Search PubMed⌕ Search

Biomedical subjects

J Herbert

Publications and source records attributed to J Herbert.

At least 73 records · Page 4Linked to original sources
PubMed1998

Fracture history and bone loss in patients with MS.

OBJECTIVES: We have previously shown that MS patients have significantly reduced bone mass and a high prevalence of abnormal vitamin D status. The object of this study was to characterize the frequency of adulthood fractures in MS patients, prospectively determine rates of bone loss in MS, and determine whether vitamin D status is a predictor of bone loss. METHODS: MS patients (36 women, 18 men) were compared with age- and gender-matched healthy controls (35 women, 14 men). Bone mass was performed by dual x-ray absorptiometry at baseline and at 12-month intervals over 2 years. RESULTS: Fractures in the absence of major trauma had occurred in 2% of controls and 22% of MS patients (p < 0.002). Over the 2 years of prospective follow-up, both women and men with MS lost substantially more bone in the femoral neck than did controls (3% and 6% per year in pre- and postmenopausal women with MS versus 0.5% and 0.8% per year in controls; 7.3% per year in men with MS versus 1.6% per year in controls). Bone loss in the spine was also greater in women with MS than in controls (1.6 to 3.5% per year loss in MS patients versus no change in controls). Duration of steroid treatment beyond 5 months and ambulatory status were both predictors of bone loss. Bone loss in the spine occurred faster in MS patients with low (<20 ng/mL) 25-hydroxyvitamin D levels (1.9% per year, p < 0.04), whereas in those with normal 25-hydroxyvitamin D levels, bone loss was insignificant. At the femoral neck, bone loss was substantial in all patients, but was somewhat faster in the group with low levels of 25-hydroxyvitamin D (5.6% per year, p < 0.0001) compared with the group with high levels of 25-hydroxyvitamin D (4.3% per year, p = 0.03). CONCLUSIONS: MS patients have more frequent fractures and lose bone mass more rapidly than do their healthy age- and gender-matched peers, in part related to insufficient vitamin D. Vitamin D repletion in MS patients who are deficient might reduce, to some extent, the rate of bone loss and decrease osteoporosis-related fractures.

Adult↗
PubMed1997

Calcium channels mediate angiotensin II-induced drinking behaviour and c-fos expression in the brain.

It is widely accepted that calcium ions are critically important in both short- and/or long-lasting responses of neurons to a stimulus. We have shown previously that NMDA receptors play a role in dipsogenic responses and c-fos expression induced by intracerebroventricular (i.c.v.) infusion of angiotensin II (Ang II). Since NMDA receptors are known to be linked to receptor-operated calcium channels, this study determined whether voltage dependent calcium channels are also involved in Ang II-induced behavioural (drinking) and endocrine responses as well as c-fos expression. The antidipsogenic actions of three L-type calcium channel antagonists, nifedipine, diltiazem and verapamil on Ang II-induced drinking behaviour were studied. These bind to the dihydropyridine, phenylalkylamine and benzothiazepine sites respectively. Rats (Lister-hooded) pre-treated i.c.v. with either 25 or 100 microg nifedipine, followed by 25 pmol Ang II, drank significantly less water than controls during the first 15 min after infusion. However, rats pre-treated with i.c.v. 100 microg diltiazem or verapamil showed no change in Ang II-induced drinking behaviour. The antidipsogenic actions of N- and P-type calcium channel antagonists omega-conotoxin GVIA and omega-conotoxin MVIIC were also evaluated. Rats pre-treated with 5 pmol or 20 pmol omega-conotoxin GVIA did show a slight but not significant suppression of water intake, particularly after the higher dose. Rats pre-treated with omega-conotoxin MVIIC drank almost the same amount of water as those pre-treated with saline. Nifedipine was found to suppress both Ang II-induced corticosterone release and c-fos expression in the following areas: organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MNPO), hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). The results described in this paper provide evidence that calcium channels play important roles in the Ang II-induced behavioural and endocrine responses, and in the expression of the immediate-early gene c-fos. This suggests that an L-type calcium channel may participate both short- and longer-term neuronal actions of Ang II.

