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Biomedical subjects

P Anand

Publications and source records attributed to P Anand.

At least 73 records · Page 4Linked to original sources
PubMed1999

Quantitative study of plasticity in the auditory nuclei of chick under conditions of prenatal sound attenuation and overstimulation with species specific and music sound stimuli.

Morphological effects of prenatal sound attenuation and sound overstimulation by species specific and music sounds on the brainstem auditory nuclei of chick have been evaluated quantitatively. Changes in length, volume, neuron number, size of neuronal nuclei and glial numbers of second and third order auditory nuclei, n. magnocellularis (NM) and n. laminaris (NL), were determined from thionine-stained serial sections of control and experimental groups on posthatch day 1 using stereological methods. Significant increase in volume of both auditory nuclei attributable to increase in length of nucleus, number and size of neurons, number of glia as well as neuropil was observed in response to both species specific and music overstimulation given during the critical period of development. The enhanced development of auditory nuclei in response to enriched environment prenatally indicates a positive effect of activity on neurons which may have clinical implications in addition to providing explanation for preference to auditory cues in the postnatal life. Reduction in neuron number with a small increase in proportion of cell nuclei of large size as well as an increase in glial numbers was seen in both NM and NL of the prenatally sound attenuated chicks. The increase in size of some neuronal nuclei may probably be evidence of enhanced synthesis of proteins involved in cell death or an attempt at recovery. The dissociated response of neurons and glia under sound attenuated and auditory stimulated conditions suggests that they are independently regulated by activity-dependent signals with glia also being under influence of other signals for a role in removal of dead cell debris.

Acoustic Stimulation↗
PubMed1999

QALYs and the integration of claims in health-care rationing.

The paper argues against the polarization of the health economics literature into pro- and anti-QALY camps. In particular, we suggest that a crucial distinction should be made between the QALY measure as a metric of health, and QALY maximization as an applied social choice rule. We argue against the rule but for the measure and that the appropriate conceptualization of health-care rationing decisions should see the main task as the integration of competing and possibly incommensurable normative claim types. We identify the main types as consequences, rights, social contracts, individual votes and community values and note situations in which the contribution of each claim type is limited. We go on to show that the integration of (at least some of) these claim types can be formalized within the mathematical framework provided by non-linear programming.

Attitude to Health↗
PubMed1999

Sensory and autonomic neuropathy in patients with idiopathic slow-transit constipation.

BACKGROUND: Slow-transit constipation (STC) is a severe disorder of unknown aetiology, which may result from an autonomic or sensory neuropathy. This study aimed to investigate patients with STC for the presence of neural dysfunction, and relate the findings to other factors, including any familial associations. METHODS: Thirty-three patients with STC were studied using standard neurophysiological tests and a range of quantitative sensory and autonomic tests. The findings were compared with those of 20 matched control subjects and nine diabetic patients with gastrointestinal symptoms. RESULTS: Twenty of the 33 patients with STC gave a family history of constipation, including an affected identical twin and Hirschsprung's disease (n = 3). None had abnormalities on neurological examination or nerve conduction studies. Fifteen of the 33 patients had abnormalities on quantitative tests, including all six who required a colectomy. Eleven patients with STC had reduced axon-reflex sweating in the presence of normal sweat gland responses (P < 0.001, all patients with STC versus controls). Twelve patients with STC had small sensory fibre dysfunction, with significantly increased thermal thresholds (cool, P < 0.05; warm, P < 0.01); these included six of nine patients with STC and rectal hyposensation. There were similar findings on quantitative testing in diabetic patients. CONCLUSION: Quantitative tests in patients with STC provide evidence of a small fibre neuropathy. The high incidence of a positive family history, particularly a possible association with Hirschsprung's disease, suggests a genetic basis, which deserves further investigation.

Adolescent↗
PubMed1999

Quantitative sensory and autonomic testing in male diabetic patients with erectile dysfunction.

