Biomedical subjects
L Kennedy
Publications and source records attributed to L Kennedy.
Analysis of the membrane-interacting domain of the sea urchin sperm adhesive protein bindin.
We have investigated the domain of the bindin polypeptide that selectively associates with gel-phase phospholipid vesicles. We found that small trypsin fragments of bindin retain the ability to selectively associate with gel-phase vesicles. The primary amino acid sequence of bindin suggests that these peptides are derived from the central portion of the polypeptide between residues 77 and 126, which is the most hydrophobic region of bindin. We have also employed 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine (TID) and novel, radioiodinated, photoactivatable derivatives of the polar head group of phosphatidylethanolamine (ASD-PE and ASA-PE) to identify membrane-associated polypeptide segments after the transfer of radiolabel from the probe to the bindin polypeptide. After photolysis, bindin was selectively labeled only from probes incorporated in gel-phase vesicles. The labeling of bindin was much more efficient from the head group probes ASA-PE and ASD-PE (8 and 2% of the total label, respectively) in comparison to the hydrophobic probe TID (less than 0.02% of the total label), suggesting that bindin is localized within the polar part of the bilayer. Protease mapping experiments with V8 protease, trypsin, and endoprotease Lys-C suggest that some of the probe label is distributed along the amino-terminal portion of bindin between residues 1 and 76 and the rest of the label is restricted to the segments between residues 77 and 126 which also selectively bind to gel-phase vesicles. The carboxyl-terminal portion of bindin between residues 127 and 236 is not labeled.
Long-term glycaemic control and diabetic retinopathy.
216 patients with insulin-dependent diabetes mellitus were studied by retinal photography, and the absence or presence of retinopathy was related to the mean of serial glycosylated haemoglobin measurements (mean HbA1) carried out every 3 months during the previous 6 years. 122 patients had no diabetic retinopathy, 86 had background retinopathy, and 8 proliferative retinopathy. Mean HbA1 levels showed a strong correlation with increasingly severe grades of retinopathy, even when differences in duration of diabetes were taken into account. Proliferative retinopathy was seen only in patients with mean HbA1 above 10%. These results support the view that the development of diabetic retinopathy is related to long-term glycaemic control and emphasise the desirability, and possible benefit, of achieving control as close to normal as is possible for each individual patient.
Male partners of women with genital human papillomavirus infection. An assessment of colposcopic abnormalities by histological examination and human papillomavirus hybridization.
Men whose female sexual partners showed histological evidence of human papillomavirus infection were examined. Human papillomavirus DNA was identified in 29 of 35 biopsy samples of colposcopically-identified penile lesions. Human papillomavirus strains that were related to human papillomavirus genotypes 6/11 were observed most commonly (seven of eight patients) in the partners of patients with warty atypia or condylomata, while human papillomavirus strains that were related to human papillomavirus genotypes 16/18 were most-commonly (eight of 15 patients) observed in tissue from the partners of patients with cervical intraepithelial neoplasia. Measurement of human papillomavirus DNA in lesions by the filter in-situ hybridization technique more-frequently indicated human papillomavirus infection (29 of 35 lesions) than did conventional histopathological assessment (21 of 35 lesions) in this "high-risk" group. We conclude that colposcopically-identifiable lesions in male sexual partners are likely to contain human papillomavirus DNA, even if is no definite histological evidence of human papillomavirus infection is present, and that such lesions frequently contain strains of human papillomavirus that have been associated with the development of anogenital carcinoma.
Urinary albumin excretion in diabetic pregnancy.
