Pretreatment synthetic MRI features for triple-negative breast cancer.

AIM: To evaluate the quantitative parameters derived from synthetic magnetic resonance imaging (SyMRI) for predicting triple-negative breast cancer (TNBC). MATERIALS AND METHODS: This prospective study enrolled participants with invasive ductal breast carcinoma (IDBC) and separated them into a TNBC group and a Non-TNBC group. Preoperative breast MRI included both the SyMRI and conventional MRI sequences. The quantitative parameters derived from the SyMRI included T1 and T2 relaxation times, proton density (PD), and their standard deviations (SD). Clinicopathological characteristics, conventional MRI findings, and quantitative synthetic parameters were assessed for all participants. Multivariable logistic regression analysis was performed to determine the potential independent imaging predictors for TNBC preoperatively. Receiver operating characteristic (ROC) curve analysis was used to evaluate the performance of these parameters. RESULTS: A total of 231 participants with histopathological proven IDBC were included in this study (n=46 in the TNBC group and n=185 in the Non-TNBC group). The TNBC group had significantly larger tumour size (p=0.011) and more frequent intratumoural cystic or necrotic lesions (p<0.001) as compared to the Non-TNBC group. The univariate analysis showed that the TNBC tumours had significantly higher T1 (p=0.006) and T2 (p<0.001) values than Non-TNBC tumours. Subsequent multivariable analysis indicated that T2 values and the presence of cystic or necrotic lesions were the independent predictors for TNBC. CONCLUSION: The T2 from synthetic imaging and the presence of cystic degeneration or necrosis within the breast cancer may serve as potential imaging biomarkers for preoperative differentiation of TNBC from Non-TNBC.

[Identification and preliminary validation of potential biomarkers in the peripheral blood mononuclear cells of atopic dermatitis].

Objective: To explore the difference of peripheral blood mononuclear cells (PBMC) transcripts between atopic dermatitis (AD) and healthy controls, and to screen and preliminarily validate potential biomarkers of AD. Methods: From January 2021 to May 2022, blood samples from 9 AD patients and 10 healthy controls were collected from the Dermatology and Cosmetic Center of the Third Affiliated Hospital of Chongqing Medical University, ribonucleic acid-sequencing (RNA-seq) was used to determine the transcriptome and relative expression of PBMC, the differentially expressed genes (DEGs) were analyzed by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and protein-protein interaction networks (PPI) analysis, and the potential biomarkers were identified by quantitative real-time PCR (qRT-PCR). Results: The age of patients in the AD group [M (Q1, Q3)] was 26.50 (22.75, 30.50) years old, and the course of disease [M (Q1, Q3)] was 15 (10, 20) years,and the age of the healthy control group [M (Q1, Q3)] was 37.00 (27.75, 40.25) years old. Compared with healthy controls, 1 044 DEGs were detected in PBMC samples in AD group, including 668 up-regulated genes and 376 down-regulated genes. Differential variable splicing (AS) showed that mutually exclusive exons (46.74%) and skipped exon (31.01%) accounted for a large proportion. GO and KEGG enrichment analysis revealed that AD is closely linked to DEGs implicated in the inflammatory response and cytokine interaction and signal pathway. Comprehensive enrichment analysis and PPI analysis selected the expression of 8 candidate genes (CCL4, CCR3, CXCR5, NFKBIA, CXCL1, IL-1B, CCL20, LY96), which was confirmed by qRT-PCR and were consistent with that of RNA-seq. Conclusions: CCL4, CCR3, CXCR5, NFKBIA, CXCL1, IL-1B, CCL20 and LY96 might be potential biomarkers of AD, participating in the occurrence and development of AD.

[Safety and efficacy of off-pump coronary artery bypass grafting in octogenarians].

