Biomedical subjects

C V Clark

Publications and source records attributed to C V Clark.

At least 19 recordsLinked to original sources

PubMed1998

Association study of the 5' flanking regions of endothelial-nitric oxide synthase and endothelin-1 genes in familial primary open-angle glaucoma.

1. Endothelium-derived substances are important regulators of the microcirculation. Endothelium-derived nitric oxide (NO), which is catalysed by nitric oxide synthase (NOS), is a potent modulator of vascular tone in the human ophthalmic artery, which is normally in a state of constant vasodilation due to the actions of NO. Endothelin-1 (ET-1) produces vasoconstriction of the anterior optic nerve vasculature and may be associated with glaucomatous optic neuropathy. The aetiology of primary open-angle glaucoma (POAG) remains largely unknown. Thus, alterations in the regulatory sequences of the genes coding for endothelium-derived NOS (eNOS) and ET-1 may have important effects in the development of POAG and were looked for in the present study. 2. In 56 patients with familial POAG and in 100 control subjects with no family history of hypertension or POAG, we examined the 5' flanking sequences of the eNOS and ET-1 genes, which contain many positive and negative regulatory regions affecting gene transcription, using polymerase chain reaction-based single strand conformation polymorphism analysis, to search for alterations. No variant in the promoter region of the ET-1 gene was observed in familial POAG or controls. Using three primer sets spanning 706 b.p. of the eNOS gene, we observed alterations in 11 of 56 (20%) familial POAG members and in seven of 100 (7%) controls. Sequence analysis demonstrated a C/T substitution at the 5' sequence position nucleotide (nt) -690 from the transcription start site, which lies between the cAMP regulatory element (nt -726 to -732) and an activator protein-1 binding domain (nt -655 to -661). 3. In summary, genotypic and allelic frequency analysis found no association between alterations in the promoter region of the ET-1 gene and familial POAG. A variant in the promoter region of the eNOS gene was seen in a significant percentage of familial POAG patients. Future expression studies will determine whether this polymorphism results in altered eNOS gene expression.

Adult↗

PubMed1997

PCR-SSCP analysis of the glucocorticoid-responsive element of the atrial natriuretic peptide gene in familial primary open-angle glaucoma.

1. Familial primary open-angle glaucoma (POAG) is a heterogeneous disease of unknown aetiology and the elucidation of the underlying genetic mechanisms contributing to phenotypic expression will be essential if earlier diagnosis of at-risk individuals and more specific medical treatment can be achieved. In a significant percentage of patients with POAG, intraocular pressure increases in response to topical ocular glucocorticoids. 2. Atrial natriuretic peptide (ANP) assists in the regulation of intraocular pressure levels and binding of the glucocorticoid receptor dimer to the glucocorticoid-responsive element in intron 2 of the ANP gene has been shown to increase ANP mRNA levels in vitro. We amplified and examined this sequence in the ANP gene by PCR-SSCP analysis in 100 patients with familial POAG and in 60 normal control subjects. No base alterations in the amplified product were found. 3. Thus, the present study found no evidence for an alteration in the sequence of the glucocorticoid-responsive element of the ANP gene that could alter ANP gene transcription in patients with familial POAG. The mechanism responsible for the increase in intraocular pressure levels in response to glucocorticoids is most likely independent of the glucocorticoid-responsive element in the ANP gene.

Atrial Natriuretic Factor↗

PubMed1996

The atrial natriuretic peptide gene in patients with familial primary open-angle glaucoma.

Family history is a major risk factor in the development of primary open-angle glaucoma. The atrial natriuretic peptide system has been implicated in the underlying pathophysiology of the disease. This study looked for any alterations in the ANP gene and 5' proximal promoter regions of the ANP gene, in 53 patients from familial primary open-angle glaucoma families. The ANP gene was amplified by a long-PCR technique from peripheral blood DNA. Gross insertions or deletions in the gene were sought and allelic frequencies at two restriction fragment length polymorphism (RFLP) sites within the gene (Sca I, Hpa II) were compared with allelic frequencies obtained from 60 normal controls with no known family history of glaucoma or ocular hypertension. PCR-based single strand conformation polymorphism analysis was then used to search for possible point mutations in the 5' proximal promoter region of the ANP gene, which is known to contain regulatory elements which modify gene transcription. No gross alterations in the ANP gene or differences in allelic frequencies at the RFLP sites within the gene were observed. PCR-SSCP analysis of the 5' proximal promoter region of the gene revealed mutations in 10 patients in the -595 to -384bp region (19% of patients). Mutations in the 5' proximal promoter region of the ANP gene may contribute to altered ANP transcription in at least a proportion of patients with familial glaucoma.