Angiotensin II↗
PubMed1997

Expression of a biologically active recombinant mouse IL-1 receptor antagonist and its use in vivo to modulate aspects of the acute phase response.

Recombinant mouse IL-1receptor antagonist protein (rmIL-1ra) was expressed in Escherichia coli. In vivo administration of rmIL-1ra, in a casein-induced murine model of acute inflammation, completely abolished the hepatic induction of the mRNAs specifying serum amyloid A1 (A-SAA1) and A-SAA2 for up to 12 h, indicating that hepatic A-SAA mRNA synthesis is totally IL-1 driven. A-SAA protein, however, was present in the serum of rmIL-1ra-treated casein-stimulated mice (although at lower levels than in untreated casein-stimulated mice) at 12 h indicating that extrahepatic A-SAA synthesis is driven in part by factors acting independently of IL-1. Hepatic mRNA levels of the other mouse acute phase reactants (APRs), serum amyloid P component, C-reactive protein, alpha1-acid glycoprotein, and C3 were also induced with casein after 12 h, as were serum protein levels of SAP and C3. These inductions were only partially inhibited by rmIL-1ra, indicating that hepatic expression of the latter APRs (unlike that of A-SAA) is driven partly by IL-1 and partly by factors acting independently of IL-1. Hepatic mRNA levels of the negative APRs apolipoprotein A-I and serum albumin were down-regulated 12 h after casein stimulation. rmIL-1ra partially restored serum albumin mRNA levels but not apo A-I mRNA levels, indicating differential regulation of these negative APRs. The rmIL-1ra will be useful in studies of IL-1-mediated gene regulation in murine models of inflammation.

Acute-Phase Reaction↗
PubMed1997

Down-regulation of the major circulating precursors of proteins deposited in secondary amyloidosis by a recombinant mouse interleukin-1 receptor antagonist.

An inflammatory response was induced in C57BL/6 mice using silver nitrate. Co-administration of a recombinant mouse interleukin-1 receptor antagonist (rmIL-1ra) significantly reduced the magnitude of hepatic induction of the mRNA specifying the serum amyloid A (A-SAA) isoforms A-SAA1 and A-SAA2 for up to 24 h. In relative terms, the amount by which the induction of serum A-SAA protein levels could be countered by the antagonist was less, probably reflecting extrahepatic A-SAA synthesis that is regulated independently of IL-1. Induction of hepatic serum amyloid P component (SAP) mRNA and other acute-phase reactant (APR) mRNA were all partially blocked by rmIL-1ra for up to 24 h, indicating that induction of these APR mRNA involves both IL-1 and additional factors acting independently of IL-1. Hepatic mRNA levels of the negative APR apolipoprotein A-I (apo A-I) and serum albumin were down-regulated by silver nitrate treatment; rmIL-1ra partially restored serum albumin mRNA levels but not those of apo A-I. The IL-1ra-mediated reduction in inflammation-induced hepatic mRNA and serum protein concentrations of A-SAA and SAP (the precursors of the main protein components of amyloid deposits in secondary amyloidosis) was, however, not sufficient to prevent or delay early amyloid deposition in the silver nitrate/amyloid enhancing factor model of accelerated amyloidosis. The rmIL-1ra may be a useful component in future therapies to control inflammation and secondary amyloidosis; in addition, it will be a useful tool for the detailed analysis of the IL-1-driven aspects of inflammation per se.

Acute-Phase Proteins↗
PubMed1997

Reduced bone mass and fat-free mass in women with multiple sclerosis: effects of ambulatory status and glucocorticoid Use.