Objective: To discuss the clinical safety and efficacy about off-pump coronary artery bypass grafting (OPCABG) in octogenarians. Methods: From June 2005 to July 2014, 252 patients (male 208, female 44, with a mean age of 81.7 years old) underwent OPCABG in Beijing Anzhen Hospital who were aged 80 years or older were enrolled. Results: Eight (3.2%) patients were diagnosed as single vessel coronary artery disease (CAD), 29 cases (11.5%) were diagnosed as bifurcation vessel CAD, and 215 cases (85.3%) were multivessel CAD. One hundred and one cases (40.1%) were diagnosed as left main artery disease, among which 51 cases (20.2%) had old myocardial infarction. Two hundred and forty-eight patients belonged to Canadian Cardiovascular Society (CCS) classⅠ-Ⅲ and 4 cases to CCS class Ⅳ. One hundred and forty-five cases belonged to New York Heart Association (NYHA) classⅠ-Ⅱ and 107 cases to NYHA class Ⅲ-Ⅳ. Mean graft number was 3. Two hundred and six patients (81.7%) received total vein graft operation. Intra-aortic balloon pump (IABP) was used in 43 patients (17.1%). In-hospital death occurred in 15 cases (6.0%). Major in-hospital complications included reoperation (16 cases), re-intubation (16 cases), dialysis (11 cases), sternum infection (2 cases), atrial fibrillation (63 cases). The follow-up time was from 1 to 11 years (with a mean time of 6 years). All-cause mortality was 18.1% (43 cases). The major out-of-hospital complications included recurrent myocardial infarction (3 cases), stroke (3 cases), re-admission (27 cases) and recurrent angina pectoris (20 cases). Conclusion: OPCABG is safe and effective for myocardial revascularization in patients aged 80 years and over.

Evolution of Welding-Fume Aerosols with Time and Distance from the Source: A study was conducted on the spatiotemporal variability in welding-fume concentrations for the characterization of first- and second-hand exposure to welding fumes.

Gas metal arc welding fumes were generated from mild-steel plates and measured near the arc (30 cm), representing first-hand exposure of the welder, and farther away from the source (200 cm), representing second-hand exposure of adjacent workers. Measurements were taken during 1-min welding runs and at subsequent 5-min intervals after the welding process was stopped. Number size distributions were measured in real time. Particle mass distributions were measured using a micro-orifice uniform deposition impactor, and total mass concentrations were measured with polytetrafluorothylene filters. Membrane filters were used for collecting morphology samples for electron microscopy. Average mass concentrations measured near the arc were 45 mg/m3 and 9 mg/m3 at the farther distance. The discrepancy in concentrations at the two distances was attributed to the presence of spatter particles, which were observed only in the morphology samples near the source. As fumes aged over time, mass concentrations at the farther distance decreased by 31% (6.2 mg/m3) after 5 min and an additional 13% (5.4 mg/m3) after 10 min. Particle number and mass distributions during active welding were similar at both distances, indicating similar exposure patterns for welders and adjacent workers. Exceptions were recorded for particles smaller than 50 nm and larger than 3 µm, where concentrations were higher near the arc, indicating higher exposures of welders. These results were confirmed by microscopy analysis. As residence time increased, number concentrations decreased dramatically. In terms of particle number concentrations, second-hand exposures to welding fumes during active welding may be as high as first-hand exposures.

Effect of p53 gene polymorphism on functions of prostate cancer cells.

Prostate cancer cells were transfected with plasmids [empty plasmids, wild-type pcDNA3.1-p53 (V/V), mutant type pcDNA3.1- p53 (G/G)] to analyze the effect of p53 gene polymorphisms on the proliferation, cycle, and apoptosis of prostatic cancer cells. Empty plasmids containing wild-type pcDNA3.1-p53 (V/V) and mutant type pcDNA3.1- p53 (G/G) were used to transfect PC3 and LNCaP cells, respectively. Cell proliferation was detected at 0, 24, 48, and 72 h using the MTT method. Cells were collected at 24 and 72 h. The distribution of cell cycles in various groups was detected using flow cytometry (propidium iodide staining method) and the apoptosis rate was detected using annexin V + propidium iodide double staining. Compared with the control group, wild-type pcDNA3.1-p53 (V/V) and mutant type pcDNA3.1-p53 (G/G) showed a significant inhibitory effect on cell proliferation (P < 0.05); the inhibitory effect of the mutant type was stronger than that of the wild-type. There was no significant difference between PC3 cells and LNCaP cells. After transfection with wild-type pcDNA3.1-p53 (V/V) and mutant type pcDNA3.1-p53 (G/G), PC3 and LNCaP cells were arrested in the G0/G1 stage. Transfection with pcDNA3.1-p53 (G/G) showed a more significant effect than transfection with pcDNA3.1-p53 (V/V). Both the wild-type pcDNA3.1-p53 (V/V) and mutant-type pcDNA3.1-p53 (G/G) led to an increased apoptosis rate of PC3 and LNCaP cells. The p53 gene polymorphism affects the proliferation, apoptosis, and cycle of prostate cancer cells and may serve as a reliable index for the diagnosis and treatment of prostate cancer.