Adult↗

PubMed1993

Changes in the anterior chamber of the eye during acute hypoglycaemia in humans.

1. The changes in the volume and depth of the anterior chamber of the eye during acute insulin-induced hypoglycaemia were examined in nine healthy non-diabetic subjects (aged 23-31 years). The dimensions of the anterior chamber of the eye were measured by a photogrammetric technique, with Polaroid photographs taken of the lower half of the mid-sagittal plane of the eye at an angle of 55 degrees at a magnification of x16. Photographs were taken before and at regular intervals after the induction of acute hypoglycaemia using an infusion of unmodified (soluble) insulin at 2.5 m-units min-1 kg-1. Plasma adrenaline was measured regularly throughout the study. 2. Plasma glucose fell from 4.5 +/- 0.2 mmol/l (mean +/- SEM) to a nadir of 1.0 +/- 0.1 mmol/l (P < 0.01), which coincided with the onset of the acute autonomic reaction. Plasma adrenaline rose from 0.3 +/- 0.1 nmol/l to a peak of 3.2 +/- 0.6 nmol/l (P < 0.01) at 15 min after the autonomic reaction. 3. The volume of the anterior chamber decreased by 8.2% from 284.7 +/- 21.5 microliters at baseline to 264.5 +/- 17.0 microliters (P < 0.01) at the onset of the autonomic reaction. No significant alteration in axial anterior chamber depth was evident, but peripheral anterior depth decreased from 2.25 +/- 0.20 mm at baseline to 2.07 +/- 0.14 mm (P < 0.05) at the onset of the autonomic response.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

PubMed1991

Age-related normal tolerance intervals for retinal vascular response to systemic autonomic nerve stimulation.

This study establishes the age-adjusted tolerance intervals for retinal vascular responses to sustained handgrip contraction (a test of sympathetic nerve function). Forty adult subjects (mean age: 39.7 +/- 14.1 years, range: 20 to 72 years; 19 males) were included in the final analysis. Mean percentage calibre change in response to sustained handgrip contraction in this population was -5.61% with a significant correlation between subject age and percentage retinal vessel calibre change (p less than 0.001). Mean retinal arteriolar calibre change in response to systemic autonomic stimulation varied significantly with age: between -8.48% at age 20 years and -2.06% at age 70 years with a mean of -5.95% at the mean age of 39.7 years. The standard deviation is 3.04% and the 95% confidence intervals were set between +/-6.17%. This autoregulatory reflex appears to be inversely related to age.

Adult↗

PubMed1990

Impaired autoregulation of the retinal vasculature and microalbuminuria in diabetes mellitus.

The relationship between microalbuminuria and retinal vessel responses to sustained handgrip contraction was studied in a group of 20 diabetic patients. The diabetics were divided into two groups based on their albumin excretion rates (AER): Group 1 (AER less than or equal to 10 mcg/min) consisted of ten diabetic patients, mean age 55.8 +/- 3.9 years (mean +/- SEM); five IDDM and five NIDDM. Group 2 (AER greater than 10 mcg/min) comprised ten diabetic patients: mean age 56.8 +/- 3.04 years; six IDDM and four NIDDM. Both groups were similar in that there were no significant differences between mean age, type of diabetes, mean duration of diabetes, glycaemic control or mean resting blood pressures. Group 2 diabetics had a higher incidence of autonomic dysfunction than Group 1, based on the results of four standard tests of autonomic nerve function. There were significantly decreased retinal vessel responses to sustained handgrip contraction in Group 2 diabetics (mean arteriolar constriction 0.1 +/- 0.32%, and mean venule constriction 1.0% +/- 0.99%) compared with Group 1 diabetics (mean arteriolar constriction 6.9 +/- 1.69%, and mean venule constriction 4.2 +/- 0.05%). Retinopathy was slightly worse in Group 2. The implications of the association of microalbuminuria (AER greater than 10 mcg/min) and loss of retinal vessel reactivity to sustained handgrip contraction are discussed.

