A new era for giant cell arteritis.

The landscape of the investigation and management of giant cell arteritis (GCA) is advancing. In this review we will outline the recent advances by searching the current English literature for relevant articles using key words of giant cell arteritis, temporal arteritis, Horton's disease, investigation, and treatment. Delay in diagnosis, diagnostic uncertainty and glucocorticoid (GC) morbidity are among the highest concerns of clinicians and patients in this disease area. The positive news is that fast track pathways, imaging techniques and new therapies are emerging for routine management of GCA. Future directions for intervention in the treatment paradigm will be discussed.

Distinct signal transduction pathways for GABA-induced GABA(A) receptor down-regulation and uncoupling in neuronal culture: a role for voltage-gated calcium channels.

Changes in GABA receptor (GABA(A)R) gene expression are detected in animal models of epilepsy, anxiety and in post-mortem schizophrenic brain, suggesting a role for GABA(A)R regulation in neurological disorders. Persistent (48 h) exposure of brain neurons in culture to GABA results in down-regulation of GABA(A)R number and uncoupling of GABA and benzodiazepine (BZD) binding sites. Given the central role of GABA(A)Rs in fast inhibitory synaptic transmission, GABA(A)R down-regulation and uncoupling are potentially important mechanisms of regulating neuronal excitability, yet the molecular mechanisms remain unknown. In this report we show that treatment of brain neurons in culture with tetrodotoxin, glutamate receptor antagonists, or depolarization with 25 mM K(+) fails to alter GABA(A)R number or coupling. Changes in neuronal activity or membrane potential are therefore not sufficient to induce either GABA(A)R down-regulation or uncoupling. Nifedipine, a voltage-gated Ca(2+) channel (VGCC) blocker, inhibits both GABA-induced increases in [Ca(2+)](i) and GABA(A)R down-regulation, suggesting that VGCC activation is required for GABA(A)R down-regulation. Depolarization with 25 mM K(+) produces a sustained increase in intracellular [Ca(2+)] without causing GABA(A)R down-regulation, suggesting that activation of VGCCs is not sufficient to produce GABA(A)R down-regulation. In contrast to GABA(A)R down-regulation, nifedipine and 25 mM K(+) fail to inhibit GABA-induced uncoupling, demonstrating that GABA-induced GABA(A)R down-regulation and uncoupling are mediated by independent molecular events. Therefore, GABA(A)R activation initiates at least two distinct signal transduction pathways, one of which involves elevation of intracellular [Ca(2+)] through VGCCs.

Induction of gastric ornithine decarboxylase in early weaning rats.

BACKGROUND/AIMS: Early weaning has been shown to induce intestinal ornithine decarboxylase (ODC) activities and cell proliferation in rats. No information is available about the effect of early weaning on ODC activity in the stomach. METHODS: Suckling rats were prematurely weaned on postnatal day 15 and followed through day 21. Oxyntic gland mucosa of stomach was obtained on postnatal days 15, 16, 18 and 21 (days 0, 1, 3 and 6 after early weaning) and assayed for ODC activity, DNA, protein and pepsinogen activity. alpha-Difluoromethyl ornithine (DFMO), a specific ODC inhibitor, was given orally to early-weaned pups and its resultant effects were assessed on days 1 and 6 after early weaning. RESULTS: Stomach mucosal wet weight, DNA, protein and pepsinogen activities significantly increased on day 6 after early weaning. ODC activity increased on days 1, 3, and 6 after early weaning, with the highest increase (3-fold) on day 1 when compared to controls. The increases of ODC activity, DNA and protein contents as induced by early weaning were significantly suppressed when pups were exposed to DFMO. However, no suppression of pepsinogen activity was observed. CONCLUSIONS: Our study shows that early weaning induces ODC activity and functional growth in the stomach. Gastric ODC activity is essential in gastric mucosal growth processes but not in differentiation. The induction of stomach ODC may act as an early marker in the growth of stomach mucosa induced by early weaning in rats.

Mechanisms involved in the immunotoxicity induced by dermal application of JP-8 jet fuel.

Dermal application of JP-8 jet fuel induces immune suppression. Classic delayed-type hypersensitivity as well as the induction of contact hypersensitivity to allergens applied to the shaved skin of JP-8-treated mice is suppressed. In addition, the ability of T cells isolated from JP-8-treated mice to proliferate in vitro is suppressed. Here we focused on further characterizing the immunotoxicity induced by JP-8 exposure and determining the mechanism involved. Suppression of T-cell proliferation was first noted 3 to 4 days after a single JP-8 treatment and lasted for approximately 3 weeks, at which time T-cell proliferation returned to normal. Cellular immune reactions appear to be more susceptible to the immunosuppressive effects of JP-8, as antibody production in JP-8-treated mice was identical to that found in normal controls. The mechanism through which dermal application of JP-8 suppresses cell-mediated immune reactions appears to be via the release of immune biological-response modifiers. Blocking the production of prostaglandin E(2) with a selective cyclooxygenase-2 inhibitor abrogated JP-8-induced immune suppression. Neutralizing the activity of interleukin-10 with a highly specific monoclonal antibody also blocked JP-8-induced immune suppression. Furthermore, injecting JP-8-treated mice with recombinant interleukin-12, a cytokine that drives cell-mediated immune reactions in vivo, overcame the immunotoxic effects of JP-8 and restored immune function. These data indicate that immune suppressive cytokines, presumably produced by JP-8-treated epidermal cells, are responsible for immune suppression in JP-8-treated mice and that blocking and/or neutralizing their production in vivo overcomes the immunotoxic effects of JP-8.