A Field Study on the Respiratory Deposition of the Nano-Sized Fraction of Mild and Stainless Steel Welding Fume Metals.

A field study was conducted to estimate the amount of Cr, Mn, and Ni deposited in the respiratory system of 44 welders in two facilities. Each worker wore a nanoparticle respiratory deposition (NRD) sampler during gas metal arc welding (GMAW) of mild and stainless steel and flux-cored arc welding (FCAW) of mild steel. Several welders also wore side-by-side NRD samplers and closed-face filter cassettes for total particulate samples. The NRD sampler estimates the aerosol's nano-fraction deposited in the respiratory system. Mn concentrations for both welding processes ranged 2.8-199 µg/m3; Ni concentrations ranged 10-51 µg/m3; and Cr concentrations ranged 40-105 µg/m3. Cr(VI) concentrations ranged between 0.5-1.3 µg/m3. For the FCAW process the largest concentrations were reported for welders working in pairs. As a consequence this often resulted in workers being exposed to their own welding fumes and to those generated from the welding partner. Overall no correlation was found between air velocity and exposure (R2 = 0.002). The estimated percentage of the nano-fraction of Mn deposited in a mild-steel-welder's respiratory system ranged between 10 and 56%. For stainless steel welding, the NRD samplers collected 59% of the total Mn, 90% of the total Cr, and 64% of the total Ni. These results indicate that most of the Cr and more than half of the Ni and Mn in the fumes were in the fraction smaller than 300 nm.

A novel method for assessing respiratory deposition of welding fume nanoparticles.

Welders are exposed to high concentrations of nanoparticles. Compared to larger particles, nanoparticles have been associated with more toxic effects at the cellular level, including the generation of more reactive oxygen species activity. Current methods for welding-fume aerosol exposures do not differentiate between the nano-fraction and the larger particles. The objectives of this work are to establish a method to estimate the respiratory deposition of the nano-fraction of selected metals in welding fumes and test this method in a laboratory setting. Manganese (Mn), Nickel (Ni), Chromium (Cr), and hexavalent chromium (Cr(VI)) are commonly found in welding fume aerosols and have been linked with severe adverse health outcomes. Inductively coupled plasma mass spectrometry (ICP-MS) and ion chromatography (IC) were evaluated as methods for analyzing the content of Mn, Ni, Cr, and Cr(VI) nanoparticles in welding fumes collected with nanoparticle respiratory deposition (NRD) samplers. NRD samplers collect nanoparticles at deposition efficiencies that closely resemble physiological deposition in the respiratory tract. The limits of detection (LODs) and quantitation (LOQs) for ICP-MS and IC were determined analytically. Mild and stainless steel welding fumes generated with a robotic welder were collected with NRD samplers inside a chamber. LODs (LOQs) for Mn, Ni, Cr, and Cr(VI) were 1.3 µg (4.43 µg), 0.4 µg (1.14 µg), 1.1 µg (3.33 µg), and 0.4 µg (1.42 µg), respectively. Recovery of spiked samples and certified welding fume reference material was greater than 95%. When testing the method, the average percentage of total mass concentrations collected by the NRD samplers was ~30% for Mn, ~50% for Cr, and ~60% for Ni, indicating that a large fraction of the metals may lie in the nanoparticle fraction. This knowledge is critical to the development of toxicological studies aimed at finding links between exposure to welding fume nanoparticles and adverse health effects. Future work will involve the validation of the method in workplace settings. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: Digestion, extraction, and analysis procedures for nylon mesh screens.].

Clinical efficacy of enhanced external counter pulsation plus sacubitril/valsartan in the treatment of patients with chronic heart failure and the effect on ankle-arm index and cardiac function.