Multiple sclerosis (MS) is associated with reduced bone mass and vitamin D deficiency. The underlying pathophysiology of the bone disease is uncertain, however, acute and long-term glucocorticoid use, progressive immobilization, vitamin D deficiency, and possibly skeletal muscle atrophy are likely to be determinants. The aims of this study were to determine (a) whether multiple sclerosis is associated with reduced fat-free mass and (b) whether in patients with multiple sclerosis, ambulation ability or glucocorticoid use is associated with bone mass and/or fat-free mass. Seventy-one female patients with MS were compared with 71 healthy, age-matched female controls. Total body bone mineral content (TBBMC, kg), fat mass (FM, kg), and fat-free mass (FFM, kg) were measured using dual X-ray absorptiometry. Disability status was graded according to the Kurtzke Expanded Disability Status Scale (EDSS) as ambulatory, with or without aide (EDSS score of 0 to 6.5), or predominantly wheelchair bound (EDSS score > 6.5). The patients with MS, when compared to age-comparable controls, had deficits in TBBMC ( approximately 8%, -0.3 +/- 0.1 SD, P < 0.04) and FFM ( approximately 5%, -0.3 +/- 0.1 SD, P < 0.01). Both TBBMC and FFM were negatively associated with EDSS score (r = 0.33, P < 0.01, and r = 0.41, P < 0.01, respectively). Patients with MS who were nonambulatory had even greater deficits in TBBMC and FFM as compared with age-matched controls (-0.6 +/- 0.1 SD, P < 0.01, and -0.6 +/- 0. 1 SD, P < 0.01, respectively). By contrast, as compared with age-comparable controls, ambulatory patients with MS had no deficits in bone mass or soft tissue mass. When compared with ambulatory patients with MS, nonambulatory patients with MS had deficits in TBBMC and FFM (P < 0.01 and P < 0.01, respectively). The difference in TBBMC was largely caused by the difference in fat-free mass, whereas the difference in FFM was largely caused by the difference in glucocorticoid use based on analysis of covariance. We conclude that in patients with multiple sclerosis, physical disuse is the main determinant for the reduction in bone mass. Glucocorticoid treatment is the major determinant of the reduction in fat-free mass and thus also contributes to the reduction in bone mass.

Adipose Tissue↗
PubMed1997

Dizocilpine maleate, an N-methyl-D-aspartate antagonist, inhibits dipsogenic responses and C-Fos expression induced by intracerebral infusion of angiotensin II.

The interactions between dizocipline, an N-methyl-D-aspartate open channel antagonist, and the induction of water drinking and c-fos expression by intracerebroventricular (i.c.v.) infusion of angiotensin II have been studied. Pretreating male rats with i.c.v. dizocilpine maleate (100 or 300 nmol) or tenocyclidine (150 nmol), both non-competitive N-methyl-D-aspartate antagonists, inhibited the subsequent dipsogenic response to i.c.v. angiotensin II (125 or 50 pmol, 5-10 min later). Dizocilpine also decreased the angiotensin II-evoked expression of c-fos in the median preoptic nucleus, supraoptic nucleus and the medial (parvicellular) and lateral (magnocellular) parts of the hypothalamic paraventricular nucleus, as well as in the nucleus of the solitary tract and the lateral parabrachial nucleus. Double staining showed that suppression of c-fos expression occurred in N-methyl-D-aspartate R1 receptor containing neurons in the hypothalamus. Pretreating rats with any of three competitive glutamate antagonists (2-amino-5-phosphonopentanoic acid, 60 or 160 nmol; gamma-D-glutamylglyine, 400 nmol; (DL-3/(R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, 0.1 nmol) or the glycine site antagonist 7-chlorokynurenic acid had no effects on angiotensin II-induced drinking. Neither did pretreating rats with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid antagonist 6-cyano-7-nitroquinoxaline-2,3-dione [two infusions, 30 min (240 nmol) and 5 min (160 nmol) before angiotensin II]. To eliminate cross-reactivity of dizocilpine with nicotinic receptors, animals were pretreated with nicotinic acetylcholine blocker mecamylamine (250 nmol, i.c.v.), but this had no effect on angiotensin II-dependent drinking or c-fos expression. These results suggest that an N-methyl-D-aspartate-type glutamate receptor is implicated in the dipsogenic and cellular responses to i.c.v. angiotensin II, and point to the existence of a novel set of interactions between excitatory amino acids and this neuropeptide.

Angiotensin II↗
PubMed1997

Increased sodium appetite stimulates c-fos expression in the organum vasculosum of the lamina terminalis.

