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Biomedical subjects

Michael Larsen

Publications and source records attributed to Michael Larsen.

At least 19 recordsLinked to original sources
PubMed2007

Transgenic mice carrying the H258N mutation in the gene encoding the beta-subunit of phosphodiesterase-6 (PDE6B) provide a model for human congenital stationary night blindness.

Mutations in the beta-subunit of cGMP-phosphodiesterase (PDE6beta) can lead to either progressive retinal disease, such as human retinitis pigmentosa (RP), or stationary disease, such as congenital stationary night blindness (CSNB). Individuals with CSNB in the Rambusch pedigree were found to carry the H258N allele of PDE6B (MIM# 180072); a similar mutation was not found in RP patients. This report describes an individual carrying the H258N allele, who presented with generalized retinal dysfunction affecting the rod system and a locus of dysfunction at the rod-bipolar interface. Also described are preclinical studies in which transgenic mice with the H258N allele were generated to study the pathophysiological mechanisms of CSNB. While Pde6b(rd1)/Pde6b(rd1) mice have severe photoreceptor degeneration, as in human RP, the H258N transgene rescued these cells. The cGMP-PDE6 activity of dark-adapted H258N mice showed an approximate three-fold increase in the rate of retinal cGMP hydrolysis: from 130.1 nmol x min(-1) x nmol(-1) rhodopsin in wild-type controls to 319.2 nmol x min(-1) x nmol(-1) rhodopsin in mutants, consistent with the hypothesis that inhibition of the PDE6beta activity by the regulatory PDE6gamma subunit is blocked by this mutation. In the albino (B6CBA x FVB) F2 hybrid background, electroretinograms (ERG) from H258N mice were similar to those obtained from affected Rambusch family members, as well as humans with the most common form of CSNB (X-linked), demonstrating a selective loss of the b-wave with relatively normal a-waves. When the H258N allele was introduced into the DBA background, there was no evidence of selective reduction in b-wave amplitudes; rather a- and b-wave amplitudes were both reduced. Thus, factors other than the PDE6B mutation itself could contribute to the variance of an electrophysiological response. Therefore, caution is advisable when interpreting physiological phenotypes associated with the same allele on different genetic backgrounds. Nevertheless, such animals should be of considerable value in further studies of the molecular pathology of CSNB.

Adult↗
PubMed2006

Evaluation of efficacy expectations for novel and non-chemical helminth control strategies in ruminants.

The interest in novel methods of controlling helminth infections in ruminants is driven primarily by the development of parasite resistance to currently available anthelmintics. While the purpose of anthelmintics is to achieve high efficacy, i.e. >90% reduction of adult and/or larval parasites in the target host animal, the purpose of novel parasite control methods is rather to assist in maintaining parasite infections below the economic threshold. The ability to maintain parasite levels below the economic threshold is related not only to the efficacy of the control method, but also to the epidemiology of the parasites, climatic conditions, the livestock management program, and integration in a sustainable parasite control program. Because of this fundamental difference, novel parasite control methods need to be evaluated using efficacy criteria different from that adopted for anthelmintics. Although the efficacy of novel parasite control methods may be demonstrated in classic dose-confirmation studies, the impact on livestock production parameters can only be evaluated when tested on-farm. In this paper, the rationale for evaluating novel methods differently from anthelmintics is reviewed, potential performance expectations are presented, and four novel parasite control methods (vaccines, nematophagous fungi, condensed tannins, and immunonutrition) are assessed based on the potential performance criteria.

Animal Husbandry↗
PubMed2006

Early lens aging is accelerated in subjects with a high risk of ischemic heart disease: an epidemiologic study.

BACKGROUND: Ischemic heart disease (IHD) is one of the most important causes of mortality and morbidity in the Western world. There is a relationship between aging of the lens of the human eye and cardiovascular disease. The present study was conducted to examine if the risk of ischemic heart disease could be estimated by fluorophotometric assessment of lens aging. METHODS: A total of 421 subjects were included. Risk of IHD was estimated from non-ocular data using the Precard software. Lens aging was quantified by lens fluorometry. RESULTS: The risk of IHD was strongly related to lens fluorophore accumulation (p = 0.001). The relationship between IHD and lens aging was attributable to tobacco smoking and dysglycemia. CONCLUSION: The risk of ischemic heart disease related to smoking and diabetes mellitus can be estimated using the aging of the lens of the eye as a biomarker for generalized tissue-damage.