We have analysed the results of urinary albumin excretion in timed overnight urine samples once every two weeks during pregnancy and post-natally in 25 non-diabetic women and 14 women with Type 1 (insulin-dependent) diabetes who were Albustix negative and had urinary albumin excretion less than 15 micrograms.min-1 at conception. Urinary albumin excretion did not vary significantly in the first two trimesters in either group and at 28 weeks was 2.73 micrograms.min-1 (0.32-251.68) (median and range) in the diabetic women and 2.53 micrograms.min-1 (0.90-13.37) in control patients (not significant). During the third trimester urinary albumin excretion increased, and levels were significantly higher in diabetic patients from 36 weeks (9.37 (0.9-31.78) vs 3.52 (0.19-33.74) micrograms.min-1, p less than 0.01) until delivery. In both groups, urinary albumin excretion reached a peak within the week following delivery - diabetic 17.42 micrograms.min-1 (2.03-46.64), control subjects 16.29 micrograms.min-1 (1.53-35.56), but six weeks after delivery, levels were similar to those in early pregnancy. The effect of pregnancy on urinary albumin excretion in these diabetic women would appear to be an exaggeration of the normal pattern, with levels returning to normal post-delivery. It is not possible to know if this has significance for future renal function, but it would be important to investigate this phenomenon in patients who already have raised urinary albumin excretion at conception.
Non-enzymatic glycosylation.
Experience with the use of glycosylated haemoglobin throughout the 1980s has confirmed its uniqueness and usefulness as an objective index of long-term glycaemia in diabetes mellitus, and has enabled the definition of realistic and achievable targets for outpatient management. Measurement of glycosylated serum proteins yields information over a much shorter time-scale which may be particularly useful in diabetic pregnancy. The formation of advanced glycosylation end-products may provide a link between hyperglycaemia and chronic diabetic complications. Therapeutic inhibition or the promotion of alternative metabolic pathways, to yield inert glycosylated products, represents an innovative approach to the problem of preventing these complications.
Basal and saline-stimulated levels of plasma atrial natriuretic factor in acromegaly.
We have studied plasma ANF before and after a 4-h intravenous infusion of normal saline in eight subjects with active acromegaly and in eight age and sex-matched control subjects. Plasma ANF, serum aldosterone and blood pressure were measured basally and after 2 and 4 h and plasma renin activity basally and after 4 h. Basal plasma ANF was similar in each group (4.4 +/- 1.5 pmol/l (mean +/- SEM) in acromegalic subjects and 5.3 +/- 0.7 pmol/l in controls NS). Plasma ANF did not rise significantly after saline in the acromegalic group (2-h value, 5.9 +/- 0.9; 4-h value, 5.1 +/- 0.9 pmol/l) but did rise significantly in the control group (2-h value, 8.9 +/- 1.9; 4-h value 9.5 +/- 1.3 pmol/l, both values P less than 0.05 vs basal level). The 4-h ANF value was significantly higher in the control group than in the acromegalic group (P less than 0.05). Basal and stimulated serum aldosterone values were similar in the two groups. Plasma renin activity suppressed to a lesser extent in the acromegalic group after 4 h. The facts that basal plasma ANF was not raised in acromegalic subjects and did not respond to saline stimulation demonstrate that an abnormality of ANF control may be an important factor in the aetiology of the expanded sodium status of patients with acromegaly and hence may contribute to the hypertension seen in patients with growth hormone excess.
Bilateral inferior petrosal sinus sampling as a routine procedure in ACTH-dependent Cushing's syndrome.
Bilateral inferior petrosal sinus sampling was successfully performed in 12 of 13 consecutive patients with ACTH-dependent Cushing's syndrome. Ten of the patients subsequently had transsphenoidal pituitary microsurgery. Eight patients in whom the inferior petrosal sinus to peripheral vein ACTH level ratio was 1.5 or greater were found to have a pituitary adenoma. One of the remaining two patients who had ratios less than 1.5 had pituitary hyperplasia while the other had no identified abnormality. In five of the patients with pituitary tumour a ratio above 1.5 was present on only one side. Bilateral petrosal sampling is therefore always necessary. Tumour localization within the pituitary was only poorly predicted by either petrosal sinus sampling (four of eight) or computed tomography scanning (three of eight). If petrosal sinus sampling is used early in the differential diagnosis of ACTH-dependent hypercortisolism, then the use of other differential diagnostic tests may not always be necessary.