Adult↗

PubMed1990

The effect of cervical sympathectomy on retinal vessel responses to systemic autonomic stimulation.

The retinal vessel calibre responses to systemic sympathetic stimulation, were studied in nine patients (eight male; mean age: 31.7 years; range: 19-58 years) with unilateral disruption of their cervical sympathetic tract. All patients had ipsilateral decreased/absent facial sweating and a Horners syndrome, evidence of unilateral sympathetic denervation. Both eyes of each patient were studied and the results were analysed in two groups: the group of nine sympathectomised eyes and the control group of unaffected fellow eyes. During handgrip contraction there was a significant difference in the mean retinal arteriolar constriction (mean +/- SEM) between the group of sympathectomised eyes (4.6 +/- 0.89%) and control eyes (7.1 +/- 1.13%), p less than 0.01. Similarly, there was a significant difference in mean venule constriction during sustained handgrip contraction between the group of sympathectomised eyes (1.5 +/- 0.67%) and control eyes (4.9 +/- 0.98%), p less than 0.05. There was no significant difference in the mean rise in diastolic blood pressure between the two groups: control eyes +27.9 +/- 2.38 mmHg and sympathectomised eyes +27.8 +/- 2.25 mmHg. There was no correlation between the blood pressure and retinal vessel responses in either group. These results suggest that the sympathetic nervous system plays an integral role in retinal blood flow regulation.

Adult↗

PubMed1990

Ocular autonomic nerve function in Lambert-Eaton myasthenic syndrome.

Autonomic innervation to the eye and ocular adnexae was assessed in seven patients with Lambert-Eaton Myasthenic Syndrome and 50 age-matched control subjects. Pupil responses to light were abnormal in 69% of LEMS patients, compared with 18% of the control group. Reflex tear production--a screening test for parasympathetic innervation to the lacrimal gland--was below the accepted normal limit in 69% of LEMS patients. Parasympathetic and sympathetic denervation hypersensitivity of the iris musculature were individually present in 57% of LEMS patients, compared with 6% of control subjects. The association between autonomic dysfunction and Lambert-Eaton Myasthenic Syndrome is discussed.

Adult↗

PubMed1989

Sympathetic denervation hypersensitivity of the iris in ocular hypertension.

Sympathetic denervation hypersensitivity of the iris was assessed in 51 patients with ocular hypertension and 36 age- and sex-matched control subjects. Significantly increased pupillary dilatation in response to topically-applied 0.5% phenylephrine hydrochloride, suggesting sympathetic denervation hypersensitivity of the iris, was present in the ocular hypertensive group (p less than 0.003). The effects of autonomic nerve function on aqueous dynamics are reviewed, and the association between autonomic dysfunction and ocular hypertension is discussed.

Aged↗

PubMed1989

Intraocular pressure responses to systemic autonomic stimulation in diabetes mellitus.

The acute changes in intraocular pressure during sustained handgrip contraction (2.5 minutes duration) and the Valsalva manoeuvre (15 seconds duration), both standard tests of autonomic nerve function were studied in 14 diabetic patients and 14 similar aged control subjects. During sustained handgrip contraction, diastolic blood pressure increased by 16.35 +/- 1.87 mmHg in the diabetic patients and 21.36 +/- 0.66 mmHg for the control group. Mean intraocular pressure decreased by 0.71 +/- 0.43 mmHg in the diabetics, p less than 0.05 and 0.64 +/- 0.27 mmHg, p less than 0.01) in the control group. There was no correlation between the blood pressure and the intraocular pressure responses in either group. On release of handgrip contraction, mean recovery intraocular pressure over 5 minutes was significantly lower than mean baseline values for the two groups; control: baseline 14.78 +/- 0.49 to 14.14 +/- 0.67, p less than 0.001 and diabetic: 14.57 +/- 0.65 to 13.86 +/- 0.72, p less than 0.001. During the Valsalva manoeuvre, there was a significant rise in intraocular pressure in the control (+7.85 +/- 0.75 mmHg, p less than 0.001) and the diabetic group (+7.93 +/- 1.18 mmHg, p less than 0.001). 5 minutes after release of intrathoracic pressure, mean recovery intraocular pressure remained significantly below baseline values for the two groups. The Valsalva ratios were in the normal range for the control group (1.21 to 2.2) while 2 diabetics had abnormal ratios.

