Biomedical subjects
Publications and source records attributed to S Love.
Three cases of spontaneous intracerebral haemorrhage treated by acute evacuation of haematoma are described. All cases proved to have cerebral amyloid angiopathy as the primary cause of the haemorrhage. Only one patient survived. Previous reports are discussed.
Intracerebral inoculation of the MS strain of herpes simplex virus type 2 (HSV-2) into mice causes an acute encephalitis associated with multifocal demyelination and necrotizing retinitis. We have studied the distribution of latent virus in mice that had recovered from the acute encephalitis. Four weeks or longer after inoculation, HSV-2 could be recovered from the trigeminal ganglia of all mice examined by co-culture of explants in roller tubes. The virus could not be recovered from explants of retina or brain stem. HSV-2 latency associated transcript (LAT) was readily detected in the trigeminal ganglia by reverse transcriptase-PCR more than 4 months after inoculation. LAT was also demonstrated in the brain but this required nested PCR for consistent detection. Both LAT and ICP0 mRNA were detected in brain tissue during the acute encephalitis but, unlike LAT, ICP0 mRNA could not be amplified from the trigeminal ganglia or brain beyond 4 weeks after inoculation of the virus. In situ hybridisation with a double-stranded DNA probe to the ICP0/LAT overlap region of HSV-2 revealed signal in trigeminal ganglion neurons and occasional cells in the brain stem. These findings indicate that HSV-2 introduced by intracerebral inoculation becomes latent in the trigeminal ganglia and that transcription of LAT also persists within the brain.
We have examined the distribution of type 1 herpes simplex virus (HSV-1) DNA in the brains of 8 humans surviving for between 4 months and 17 years after acute encephalitis. Histological examination showed neuronal loss and gliosis largely confined to the temporal and frontal lobes, typical of HSV-1 encephalitis. There was a widespread persistent inflammatory infiltrate, present in both the cerebrum and brainstem. Viral DNA was detected in paraffin sections of formalin-fixed paraffin-embedded autopsy brain by use of the polymerase chain reaction to amplify a fragment of the HSV-1 thymidine kinase gene. HSV-1 DNA was amplified from the cerebrum in 6/8 cases and from the brainstem in 4/8 cases. These findings suggest the possibility that HSV-1 may persist within the human central nervous system after acute herpes simplex encephalitis. The distribution of the viral DNA correlates better with that of the persistent inflammatory infiltrate than with the destructive lesions of the acute encephalitis.
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A natural outbreak of strangles occurred in a group of 19 young experimental ponies. The disease was diagnosed in 11 of them within two days of their arrival at Glasgow University veterinary school and five others developed clinical signs within a further four days, a morbidity rate of 84 per cent. All of the affected ponies had typical signs of strangles including dullness, anorexia, pyrexia, regional lymphadenitis, occasionally with rupture of the lymph node, conjunctivitis and a mucopurulent nasal discharge. Nine of the affected ponies were destroyed during the clinical phase of the disease for post mortem studies. The clinical disease in the remaining animals lasted approximately 21 days although one pony had to be destroyed 10 days after the onset of clinical signs because of the development of septic arthritis. All 16 affected animals exhibited peripheral blood neutrophilia and high plasma fibrinogen levels. beta haemolytic streptococci were isolated by nasopharyngeal swabbing from 18 of the 19 ponies. Streptococcus equi was confirmed only in three animals within the first four days of the outbreak. The majority of the other isolates identified to species were S zooepidemicus. beta haemolytic streptococci were still present in six ponies 40 days after they had clinically recovered and were isolated regularly from three ponies which did not develop clinical strangles but remained in contract with affected animals throughout the study.
Ultrasonographic examination was used to define the severity of injuries to the superficial digital flexor tendon in 73 National Hunt or point-to-point racehorses and the factors influencing the outcome of the cases were examined. Thirty-four of the horses (46 per cent) returned to work with an average time out of training of 13.5 months. The rate of recurrence of the injury was 35 per cent. The severity of the lesions was related to the outcome; all the mildly affected horses returned to work, with 63 per cent of them racing and an average time out of training of 10.2 months; 50 per cent of the moderately affected horses returned to work, and 30 per cent raced with an average time out of training of 11.3 months; 30 per cent of the severely affected horses worked, and 23 per cent raced with an average time out of training of 18.3 months. The differences in outcome between unilateral and bilateral injuries within each severity group were not statistically significant. Seventy-six per cent of horses treated with polysulphated glycosaminoglycans returned to work, compared with 46 per cent of conservatively managed horses and 50 per cent of horses treated with laser therapy. However, these differences were not statistically significant and the rate of recurrence of the injury in the horses treated with polysulphated glycosaminoglycans was 50 per cent compared with only 31 per cent in the conservatively managed horses. Seventy per cent of the mares and 47 per cent of the geldings were retired from racing.