Phaeochromocytoma in pregnancy. Five cases and a review of the literature.
We report five patients with phaeochromocytoma associated with pregnancy and review the 42 other cases reported in the literature from 1980 to 1987. The overall maternal mortality was 17% and the fetal loss 26%; antenatal diagnosis of phaeochromocytoma reduced the maternal mortality to zero and the fetal loss to 15%, but was made in only 53% of the patients. Although phaeochromocytoma is rare, a high index of clinical suspicion must be maintained and all those at risk investigated if earlier diagnosis and improved outcome are to be achieved. Once the diagnosis is confirmed, alpha-blockade is essential and beta-blockade may be required. CT scan or magnetic resonance imaging may be used to localize the tumour during the antenatal period. In the first and second trimesters, tumour resection has a good fetal outcome; in later pregnancy, delivery by elective caesarean section followed by tumour resection is recommended.
Serum fructosamine in uraemia, myeloma and acute inflammatory disorders--relationship to serum glucose and albumin levels.
There has been considerable interest in the serum fructosamine assay as a measure of glycated serum proteins. We have measured serum fructosamine in three groups of patients--those with uraemia; those with multiple myeloma; and those with acute inflammatory conditions--none of whom were known to have diabetes. Serum fructosamine was significantly higher in the uraemic group than in the other two, and also than in a control group. When allowance was made for prevailing serum albumin levels fructosamine was shown to be increased in the acute inflammatory group also. There was a significant correlation between random plasma glucose and serum fructosamine only when fructosamine was adjusted for prevailing albumin levels. In control and uraemic subjects there was a significant positive correlation between serum fructosamine and albumin levels, whereas in the myeloma group there was a negative correlation with serum protein. These data would suggest the need to take into account serum albumin levels and protein composition if serum fructosamine is accurately to reflect short-term integrated glycaemia.
A weight-related intravenous dexamethasone suppression test distinguishes obese controls from patients with Cushing's syndrome.
To establish a rapid test for Cushing's syndrome we measured serum cortisol during and following iv dexamethasone infusion (5 micrograms.kg-1.h-1 for 5 h from 10.00 h) in simple obesity (N = 19) and in Cushing's syndrome (N = 12). We had first established that 5 micrograms.kg-1.h-1 was the lowest dose which consistently lowered serum cortisol in simple obesity. In obesity, serum cortisols ranged from undetectable (less than 30) to 48 nmol/l at 17.00, less than 30 to 37 at 19.00 and less than 30 to 38 at 08.00 h the following day. Serum cortisol at these three times did not show any overlap between simple obesity and Cushing's syndrome. Having established these findings we proceeded to study a group of patients with polycystic ovarian disease. These patients behaved differently. Their values at 17.00 and 19.00 h did not overlap those of Cushing's syndrome. However, at 08.00 h, 5 of the 7 had values within the range seen in Cushing's syndrome with a mean of 290 +/- 99 nmol/l. In conclusion, 17.00 and 19.00 h serum cortisol levels distinguish between Cushing's syndrome and both simple obesity and polycystic ovarian disease. However, in the latter, cortisol suppression is less prolonged than in simple obesity. This finding may be important for our understanding of the pathogenesis of the disease.
Anti-HLA antibodies following the transplantation of highly sensitised renal allograft recipients.
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Diverse endocrine presentations of the syndrome of acanthosis nigricans and insulin resistance.
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Preventing staff-patient sexual relationships.
Just as the awareness of incest and childhood sexual abuse has grown in recent years, so too has knowledge of sexual exploitation of patients by psychotherapists and other mental health professionals. Almost no one, however, has discussed the prevalence of this problem in the hospital setting. The authors were members of a study group that thoroughly reviewed reported incidents in their own institution, leading to the recommendation that education is the best preventive measure currently available. The authors discuss fundamental issues involved in such a study, summarize profiles of patients and staff members who may be vulnerable to sexual involvement, and describe the main components of a preventive educational approach.