OBJECTIVE: The aim of this study was to evaluate the clinical efficacy of enhanced external counter pulsation (EECP) plus sacubitril/valsartan in the treatment of patients with chronic heart failure (CHF) and the effect on ankle-arm index and cardiac function. PATIENTS AND METHODS: In this retrospective study, 106 patients with chronic heart failure treated in our hospital from September 2020 to April 2022 were recruited and randomly assigned to receive either sacubitril/valsartan (observation group) or EECP plus sacubitril/valsartan (combination group) alternately at the point of admission, with 53 patients in each group. Outcome measures included clinical efficacy, ankle brachial index (ABI), cardiac function indices [N-terminal brain natriuretic peptide precursor (NT-proBNP), 6 min walking distance (6MWD), left ventricular ejection fraction (LVEF)], and adverse events. RESULTS: EECP plus sacubitril/valsartan resulted in significantly higher treatment efficiency and ABI levels vs. sacubitril/valsartan (p<0.05). Patients receiving combined therapy showed significantly lower NT-proBNP levels than those given monotherapy (p<0.05). EECP plus sacubitril/valsartan resulted in longer 6MWD and higher LVEF than sacubitril/valsartan alone (p<0.05). No significant differences were observed in the adverse events between the two groups (p>0.05). CONCLUSIONS: EECP plus sacubitril/valsartan substantially improves the ABI levels, cardiac functions, and exercise tolerance of patients with chronic heart failure, with a high safety profile. EECP improves blood supply to myocardial ischemic tissues by increasing ventricular diastolic blood return and blood perfusion to ischemic myocardium, raises aortic diastolic pressure, restores pumping function, improves LVEF, and reduces NT-proBNP secretion.

Pulmonary and cardiovascular responses of rats to inhalation of a commercial antimicrobial spray containing titanium dioxide nanoparticles.

Our laboratory has previously demonstrated that application of an antimicrobial spray product containing titanium dioxide (TiO(2)) generates an aerosol of titanium dioxide in the breathing zone of the applicator. The present report describes the design of an automated spray system and the characterization of the aerosol delivered to a whole body inhalation chamber. This system produced stable airborne levels of TiO(2) particles with a median count size diameter of 110 nm. Rats were exposed to 314 mg/m(3) min (low dose), 826 mg/m(3) min (medium dose), and 3638 mg/m(3) min (high dose) of TiO(2) under the following conditions: 2.62 mg/m(3) for 2 h, 1.72 mg/m(3) 4 h/day for 2 days, and 3.79 mg/m(3) 4 h/day for 4 days, respectively. Pulmonary (breathing rate, specific airway resistance, inflammation, and lung damage) and cardiovascular (the responsiveness of the tail artery to constrictor or dilatory agents) endpoints were monitored 24 h post-exposure. No significant pulmonary or cardiovascular changes were noted at low and middle dose levels. However, the high dose caused significant increases in breathing rate, pulmonary inflammation, and lung cell injury. Results suggest that occasional consumer use of this antimicrobial spray product should not be a hazard. However, extended exposure of workers routinely applying this product to surfaces should be avoided. During application, care should be taken to minimize exposure by working under well ventilated conditions and by employing respiratory protection as needed. It would be prudent to avoid exposure to children or those with pre-existing respiratory disease.

Nanoparticle inhalation impairs endothelium-dependent vasodilation in subepicardial arterioles.

Exposure to fine particulate matter (PM, mean aerodynamic diameter

The long non-coding RNA AK001796 contributes to poor prognosis and tumor progression in hepatocellular carcinoma.

OBJECTIVE: Increasing studies have indicated the important functions of long non-coding RNAs (lncRNAs) in tumorigenesis and progression including hepatocellular carcinoma (HCC). The study aims to explore the role of long non-coding RNA AK001796 in HCC progression. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (QRT-PCR) analysis was performed to examine the lncRNA AK001796 expression in 73 cases of human HCC tissue samples and matched adjacent normal tissues. Besides, the relationship between lncRNA AK001796 expression and clinicopathologic characteristics was analyzed. Overall survival (OS) curves of patients were constructed by the Kaplan-Meier methods. Multivariate Cox regression analysis was used to evaluate independent risk factors affecting HCC prognosis. Cell proliferation and invasion abilities are analyzed by cell counting kit-8 (CCK-8) and transwell invasion assays. RESULTS: We showed that the lncRNA AK001796 expression was significantly up-regulated in HCC tissues and cell lines, compared to their controls, respectively. Higher lncRNA AK001796 expression closely correlated with tumor size (p<0.05), TNM stage (p<0.05) and the poor overall survival (OS) rate of HCC patients (p<0.05). Besides, multivariate Cox regression analysis found that lncRNA AK001796 expression was identified as an independent risk factor for HCC prognosis. In vitro, we showed that lncRNA AK001796 knockdown markedly suppressed cell proliferation and cell invasion abilities. CONCLUSIONS: Our results suggested that lncRNA AK001796 acts as a predictor of HCC prognosis and may provide an important clinical value for HCC treatment.

