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Biomedical subjects

S L Lightman

Publications and source records attributed to S L Lightman.

At least 145 records · Page 8Linked to original sources
PubMed1995

Retinal detachment and herpesvirus retinitis in patients with AIDS.

BACKGROUND: The prolongation of survival of patients with herpesvirus retinitis and AIDS has been associated with a rise in the incidence of retinal detachment. In such cases, however, retinal reattachment may be difficult to achieve, and postoperative visual acuity may be poor despite anatomically successful surgery. METHODS: In order to examine factors affecting the visual outcome of surgery, a retrospective review of 29 patients with retinal detachment, herpesvirus retinitis, and AIDS was performed. Retinal reattachment surgery (32 procedures) or prophylactic laser demarcation (five procedures) was performed in 28 eyes of 23 patients. RESULTS: The macula was attached in 23/28 (82%) eyes at the last outpatient visit. Best postoperative visual acuity (median 6/18, range 6/6-hand movements) was significantly greater than final postoperative acuity (median counting fingers, range 6/6-no perception of light) (Wilcoxon sign rank test, p = 0.003), and was retained for a median of 3 months (1-91 weeks) after surgery. Poor visual outcome as evidenced by submedian final visual acuity was invariably associated with persistence of macular detachment, and significantly associated with the occurrence of optic atrophy (odds ratio = 5, p = 0.02). CONCLUSION: Retinal reattachment surgery appears justified in patients with herpesvirus retinitis and AIDS, but postoperative visual deterioration may occur in association with optic atrophy.

AIDS-Related Opportunistic Infections↗
PubMed1995

Hypothalamic nitric oxide synthase gene expression is regulated by thyroid hormones.

We investigated the effects of thyroid status on nitric oxide synthase (NOS) gene expression in the rat hypothalamic paraventricular (PVN) and supraoptic nuclei (SON). Propylthiouracil (PTU)-induced hypothyroidism in male rats produced a highly significant reduction in NOS gene transcripts in the PVN and SON, as assessed by quantitative in situ hybridization histochemistry with a specific oligodeoxynucleotide probe. The addition of T3 (40 micrograms/kg) to the PTU-containing diet completely prevented the reduction in NOS transcripts. Hyperthyroidism, induced by adding 160 micrograms/kg T3 to the food, more than doubled the prevalence of NOS transcripts in the PVN and SON after a similar time. Up-regulation of NOS gene transcripts induced by the osmotic stimulus of chronic salt loading was markedly attenuated by PTU-induced hypothyroidism. These results demonstrate a major effect of thyroid status on regulation of NOS gene expression in the hypothalamus.

Amino Acid Oxidoreductases↗
PubMed1995

Hypothalamic GH receptor gene expression in the rat: effects of altered GH status.

GH synthesis and release from the anterior pituitary is governed by the opposing actions of somatostatin (SS) and GH-releasing factor (GRF), derived from the periventricular and arcuate nucleus (ARC) of the hypothalamus respectively. GH is known to regulate its own release by hypothalamic autofeedback mechanisms, but the extent to which this is a direct effect rather than indirectly via the generation of IGFs is still a subject of debate. GH receptors are known to be present in the hypothalamus, but their physiological regulation is poorly understood. We therefore used in situ hybridization histochemistry to investigate the effects of GH status on hypothalamic GH receptor gene expression, using hypophysectomized normal and dw/dw dwarf rats as models of acquired and congenital GH deficiency. Hypophysectomy resulted in a time-dependent reduction in GH receptor gene expression. ARC GH receptor transcripts in untreated dw/dw dwarf rats were half those found in normal animals of the same background strain (16.8 +/- 1.7 vs 9.3 +/- 1.9 d.p.m./mg, P < 0.05). Increasing circulating GH by peripheral infusion of 200 micrograms human GH (hGH)/day for 6 days increased ARC GH receptor expression in dw/dw rats to normal. In contrast, central infusions of hGH at 26.4 and 79.2 micrograms/day for 6 days in normal rats lowered ARC GH receptor gene expression. The sensitivity of GH receptor gene expression within the central nervous system to peripheral and central GH levels suggests that feedback regulation of GRF and/or SS may be mediated directly by these receptors, and that the sensitivity to GH feedback is also subject to autoregulation by GH altering its own receptor expression.