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) is a clinically devastating disease of children and young adults. The cause of the stroke-like episodes is not known. We have sequenced the mitochondrial DNA (mtDNA) in archival paraffin-embedded material from two cases. In only one of these did the mitochondrial tRNA(Leu(UUR) gene contain the nucleotide 3243 A-to-G mutation that is most commonly responsible for MELAS. In this case, we determined the relative proportion of mutant:wild-type mtDNA in sections of the central nervous system and other tissues by PCR amplification, PalI digestion, DNA electrophoresis, and scanning densitometry of the ethidium bromide-stained gels. The technique allowed the proportion of mitochondria that contain the mutant genome to be compared with the histological findings in immediately adjacent sections of tissue. The mutant mtDNA was detectable in most tissues, the percentage of mtDNA ranging from barely detectable levels to 78 per cent. The relative amount of mutant mtDNA correlated poorly with the distribution of histological lesions, both within the central nervous system and in other tissues examined. The proportion was high in tissues such as liver, kidney, adrenal, and pancreas that appeared histologically normal. Relatively low levels were present in some regions of the central nervous system, such as the occipital lobe, which contained many of the characteristic infarct-like lesions. These observations do not support previous speculation that the distribution of these lesions reflects that of the defective mitochondria. The results emphasize the usefulness of the polymerase chain reaction in correlative histogenetic studies.
Russet Burbank potato plants have been genetically improved to resist insect attack and damage by Colorado potato beetles (Leptinotarsa decemlineata (Say)) by the insertion of a cryIIIA gene encoding the insect control protein of Bacillus thuringiensis var. tenebrionis. A modified gene that dramatically improved plant expression of this protein was utilized. Its expression in Russet Burbank potato plants resulted in protection from damage by all insect stages in the laboratory and in dramatic levels of protection at multiple field locations. Analysis of these genetically modified potatoes indicated that they conform to the standards for Russet Burbank potatoes in terms of agronomic and quality characteristics including taste.
Intracerebral inoculation of mice with the MS strain of type 2 herpes simplex virus (HSV-2) causes a brief encephalitis associated with multifocal central nervous system demyelination. Many of the mice develop unilateral or bilateral impairment of the pupillary light reflex. We have examined the development of ocular disease in inbred NIH mice inoculated intracerebrally with a low dose (10 pfu) of HSV-2 (MS). The resulting acute encephalitis was fatal in 30-50% of the mice. By 1 month after inoculation, the pupillary response to light was absent or impaired in approximately 80% of the surviving mice. Infectious virus could be isolated from the trigeminal ganglia and optic nerves from day 2 and from the eyes by day 4. Viral antigen was first immunohistochemically detectable in the optic nerves on day 5 and in the retinae on day 6. During the second week after inoculation up to half of the mice developed unilateral or bilateral necrotising retinitis associated with high titres of virus in the eyes and abundant viral antigen in the retinae. Electron microscopy confirmed the presence of viral particles in the retinae, in glia and degenerating neurons. No viral antigen was detected in the corneas and only rarely was antigen found in the ciliary body or iris. Infectious virus persisted longer in the eyes than in the trigeminal ganglia or optic nerves and could still be isolated from a few of the animals 2 weeks after inoculation. By 1 month the titres of virus within the eyes had fallen to undetectable levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Levels of the tumour markers neurone specific enolase (NSE), lactate dehydrogenase (LDH), chromogranin A (ChrA) and carcinoembryonic antigen (CEA) were measured in serum taken at presentation and during treatment, remission and relapse from 154 patients who received chemotherapy for small cell lung cancer at a single centre over a 6 year period. At presentation NSE was the most frequently elevated marker, being raised in 81% of patients and significantly higher in extensive as opposed to limited disease, as were LDH and ChrA. The response rate to therapy was best correlated with presentation level of ChrA, being 79% for those whose levels were within twice the upper limit of normal and 51% above (P < 0.01). Multivariate regression analysis showed NSE, performance status and albumin at presentation to be the best independent predictors of survival. Patients with NSE below twice the upper limit of normal, Karnofsky performance status of 80 or above and albumin 35 g l-1 or above had a median survival of 15 months with 25% alive at 2 years, whilst those with NSE above twice normal, Karnofsky below 80 and albumin less that 35 g l-1 had all died by 8 months. Changes in marker levels during therapy were of low predictive value for outcome although the finding of rising NSE during chemotherapy after an initial fall correlated with significantly reduced duration of remission. There was a strong inverse correlation between the NSE level at the time of response and duration of remission (P < 0.0001). Prediction of relapse was most reliable with ChrA, 52% of patients having rising levels before clinical evidence of disease recurrence.