Adult↗
PubMed2006

Lens fluorescence in relation to glucose tolerance and genetic predisposition to type 2 diabetes mellitus in a population-based study.

PURPOSE: The fluorescence of the lens has the characteristics of a life-long cumulative index of glycemia, and it is elevated in patients with diabetes in proportion to the duration of diabetes and the level of glycemia. Consequently, lens fluorometry should be capable of providing an estimate of prediagnostic disease duration when patients are diagnosed with type 2 diabetes. Among euglycemic subjects, first-degree relatives of patients with type 2 diabetes tend to have higher glycemia levels than subjects who are unrelated to diabetes patients. They should therefore also have the higher lens fluorescence values. METHODS: The study comprised 218 Caucasian subjects in self-reported good health aged 30-88 years who were recruited from population-based studies to represent approximately equal proportions of different type 2 diabetes family history characteristics: no diabetic relative, first-degree offspring, second-degree offspring, not first-degree offspring but possibly second-degree offspring, or uncertain family history. Characterization of subjects included oral glucose tolerance testing and lens fluorometry. RESULTS: Type 2 diabetes was diagnosed in 10 subjects (4.6% of the population) and impaired glucose tolerance in 12 subjects (5.5%). Regression analysis indicated a prediagnostic duration of type 2 diabetes of 2.7 years versus 0.1 years for impaired glucose tolerance. Neither group demonstrated significantly increased lens fluorescence compared with euglycemic subjects. Being a first-degree relative of a patient with type 2 diabetes was associated with higher lens fluorescence than having no relative with diabetes (p = 0.02). CONCLUSIONS: Population screening by fasting blood glucose measurement can advance the diagnosis and initiation of treatment of type 2 diabetes mellitus by nearly a decade, compared with previous studies of patients diagnosed in routine clinical practice. In addition to higher than normal glycemia, euglycemic subjects who are offspring of patients with type 2 diabetes also have both elevated lens fluorescence and elevated glycemia. Fasting blood glucose measurement remains the method of choice for type 2 diabetes screening.

Adult↗
PubMed2006

Heritability of retinal vessel diameters and blood pressure: a twin study.

PURPOSE: To assess the relative influence of genetic and environmental effects on retinal vessel diameters and blood pressure in healthy adults, as well as the possible genetic connection between these two characteristics. METHODS: In 55 monozygotic and 50 dizygotic same-sex healthy twin pairs, aged 20 to 46 years, interpolated diameter estimates for the central retinal artery (CRAE), the central retinal vein (CRVE), and the artery-to-vein diameter ratio (AVR) were assessed by analysis of digital gray-scale fundus photographs of right eyes. RESULTS: The heritability was 70% (95% CI: 54%-80%) for CRAE, 83% (95% CI: 73%-89%) for CRVE, and 61% (95% CI: 44%-73%) for mean arterial blood pressure (MABP). Retinal artery diameter decreased with increasing age and increasing arterial blood pressure. Mean vessel diameters in the population were 165.8 +/- 14.9 microm for CRAE, 246.2 +/- 17.7 microm for CRVE, and 0.67 +/- 0.05 microm for AVR. No significant influence on artery or vein diameters was found for gender, smoking, body mass index (BMI), total cholesterol, fasting blood glucose, or 2-hour oral glucose tolerance test values. CONCLUSIONS: In healthy young adults with normal blood pressure and blood glucose, variations in retinal blood vessel diameters and blood pressure were predominantly attributable to genetic effects. A genetic influence may have a role in individual susceptibility to hypertension and other vascular diseases. The results suggest that retinal vessel diameters and the possible associated variations in risk of vascular disease are primarily genetic characteristics.

Adult↗
PubMed2005

[The ocular ischemic syndrome].

The ocular ischemic syndrome is caused by severely reduced ocular perfusion, usually secondary to carotid artery stenosis. Because of the low perfusion pressure, anterior chamber rubeosis does not invariably lead to increased intraocular pressure. The characteristic ocular pain is unrelated to the intraocular pressure. Patients adapt slowly to increasing light intensity (bright light amaurosis fugax). Retinal hemorrhages often lead to the mistaken assumption that the patient has diabetic retinopathy, especially when the patient has diabetes. A definite diagnosis is made by the demonstration of severely decreased ocular perfusion pressure. Supporting evidence is delayed filling on fundus fluorescein angiography in a patient with high-grade carotid artery stenosis. The majority of affected eyes lose vision for finger counting within one year. No treatment of documented value is available. Patients without neovascularization of the anterior chamber angle may occasionally experience improved vision after carotid surgery.