Animals↗
PubMed1994

The effects of restraint or hypertonic saline stress on corticotrophin-releasing factor, arginine vasopressin, and proenkephalin A mRNAs in the CFY, Sprague-Dawley and Wistar strains of rat.

It is generally assumed that the stress response of different strains of rat will be identical following exposure to acute stress. In the present study we have examined the activation of the hypothalamo-pituitary-adrenal axis in the Wistar, Sprague-Dawley and CFY strains of rat following exposure to either the predominantly psychological stress of restraint or the physical stress of i.p. hypertonic saline injection. We have investigated the hypothalamic activation of corticotrophin-releasing factor (CRF) and proenkephalin A (PEA) mRNAs in the parvocellular cells of the paraventricular nucleus (PVN) and arginine vasopressin (AVP) in both the magnocellular and parvocellular regions in the PVN following acute stress. In addition we have measured corticosterone as an index of end-point activation. Circulating corticosterone and CRF mRNA were increased in all three strains following either stress. AVP and PEA mRNAs were increased following hypertonic saline but only in the CFY strain following restraint. Overall the relative increase in the parameters measured was greater in the CFY strain of rat than the other strains. These data demonstrate marked differences in response to acute stress in the three strains of rat examined. These varying responses must be taken into consideration when designing or interpreting any study investigating the stress response.

Animals↗
PubMed1994

Ectopic vasopressin expression in MMTV-Wnt-1 transgenic mice modifies mammary tumor differentiation and pathology.

A transgenic mouse model has been developed to test the involvement of ectopic neuropeptide production as a secondary factor in cancer. Mice bearing a mouse mammary tumor virus-vasopressin (MMTV-VP) fusion transgene synthesized authentic vasopressin in mammary ducts and alveoli, but this had no effect on mammary gland development and growth. Mice bearing the MMTV-VP transgene were then mated with mice bearing the MMTV-Wnt-1 transgene to produce bitransgenic animals. Two types of mammary tumor develop in MMTV-Wnt-1 mice; type A mammary adenocarcinomas are uniform with fine acinar structure composed of small epithelial cells arranged to form round cavities and elongated tubules, while adenocarcinoma type B tumors have acinar areas, cystic spaces filled with blood or fluid, intracystic papillary projections, and cords as well as sheets of cells. Compared to the MMTV-Wnt-1 mice, the bitransgenic animals developed proportionally less type B tumors. Further, type B mammary adenocarcinomas from bitransgenic mice exhibited increased proliferation and growth, as judged by mitotic index and argyrophilic nucleolar organizer region counts, compared to type B tumors from MMTV-Wnt-1 mice. These data provide evidence that ectopic neuropeptide production can modulate the development of tumors in vivo.

Adenocarcinoma↗
PubMed1994

Activation of specific ATP receptors induces a rapid increase in intracellular calcium ions in rat hypothalamic neurons.

We have used real-time dynamic video imaging of Fura-2 fluorescence to study the acute effects of external ATP on [Ca2+]i in cultured rat hypothalamic neurons. The addition of ATP at microM concentrations, but not adenosine, AMP, ADP or GTP, produced a rapid, dose-dependent increase in cytosolic Ca2+. The hydrolysis-resistant ATP analogues 3-thio-ATP and beta,gamma-imido-ATP produced a similar response but alpha,beta-methylene ATP had much lower efficacy. The ATP response was inhibited by 10 microM nifedipine, abolished by 50 microM cadmium and by the absence of extracellular Ca2+, but was unaffected by ryanodine or omega-conotoxin GVIA. The P2-purinoceptor antagonist suramin reversibly and selectively inhibited the ATP response but had no effect on other neurotransmitter-induced Cai2+ responses. Antagonists to muscarinic, nicotinic, NMDA, non-NMDA, GABA, 5-HT and adenosine receptors had no effect on the ATP response. Thus the Ca2+ response of hypothalamic neurons to ATP is mediated by specific suramin-sensitive ATP-receptors, activation of which is independent of ATP hydrolysis and results in an influx of extracellular Ca2+ largely through high voltage-gated Ca2+ channels. These findings support the assertion that ATP acts in the CNS as an excitatory neurotransmitter.

Adenosine↗
PubMed1994

Differential lymphokine expression by rat antigen-specific CD4+ T cell lines with antigen and mitogen.