OBJECTIVE: The aims of the study were to determine the effect of chronic pressure overload of the left ventricle on the density and distribution of neuropeptide-Y-like immunoreactive (NPY-LI) nerve fibres in heart and to compare any changes to those observed in adrenergic nerve fibres, identified by dopamine beta-hydroxylase immunoreactivity. METHODS: Pressure overload was produced in female adult guinea pigs by constriction of the abdominal aorta, using a modified Weck haemoclip. The same operation was performed on a separate group of animals except that no clip was placed around the aorta. Five weeks after surgery, animals were anaesthetised, and the hearts were fixed by perfusion for immunohistochemistry. Cryostat sections were stained, using an indirect peroxidase/antiperoxidase method, for NPY or dopamine beta-hydroxylase. RESULTS: Aortic stenosis caused a 45% increase in left ventricular weight and a 58% increase in left atrial weight at 5 weeks postsurgery. Pulmonary oedema, a sign of cardiac failure, was evident in most of the animals with aortic stenosis. Immunohistochemical studies showed that in atria and right ventricles from animals with abdominal aortic stenosis the distribution and density of NPY-LI nerve fibres were similar to those in the sham operated guinea pigs. However, the left ventricles obtained from the animals with aortic stenosis were nearly devoid of NPY-LI nerve fibres. The density of dopamine beta-hydroxylase-LI nerve fibres was also substantially reduced in the hypertrophied left ventricles. CONCLUSIONS: Aortic stenosis resulting in left ventricular hypertrophy caused a nearly complete loss of NPY-LI and dopamine beta-hydroxylase-LI nerve fibres from the left ventricle. The parallel reduction in both neuropeptide Y and dopamine beta-hydroxylase is in accordance with the association of neuropeptide Y with sympathetic (adrenergic) nerve fibres in the left ventricle and suggests that chronic left ventricular hypertrophy causes a severe degeneration of sympathetic axons supplying this chamber and/or reduces the ability of these sympathetic neurones to maintain normal levels of neurotransmitter related enzymes and neuropeptides.
One hundred and sixty-two patients initially treated at St Bartholomew's Hospital between 1974 and 1988 developed recurrent acute myelogenous leukaemia (AML). In the majority, the intention was to administer intensive chemotherapy again; 22/162 were re-treated palliatively. A second complete remission (CR) was achieved in 50/126 (40%) evaluable patients. Several different regimens were employed over this time period; the treatment used was the only factor that correlated with achievement of second CR (P = 0.04). Ten of the 50 patients received myeloablative therapy with either allogeneic or autologous bone marrow transplantation in second CR. The median duration of second CR for those patients who did not proceed to intensive consolidation with bone marrow transplantation was 7 months. There was no correlation between second remission duration and age, or with the administration of either intensive or conventional consolidation therapy. The median survival from first recurrence for all patients was 4 months, increasing to only 5 1/2 months for those re-treated with chemotherapy and to 12 months for those patients in whom a second CR was achieved, confirming the very poor prognosis of these patients.
The duration of symptoms before diagnosis (lag time) was defined for 184 of 236 children diagnosed as having a malignancy at the Royal Hospital for Sick Children, Edinburgh for the time period January 1982 until December 1990. The natural logarithm of the lag time was correlated with age, gender, diagnostic group, white cell count in acute leukaemia, clinical stage of disease in solid tumours, and event free survival. Age was significantly associated with lag time, older children presenting later. In the diagnostic groups, mean lag time ranged from 2.8 weeks in nephroblastoma to 13.3 weeks for brain tumours. Diagnostic group was predictive for lag time after adjustment for age, with for example, a significantly longer lag time for those with brain tumours. However lag time was not predictive of event free survival and it is likely that lag time has other major determinants. When compared with previous studies, there also appears to be a regional variation in lag time for diagnostic groups. It seems likely that this is a reflection of geographical difference in the structure of health systems and is therefore yet another important determinant.
