Effect of the synthetic glucocorticoid, deflazacort, on body growth, pulsatile secretion of GH and thymolysis in the rat

DESIGN: Deflazacort (DFZ) is a relatively new glucocorticoid that has been reported to exhibit fewer side-effects than other commonly used corticosteroids. The present study was designed to test the effects of DFZ on thymus gland involution (thymolysis), as compared with body growth and the secretory pattern of GH in the rat. Beginning at 38 days of age, male animals were treated for 8 consecutive days by s.c. injection of DFZ (0.15mg/day), cortisone (CORT) (5mg/day) or vehicle (control, CTRL). RESULTS: Both glucocorticoids had a similar thymolytic effect and caused growth failure, but the growth rate for the DFZ group was significantly higher than that of the CORT group. On day 46, pulsatile GH secretion was quantitated by blood sampling via an indwelling catheter at 10 min intervals for 6h. GH was assayed by RIA and analyzed by multiparameter deconvolution. CORT caused an increase in pulse frequency (5.8+/-0.4 (s.e.m.)) in comparison to DFZ (4.4+/-0. 4) and CTRL (3.8+/-0.3). Both glucocorticoids significantly shortened the interval between secretory bursts. In CTRL animals the interval between bursts was 69.3+/-4.5 min. In DFZ animals this was reduced to 58.5+/-7.1 min, and in CORT rats it was further reduced to 47.0+/-2.6 min. The mass of GH secreted per burst was reduced in CORT animals (52% of CTRL), while DFZ did not alter this parameter. A similar trend was observed for total GH production, with CORT causing a reduction and DFZ not affecting the secretion. CONCLUSION: Rats treated with glucocorticoid show a profound thymolytic effect, as well as important changes in growth. While CORT suppresses GH secretion and alters its pulsatile mode of release, DFZ causes a less significant alteration in the pattern of GH secretion and does not negatively affect the overall amount of GH secreted.     

Duration of ischemia is vital for collateral development: repeated brief coronary artery occlusions in conscious dogs

The effects of two types of repeated transient coronary artery occlusions on collateral development were examined in chronically instrumented, conscious dogs. A 2-minute coronary occlusion at 32-minute intervals (group 1, n = 11) or a 15-second occlusion at 4-minute intervals (group 2, n = 7) were repeated day and night without interruption. In both groups, the total duration of coronary occlusions each day was the same (90 minutes). Before and after repetitive occlusions of either group, effects of transient 2-minute coronary occlusion on regional segment shortening in the ischemic area were examined to assess the functional state of the collateral vessels. In group 1, systolic segment shortening in the area rendered ischemic was reduced to -97.8 +/- 17.7% of the preocclusive control value during 2 minutes of coronary occlusion. After 125-478 repetitive occlusions (3-11 days), the degree of hypokinesia during the 2-minute occlusion was significantly improved to -0.6 +/- 4.6% of the preocclusive value (p less than 0.001 vs. before the repetition). In group 2, it remained unchanged even after 3,500-5,450 repetitive occlusions (11-16 days): -111.8 +/- 8.2% before and -111.4 +/- 13.8% after the repetition of 15-second occlusions (NS). The ratio of peripheral coronary arterial pressure to aortic pressure during transient-coronary occlusion, measured by selective catheterization, was significantly higher in group 1 than in group 2 (64.4 +/- 5.3% vs. 20.7 +/- 1.3%, p less than 0.001). These findings suggest that myocardial ischemia of 2 minutes but not 15 seconds is vital to provide effective stimuli for angiogenesis.     