Retinal soluble antigen (S-Ag) and purified protein derivative (PPD)-specific T cell lines established from Lewis rats were used to study the pattern of lymphokine expression to see if it varied with the inducing stimulus. Lymphokine mRNA expression was detected by PCR combined with Southern analysis after 6-hr stimulation and protein secretion assessed by bioassays at 24 hr poststimulation. S-Ag-specific T cell lines when stimulated with antigen expressed IL-2, IFN-gamma, and IL-4 mRNA, whereas only IL-2 and IFN-gamma could be detected in the supernatants. This is in contrast to the findings after stimulation of the PPD cell lines with PPD where IL-4 could be detected in the supernatants. The time course studies (3, 6, 24, 48, and 72 hr) with one of the S-Ag-specific T cell lines showed that S-Ag activation did not induce any detectable IL-4 bioactivity. However, when the S-Ag T cell line was stimulated by Con A or PMA, IL-4 was detected in the supernatants following Con A activation, suggesting that the way in which the T cell is activated has an effect on its resultant lymphokine secretion.

Animals↗
PubMed1994

Hyponatremia associated with laryngeal squamous cell carcinoma.

An association between laryngeal squamous cell carcinoma and inappropriate antidiuresis is described in a 76-year-old man. Even though all accepted diagnostic criteria for the syndrome of inappropriate secretion of antidiuretic hormone were fulfilled, abnormal levels of antidiuretic hormone were not demonstrated, leaving the mechanisms of this hyponatremia unclear.

Aged↗
PubMed1994

Release of alpha-melanocyte-stimulating hormone from rat splenocytes in vitro is dependent on protein synthesis.

The pro-opiomelanocortin (POMC) peptide product alpha-melanocyte-stimulating hormone (alpha-MSH) has a variety of anti-inflammatory effects within the immune system. Using an antiserum specific for alpha-MSH, we have now demonstrated for the first time that this peptide is secreted from splenocytes. Basal secretion of alpha-MSH from the spleen in vitro was some 300-fold less than that detected from the neurointermediate lobe. Secretion of alpha-MSH from the spleen was increased 5-fold in the presence of puromycin, indicating that splenocyte alpha-MSH secretion is under the regulation of a product of endogenous protein synthesis. ACTH and beta-endorphin were also released from splenocytes in vitro, but their release was not affected by incubation with puromycin. Secretion of the POMC peptides from splenocytes or NIL was not affected by corticosterone. These data show that the many anti-inflammatory effects within the immune system ascribed to alpha-MSH may actually be mediated through paracrine effects of immune alpha-MSH.

Adrenocorticotropic Hormone↗
PubMed1994

Priming of the anterior pituitary with corticotropin-releasing hormone in vitro does not facilitate an ACTH response to interleukin-1 beta.

Stimulation of the hypothalamo-pituitary-adrenal axis by the cytokine interleukin-1 beta (IL-1 beta) is an important facet of the functional interaction between the endocrine and immune systems. IL-1 beta can act by releasing corticotropin-releasing hormone (CRH) from the hypothalamus, but it has also been proposed to act directly at the anterior pituitary when the pituitary has been primed with CRH. We tested this hypothesis using in vitro experiments in which anterior pituitaries were primed with low doses of CRH. We were unable to demonstrate a direct effect of IL-1 beta on the release of ACTH from freshly harvested anterior pituitary tissue. Neither continuous nor discontinuous priming of the cells with CRH or arginine vasopressin, at concentrations by themselves insufficient to cause ACTH release, facilitated an ACTH response to IL-1 beta. Therefore our data do not support the hypothesis that IL-1 beta can have a direct effect upon ACTH release from the anterior pituitary primed with CRH.

Adrenocorticotropic Hormone↗
PubMed1994

Contents of corticotropin-releasing hormone and arginine vasopressin immunoreactivity in the spleen and thymus during a chronic inflammatory stress.