Autonomic Nervous System↗

PubMed1989

Carcinoid tumour in the lacrimal gland.

A case of carcinoid tumour in the lacrimal gland is described, thought to be a metastasis from a known primary lesion in the mediastinum. The results of light and transmission electron microscopic examination are presented, and the possibility of the lesion representing a second primary tumour discussed.

Aged↗

PubMed1989

Autonomic denervation hypersensitivity in the primary glaucomas.

Autonomic denervation hypersensitivity of the iris was assessed in 44 patients with primary closed-angle glaucoma, 20 patients with primary open-angle glaucoma, and 40 age- and sex-matched control subjects. Significantly increased pupillary constriction in response to 2.5% methacholine chloride, indicating parasympathetic denervation hypersensitivity, was present in both closed-angle (p less than 0.02) and open-angle glaucoma patients (p less than 0.001), compared with the control group. Significantly increased pupillary dilatation in response to 0.5 per cent phenylephrine hydrochloride, indicating sympathetic denervation hypersensitivity of the iris, was also present in both closed-angle glaucoma (p less than 0.01) and open-angle glaucoma patients (p less than 0.05). The association between autonomic neuropathy and the primary glaucomas is discussed, with particular reference to the potential effects of autonomic dysfunction on aqueous dynamics.

Aged↗

PubMed1989

Responses of the retinal circulation to systemic autonomic stimulation in diabetes mellitus.

The retinal vessel calibre responses to systemic sympathetic stimulation, were studied in 22 randomly selected diabetic patients (mean age +/- SEM: 54.7 +/- 2.59 years, range 25-73; 13 IDDM, 9 NIDDM; 4 females), using sustained isometric muscle contraction as the stimulus. At a different session the integrity of the autonomic nerve function in these diabetic patients was assessed using 3 standard tests of autonomic nerve function, based on cardiovascular reflexes. Diabetic patients with an intact autonomic nervous system: Group 1, (n = 11, mean age: 54.9 +/- 4.55 years, 7 IDDM 4 NIDDM) showed a mean arteriolar constriction of 9.2% (SEM 2.89, p less than 0.01) and a mean venule constriction of 5.1% (SEM 1.73, p less than 0.02), for a mean rise in diastolic blood pressure of 23.7 mmHg (SEM 2.19 range: 13-33). There were no significant mean retinal vessel responses however, in diabetics with autonomic dysfunction (Group 2): mean arteriolar constriction of 1.2% (SEM 1.38 p greater than 0.05) and venule constriction of 2.1% (SEM 1.38, p greater than 0.05); for a mean rise in diastolic blood pressure of 19.8 mmHg (SEM 4.49, range: 2-50). There was no correlation between the rise in diastolic blood pressure and the retinal arteriolar constriction in the 2 groups (Group 1:r = 0.45, p greater than 0.01 and Group 2: r = 0.56, p greater than 0.05). Duration, type and control of diabetes were not significantly different between the 2 groups. The severity of retinopathy was slightly worse in Group 2 compared to Group 1. These results point to an association between autonomic neuropathy and failure of regulation of retinal blood flow.

Adult↗

PubMed1989

Intraocular pressure responses to systemic autonomic stimulation.

The intraocular pressure (IOP) responses to two standard tests of autonomic nerve function were studied in 15 healthy subjects, mean age 33 years (range: 20-64). Both tests are based on cardiovascular reflexes: (1) The rise in diastolic blood pressure provoked by sustained isometric muscle contraction, a response mediated by the sympathetic nervous system and (2) The heart-rate responses to the Valsalva manoeuvre, a response mediated by the parasympathetic nervous system. During sustained isometric exercise, the mean IOP decreased significantly from baseline values of 12.60 mmHg (SEM 0.55) to 11.26 mmHg (SEM 0.32, p less than 0.05) while mean diastolic blood pressure increased by 20.80 mmHg (range: +12 to +53 mmHg). However there was no direct correlation between them (r = -0.05). Post exercise the mean IOP remained significantly lower than baseline values for five minutes (p less than 0.01). During the Valsalva manoeuvre, there was a significant increase in IOP of 7.20 mmHg from a baseline of 12.80 mmHg (SEM 0.45) to 20.00 mmHg (SEM 0.78, p less than 0.001); during the recovery period, mean IOP was significantly lower than baseline values at 12.13 mmHg (SEM 0.39, p less than 0.05). The mean Valsalva ratio was normal at 1.68 (range: 1.2-2.6). The possible mechanisms involved in these responses are discussed.