Development of varicella vaccine

The Oka strain of varicella-zoster virus (VZV) was first isolated from vesicles of an otherwise healthy 3-year-old boy with typical varicella. The virus was passaged 11 times in human embryonic lung fibroblasts at 34 degrees C and 12 times in guinea pig embryo fibroblasts (GPEFs) at 37 degrees C. GPEFs were the only nonprimate cells tested in which some degree of viral replication occurred. The resultant virus was temperature sensitive and showed host dependency, measured as better replication in GPEFs than that shown by the parental virus. The passaged virus was used as a candidate varicella vaccine and proved safe and effective for healthy and immunocompromised children. During the follow-up of vaccinated children with acute lymphocytic leukemia, the incidence of herpes zoster (HZ) was significantly lower among children who did not have a rash after vaccination, compared with those who had a rash caused by VZV (6 [2.3%] of 260 vs. 12 [17.1%] of 70, respectively). Because of the pathogenesis of VZV, the incidence of latency and of HZ is predicted to be lower among vaccine recipients than among individuals who have experienced varicella.     

Assessment of diabetic autonomic neuropathy using twenty-four-hour spectral analysis of heart rate variability: a comparison with the findings of the Ewing battery

A power spectral analysis of heart rate variability has been applied in order to assess diabetic autonomic neuropathy and high frequency spectra are thus considered to possibly reflect vagal nerve integrity in patients with diabetes mellitus. The purpose of this study was to investigate the relationship between the findings of high frequency spectra analysis and the results of the Ewing battery. We performed 24-hour power spectral analysis using an ambulatory ECG monitoring system and standard tests in order to assess diabetic autonomic neuropathy (Ewing battery) in 18 diabetic patients to compare their diagnostic values for diabetic autonomic neuropathy. We used the high frequency amplitude (high frequency spectra; 0.15-0.40 Hz) as a direct measure of vagal nerve integrity from each hourly spectral plot. All hourly high frequency spectra decreased along with the impaired assessment of the battery, especially during the night when the high frequency spectra showed a manifest increase in patients classified as normal according to the battery. High frequency spectra during the night while asleep (22:00-05:00) and during a 24-hour period significantly correlated with the results of the battery. These values markedly decreased even in patients classified as having early vagal damage when compared with those classified as normal. High frequency spectra during night closely reflected the intrinsic vagal nerve integrity in patients with diabetes mellitus. High frequency spectra during night or a 24-hour period is a simple and sensitive measure of diabetic autonomic neuropathy and is considered to be a useful modality for detecting even early changes in autonomic dysfunction.     

Modulation of inhibitory synaptic activity by a non-alpha4beta2, non-alpha7 subtype of nicotinic receptors in the substantia gelatinosa of adult rat spinal cord

The GABA/glycine-mediated inhibitory activity in the substantia gelatinosa (SG) of the spinal cord is critical in the control of nociceptive transmission. We examined whether and how SG inhibitory activity might be regulated by neuronal nicotinic receptors (nAChRs). Patch-clamp recordings were performed in SG neurons of spinal slice preparations from adult rats. We provided electrophysiological evidence that inhibitory presynaptic terminals in the SG expressed nAChRs and their activation resulted in large increases in the frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) in over 90% SG neurons tested. The enhancement of inhibitory activity was mediated by increases in the release of GABA/glycine, and direct Ca(2+) entry through SG presynaptic nAChRs appeared to be involved. Miniature IPSC frequency could be enhanced by the nAChR agonists nicotine or cytisine. Nicotine could still elicit large increases in mIPSC frequency in the presence of the alpha4beta2 nAChR antagonist dihydro-beta-erythroidine (5 microM) and the alpha7 nAChR-selective antagonist methyllycaconitine (40 nM). However, nicotine did not produce a significant enhancement of mIPSC frequency in the presence of the broad spectrum nAChR antagonist mecamylamine (5 microM). Nicotinic agonist-evoked whole-cell currents from SG neurons and the antagonist profiles also indicated the presence of a subtype of nAChRs, which were different from the major central nervous system nAChR subtypes, i.e. alpha4beta2* or alpha7 nAChRs. Together, our results suggest that a subtype of nAChR, possibly alpha3beta4* nAChR or a new nAChR type, is highly expressed at the inhibitory presynaptic terminals in SG of adult rats and play a role in the control of inhibitory activity in SG.     