The relation between c-fos expression in the forebrain of Lister hooded rats and water and NaCl intakes was examined in response to systemic injection of angiotensin II, desoxycorticosterone, angiotensin II and desoxycorticosterone together, frusemide or low sodium diet, all treatments that induce a sodium appetite. Angiotensin II (1 mg/kg subcutaneously) caused significant increases in the 1-h intakes of water and 1.8% NaCl compared to controls, the effect on water intake being the greater. There was a similar increase in NaCl intake after four days' treatment with desoxycorticosterone (20 mg pellet subcutaneously) but water intake was not increased. The NaCl intake of rats given angiotensin II following desoxycorticosterone treatment was approximately the sum of the intakes after angiotensin II or desoxycorticosterone alone, but the water intake was slightly less than after angiotensin II alone. Frusemide pretreatment (4 mg/kg subcutaneously) caused an NaCl intake similar to that following angiotensin II and desoxycorticosterone but water intake was little affected. Low dietary sodium also increased salt appetite, as expected. These treatments were repeated in rats that were not allowed to drink NaCl, after which the brains were processed for c-fos immunocytochemistry. This showed intense staining of the subfornical organ, median preoptic nucleus, organum vasculosum of the laminal terminalis, paraventricular nucleus and supraoptic nucleus after subcutanous angiotensin II. Animals given angiotensin II following desoxycorticosterone pretreatment showed patterns of c-fos expression that did not differ from those of angiotensin II alone. Treatment with desoxycorticosterone alone produced intense staining in the organum vasculosum of the laminal terminalis and some staining in the median preoptic nucleus. Frusemide gave a similar pattern of staining to desoxycorticosterone, stimulating c-fos expression in the same regions but to a lesser extent. A low salt diet resulted in increased c-fos expression only in the organum vasculosum of the laminal terminalis. Therefore, five different treatments that induced increased sodium appetite evoked distinct patterns of c-fos expression in the anteroventral region of the third ventricle of the rat forebrain. Since the common feature was induction of c-fos in the organum vasculosum of the laminal terminalis, these results suggest a key role for this structure in the development of increased sodium appetite.

Angiotensin II↗
PubMed1997

Angiotensin II interacts with nitric oxide-cyclic GMP pathway in the central control of drinking behaviour: mapping with c-fos and NADPH-diaphorase.

Recognition of the role of nitric oxide in cell-to-cell communication has changed the concept of traditional neurotransmission. We have shown previously that N-methyl-D-aspartate receptors mediate dipsogenic responses and c-Fos expression induced by intracerebroventricular infusion of angiotensin II. Since these receptors are known to be linked to the nitric oxide-cyclic GMP pathway, the present study explores the contribution of this path to the behavioural and cellular effects of intracerebroventricular angiotensin II by using behavioural testing, NADPH-diaphorase histochemistry and immunocytochemical staining for the immediate-early gene, c-fos. N(G)-nitro-L-arginine methyl ester (125 and 250 microg, intracerebroventricular), an inhibitor of nitric oxide synthase, and Methylene Blue (100 microg), an inhibitor of guanylate cyclase activation, antagonized water intake induced by intracerebroventricular injection of 25 pmol angiotensin II. The effects of N(G)-nitro-L-arginine methyl ester were reversed by co-injection of L-arginine, the substrate for nitric oxide synthase. However, N(G)-nitro-L-arginine methyl ester did not alter the pattern of angiotensin II-induced c-fos expression in the organum vasculosum of the lamina terminalis, median preoptic nucleus, hypothalamic paraventricular nucleus and supraoptic nucleus. Double staining with NADPH-diaphorase histochemistry and c-Fos immunocytochemistry showed that neurons staining for both were localized to the anterior third ventricle. However, only 19-25% of the c-Fos-positive neurons expressed NADPH. There were also substantial numbers of neurons in which angiotensin II induced c-Fos that were NADPH-negative. Extensive co-distribution of NADPH-diaphorase-stained cells and those expressing c-fos in response to intracerebroventricular injection of angiotensin II, especially in the median preoptic nucleus, imply that nitric oxide might participate in the mechanism of angiotensin II-induced drinking behaviour. However, a low rate of co-localization of the two markers to individual cells suggests that angiotensin II stimulated the production of nitric oxide and c-Fos in different populations of neurons. Since our previous results showed that glutamate blockade, but not nitric oxide synthase inhibition, suppressed angiotensin II-induced c-Fos, the experiments reported here further suggest that nitric oxide release is not an essential requirement for the expression of c-fos elicited by angiotensin II. They also provide evidence that the dipsogenic and c-Fos responses to angiotensin II are dissociated at a cellular level.