Turnover and down-regulation of GABA(A) receptor alpha1, beta2S, and gamma1 subunit mRNAs by neurons in culture.

Benzodiazepines (BZDs), barbiturates, ethanol, and general anesthetics potentiate the action of gamma-aminobutyric acid (GABA) at the type A GABA receptor (GABA(A)R) and have profound effects on mood, arousal, and susceptibility to seizures. GABA(A)R number and subunit mRNA levels change in animal models of epilepsy and anxiety and following exposure to GABA(A)R agonists and positive modulators, but the mechanism of receptor down-regulation remains unknown. Persistent exposure (48 h) of brain neurons in primary culture to GABA results in a 30% decrease in the levels of mRNA encoding the alpha1, beta2S, and gamma1 GABA(A)R subunit isoforms, which form a receptor enhanced by nonselective BZDs. Down-regulation of alpha1 mRNA (t1/2 = 8 h) precedes down-regulation of receptor number (t1/2 = 25 h), suggesting that GABA-induced GABA(A)R down-regulation is a consequence of decreased mRNA levels. The apparent half-life of the alpha1 mRNA in the presence of alpha-amanitin (9 h) is consistent with the time course of alpha1 mRNA down-regulation. Moreover, the stability of the alpha1, beta2S, and gamma1 subunit mRNAs is not altered by chronic GABA exposure. The results demonstrate that GABA(A)R subunit mRNA down-regulation is not a consequence of accelerated mRNA degradation and argue that GABA-induced GABA(A)R down-regulation is due to inhibition of transcription.

Potassium-induced secretion of melanocyte-stimulating hormone from the melanotrophs of the neurointermediate lobe of the lizard Anolis carolinensis.

Secretion of melanocyte-stimulating hormone (MSH) from the melanotrophs of the neurointermediate lobe (NIL) of the lizard Anolis carolinensis was studied to investigate the role of membrane potential and extracellular calcium ions in the control of secretion in this species. MSH secretion was monitored from perifused NILs which had been in organ culture for 7-14 days prior to experiment to allow the nerve terminals present in the tissue to degenerate. Elevation of the K(+) concentration in the perifusate induced a marked increase in MSH secretion. Perifusion of the cultured NILs with a nominally Ca-free solution did not reduce basal MSH secretion but blocked K-induced secretion. Moreover, nimodipine, an antagonist of voltage-gated Ca(2+) channels, inhibited K-induced secretion, whereas BAY K 8644, a Ca(2+) channel agonist, potentiated it; but neither drug affected basal secretion. High ¿K(+) perifusate also stimulated MSH secretion from freshly excised (acute) NILs. Furthermore, in these preparations nominally Ca-free solution reduced basal secretion by 40% in addition to blocking K-induced secretion. As in the cultured NILs, nimodipine blocked and BAY K 8644 potentiated K-induced secretion in the acute NILs while not affecting basal secretion. The results from the cultured NILs are consistent with the hypothesis that stimulated MSH secretion from the melanotrophs of the anole is dependent upon Ca(2+) influx through voltage-gated calcium channels. The qualitatively similar results obtained from the acute NILs in response to high ¿K(+), nimodipine, and BAY K 8644 suggest that, for the most part, what is being observed are the direct effects of these substances on the melanotrophs. Basal secretion of MSH in cultured NILs is significantly less than that in the acute preparations. The calcium-sensitive fraction of basal secretion present in acute NILs may require the presence of nerve terminals.

Verapamil decreases ethanol-induced gastric acid secretion in rats.

The present study examined the effect of verapamil, a calcium channel blocker, on gastric acid secretion and circulating gastrin levels in rats after ethanol challenge. Normal saline or verapamil were given intraperitoneally to different groups of rats at 1 min, 1 h or 2 h before the administration of ethanol. One hour later, gastrin and gastric acid concentrations were determined. Regression analysis revealed the relationship between gastric acid output and serum gastrin levels in the group receiving saline intraperitoneally and ethanol orogastrically and the group receiving saline both intraperitoneally and orogastrically is similar. The slope of the regression line of the ethanol-challenged group treated with verapamil, however, was significantly lower than the slopes of the other two groups (P less than 0.001). Furthermore, verapamil decreased gastrin levels and acid output significantly in the ethanol-challenged group (P less than 0.01). When given 10 min prior to ethanol challenge, verapamil had a greater acid suppression effect than when given 60 or 120 min before the challenge. Verapamil at 20 mg/kg was more effective in acid secretion than at 10 mg/kg bodyweight, when administered 60 min before ethanol challenge.