We have previously found that proopiomelanocortin (POMC) mRNA and levels of adrenocorticotropin (ACTH) and beta-endorphin peptides are increased in the spleen and thymus of rats with adjuvant-induced arthritis (AA), and immunologically mediated inflammatory disease. To determine whether alterations in immune tissue POMC during AA are also accompanied by changes in immune tissue corticotropin-releasing hormone immunoreactivity (ir-CHR) and arginine vasopressin (AVP), we measured ir-CRH and AVP by radioimmunoassays in spleen and thymic extracts 14 days following injection of adjuvant. Ir-CRH was detectable in all extracts of spleen and thymus. Total contents of ir-CRH in the spleen and thymus were not altered following arthritis, although a significant decrease was observed in splenic extracts from arthritis rats (40.0 +/- 4.2 fmol/g tissue) compared to controls (69.5 +/- 8.4 fmol/g tissue) when contents were expressed as amount per weight of tissue. Low levels of AVP were also detected in immune tissues, with contents significantly increased in spleens from arthritis animals (17.4 +/- 1.6 fmol/g tissue) compared to controls (10.6 +/- 1.9 fmol/g) but thymic contents of AVP were not altered by arthritis (10.6 +/- 1.3 fmol/g) compared to controls (9.2 +/- 0.7 fmol/g). Control levels of AVP were significantly higher in spleens and thymuses from female rats (53 +/- 5 and 25 +/- 4 fmol/g tissue, respectively) compared to males. G-50 chromatography revealed that the principal form of splenic ir-CRH is CRH(1-41), although in non-arthritic animals some ir-CHR eluted in a position indicating a slightly larger form.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effects of a chronic inflammatory stress on levels of pro-opiomelanocortin-derived peptides in the rat spleen and thymus.

Adjuvant-induced arthritis (AA) in specific strains of rats is an immunologically mediated inflammatory disease which is also characterised by activation of the endocrine system. To further investigate the effects of AA on processing of the pro-opiomelanocortin (POMC) precursor in rat immune tissues, we utilised radioimmunoassays for adrenocorticotrophin (ACTH), beta-endorphin and alpha-melanocyte-stimulating hormone (alpha-MSH) to measure these peptides in the spleen and thymus. 14 days following adjuvant injection, spleen levels of ACTH were elevated in the AA group (4.47 +/- 1.04 ng/g tissue, n = 9) compared to controls (2.42 +/- 0.4 ng/g) and exacerbation of the disease by removal of circulating glucocorticoids through bilateral adrenalectomy (ADX) resulted in further elevation of spleen ACTH (5.11 +/- 1.22 ng/g). beta-Endorphin levels in both the AA (10.60 +/- 1.61 ng/g) and AA/ADX (13.37 +/- 2.36 ng/g) groups were higher than controls (5.57 +/- 0.65 ng/g). Conversely, alpha-MSH spleen levels were decreased in the AA (2.89 +/- 0.22 ng/g) and AA/ADX (2.22 +/- 0.33 ng/g) groups compared to controls (4.62 +/- 0.45 ng/g) and were also decreased following adrenalectomy. In the thymus, ACTH levels were elevated in the AA group (8.95 +/- 1.41 ng/g) compared to controls (5.79 +/- 0.63 ng/g), and the same pattern was evident for thymic alpha-MSH (0.64 +/- 0.08 ng/g in AA animals compared to control levels of 0.35 +/- 0.03 ng/g). Following G50 gel filtration, ACTH and beta-endorphin immunoreactivities (ir) were present in both spleen and thymus as two peaks, one which eluted near the void volume and one which eluted in a lower molecular mass position than the standards.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1994

Up-regulation of lipocortin-1 and its mRNA in reactive astrocytes in kainate-lesioned rat cerebellum.

We have used a combined molecular and immunocytochemical approach to examine the expression of lipocortin-1 (LC-1) in kainate-lesioned rat cerebellum. Using immunocytochemistry, Western and Northern blotting, we have shown upregulation of LC-1 mRNA and expression of LC-1 localised specifically to reactive astrocytes. These studies suggest that reactive astrocytes are a major synthetic compartment for the expression of LC-1. The well-reported immuno-suppressive effects of lipocortin(s), suggests that reactive astrocytes could serve to negatively modulate inflammatory reactions in the central nervous system.

Animals↗
PubMed1994

Hormones, peripherally activated prohormones and regulation of the Th1/Th2 balance.

There is much interest in the factors that control the cytokine profile of T-helper (Th) lymphocytes, and attention has focused on feedback from the cytokines themselves. In general, Th1 cytokines promote Th1 activity and inhibit Th2 activity, and vice versa. Both Th1 and Th2 responses should therefore be stable. However, in vivo, many responses start predominantly as Th1 and then shift to Th2. Why do they do this? As discussed here, an important influence on this shift that has been largely ignored in in vitro work is the endocrine system.