A retrospective analysis has been conducted of regression patterns following treatment of retinoblastoma by external beam irradiation. There were 180 tumours in 105 eyes of 83 patients. Type I regression was found to be the commonest pattern and occurred in 50% of cases. Initial tumour size was found to be the only statistically significant determinant of regression pattern (p < 0.01). Thirteen tumours (7%) recurred within a median interval to recurrence of 12 months. All recurrences occurred within 40 months of completion of treatment and none occurred after age 4 years. No tumour less than 6 mm in diameter recurred. Although 10 out of 13 recurrences were of Type I, Cox model regression analysis showed initial tumour size to be the only independent predictor of recurrence (p < 0.01).
Leuprolide acetate, [D-Leu6-desGly10]LH-RH ethylamide, a highly potent superagonist of luteinizing hormone-releasing hormone (LH-RH), was administered by intraduodenal (ID) injection to male castrate rats in a saline solution. Absorption was low, approximately 0.01% and 0.08% by oral (PO) and ID administration respectively, compared with intravenous (i.v.) controls. An aqueous formulation and a water in oil emulsion of a lipophilic salt, a decane sulfonic acid derivative of [D-Leu6-desGly10]LH-RH ethylamide gave ID bioavailabilities of approximately 0.2% and 1%, respectively. Evaluation of formulation effects on the oral absorption of leuprolide showed that lipophilicity, surfactant and vehicle properties significantly affected ID absorption of leuprolide. Absolute bioavailability of the drug in typical emulsion systems ranged from approximately 3 to 10% and represent an improvement of about 100 fold in gastrointestinal bioavailability of this peptide. The implications of these findings relative to the effect of formula adjuvants on oral absorption of leuprolide and other peptides following ID administration are discussed.
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The background, clinical signs, blood biochemistry and management of 18 cases of equine hyperlipaemia are described. Eleven of the animals were Shetland ponies, four were Welsh mountain ponies or their crosses, one was a fell pony and two were riding ponies of mixed breeding. Their average age was nine years. Fourteen of the cases were mares, of which nine were in foal and two were lactating; the remainder were geldings. Underlying or concurrent diseases were identified in only six animals, but in one other animal the hyperlipaemia appeared to have been precipitated by stress, and in another by undernutrition to prevent laminitis. Twelve of the animals were considered obese. There was no age, seasonal, or geographic bias to the distribution of cases. Plasma triglyceride concentrations were increased by between five- and 80-fold, and ranged from 4.7 to 78.8 mmol/litre. There was biochemical evidence of hepatic damage in 17 cases, of renal insufficiency in 15, and pancreatic pathology in three cases. Four animals were euthanased without therapy. The others were treated with oral glucose solutions, which were supplemented with injections of insulin and heparin in four cases, and insulin alone in two cases. Eight of the treated animals died, to give an overall mortality of 67 per cent. The outcome of the treatment was unrelated to the degree of hypertriglyceridaemia, to the presence and severity of hepatic, renal or pancreatic pathology or to the therapeutic regimen.
A retrospective analysis of the clinical and laboratory findings from 51 adult horses with chronic diarrhoea revealed that the most common conditions were larval cyathostomiasis (14 cases), idiopathic chronic colitis (nine cases) and alimentary lymphoma (five cases). Five animals had diarrhoea as a result of non-alimentary disease. A diagnosis was reached in 37 cases, but only 15 were made ante mortem. Among the 18 animals (35 per cent) which survived, there were five cases of larval cyathostomiasis, one case of colonic impaction and 12 cases were undiagnosed. The most frequent abnormalities detected in blood samples from the horses were neutrophilia, hypoalbuminaemia, hyperglobulinaemia and high alkaline phosphatase activity. Evidence of carbohydrate malabsorption was found in 16 of 28 cases in which oral glucose tolerance tests were performed. No diagnostic specificity was apparent in either the clinical signs or the laboratory findings.