OBJECTIVE: To correlate abnormalities of nerve fibres in the lower limbs with erectile dysfunction in male diabetic patients, using a range of quantitative sensory and autonomic function tests. PATIENTS AND METHODS: The study included 68 male diabetic patients with symptomatic erectile dysfunction and 11 matched diabetics without erectile dysfunction; none had clinical evidence of peripheral vascular disease or psychological disorder. Patients were evaluated with a symptom questionnaire based on the Michigan Neuropathy Screening Instrument questionnaire and examined clinically. Sural and peroneal nerve-conduction studies, and quantitative sensory and autonomic tests (vibration, thermal, light-touch thresholds, sensory and autonomic cutaneous axon-reflexes) were used to detect nerve abnormalities in the lower limbs, which were correlated with erectile dysfunction. RESULTS: Symptoms of neuropathy were more common in the group with male erectile dysfunction (MED), but statistically significant only for neuropathic pain (53% MED, 18% nonMED, P<0.05, chi-square test) and gastroparesis (44% MED, 0% nonMED, P<0.05). Tests of unmyelinated afferents (warming perception and capsaicin-induced sensory axon-reflex vasodilatation) were most often abnormal, sometimes with no other abnormalities on tests or neurological examination. However, abnormality of warm perception was not significantly different between groups (81% MED, 70% nonMED), suggesting that it is a poorer discriminant than abnormal sensory axon-reflex vasodilatation (89% MED, 22% nonMED, P<0.001). The only other significant test difference was decreased sural nerve action potential (70% MED, 22% non-MED, P<0.01). CONCLUSIONS: There appeared to be preferential involvement of unmyelinated sensory fibres that mediate axon-reflex vasodilatation in the limbs of diabetic patients with erectile dysfunction. This test appears to be a helpful indicator of neurological involvement in erectile dysfunction, and may be used to monitor the effect of new treatments.

Adult↗
PubMed1999

Increased nerve growth factor mRNA in lateral calf skin biopsies from diabetic patients.

AIMS: This study set out to establish a novel procedure for the measurement of human nerve growth factor (NGF) messenger ribonucleic acid (mRNA) and to use this method to measure NGF expression in skin biopsies from control subjects and from patients with early neuropathies. NGF mRNA levels were related to functional measures of the competence of NGF-responsive nerves. METHODS: mRNA levels were measured by competitive reverse transcription with polymerase chain reaction amplification (cRT-PCR). Functional correlates of this observation were assessed by indices of thermal sensitivity--mediated by C-fibres, whose phenotype is regulated by NGF. RESULTS: NGF mRNA was increased in skin biopsies from 19 diabetic patients (5.12+/-3.88 (SD)) compared with samples from eight controls (1.57+/-0.95; P=0.001). Diabetic patients showed significantly (P < 0.001) diminished detection of cool and warm stimuli compared to age matched control group (n=24), but there were no differences in detection of heat as pain, or correlation with NGF mRNA levels. CONCLUSIONS: These findings suggest abnormally increased expression of NGF in diabetic neuropathy, which may represent a compensatory mechanism for impaired phenotype in NGF-responsive neurones.

Adult↗
PubMed1999

Decreased CGRP, but preserved Trk A immunoreactivity in nerve fibres in inflamed human superficial temporal arteries.

The peptidergic sensory innervation of cranial blood vessels may play an important part in vascular head pain. The neuropeptides calcitonin gene-related peptide (CGRP) and substance P in sensory fibres are dependent on nerve growth factor (NGF) produced by the blood vessels, and when released from nerve terminals mediate neurogenic inflammation. NGF is increased in inflamed tissues, and acts via its high affinity receptor trk A on nociceptor fibres to produce hyperalgesia. CGRP and trk A immunoreactive nerve fibres have therefore been studied, for the first time, in inflamed (n=7) and non-inflamed (n=10) temporal arteries biopsied from patients with headache and suspected giant cell arteritis. CGRP immunoreactivity was markedly decreased to absent in adventitial nerve fibres in inflamed regions of vessels, which may reflect secretion from nerve terminals, as CGRP immunoreactivity could still be seen in nerve trunks in periadventitial tissue. Trk A immunoreactive nerve fibres were found in a similar distribution to CGRP containing nerve fibres in non-inflamed vessels, and the trk A immunoreactivity was virtually unchanged in inflamed vessels. The evidence supports a role for NGF related mechanisms in inflammatory vascular head pain. Anti-NGF or anti-trk A agents may represent novel analgesics in this condition.