Carotid Stenosis↗
PubMed2005

[Treatment of neovascular age-related macular degeneration with intravitreal vascular endothelial growth factor inhibitor--secondary publication].

Subfoveal neovascularization is the most frequent cause of severe visual loss in patients with age-related macular degeneration (AMD). Pharmacologic inhibition of vascular endothelial growth factor (VEGF) is a new principle of treatment of this condition. The effects of intravitreal pegaptanib administered every sixth week for 48 weeks in three different dosages were examined in a prospective, double-masked, randomised trial against subconjunctival sham injection with change in visual acuity as the outcome parameter in 1,186 patients with subfoveal neovacularization in AMD. 70% of the patients treated with pegaptanib avoided moderate visual loss, compared to only 55% of the control group (p < 0.001 for 0.3 mg pegaptanib versus the control group, p < 0.001 for 1.0 mg and p = 0,03 for 3.0 mg). The improved visual prognosis was detectable beginning six weeks after the first injection (p < 0.002). Adverse events included endophthalmitis (1.3% of patients), traumatic lens damage (0.7%), retinal detachment (0.6%) and severe visual loss in one patient (0.1%). Intravitreal pegaptanib improves the visual prognosis in neovascular AMD. The long-term effect and safety of the treatment are not known.

Aged↗
PubMed2005

Unilateral macular oedema secondary to retinal venous congestion without occlusion in patients with diabetes mellitus.

OBJECTIVE: To identify fundus characteristics associated with intraocular and intra-individual variations in the distribution of macular oedema in patients with diabetes. METHODS: A review was carried out of fundus photographs and fluorescein angiograms from 226 diabetes patients who received photocoagulation treatment for macular oedema. Cases with strictly unilateral clinically significant macular oedema were identified. RESULTS: Strictly unilateral macular oedema was identified in five patients with non-proliferative diabetic retinopathy, three of whom demonstrated angiographic leakage confined to a single venous drainage unit, and two of whom demonstrated leakage confined to two adjacent venous drainage units opposing one another on either side of the temporal circulatory watershed. Involved drainage units were delimited by arteriovenous crossings displaying signs of venous compression. Affected eyes had more frequent and more severe crossing signs involving macular drainage than fellow eyes. Although all patients had been examined regularly, no patient had had branch retinal vein occlusion and no patient developed such occlusion during 5 years of follow-up. CONCLUSION: In the present study, unilateral macular oedema in patients with diabetes was associated with angiographic leakage from venous drainage units where compression signs indicated a higher than normal likelihood of upstream congestion being present. Presumably, a modest increase in venous pressure induced macular oedema because of an underlying abnormal vascular vulnerability induced by diabetes.

Aged↗
PubMed2005

Intravitreal triamcinolone for macular oedema: efficacy in relation to aetiology.

PURPOSE: To evaluate the efficacy and safety of intravitreal triamcinolone in patients with macular oedema of varying aetiology. METHODS: Two milligrams of intravitreal triamcinolone acetonide was injected into 34 eyes with persistent macular oedema (17 eyes with macula oedema secondary to posterior uveitis, 13 eyes with diabetic retinopathy, and four with pseudophakic macular oedema). Best corrected visual acuity was determined and transfoveal optical coherence tomography performed after 1 week, 1 month, 3 months and 6 months. RESULTS: Treatment improved visual acuity and subjective visual quality, and reduced foveal thickness in eyes with posterior uveitis and eyes with macular oedema secondary to diabetic retinopathy. Eyes treated for pseudophakic cystoid macular oedema demonstrated no improvement. A total of 32% of patients experienced a significant post-injection increase in intraocular pressure. Endophthalmitis, rhegmatogenous retinal detachment and cataract were absent. CONCLUSION: Intravitreal triamcinolone appears to induce marked a improvement in macular oedema secondary to non-infectious uveitis and diabetic retinopathy.