Animals↗
PubMed1994

The diurnal expression of genes encoding vasopressin and vasoactive intestinal peptide within the rat suprachiasmatic nucleus is influenced by circulating glucocorticoids.

The mammalian suprachiasmatic nucleus (SCN) is the endogenous pacemaker generating the diurnal rhythm of the stress hormones ACTH and glucocorticoid secretion. In the present study, we have employed male rats entrained to a 12:12 h (light:dark) photoperiod to investigate the effects of chronic and acute administration of exogenous glucocorticoids upon the diurnal expression of vasopressin and vasoactive intestinal peptide (VIP) mRNA in the SCN by semiquantitative in situ hybridization histochemistry. Chronic administration of exogenous glucocorticoids significantly enhanced vasopressin mRNA expression only at zeitgeber time (ZT) 5, while the otherwise rhythmic expression of vasopressin mRNA was unaffected at ZT11, ZT17 and ZT23. In contrast, the same treatment abolished the rhythmic expression of VIP mRNA resulting in constantly elevated mRNA levels. In adrenalectomized rats given an overnight supplement of dexamethasone in their drinking water, the expression of both vasopressin and VIP mRNA in the SCN was elevated the following morning at ZT6 when compared to adrenalectomised rats kept on 0.9% saline. These results suggest that glucocorticoids influence the expression of vasopressin during a narrow window of time in the diurnal cycle coinciding with the time where entrainment of the circadian pacemaker with non-photic cues is possible. Constantly elevated levels of glucocorticoids may also interfere with the suprachiasmatic expression of VIP mRNA which is thought to be driven by photic cues.

Animals↗
PubMed1994

Role of central catecholamines in the modulation of corticotrophin-releasing factor mRNA during adjuvant-induced arthritis in the rat.

The development of adjuvant-induced arthritis in the rat is associated with an activation of the hypothalamo-pituitary-adrenal axis. In the Piebald-Viral-Glaxo strain of rat there is however a paradoxical decrease in corticotrophin-releasing factor (CRF) mRNA in the hypothalamic paraventricular nucleus (PVN) and a decrease in CRF-41 peptide release into the hypophysial portal blood with increasing severity of disease. In the present study we have investigated the role of endogenous catecholamines within the PVN as possible inhibitory factors acting on CRF neurons during adjuvant-induced arthritis. Noradrenaline (NA) concentrations were approximately doubled in the PVN of arthritic animals. Depletion of endogenous catecholamines following direct 6-OHDA lesions of the PVN resulted in a significant depletion in PVN NA. The increase in NA observed in arthritic animals appears to have a protective role since depletion of NA increased the severity of the disease. Neither the increase in circulating levels of corticosterone nor the decrease in CRF mRNA in the PVN were prevented following NA depletion. Our results suggest that modification of central neurotransmitter systems are able to influence the severity of adjuvant-induced arthritis.

Animals↗
PubMed1994

The diagnosis of delayed post-operative endophthalmitis by polymerase chain reaction of bacterial DNA in vitreous samples.

Delayed post-operative endophthalmitis is a complication of modern cataract extraction and posterior chamber lens implantation. Propionibacterium acnes has been isolated in a few such cases but the majority are culture-negative, compounding surgical and medical management decisions. A method of detecting bacterial, and specifically P. acnes, DNA by the polymerase chain reaction (PCR) directed at 16S rDNA is reported. Nested PCR with universal eubacterial primers complimentary to regions of 16S rDNA conserved sequences detected 50 fg of bacterial DNA spike in normal vitreous. Nested PCR with P. acnes primers detected 10 fg of DNA. Vitreous samples from 29 patients undergoing vitrectomy for reasons unrelated to infection and 23 samples from 19 patients with delayed post-operative endophthalmitis were analysed. Four (14%) of 29 normal individuals and 17 (74%) of 23 delayed cases gave positive results with universal eubacterial primers. None of 29 and eight of 23 samples gave positive results with P. acnes primers. The 14% positive rate with universal primers in non-infected cases may limit their use in delayed post-operative endophthalmitis. PCR detection of bacterial DNA with specific primers from vitreous samples may prove a useful means of diagnosing delayed post-operative endophthalmitis and facilitating management decisions when conventional bacterial culture is negative.

Base Sequence↗