Human papillomavirus--a study of male sexual partners.
Male sexual partners of a cohort of women with genital-tract abnormalities which were associated with human papillomavirus infection were examined for evidence of infection with human papillomavirus. Of the 214 male partners who were examined, 93.5% had visible genital lesions. Of the 196 lesions that were biopsied, 72.5% showed histological evidence of infection with human papillomavirus, and only 20.4% of subjects with histological evidence of human papillomavirus were aware of a lesion. An unexpectedly high proportion (6.1%) of lesions on which a biopsy was performed, particularly those with flat, red, indurated morphology, also showed histological evidence of penile intraepithelial neoplasia. This was not significantly more common among the partners of the women with cervical intraepithelial neoplasia than it was among the partners of the women with other evidence of genital human papillomavirus infection. Penile intraepithelial neoplasia was significantly (P less than 0.001) more common among subjects with no history of non-genital warts. We conclude that the male partners of women with human papillomavirus-associated lesions are very likely to be infected with human papillomavirus, and thus may act as a significant reservoir for the reinfection of their female partners. As the awareness of human papillomavirus-associated lesions was low among the male partners, colposcopic examination and treatment of their male partners, and/or barrier contraception, may be a necessary part of the management of women who are undergoing treatment for human papillomavirus-associated genital disease.
Chromatography of proteins on hydrophobic interaction and ion-exchange chromatographic matrices: mobile phase contributions to selectivity.
The effect of mobile phase pH on the retention characteristics of eleven proteins was examined in hydrophobic interaction chromatography (HIC) on a SynChropak propyl stationary phase. Selectivity was shown to change with eluent pH. The effect of the displacing salt on the separation of proteins on a weakly hydrophobic weak-anion-exchange chromatography (AEC) packing was examined. Some differences in selectivity were observed when sodium sulfate was used as the displacing salt, compared to that observed with sodium chloride in the eluent. It was demonstrated that these AEC packings exhibited both electrostatic and hydrophobic properties, depending upon the type and concentration of salt used in the mobile phase. The addition of 20% ethylene glycol to the mobile phase was shown to reduce the hydrophobic interactions. The application of weakly hydrophobic weak-cation-exchange packings to HIC of proteins was demonstrated. Elution of such columns with descending sodium sulfate gradients was found to provide a selectivity different from that observed with a propyl stationary phase. Manipulation of mobile phases was shown to provide useful selectivity as a result of the combination of electrostatic and hydrophobic contributions to the separation process.
Non-enzymatic glycosylation of low-density lipoprotein. Results of an affinity chromatography method.
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Natural history of pancreatic islet B-cell function in type 2 diabetes mellitus studied over six years by homeostasis model assessment.
Islet B-cell function and insulin sensitivity were estimated with the aid of a mathematical model from repeated fasting plasma glucose and insulin measurements over a 6 year period in 131 patients with type 2 diabetes mellitus who could be managed satisfactorily on dietary therapy alone. They presented between the ages of 40 and 69 years, and were studied before and after one year of treatment, and then at regular intervals from 12 until 72 months later. A method of averaging the individual trends by means of a linear model regression technique was used to assess the progression of their diabetes. Dietary management over the first 12 months resulted in weight loss from 118% to 106% average body weight, and improved insulin sensitivity from 26% to 40% of normal (p less than 0.001). From 12 to 72 months, the fasting plasma glucose rose at a mean rate of 0.23 mmol/l per year (p less than 0.001) despite a rate of weight loss of 0.2% average body weight per year (p less than 0.01). The estimated islet B-cell function, expressed as a percentage of normal, decreased significantly (p less than 0.05) at a rate of 1.5% per year, with no statistically significant change in insulin sensitivity. Extrapolation suggests the reduction in B-cell function predated the departure of fasting plasma glucose from the normal range.