Adult↗
PubMed2005

Impact of UVR-A on whole human lenses, supernatants of buffered human lens homogenates, and purified argpyrimidine and 3-OH-kynurenine.

PURPOSE: Yellow chromophores and fluorescent compounds accumulate in the lens with age. Some of these compounds are photochemically active. The present study aimed to examine the photochemical effect of ultraviolet radiation-A (UVR-A) on the human lens. METHODS: Intact human lenses and supernatants of buffered lens homogenates were exposed to UVR-A. The effect of UVR-A was evaluated by time-resolved and steady-state fluorescence spectroscopy, visual evaluation of colour and protein gel electrophoresis. RESULTS: Intact lenses exposed to UVR-A showed no changes in time-resolved or steady-state fluorescence properties but the yellow coloration was visibly attenuated. The supernatants of buffered lens homogenates exposed to UVR-A demonstrated a reduction in time-resolved and steady-state fluorescent properties and protein cross-linking. CONCLUSIONS: Exposure of the intact lens to UVR-A causes chromophore bleaching without affecting fluorescence, indicating that non-fluorescent chromophores have been destroyed. After homogenization, both chromophores and fluorophores from the lens suffer damage and proteins aggregate. This indicates that powerful mechanisms of protection against UVR-A found in the intact lens are disturbed by homogenization of the lens, suggesting that isolated lens proteins cannot be used as a model system for studying cataractogenesis. Hypothetically, the protective mechanism could be related to the rigidly packed three-dimensional structure of the lens proteins or to the abundance of antioxidative and free radical scavenging defence systems.

Aged↗
PubMed2005

Clinical characteristics of subretinal deposits in central serous chorioretinopathy.

PURPOSE: To describe abnormal subretinal material in central serous chorioretinopathy (CSC). DESIGN: Retrospective observational case series. PARTICIPANTS: 168 consecutive patients (336 eyes) with a definite diagnosis of serous foveal detachment attributable to CSC in one or both eyes, on one or more occasions. METHODS: Review of all cases seen during a six-year period. Grading of the amount of subretinal material at presentation as absent, questionable, mild, moderate or severe. RESULTS: Of 168 patients with CSC, 133 (79%) were men and 35 (21%) women. The median age was 45.2 years (range 22-70 yrs). The median duration of symptoms was 2 months (range 0.1-144 months). Subretinal material was found in the symptomatic eye or, in bilateral cases, in the eye that had most recently become symptomatic in 138 patients and in increasing amounts with increasing duration of symptoms (p < 0.001) but unrelated to age or sex. A substantial fraction of the material was shown by optical coherence tomography to be attached to the photoreceptor outer segments of the detached retina. CONCLUSIONS: Increasing amounts of subretinal material are found with increasing duration of symptoms in eyes with CSC. This suggests that early granular deposits may be composed of fragments of photoreceptor outer segments that accumulate when the phagocytosis photoreceptor outer segment material is disrupted by the serous detachment of the retina. Other possible origins that cannot be excluded include plasma proteins excluding from the choriocapillaris, inflammatory debris, and lipid exudate originating from occult choroidal neovascularization secondary to CSC.

Adult↗
PubMed2005

Retinal artery and vein diameters during pregnancy in diabetic women.

PURPOSE: To study systemic and retinal circulatory variables and vasoactive hormones during pregnancy in women with and without diabetes. METHODS: Prospective study of 45 women with type 1 diabetes and 6 healthy pregnant women, from the first trimester of pregnancy to half a year after delivery, by using a fundus photographic method of determining retinal vessel diameters. RESULTS: In diabetic women, the mean arterial blood pressure increased from 90.7 +/- 10.9 mm Hg (mean +/- SD) in the first trimester to 102.4 +/- 16.4 mm Hg in the third trimester, accompanied by retinal arteriolar constriction, from a mean diameter of 95.5 +/- 11.3 to 92.2 +/- 12.9 microm (P = 0.007), arteriolar constriction being prominent in nonsmokers, from 96.6 +/- 11.1 to 92.3 +/- 13.0 microm (P < 0.001; n = 38), but absent in smokers, from 89.2 +/- 11.5 to 92.0 +/- 13.6 microm (P = 0.28). Healthy nonsmoking women demonstrated an increase in blood pressure during pregnancy comparable to that in diabetic women, but the change in mean retinal arteriolar diameter, from 88.5 +/- 10.9 microm in the first to 91.6 +/- 10.2 microm in the third trimester, did not reach statistical significance (P = 0.38). Diabetic retinopathy levels increased during pregnancy, but the change in arteriolar diameter from the first to the third trimester did not correlate with retinopathy, arterial blood pressure, HbA(1c), or atrial natriuretic peptide. Plasma angiotensin II correlated positively with the change in arteriolar diameter in women who did not smoke (P < 0.05). After delivery, retinal vessel diameters returned to the first trimester range in all subgroups. CONCLUSIONS: From the first to the third trimester of pregnancy, blood pressure increased and retinal arteriolar diameter decreased in diabetic women, but the arteriolar constriction associated with pregnancy and systemic arterial blood pressure increase was remarkably absent in diabetic women who smoked tobacco before and during pregnancy. It is unknown whether smoking inhibits this vasoconstrictive response by deactivating mechanisms of physiological adaptation or by activating these mechanisms before the first trimester of pregnancy.