Novel Ca2+ dependence and time course of somatodendritic dopamine release: substantia nigra versus striatum.

Somatodendritic release of dopamine (DA) in midbrain represents a novel form of intercellular signaling that inherently differs from classic axon-terminal release. Here we report marked differences in the Ca(2+) dependence and time course of stimulated increases in extracellular DA concentration ([DA](o)) between the substantia nigra pars compacta (SNc) and striatum. Evoked [DA](o) was monitored with carbon-fiber microelectrodes and fast-scan cyclic voltammetry in brain slices. In striatum, pulse-train stimulation (10 Hz, 30 pulses) failed to evoke detectable [DA](o) in 0 or 0.5 mm Ca(2+) but elicited robust release in 1.5 mm Ca(2+). Release increased progressively in 2.0 and 2.4 mm Ca(2+). In sharp contrast, evoked [DA](o) in SNc was nearly half-maximal in 0 mm Ca(2+) and increased significantly in 0.5 mm Ca(2+). Surprisingly, somatodendritic release was maximal in 1.5 mm Ca(2+), with no change in 2.0 or 2.4 mm Ca(2+). Additionally, after single-pulse stimulation, evoked [DA](o) in striatum reached a maximum (t(max)) in <200 msec, whereas in SNc, [DA](o) continued to rise for 2-3 sec. Similarly, the time for [DA](o) to decay to 50% of maximum (t(50)) was 12-fold longer in SNc than striatum. A delayed t(max) in SNc compared with striatum persisted when DA uptake was inhibited by GBR-12909 and D(2) autoreceptors were blocked by sulpiride, although these agents eliminated the difference in t(50). Together, these data implicate different release mechanisms in striatum and SNc, with minimal Ca(2+) required to trigger prolonged DA release in SNc. Coupled with limited uptake, prolonged somatodendritic release would facilitate DA-mediated volume transmission in midbrain.

Simulation of thermal ablation by high-intensity focused ultrasound with temperature-dependent properties.

An integrated computational framework was developed in this study for modeling high-intensity focused ultrasound (HIFU) thermal ablation. The temperature field was obtained by solving the bioheat transfer equation (BHTE) through the finite element method; while, the thermal lesion was considered as a denatured material experiencing phase transformation and modeled with the latent heat. An equivalent attenuation coefficient, which considers the temperature-dependent properties of the target material and the ultrasound diffraction due to bubbles, was proposed in the nonlinear thermal transient analysis. Finally, a modified thermal dose formulation was proposed to predict the lesion size, shape and location. In-vitro thermal ablation experiments on transparent tissue phantoms at different energy levels were carried out to validate this computational framework. The temperature histories and lesion areas from the proposed model show good correlation with those from the in-vitro experiments.

Ion transport and regulation of respiratory tract fluid output in dogs.

To investigate the regulation of respiratory tract fluid output (RTFO), we collected the RTFO in an anesthetized canine model after a series of pharmacological interventions (inhibition of Na(+)-K(+)-ATPase or Na(+)-K(+)-2Cl(-) cotransporter, 250 microl) and physiological challenges (ionic and/or osmotic perturbation in airway lumen, 250 microl). Whereas 250 microl of aerosolized 0.9% saline caused a transient increase in RTFO, a 250-microl bumetanide-induced increase in RTFO was evident for 18 min and a 250-microl acetylstrophanthidin-induced increase in RTFO persisted for at least 30 min. Dry air ventilation decreased the responses of RTFO to the saline (sham) and acetylstrophanthidin intervention but not the bumetanide intervention. Delivery of 250 mosmol/kgH(2)O ion-free mannitol (250 microl) caused marked increases in RTFO that were little affected by the administration of acetylstrophanthidin or bumetanide 30 min before these challenges. A 250-microl 550 mosmol/kgH(2)O ion-free mannitol challenge caused a more marked and prolonged increase in RTFO. Thus aerosol delivery of a low dose of a cardiac glycoside or a near-isosmotic, ion-free, impermeant osmolyte solution may be therapeutically useful by increasing the clearance of secretions from the tracheobronchial airways.