Elevated cholesterol and decreased sterol carrier protein-2 in peroxisomes from AS-30D hepatoma compared to normal rat liver.

Peroxisomes were isolated from AS-30D hepatoma and compared to normal rat liver cells for the purpose of investigating the cholesterol accumulation in the hepatoma cells. Cholesterol was found to be approximately 10-fold higher relative to protein in AS-30D peroxisomes as compared to peroxisomes from normal liver. The peroxisomes from the hepatoma cells were found to be more stable; catalase was not released from these peroxisomes during isolation or osmotic shock of the peroxisomal fraction. The elevated cholesterol level may stabilize the peroxisomal membrane. Sterol carrier protein-2 (SCP-2) levels were measured using a radioimmunoassay (RIA), which indicated the highest concentration of SCP-2 to be in peroxisomes. Hepatoma peroxisomes had a lower concentration of SCP-2 (2.5 micrograms/mg) than normal liver peroxisomes (8 micrograms/mg). Approximately half of all SCP-2 detected was found to be soluble in both hepatoma and normal rat liver cells. Immunoblots from both rat liver and AS-30D fractions demonstrated the presence of the 14-kDa form of SCP-2. The liver fractions also had a 57-kDa immunoreactive protein, which was barely detectable in the AS-30D fractions. The low abundance of the high molecular weight form of SCP-2 from hepatoma peroxisomes and the lower amounts of SCP-2 detected in the AS-30D peroxisomes may be related to the accumulation of cholesterol in the cells.

Histopathologic features of the liver in pediatric acquired immune deficiency syndrome.

Autopsy and liver biopsy specimens from 30 pediatric patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC) were retrospectively reviewed. Of 28 cases with histologic abnormalities, the following findings were noted singly or in combination: giant-cell transformation, cytomegalovirus inclusions, Kaposi's sarcoma, diffuse lymphoplasmocytic infiltrate, granulomatous hepatitis, mild portal inflammation, necrosis around central veins, steatosis, and cholestasis. For the most part, abnormalities in the liver were not predictive of those in other organs, but the two children with the diffuse parenchymal lymphoplasmocytic infiltrate also had lymphoid interstitial pneumonitis (LIP). Liver histopathology in pediatric patients with AIDS shares some features with that in adults, but appreciable differences are noted. In particular, these differences include the higher frequency of giant-cell transformation and the lower frequency of granulomas in children and the observation of diffuse lymphoplasmocytic infiltrate associated with LIP.

Seminal vesicle and coagulating gland growth induced by intraperitoneal inoculation of fungi in mice.

The effect of fungi on the growth of body organs in mice was investigated. Single, intraperitoneal injections of yeasts (Cryptococcus albidus, Saccharomyces cerevisiae, Schizosaccharomyces octosporus) or molds (Aspergillus niger, Geotrichum candidum, Mucor haemalis) induced an increase in the mass of seminal vesicles and coagulating glands independent of whole body weight changes in mice.

Glycosaminoglycans of the rat renomedullary interstitium: ultrastructural and biochemical observations.

The rat renal papillary interstitum which contains abundant proteoglycans is a unique area important in renal function. These proteoglycans were studied ultrastructurally by ruthenium red fixation and staining and phosphate-buffered fixation before and after enzyme digestion. A tissue culture of rat renomedullary interstitial cells, the predominant cell of the renal papillary interstitum, was studied for its ability to synthesize proteoglycans and the proteoglycans were then analyzed. Tissue slices of whole rat renal inner medulla were also evaluated for their synthetic ability. In combination, these studies indicate that the dominant glycosaminoglycan is hyaluronic acid. The tissue culture of rat renal medullary interstitial cells synthesized glycosaminoglycans and on analysis, hyaluronic acid was found to be the chief glycosaminoglycan secreted by the renomedullary interstitial cells. Combined with the removal of the proteoglycans from tissue by leech hyaluronidase and testicular hyaluronidase, this suggests that the dominant glycosaminoglycan is hyaluronic acid. Hyaluronic acid is also synthesized by the intact papilla confirming the findings with the tissue culture. However, in addition, sulfated glycosaminoglycans were also synthesized by the intact papilla, presumably the product of the noninterstitial components of the papilla.

Seminal vesicle growth induced by Ascaris suum infection.

This study was designed to determine the effect of Ascaris suum infection upon growth of mouse vesicular glands. Mice were infected with varying dosages of A. suum eggs and killed after six weeks. Results indicated a dose dependent increase in seminal vesicle weight, independent of total body weight.

Pulmonary tuberculosis and bronchocentric granulomatosis.

Bronchocentric granulomatosis (BG) is an uncommon inflammatory lesion of unknown etiology defined on morphologic grounds by the presence of necrotizing granulomata centered on bronchi and bronchioles. We report the typical pathologic features of BG in a patient with tuberculosis. Mycobacterial and other types of infection should be excluded by appropriate stains and cultures in all patients with BG on lung biopsy, especially those who are nonasthmatic.