Adult↗

PubMed1989

Topical dexamethasone lowers rabbit ocular tension, as does topical mifepristone (RU 486), a peripheral blocker of dexamethasone and progesterone.

The variability of the response of the rabbit eye to topical 1% dexamethasone has been shown in two groups of 20 young albino rabbits each (total 40) tested in succession. The pressure anomalously fell significantly (but by only 1 mm Hg) in both groups in the first 4 weeks of administration, but not in subsequent weeks. Mifepristone (RU 486), a peripheral antagonist of dexamethasone and progesterone, reduced the pressure significantly, again by only 1 mm Hg, in the first group of 20 rabbits, not the second. Accordingly, no conclusion was possible on the originating question: does pre-treatment with mifepristone prevent the dexamethasone-induced rise in rabbit intra-ocular pressure?

Administration, Topical↗

PubMed1989

Diabetes mellitus in primary glaucomas.

The association between diabetes mellitus and primary glaucomas is evaluated. Diabetes is specifically associated with narrow-angle categories of primary glaucoma: closed-angle glaucoma and narrow-angle patients with ocular hypertension or open-angle glaucoma. The prevalence of diabetes mellitus in wide-angle glaucoma patients is not significantly different from normal age-matched control subjects. The association between diabetes and glaucoma is restricted to non-insulin dependent diabetes mellitus and impaired glucose tolerance; the prevalence of insulin-dependent diabetes mellitus in the primary glaucomas is equivalent to age-matched normal values. These conclusions are supported by 75-gram oral glucose tolerance testing, estimation of glycosylated haemoglobin, retrospective analysis of positive diabetic family history, and prospective follow-up examining progression of impaired glucose tolerance to diabetes mellitus in patients with primary glaucoma.

Anterior Chamber↗

PubMed1988

Ocular autonomic function in progressive autonomic failure.

Ocular autonomic function was assessed in 4 patients with progressive autonomic failure (PAF) and age-matched control subjects, by measurement of the pupil cycle time, and determination of autonomic denervation hypersensitivity of the iris. Pupil cycle time was abnormal in all patients with PAF; sustained pupil cycling was absent in 5 of the 8 eyes tested of the PAF patients, compared with only 16 eyes from 70 control subjects. Pupil constriction in response to 2.5% methacholine, indicative of parasympathetic denervation hypersensitivity, was significantly increased in patients with PAF (p less than 0.001), whilst pupil dilation in response to 0.5% phenylephrine, indicative of sympathetic denervation hypersensitivity, was also significantly higher in the PAF patients (p less than 0.001). The results suggest that ocular autonomic function may provide a sensitive early indicator of generalised autonomic dysfunction.

Aged↗

PubMed1988

Ocular autonomic nerve function in proliferative diabetic retinopathy.

Ocular autonomic nerve function was assessed in 28 diabetic patients with proliferative retinopathy (PDR) and 61 age- and sex-matched control subjects, by measurement of the pupil cycle time and determination of autonomic denervation hypersensitivity of the iris. Sustained pupil cycle time was absent in 88.5 per cent of PDR compared with 9.8 per cent of control subjects (p less than 0.001). Pupil constriction in response to 2.5 per cent methacholine--indicative of parasympathetic denervation hypersensitivity--was significantly increased in PDR (p less than 0.001), whilst pupil dilation in response to 0.5 per cent phenylephrine--indicative of sympathetic denervation hypersensitivity--was also significantly higher in PDR (p less than 0.001). Pupil reflexes were abnormal in 88.5 per cent of diabetics with proliferative retinopathy, with established autonomic denervation hypersensitivity in 57 per cent of patients.

Adult↗