Adult↗
PubMed1998

Rapid increase of NGF, BDNF and NT-3 mRNAs in inflamed bladder.

Nerve growth factor (NGF) is a mediator of hyperalgesia and has been previously associated with sensory and reflex changes after inflammation of the urinary bladder. A sensitive assay was developed to examine neurotrophin gene expression after bladder inflammation by turpentine, which causes a short-lived inflammatory response. Two hours, but not 6 or 24 h after induction of inflammation, there were significant increases in levels of NGF, brain-derived neurotrophic factor and neurotrophin-3 mRNAs. NGF immunoreactivity was elevated with a similar time course to its mRNA. Our results suggest that during bladder inflammation, endogenous NGF is rapidly up-regulated and released to mediating sensory and reflex changes. Brain-derived neurotrophic factor and neurotrophin-3 may also have a role in the inflammatory response.

Animals↗
PubMed1998

RET-like immunostaining of spinal motoneurons in amyotrophic lateral sclerosis.

The receptor tyrosine kinase RET is part of a functional receptor for glial cell derived neurotrophic factor (GDNF) and neurturin (NTN) which are potent neurotrophic factors for motoneurons. Here, we have studied RET-like immunoreactivity of motoneurons in post-mortem spinal cords of patients with amyotrophic lateral sclerosis (ALS) and in controls. We report that the intensity of RET-like immunostaining of motoneurons in ALS is decreased significantly to 81% of control values. Despite this change, the proportion of all large (>40 micron diameter) motoneurons showing RET-like immunoreactivity in ALS remains high (82-85%) and is not significantly different to controls. The persistence of RET-like immunoreactivity in the majority of large motoneurons in ALS could be important in the design of clinical trials of GDNF and NTN.

Aged↗
PubMed1998

GDNF and its receptor component Ret in injured human nerves and dorsal root ganglia.

Glial cell line-derived neurotrophic factor (GDNF) is trophic to motor and sensory neurones in animal models. GDNF mRNA is up-regulated in Schwann cells after peripheral nerve injury in rats. We have quantified and localized GDNF and its receptor component Ret, for the first time in any species, in injured human peripheral nerves and dorsal root ganglia (DRG) avulsed from the spinal cord. Significantly higher levels of GDNF were found in nerve distal to the site of the injury than in proximal or intact nerve, and in avulsed DRG than in post-mortem control DRG. GDNF immunostaining was seen in Schwann cells and in DRG neurones, especially of small and medium size, with significantly increased numbers of medium sized sensory neurones immunoreactive for GDNF after avulsion. Ret immunoreactivity was restricted to DRG neurones and axons, with no significant changes in numbers of positive DRG cells after injury. Our findings suggest that GDNF may play a role in injured human nerves and sensory ganglia, particularly in medium sized sensory neurones.

Adolescent↗
PubMed1998

Pain following human brachial plexus injury with spinal cord root avulsion and the effect of surgery.

Brachial plexus injury leading to spinal cord root avulsion in humans produces a characteristic constant crushing and intermittent shooting pain, which is often intractable. Preliminary observations suggested that this pain might be alleviated after successful nerve transfers to restore limb function. We therefore studied a group of 14 patients prospectively, to establish the validity of this observation, and to elucidate the underlying mechanisms. We found a strong correlation and temporal relationship between reduction in pain and successful nerve repair. All five patients with motor recovery experienced significant relief of de-afferentation pain, while in the seven patients with persistent pain, none had motor recovery. There was no correlation between pain relief and the minimal recovery of sensation in some cases, and no case had any return of sensory or sympathetic cutaneous axon-reflexes. While skin sympathetic axon-reflexes were reduced with T1 root lesions, there was no relationship between T1 root damage and pain. It was concluded that nerve repair can reduce pain from spinal root avulsions and that the mechanism may involve successful regeneration, and/or restoration of peripheral connections prior to their function, possibly in muscle.

