). In this study, in the dose and regimen of NPH insulin used, insulin did not delay or prevent the development of type 1 diabetes. However, preservation of C-peptide production in the prediabetic period appears to indicate non-progression to clinical disease and may serve as a new surrogate for determining response to preventative efforts.
Molecular pathways altered by insulin b9-23 immunization.
Type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse can be delayed by administration of insulin or specific insulin peptides. To better understand how insulin treatment delays diabetes development, NOD mice treated with an insulin peptide (B9-23) were compared with age-matched NOD and NOD congenic mice for gene expression changes in spleen using cDNA microarray. Fifty genes were identified that were significantly altered by B9-23 treatment. Thirty-three of these genes are downregulated by the treatment while they are upregulated during the natural disease progression in NOD from immature (3-4 weeks) to mature (10 weeks) stages. Taken together, our data suggest that the B9-23 treatment, like the protective genes in NOD congenic strains, reduces pro-inflammatory activation of lymphocytes that normally occurs in NOD mice. Furthermore, our studies discovered two genes (Irf4 and Tra1) with increased expression in B9-23-treated mice that promote the Th2 response, providing a molecular basis for the B9-23-protective therapy.
Novel TSHbeta subunit gene mutation causing congenital central hypothyroidism in a newborn male.
Newborn screening programs that use only high TSH levels as a marker for hypothyroidism may overlook neonates with congenital hypothyroidism (CH) due to TSH deficiency. We sought the cause of TSH deficiency in a neonate with low levels of thyroxine and TSH. The coding region of the TSHbeta gene was amplified and its sequence examined for mutations. Two mutations in exon 3 were identified: 1) a nucleotide deletion of T410 in codon 105 resulting in a frameshift in one allele, and 2) a previously unreported nucleotide deletion of T266 in codon 57, causing a frameshift and a premature stop at codon 62 in the other allele. We describe a compound heterozygous patient with TSHbeta mutations at codons 57 and 105 that interfered with a critical disulfide bond in the TSH molecule and caused CH. State screening programs that measure both T4 and TSH levels have the potential to detect newborns with congenital central hypothyroidism.
Advances in telemedicine in the 21st century.
Increasing demands on practitioners' time and increasing complexity of patient education and management have created a demand for creative solutions to providing for those needs. Telemedicine can answer some of those needs. Further documentation of the efficacy and cost-effectiveness of telemedicine and education is important but should not hinder the provision of care that is required yet unavailable by traditional means.
Erythropoietin for ribavirin-induced anemia in hepatitis C: more answers but many more questions.
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Intensive telehealth management of five at-risk adolescents with diabetes.
Five adolescents with diabetes participated in an intensive outpatient treatment programme designed to improve adherence to their regimen and improve metabolic control. Families reported blood sugar levels, injections and food intake daily by telephone. After four weeks they were offered a video-phone. Nine subjects were recruited but four of them dropped out. Of the remaining five, one subject used a video-phone and one subject reported blood sugar results by email. Most of the children improved their metabolic control and all five subjects showed reduced HbA(1c) levels during the three months of the study. The use of telehealth facilitated the treatment of adolescents with poor glycaemic control.
Treatment of acute hepatitis C with interferon alfa-2b.
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