Mechanisms underlying H(2)O(2)-mediated inhibition of synaptic transmission in rat hippocampal slices.

Hydrogen peroxide (H(2)O(2)) inhibits the population spike (PS) evoked by Schaffer collateral stimulation in hippocampal slices. Proposed mechanisms underlying this effect include generation of hydroxyl radicals (.OH) and inhibition of presynaptic Ca(2+) entry. We have examined these possible mechanisms in rat hippocampal slices. Inhibition of the evoked PS by H(2)O(2) was sharply concentration-dependent: 1.2 mM H(2)O(2) had no effect, whereas 1.5 and 2.0 mM H(2)O(2) reversibly depressed PS amplitude by roughly 80%. The iron chelator, deferoxamine (1 mM), and the endogenous.OH scavenger, ascorbate (400 microM), prevented PS inhibition, confirming.OH involvement. Isoascorbate (400 microM), which unlike ascorbate is not taken up by brain cells, also prevented PS inhibition, indicating an extracellular site of.OH generation or action. We then investigated whether H(2)O(2)-induced PS depression could be overcome by prolonged stimulation, which enhances Ca(2+) entry. During 5-s, 10-Hz trains under control conditions, PS amplitude increased to over 200% during the first three-four pulses, then stabilized. In the presence of H(2)O(2), PS amplitude was initially depressed, but began to recover after 2.5 s of stimulation, finally reaching 80% of the control maximum. In companion experiments, we assessed the effect of H(2)O(2) on presynaptic Ca(2+) entry by monitoring extracellular Ca(2+) concentration ([Ca(2+)](o)) during train stimulation in the presence of postsynaptic receptor blockers. Evoked [Ca(2+)](o) shifts were apparently unaltered by H(2)O(2), suggesting a lack of effect on Ca(2+) entry. Taken together, these findings suggest new ways in which reactive oxygen species (ROS) might act as signaling agents, specifically as modulators of synaptic transmission.

The effect of in vivo ethanol consumption on cyclic AMP and delta-opioid receptors in mouse striatum.

In this study the effect of in vivo ethanol consumption on cyclic AMP (cAMP) and [D-Ala2,D-Leu5]enkephalin (DADLE) inhibition of forskolin-stimulated cAMP production was examined in mouse striatum. Effects of ethanol on striatal delta-opioid receptor (DOR) density and mRNA were also examined. Mice had unlimited access to 7% (v/v) ethanol alone or water for 1 or 7 days and were then sacrificed and striatum removed for analysis. There was no difference in basal cAMP formation between water and ethanol-treated mouse striatum following 7 day treatment, and a small, but statistically significant increase in basal cAMP in the ethanol group following 1 day treatment. Both 1 day and 7 day ethanol treatment did not significantly alter the percentage increase in cAMP following treatment with 10 microM forskolin. There was a significant effect of ethanol treatment on the maximum inhibitory effect of DADLE on forskolin-stimulated cAMP formation following both 1 and 7 day ethanol treatment. The DADLE IC50 was unaffected by ethanol treatment. Saturation binding studies ([3H]Deltorphin II) indicated no effect of ethanol on Bmax or Kd in striatum. Similarly, no difference between water and ethanol-treated was observed for DOR mRNA in striatum. These data indicate that ethanol consumption can alter opioid regulation of cAMP formation. However, this effect is not related to changes in any delta-opioid receptor parameters that were examined.

Cytogenetic effects of cigarette smoke on pulmonary alveolar macrophages of the rat.

