Biological lung volume reduction: a new bronchoscopic therapy for advanced emphysema

BACKGROUND: Biological lung volume reduction (BLVR) using biological reagents to remodel and shrink damaged regions of lung has previously been accomplished in sheep with experimental pulmonary emphysema. This report summarizes the initial clinical experience including a 3-month follow-up using this technique in humans. METHODS: An open-label phase 1 trial designed to evaluate the safety of BLVR in patients with advanced heterogeneous emphysema enrolled six patients. Of these, three patients received unilateral treatment at two pulmonary subsegments (group 1) and three patients received unilateral treatment at four pulmonary subsegments (group 2). The incidence of adverse events and changes in pulmonary function test results, symptoms, and exercise capacity were evaluated. RESULTS: The mean (+/- SD) age of the six men enrolled in the study was 66 +/- 5.7 years (age range, 57 to 73 years). BLVR was well tolerated in both treatment groups and was not associated with any serious complications. All patients were discharged from the hospital on posttreatment day 1. Although the primary purpose of the study was to examine safety, improvements were observed in mean vital capacity (+7.2 +/- 9.5%; range, -2% to + 19%), mean residual volume (RV) [-7.8 +/- 8.5%; range, + 1% to -22%], mean RV/total lung capacity ratio (-6.6 +/- 4.7%; range, -1% to -15%), mean 6-min walk distance (+14.5 +/- 18.5%; range, 0 to + 51%), and in mean dyspnea score. On average, group 2 patients experienced greater benefit from BLVR than group 1 patients, suggesting a dose-response pattern. CONCLUSIONS: Preliminary results indicate that BLVR can be safe and may produce benefits in appropriately selected patients with advanced heterogeneous emphysema.     

Interferon beta treatment: Bioavailability and antiviral activity in multiple sclerosis patients

Viral infections have been appointed as the main component of environmental susceptibility to multiple sclerosis (MS). Interferon beta is an immunomudulatory treatment that is able to modify the natural course of the disease; nonetheless, its mechanism of action in not well established yet. The objectives of the present study were (1) to evaluate the bioavailability of interferon beta through the measurement of the expression of myxovirus resistance protein (MxA), metalloproteinase 9 (MMP-9), and its inhibitor (TIMP-1); (2) to analyze its antiviral efficiency through the measurement of human herpesvirus-6 (HHV-6) prevalence; and (3) to correlate both parameters (bioavailability and antiviral efficiency) with the relapse rate in multiple sclerosis (MS) patients treated with interferon beta. Pairs of blood and serum samples were collected from 54 MS patients during five visits in 1 year: one before the start of the treatment and four during interferon beta treatment. Expression of MxA, MMP-9, and TIMP-1 was analyzed by quatitative real-time polymerase chain reaction (qRT-PCR) and HHV-6 genomes were detected by qPCR. The results showed a correlation between MxA and relapse rate (P = .014). MMP-9/TIMP-1 ratio was increased among the patients with relapses, and decreased among the relapse-free patients, although differences were not statistically significant. Furthermore, our results suggest a possible role for HHV-6 in MS, because 42.8% of patients with viral reactivations experienced at least one relapse versus 22.5% of patients without viral reactivations. Lastly, regarding the antiviral effectiveness of the interferon beta, the HHV-6 prevalence decreased from 58% to 36% in PBMCs and from 18.5% to 12.2% in sera; furthermore, a good correlation with the bioavailability of interferon beta was found, because patients with a decrease in HHV-6 prevalence had higher levels of MxA (P = .046, at the third month).     

Activated protein C attenuates microvascular injury during systemic hypoxia

In response to hypoxia, an inflammatory cascade is initiated and microvascular injury ensues. Specifically, within 10 min, leukocyte adherence to the endothelium begins, and leukocyte emigration and vascular leak soon follow. Activated protein C (APC) has been reported to have both anticoagulant and anti-inflammatory properties. Activated protein C is best described in its role as a treatment for sepsis. However, it has been used, with some success, in experimental models of hypoxic injury. We hypothesized that APC would be protective against microvascular injury during systemic hypoxia. Randomized prospective animal study. Adult male Sprague-Dawley rats. To characterize the microvascular response to APC exposure during hypoxia, four rat groups were used: saline control, APC infusion alone (100 mg/kg bolus), hypoxia alone (10% O2), and simultaneous hypoxia + APC infusion. Measurements of leukocyte adherence (no. per 100-microm venule), leukocyte emigration (no. per 4,000 microm(2)), and venular leak by fluorescein isothiacyanate-labeled albumin (Fo/Fi) were performed during intravital microscopy of the intact venular bed. Leukocyte adherence decreased from 14.5 (+/-1.2) cells/100-microm venule in hypoxic rats to 4.4 (+/-1.5) cells/100-microm venule in those treated with both hypoxic gas and APC infusion (P < 0.001). Similarly, leukocyte emigration in hypoxic rats reached 12.3 (+/- 2.2) cells/4,000-microm(2) venule, but was reduced to 3.5 (+/-0.3) cells/4,000-microm(2) venule (P <.001). Venular permeability to protein was also significantly decreased in the APC-treated group from 0.82 (+/-0.14) to 0.25 (+/-0.14) (P < 0.001). The infusion of APC attenuates the inflammatory response during systemic hypoxia at the microvascular level, as evidenced by measurements of leukocyte adherence, emigration, and venular permeability. Further investigation is needed to examine the potential role of APC in the treatment of hypoxic injury.     