Phospholipase A2 activation enhances inhibitory synaptic transmission in rat substantia gelatinosa neurons

Phospholipase A(2) (PLA(2)) activation enhances glutamatergic excitatory synaptic transmission in substantia gelatinosa (SG) neurons, which play a pivotal role in regulating nociceptive transmission in the spinal cord. By using melittin as a tool to activate PLA(2), we examined the effect of PLA(2) activation on spontaneous inhibitory postsynaptic currents (sIPSCs) recorded at 0 mV in SG neurons of adult rat spinal cord slices by use of the whole cell patch-clamp technique. Melittin enhanced the frequency and amplitude of GABAergic and glycinergic sIPSCs. The enhancement of GABAergic but not glycinergic transmission was largely depressed by Na(+) channel blocker tetrodotoxin or glutamate-receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione and/or dl-2-amino-5-phosphonovaleric acid) and also in a Ca(2+)-free Krebs solution. The effects of melittin on glycinergic sIPSC frequency and amplitude were dose-dependent with an effective concentration of approximately 0.7 microM for half-maximal effect and were depressed by PLA(2) inhibitor 4-bromophenacyl bromide or aristolochic acid. The melittin-induced enhancement of glycinergic transmission was depressed by lipoxygenase inhibitor nordihydroguaiaretic acid but not cyclooxygenase inhibitor indomethacin. These results indicate that the activation of PLA(2) in the SG enhances GABAergic and glycinergic inhibitory transmission in SG neurons. The former action is mediated by glutamate-receptor activation and neuronal activity increase, possibly the facilitatory effect of PLA(2) activation on excitatory transmission, whereas the latter action is due to PLA(2) and subsequent lipoxygenase activation and is independent of extracellular Ca(2+). It is suggested that PLA(2) activation in the SG could enhance not only excitatory but also inhibitory transmission, resulting in the modulation of nociception.     

Do antihypertensive drugs really have antitumor effects? Baseline differences in hypertensive and non-hypertensive patients with advanced pancreatic cancer

Although the antitumor effects of antihypertensive drugs for patients with advanced pancreatic cancer (APC) have been investigated, their efficacy remains unclear. Previous studies suggest that hypertensive (HT) patients with APC are significantly older than non-HT patients with APC, and that other major baseline differences in patient characteristics which may affect prognosis exist between HT and non-HT patients. It is also possible that antihypertensive drugs lack antitumor activity. Therefore, we herein retrospectively investigated the baseline differences between HT and non-HT patients with APC. From January 2015 to April 2020, 56 patients with APC received nab-paclitaxel plus gemcitabine as first-line chemotherapy at Higashiosaka City Medical Center (Higashiosaka, Japan). Of these 56 patients, 30 were diagnosed with hypertension (HT group); the remaining 26 did not have hypertension (non-HT group). Differences between the two groups were compared and prognostic factors were evaluated. Patients in the HT group had significantly less sarcopenia, a significantly larger body mass index, were significantly older, and significantly more likely to have a regular doctor and primary site in the body and tail of the pancreas than those in the non-HT group. Although no significant difference was found in the treatment response, patients in the HT group were significantly more likely to move to second-line chemotherapy than those in the non-HT group. Survival curves showed that median overall survival (OS) in the HT group was significantly longer (10.5 months) than in the non-HT group (6.8 months, P = .04). Multivariate analysis did not identify the use of antihypertensive drugs as an independent prognostic factor of OS. We identified key baseline differences in the characteristics of APC patients with and without HT, suggesting that major selection bias could occur when investigating the efficacy of antihypertensive drugs in all populations. Therefore, it is possible that antihypertensive drugs lack antitumor activity. To determine the true efficacy of antihypertensive drugs for APC, HT, and non-HT patients in another population should be investigated, or a prospective, randomized, controlled trial conducted that is stratified by HT or non-HT status.