Analgesics↗
PubMed1998

Correlation of quantitative tests of nerve and target organ dysfunction with skin immunohistology in leprosy.

Loss of nociception and hypohidrosis in skin are hallmarks of leprosy, attributed to early invasion by Mycobacterium leprae of Schwann cells related to unmyelinated nerve fibres. We have studied skin lesions and contralateral clinically unaffected skin in 28 patients across the leprosy spectrum with a range of selective quantitative sensory and autonomic tests, prior to biopsy of both sites. Unaffected sites showed normal skin innervation, when antibodies to the pan-neuronal marker PGP (protein gene product) 9.5 were used, with the exception of intraepidermal fibres which were not detected in the majority of cases. Elevation of thermal thresholds and reduced sensory axon-reflex flare responses in affected skin correlated with decreased nerve fibres in the subepidermis, e.g. axon-reflex flux units (means+/-SEM) for no detectable innervation; decreased innervation; and clinically unaffected skin, were 23+/-3.1; 41.2+/-7.3; and 84.5+/-4.0, respectively. Reduced nicotine-induced axon-reflex sweating was correlated with decreased innervation of sweat glands. Where methacholine-induced direct activation of sweat glands was affected, there was inflammatory infiltrate and loss of sweat gland structure. This study demonstrates a correlation between selective nerve dysfunction on clinical tests and morphological changes in skin, irrespective of the type of leprosy, and is the first to show that loss of sweating in leprosy may result either from decreased innervation and/or involvement of the sweat glands. The findings have implications for the selection and monitoring of patients with leprosy in clinical trials which aim to restore cutaneous function.

Autonomic Nervous System↗
PubMed1998

Neurotrophin-3 is increased in skin in human diabetic neuropathy.

Neurotrophin-3 (NT-3), a member of the neurotrophin family, has been shown to be necessary for the development of muscle spindle and Merkel cell afferent nerve fibres in animal models. The presence of NT-3 in the suprabasal epidermis, where many unmyelinated sensory fibres terminate, has been shown for the first time. As these fibres are affected in early diabetic neuropathy and a clinical trial of recombinant human NT-3 in diabetic neuropathy is in progress, the concentrations of endogenous NT-3 in skin of 24 patients at different stages of diabetic polyneuropathy have been investigated. NT-3 concentrations, measured with a specific immunoassay, were significantly higher in affected skin biopsies from patients with diabetic neuropathy than matched control skin (diabetic skin 6.32 (1.18) pg/mg v control skin 1.28 (0.05) (mean (SEM)); p<0.004, Mann-Whitney U test), particularly in the later stages. The optical density of NT-3-immunostaining was also significantly greater in the epidermis in diabetic patients (diabetic epidermis 0.30 (0.06) v controls 0.24 (0.01); p<0.02). No correlation was found between individual quantitative sensory tests and the increase of NT-3 concentration. The increase of NT-3 seems to reflect the degree of skin denervation in diabetic neuropathy, and may represent a compensatory mechanism. The concentrations of NT-3 in other peripheral targets deserve study in diabetic neuropathy.

Adult↗
PubMed1997

Selective autonomic and sensory deficits in slow transit constipation.