Dual and selective actions of glucocorticoids upon basal and stimulated growth hormone release in man

In humans, corticoids suppress growth and growth hormone (GH) secretion elicited by a variety of stimuli, while in the rat they potentiate both in vivo and in vitro GH release. To further study this problem, growth-hormone-releasing hormone (GHRH) tests were performed in 6 nonobese Cushing's syndrome patients and 6 controls. The normal GHRH-induced GH secretion was completely abolished in the Cushing's syndrome group. To study the action of shorter corticoid exposures, 34 volunteers were subjected to four tests each: placebo treatment (control); dexamethasone (Dex) administration 4 mg i.v., 3 h before; Dex 8 mg p.o., 12 h before, and Dex 22 mg p.o. over the 2 days before the pituitary challenge that was always administered at 0 min (12.00 h). In the first test (n = 9), GHRH (1 microgram/kg i.v.) induced a GH peak of 14.5 +/- 3.8 ng/ml (control) that was potentiated by Dex 4 mg i.v. administered 3 h before (26.4 +/- 6.8 ng/ml). On the contrary, longer Dex treatments suppress GHRH-induced GH values (6.0 +/- 1.1 ng/ml after Dex 8 mg and 1.8 +/- 0.3 ng/ml after Dex 22 mg). Clonidine administration 300 micrograms p.o. (n = 7) increased GH secretion with an area under the secretory curve (AUC) of 1,274 +/- 236 that was potentiated by Dex 4 mg i.v. given 3 h before clonidine (2,380 +/- 489) and reduced by Dex 8 mg, the reduction being significant only after 22 mg Dex (595 +/- 47).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of acute and chronic lithium treatment on amphetamine-induced dopamine increase in the nucleus accumbens and prefrontal cortex in rats as studied by microdialysis

Summary The effects of acute and chronic administration of lithium (Li) on the basal levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA), and the amphetamine-induced DA increase were assessed in the Nucleus Accumbens (NAC) and Prefrontal Cortex (PFC) by brain dialysis in freely-moving rats. Acute Li (2meq/L) was locally administered by reverse dialysis. Chronic Li (2 meq/kg) was intragastrically administered for 14 days. No effect was observed after acute Li administration. However, after chronic Li administration, the basal levels of DOPAC and the amphetamine-induced DA increase in the NAC were significantly higher in the Li-treated rats than in the saline-treated controls. In the PFC, while the amphetamine-induced DA increase was not affected by chronic Li, the basal levels of DA and DOPAC were significantly decreased after Li administration. The effects of chronic Li in the NAC could be due to increased synthesis and/or decreased release of DA, whereas in the PFC the effects could be due to a decreased synthesis of DA. The absence of effects of acute Li administration is in agreement with the therapeutic inefficacy of the acute use of the cation. The changes observed after chronic treatment in the NAC and the PFC could be related to the effects of Li on mood disorders and cognitive functions, respectively.     

Development of adrenergic receptor binding sites in brain regions of the neonatal rat: effects of prenatal or postnatal exposure to methylmercury

In order to understand the effects of developmental exposure to methylmercury on the ontogeny of synaptic function, we examined the impact of prenatal or postnatal exposure on acquisition of receptor binding sites for norepinephrine. The actions of the mercurial were both regionally- and receptor subtype-selective and depended upon the maturational profile of each region. alpha 1- alpha 2- and beta-receptor sites in the cerebellum, the region which develops last, were the most vulnerable to methylmercury. In contrast, the same receptor subtypes in the midbrain + brainstem, which develops earliest, were resistant to methylmercury. The cerebral cortex, which matures at a time midway between cerebellum and midbrain + brainstem, also displayed intermediate vulnerability to actions of methylmercury on receptors. Within the cerebellum, prenatal exposure to 1 mg/kg of methylmercury interfered the most with ontogeny of alpha 1-receptor binding, less so for alpha 2-receptors and least for beta-receptors. Lower doses of methylmercury tended to increase receptor binding for all subtypes, a fact which may contribute to promotion of neurological development seen in animals exposed to those levels. These data support the view that methylmercury exerts a dual spectrum of action on developing synapses, with promotional effects predominating at low doses and inhibitory actions at higher doses. The net effect on responsiveness to neurotransmitters is influenced, in part, by the actions on developing receptor sites which are in turn dependent upon the specific regional timetables for cellular maturation and receptor acquisition.     

Central and sympatho-adrenal responses to insulin in adult and neonatal rats

In the mature rat, subcutaneous administration of insulin (0.02 IU/g body wt.) produced hypoglycemia and a profound activation of the sympatho-adrenal pathway, as indicated by a marked depletion of adrenal catecholamines. Cellular glucopenia caused by administration of 2-deoxyglucose also produced a sympatho-adrenal response. In contrast, in 2-day-old rats, the systemic injection of insulin evoked only a small depletion of catecholamines even though severe hypoglycemia was present, and 2-deoxyglucose also produced a diminished response. The central administration of insulin at an equivalent dose (0.02 IU/g brain) stimulated brain ornithine decarboxylase activity in both neonates and adults, but was ineffective in evoking hypoglycemia or adrenal catecholamine release. These results suggest that: (a) direct interaction of insulin with its receptors in the central nervous system is not required for activation of the sympatho-adrenal pathway, and (b) the lack of sensitivity of neonatal adrenal catecholamine release to subcutaneous administration of insulin is likely associated with immaturity of splanchnic neurotransmission rather than with absence of central insulin receptors or impaired peripheral responsiveness to insulin.