Adult↗
PubMed2005

Overnight thickness variation in diabetic macular edema.

PURPOSE: To study the evening-to-morning variation in retinal thickness in patients with fovea-involving diabetic macular edema. METHODS: Twelve eyes in 12 patients aged 39 to 78 years (mean, 57) with fovea-involving diabetic macular edema and 14 eyes in 7 healthy volunteers aged 30 to 70 years (mean, 57) were examined by optical coherence tomography, in the evening and in the morning after > or =6 hours of sleep in the recumbent position in darkness followed by 0.5 hour wakefulness in the same position in room light with both eyes open. RESULTS: In patients with diabetic macular edema, macular thickness increased overnight, from 316 +/- 72 microm in the evening to 336 +/- 81 microm in the morning (P = 0.003). Visual acuity decreased from a mean of 41 ETDRS letters (Early Treatment of Diabetic Retinopathy Study; range, 4-61) in the evening, to a mean of 36 letters (range, 2-60) in the morning (P = 0.03). No overall change was found in mean arterial blood pressure (MABP; P = 0.48), blood glucose (P = 0.25), or corneal thickness (P = 0.26). The overnight change in macular thickness correlated directly with the change in MABP (r = 0.65, P = 0.03) but not with baseline MABP or blood glucose. The overnight increase in retinal thickness remained significant after statistical adjustment for the effect of arterial blood pressure (P = 0.002). Healthy subjects demonstrated no significant change in any parameter. CONCLUSIONS: In fovea-involving diabetic macular edema, a reduction in visual acuity accompanies overnight retinal thickening, the magnitude being related to the nocturnal change in blood pressure. The results indicate that deficient regulation of retinal capillary filling pressure promotes edema, but the bulk of the overnight increase in macular edema is caused by other mechanisms, of which postural variation in venous blood pressure and increased retinal metabolism in the dark merit further study.

Adult↗
PubMed2005

Objective signs of photoreceptor displacement by binocular correspondence perimetry: a study of epiretinal membranes.

PURPOSE: To describe a method for quantitative mapping of metamorphopsia and abnormalities of oculocentric direction in subjects with epiretinal membranes. METHODS: Binocular correspondence perimetry was performed using red and green dichoptic stimuli applied in a rectangular grid pattern. The study included 9 healthy subjects and 10 subjects with a unilateral premacular epiretinal membrane and a healthy fellow eye. Interocular visuospatial correspondence was expressed in a visuospatial deviation score and the binocular correspondence perimetry plots were displayed in proportion to fundus photographs. A reference interval was defined as the 95% CI for the average visuospatial deviation score in healthy subjects. RESULTS: In 6 out of 10 subjects with epiretinal membranes, visuospatial alignment deviated beyond the reference interval found in healthy subjects, whereas 4 subjects were within the normal range. The deviation score increased with decreasing visual acuity, although indications of heterogeneity of the subject population were identified, suggesting that visual acuity reduction and metamorphopsia may be dissociated in some types of epiretinal membranes. CONCLUSIONS: Binocular correspondence perimetry enables quantitative mapping of metamorphopsia and stratification of subjects with epiretinal membranes with respect to normative references. Data from healthy subjects appear to describe a physiological level of tolerance for changes in oculocentric direction, which may apply also to the changes induced by retinal traction.

Adult↗