To determine accurately the potential genetic damage induced by toxic inhaled agents, the cells that receive a high concentration of such agents should be analyzed. Pulmonary alveolar macrophages (PAMs) represent such cells. We compared the cytogenetic effects of cigarette smoke on PAMs of rats exposed repeatedly by different methods. This study was part of a larger investigation of the health effects resulting from different methods of exposing rats to cigarette smoke. Fischer 344/N male rats (4/group) were randomly selected from five different exposure groups: 1) nose-only sham-exposed (air) control, 2) whole-body sham-exposed control, 3) nose-only intermittent, 4) nose-only continuous, and 5) whole-body continuous. The rats were exposed 6 hr/day, 5 days/week for 22-24 days. All smoke-exposed rats received the same daily concentration x time product (600 mg.hr.m-3 for the first week, 1200 mg.hr.m-3 thereafter) of cigarette smoke. Rats were injected intraperitoneally with colchicine at the end of exposure. PAMs were obtained by lung lavage and chromosomal damage was measured. Highly significant smoke-induced differences in both structural and numerical aberrations were observed in continuously exposed rats vs. sham controls, regardless route of exposure. The structural aberrations observed were chromatid-type deletions. Both hypoploid and hyperploid cells were detected. Our data suggest that cigarette smoke is clastogenic and may disrupt spindle-fiber formation. These activities may play a role in the induction of human carcinogenesis caused by cigarette smoke exposure.

The effect of mu-opioid receptor antisense on morphine potency and antagonist-induced supersensitivity and receptor upregulation.

The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and mu-opioid receptor up-regulation in mice. On day 1 mice were implanted S.C. with a NTX or placebo pellet and injected I.T. and I.C.V. with dH2O or oligodeoxynucleotides. The oligodeoxynucleotides were designed so that they were either perfectly complementary to the first 18 bases of the coding region of mouse mu-opioid receptor mRNA, or had one (Mismatch-1) or four (Mismatch-4) mismatches. On days 3, 5, 7, and 9, mice were again injected I.T. and I.C.V. with dH2O or one of the oligodeoxynucleotides. After the final injections on day 9, placebo and NTX pellets were removed, and 24 h later mice were tested for morphine analgesia or sacrificed for saturation binding studies ([3H]DAMGO). Naltrexone increased the analgesic potency of morphine in dH2O treated mice by approximately 70%. In binding studies, NTX significantly increased density of brain (approximately 60%) and spinal cord (approximately 140%) mu-opioid receptors without affecting affinity. The mu-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by approximately twofold in placebo-treated mice. The oligodeoxynucleotide with four mismatches (Mismatch-4) did not significantly alter morphine potency. When placebo-treated mice were treated with either the antisense to the mouse mu-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of mu-opioid receptors. Thus, mu-opioid antisense significantly reduced morphine potency without changing mu-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and mu-opioid receptor upregulation. These data suggest that opioid antagonist-induced supersensitivity and upregulation of mu-opioid receptors does not involve changes in gene expression.

Henoch-Schoenlein syndrome: a clinical and morphological study of renal biopsies.

Twenty-four patients, 12 children and 12 adults, with the Henoch-Schoenlein syndrome had their renal biopsy specimens studied by light and electron microscopic and immunofluorescent antibody techniques. The principal glomerular lesion was a focal and segmental proliferative glomerulonephritis in 15, a diffuse proliferative glomerulonephritis in 6 and a animal or minor change lesion with mesangial hypertrophy in 3 cases. The proliferation of the cells was mainly mesangial. Renal biopsies taken earlier in the course of the disease showed a greater number with a focal lesion. Electron dense deposits with cellular proliferation and increased matrix were seen in the mesangium. Less frequent subendothelial and occasional subepithelial deposits were found. Capillary loop changes were seen more frequently in the later stages of the disease. Heavy deposits of IgA were found in the mesangium in all cases, and less intense deposits of IgG in 60%. beta 1 C globulin and fibrinogen were found in 80% and IgD and IgM less frequently. Complement activation was via the alternate pathway as early complement components C1q and C4 were absent. Overt allergies, streptococal infections and the HBsAg could not explain the pathogenesis of the disease. Henoch-Schoenlein syndrome is a chronic disease of the mesangium; only 5 patients showed complete recovery, 15 had persistent microscopic hematuria and 3 died or developed renal insufficiency within 8 years. The prognosis was worst with diffuse proliferative glomerulonephritis, widespread focal glomerulonephritis or epithelial cresents formation.