Angiotensin II↗
PubMed1997

Amyloid deposition is delayed in mice with targeted deletion of the serum amyloid P component gene.

The tissue amyloid deposits that characterize systemic amyloidosis, Alzheimer's disease and the transmissible spongiform encephalopathies always contain serum amyloid P component (SAP) bound to the amyloid fibrils. We have previously proposed that this normal plasma protein may contribute to amyloidogenesis by stabilizing the deposits. Here we show that the induction of reactive amyloidosis is retarded in mice with targeted deletion of the SAP gene. This first demonstration of the participation of SAP in pathogenesis of amyloidosis in vivo confirms that inhibition of SAP binding to amyloid fibrils is an attractive therapeutic target in a range of serious human diseases.

Amyloid↗
PubMed1997

Serum amyloid A protein is a clinically useful indicator of acute renal allograft rejection.

BACKGROUND: Early diagnosis of acute rejection after renal transplantation is important. There is evidence that measurement of the acute phase proteins, C-reactive protein (CRP) and serum amyloid A protein (SAA) is helpful. METHODS: In 64 consecutive patients, CRP was measured in a routine clinical system (Technicon RA1000, Bayer) and SAA in a new sensitive automated immunoassay on the Abbott IMx instrument, daily or on alternate days for 30 days after renal transplantation. RESULTS: Patients all received triple immunosuppression with cyclosporin, azathioprine, and prednisolone and all mounted a post-surgical acute phase response of SAA, but the CRP response was reduced or absent. Serum creatinine rose significantly in 36 patients, leading to treatment for first rejection. Thirty of these episodes were confirmed rejection, three were definitely not and three were uncertain. SAA. normally < 10 mg/l, rose to more than 100 mg/l in all episodes except when rejection was definitely absent. In six cases SAA rose above 100 mg/l 1-3 days before the rise in creatinine leading to antirejection therapy, and only twice did creatinine rise 1 day before SAA. In contrast, CRP responses to rejection were modest or absent. In four patients there were SAA and CRP responses unrelated to rejection, three associated with intercurrent infection and one with administration of antilymphocyte globulin. There were also two unexplained isolated spikes of SAA. CONCLUSIONS: SAA is a sensitive marker of acute renal allograft rejection. It is not specific, but the differential behaviour of CRP in patients receiving cyclosporin helps to distinguish infection from rejection. Availability of rapid assays for these analytes should facilitate management of renal allograft recipients.

Acute Disease↗
PubMed1997

Short-term outcome of major depression: I. Comorbidity and severity at presentation as predictors of persistent disorder.

OBJECTIVE: To determine whether there is a pattern of clinical characteristics at presentation that specifically predicts persistent major depression at 36 weeks follow-up. METHOD: Sixty-eight consecutive cases with a first episode DSM-III-R diagnosis of major depression were interviewed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode version and completed the mood and feelings self-report depression questionnaire (MFQ) at presentation and again at 36 weeks. RESULTS: At presentation, 63 (93%) had one or more comorbid psychiatric disorders (median = 3). At 36 weeks, 17 (25%) cases were recovered; 17 (25%) continued to meet criteria for one or more psychiatric disorder but not major depression; 34 (50%) still met criteria for DSM-III-R major depression, of whom 25 (73%) had been persistently depressed and 9 (27%) had recovered and subsequently relapsed. Major depression at follow-up was specifically predicted by the additive effect of three features at presentation, comorbid obsessive-compulsive disorder, higher MFQ score, and being older. Comorbid oppositional defiant disorder at presentation was a significant predictor of persistent psychiatric disorder. Individuals with persistent depression (n = 25) were more likely to have a longer duration of illness before presentation. CONCLUSION: Systematic assessment of comorbid psychiatric conditions at initial interview, together with the use, in older subjects, of a self-report questionnaire to determine subjective severity, will provide valid clinical information concerning the potential short-term outcome of major depression.