Chronic idiopathic constipation is likely to be a heterogeneous condition. Our previous studies on the stimulated sweating response suggested that autonomic dysfunction may be a cause in a subset of patients. Our aims were to test selectively the neural and sweat gland components of the sweat response and to test unmyelinated sensory fibres so as to determine whether a small fibre neuropathy is present. Twelve female patients with proven slow transit constipation and nineteen age-matched healthy volunteers took part in the study. The sensory tests included thermal thresholds and axon reflex vasodilatation in response to intradermal capsaicin, measured with a laser Doppler. Direct and axon reflex sweating was induced with intradermal methacholine and nicotine, respectively, and measured with an evaporimeter. Non-parametric tests were used for statistical comparison with a group of seven control subjects. Results are expressed as medians and range. All four patients who reported constipation from childhood had a selective deficit of unmyelinated afferent fibre function in the feet, with markedly elevated thresholds to warm sensation (controls 5.2; 4.3-10.6, patients 13.8; 11.8-16.1 delta T (degree C), P < 0.02) and heat pain (controls 10.6; 8.2-14.7, patients 18.1; 13.9-22.6 delta T (degree C), P < 0.05) and a reduced response to capsaicin (controls 47.0; 24-117, patients 13.5; 12-30 delta Flux (V), P < 0.005). In contrast, patients with adult onset constipation (n = 7) had a selective neural sweating deficit (controls 49.8; 32.0-61.8; patients 27.7; 7.3-44.3 g/m2 h, P < 0.05), indicating dysfunction of post-ganglionic sympathetic cholinergic fibres. Patients from both groups were shown to have normally functioning sweat glands in direct response to methacholine. Our findings suggest that patients with severe chronic idiopathic constipation may have selective small fibre neuropathies, of which constipation is a manifestation.

Adult↗
PubMed1997

Immunocytochemical studies of neurotrophins in cerebral motor cortex in Amyotrophic Lateral Sclerosis.

Neurotrophin-like immunoreactivity was studied in post-mortem motor cerebral cortex from patients with Amyotrophic Lateral Sclerosis (ALS) and controls. Neurotrophin-4/5 immunoreactivity was seen in small-(12-25 microm), medium-(26-39 microm), and large-(> 40 microm), neurones, neurotrophin-3 was seen in medium and small neurones, while brain-derived neurotrophic factor was restricted to small neurones. No difference in number or intensity of immunostained neurones was found between ALS and controls.

Aged↗
PubMed1997

trkA and trkC expression is increased in human diabetic skin.

Nerve growth factor (NGF) is reduced in epidermal keratinocytes in human diabetic skin, and this decrease has been related to dysfunction of cutaneous sensory fibres. In vitro studies show that keratinocytes express both NGF and its high-affinity receptor, trkA, and that NGF may increase keratinocyte proliferation and its own expression via an autocrine loop. However, the level of trkA expression in vivo by keratinocytes in normal and diabetic skin is unknown. We have therefore measured trkA expression in calf skin biopsies from patients with early subclinical diabetic neuropathy and control subjects, using in situ hybridisation combined with image analysis quantification. Expression of trkC was also studied, as its endogenous ligand neurotrophin-3 (NT-3) is related to NGF, and is present in human epidermis. Hybridisation signal was seen for both trkA and trkC localised throughout the epidermal layer of control skin, with a higher density of silver grain deposition observed for trkA mRNA. However, in diabetic epidermis there was a significant increase (P < 0.001) for both trk A (control, 0.178 +/- 0.013; diabetic, 0.304 +/- 0.032; mean silver grain counts/microm2 +/- SEM) and trkC expression (controls, 0.059 +/- 0.004; diabetics, 0.191 +/- 0.010). The up-regulation of epidermal trk receptors may result from decreased autocrine neurotrophin action, and could represent a compensatory mechanism.

Adult↗
PubMed1997

Endogenous NGF and CNTF levels in human peripheral nerve injury.

Nerve growth factor (NGF) is trophic to sensory and sympathetic fibres, and ciliary neurotrophic factor (CNTF) to motoneurones, in animal models of peripheral nerve injury: NGF excess produces hyperalgesia. In this first study of injured human nerves and sensory ganglia, we quantified and localized endogenous NGF and CNTF in 59 neonate and adult patients with brachial plexus and peripheral nerve injury. NGF levels were generally depleted in injured nerves, but relatively preserved acutely in nerve segments distal to injury. NGF immunostaining was observed in Schwann cells in distal nerve segments with pockets of high levels in some neuromas. CNTF levels and immunostaining in Schwann cells were markedly decreased distally within days of injury. We propose that early local administration of NGF and CNTF-like agents may help prevent degenerative changes in injured nerves, while at later stages local anti-NGF treatment (e.g. of some neuromas) may ameliorate chronic pain.

Adolescent↗