Adolescent↗
PubMed1997

Short-term outcome of major depression: II. Life events, family dysfunction, and friendship difficulties as predictors of persistent disorder.

OBJECTIVE: To determine whether there is a pattern of social characteristics that specifically predicts persistent major depression at 36 weeks follow-up. METHOD: Sixty-eight consecutive cases with a first-episode DSM-III-R diagnosis of major depression completed a life events and friendship difficulties interview at presentation and again at 36 weeks. RESULTS: Four factors were associated with persistent psychiatric disorder in general: lack of a maternal confiding relationship with current partner, family dysfunction and poor friendships at presentation, and severely disappointing events between presentation and follow-up. There was no association between these adverse experiences. No combination of long-term or recent life events or difficulties was, however, specifically associated with persistent depression. CONCLUSION: Nonsocial factors may need to be taken into account to specifically explain the phenotypic persistence of major depressive disorder in first-episode nonrecovered cases within a year of presentation. Psychosocial interventions with first-degree relatives and current close friendships should be considered as a part of the treatment strategy for first-episode major depression.

Adolescent↗
PubMed1997

Risperidone dose and blood level variability: accumulation effects and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting.

Risperidone blood levels were measured every 2 weeks after initiation of therapy in 24 refractory chronic schizophrenic patients referred to a locked, skilled nursing facility for long-term treatment. Blood levels were assessed on 285 occasions over a 1- to 16-month treatment program. Drug plasma level increases peaked by 2 months for risperidone at 334% and by 6 months for 9-hydroxy-risperidone at 104% over the baseline levels. Total blood levels (risperidone plus 9-hydroxy-risperidone) peaked at 111% increase at 6 months and then declined 8% per month to 12 months, stabilizing at a value 31% higher than the initial value. Significant dose to blood level interindividual variation was noted. Considerable blood level variation was evident in single blood level sample determinations. The results suggest the value of risperidone blood levels, consideration of reduction of initial recommended starting dosages, and a need to optimize risperidone dosage approaches individually to patients.

Adult↗
PubMed1996

Studying the central actions of angiotensin using the expression of immediate-early genes: expectations and limitations.

Intracerebral infusions of angiotensin II (Ang-II) elicit a widespread but discrete expression of c-fos (and other immediate-early genes: IEGs) in the basal forebrain and brainstem. This has given us a new approach to the study of the central actions of Ang-II (and other peptides). It is unlikely that the dipsogenic response to Ang-II is directly related to c-fos expression in the AV3V, since the onset of behaviour occurs much before that of gene expression, and suppression of drinking by preloading rats with water does not alter Ang-II-induced c-fos in this part of the brain. Whether endocrine or cardiovascular actions are directly related to c-fos needs to be established. Water intake inhibits c-fos in the SON and PVN; whether this is a direct interaction between Ang-II and altered osmolality on magnocellular neurons or a secondary event of an action elsewhere (e.g., in the AV3V) remains uncertain. AV3V (median preoptic nucleus) lesions also inhibit Ang-II-evoked c-fos in the SON and PVN as well as in brainstem Ang-II sensitive sites such as the NTS and parabrachial nucleus, suggesting that the AV3V may be a nodal site for the distributed action of Ang-II. The rapid dipsogenic effects of Ang-II may involve glutamate receptors, since i.c.v. dizocilpine (an NMDA open channel antagonist) reduces both drinking and c-fos expression after i.c.v. Ang-II. This relatively new IEG technique acts as an anatomical and temporally specific marker of neuronal response to Ang-II, and has already added to knowledge about the central actions of Ang-II at the level of the neuron. Combining this approach with other methods allows cellular events in the brain to be related to the functional effects of Ang-II and its adaptive role in regulating water and salt metabolism.

Angiotensin II↗