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PubMed1990

2',5'-Oligoadenylate synthetase gene expression in revertants of ras-transformed NIH3T3 fibroblasts.

Persistent revertant (PR) cells of Ha-ras-transformed NIH3T3 fibroblasts, isolated after prolonged treatment with interferon (IFN), have been previously described. PR cells remain nontumorigenic even after IFN withdrawal. To investigate the mechanisms responsible for the stable phenotypic reversion, we have now examined the potential involvement of an endogenous IFN and the 2',5'-oligoadenylate (2-5A) synthetase pathway. Northern blot analysis revealed an increased level of 2-5A synthetase transcripts in PR cells compared to parental Ha-ras-transformed cultures. Although inducible on treatment with exogenous IFN alpha/beta, this mRNA was not detectable in untreated NIH3T3 cells. 2-5A synthetase expression following IFN treatment was also significantly higher in PRs than in the normal or ras-transformed NIH3T3. The increased levels of synthetase mRNA correlated with a similarly elevated enzymatic activity in cell extracts from PR cells. This increased expression was biologically functional, since the revertant cells were more resistant to the cytolytic action of mengovirus than normal or ras-transformed NIH3T3 fibroblasts. Another class of IFN-induced genes, H-2 class I antigens, showed enhanced expression in PRs. Antibodies directed against mouse IFN alpha/beta did not reduce the constitutive expression of 2-5A synthetase in PR cells. Furthermore, conditioned medium from PR cultures or cocultivation with PRs failed to induce the enzyme message in NIH3T3 cells. Finally, there was no detectable elevation in the mRNA specific for IFN beta in the PR cultures, as determined using a sensitive polymerase chain reaction amplification protocol. These results show that the Ha-ras revertants constitutively produce a functional 2-5A synthetase, which appears to be independent of the production of an endogenous interferon alpha or beta.

2',5'-Oligoadenylate Synthetase↗

PubMed1993

The range of subtle rise in serum progesterone levels following controlled ovarian hyperstimulation associated with lower in vitro fertilization pregnancy rates is determined by the source of manufacturer.

Two previous studies found a correlation of higher pregnancy rates (PRs) with lower serum progesterone (P) levels at the time of human chorionic gonadotropin (hCG) injection in in vitro fertilization (IVF) cycles when luteal phase leuprolide acetate (LA)-human menopausal gonadotropin (hMG) was used for the controlled ovarian hyperstimulation (COH) regimen. In these two studies the radioimmunoassay (RIA) by Diagnostic Products Corporation (DPC) was used to measure P levels. This study attempted to corroborate these findings using a different RIA for P (Amersham) when the same COH regime was administered. The PR was significantly higher in the group where P was < or = 1 ng/ml at the time of hCG (43.2%) versus the groups where the P level ranged from 1.1 to 2 ng/ml (15.8%). Viable PRs were also significantly higher in the lower P group. In contrast to the previous data with the DPC assay, no differences were seen with P < 0.5 ng/ml (36.4%) versus 0.5-1 ng/ml (44.6%). Nevertheless, using the Amersham RIA, the data does suggest decreasing PRs with higher serum P levels at time of hCG when using luteal phase LA-hMG COH regimen.

Chorionic Gonadotropin↗

PubMed1979

Measurement of the distensibility of the parabronchi in duck lungs.

Air flow resistance in the parabronchial lung of the duck was measured at various pressure differences between the lung and the body surface (Prs) using a body plethysmograph. One lung of the anesthetized animal was ventilated at a steady flow rate, from trachea, through the parabronchial lung, and out via a cannula in the caudal thoracic air sac (Tr leads to CS flow), or vice versa (CS leads to Tr flow), all flow being directed over the parabronchi (Pb) by blocking the main bronchus between the medioventral (MV) and mediodorsal secondary bronchi (MD). Pressure differences were measured between MV and MD (Ptot), and between the clavicular air sac and MD giving the pressure drop along the parabronchial tubes (PPb). The pressure drop along MV, PVb, was derived as Ptot-PPb. Air flow resistances, Rtot, RPb, RVb, were calculated from the ratio of the corresponding pressure difference to the flow rate. Results show: (1) All resistances decreased with increasing distending pressure (Prs) from -20 to +20 cm H2O this change being most pronounced around Prs = 0; (2) The flow resistance of these structures depended on the flow direction, being smaller with Tr leads to CS flow during distension than in the opposite direction; (3) Arterial blood gases did not significantly change with varying distending pressure, suggesting unimpaired gas exchange even when the lung is significantly compressed. The results indicate that the parabronchi and the secondary bronchi of the duck lung have a finite compliance but that changes in intrapulmonary pressure, compression of the lung, do not result in significant collapse of the air capillaries with ensuing impairment of gas exchange.

Airway Resistance↗

PubMed1989

Pregnenolone sulfate antagonizes barbiturate-induced hypnosis.

The potential influence of the neurosteroid pregnenolone sulfate (PrS) on barbiturate-induced hypnosis was tested in rats. PrS, when injected intracerebroventricularly or intraperitoneally, significantly shortened the sleep-time produced by pentobarbital. The results suggest an important physiological and pharmacological role for PrS in the regulation of CNS excitability.

Animals↗

PubMed1984

Plasmid vectors based on Tn10 DNA: gene expression regulated by tetracycline.

The regulatory region of the tetracycline resistance determinant from transposon Tn10 has been used to construct plasmid vectors for gene expression regulated by tetracycline. Plasmids pRS tetBam-8 and pRS tetBam-16 include the tet regulatory region, the segment coding for the first four amino acids of the tetracycline resistance protein (tetA protein), and a linker region with SalI, HpaII, and BamHI restriction sites for gene fusions. Plasmid pTB-1, a derivative of pRS tetBam-8 and of the beta-galactosidase gene-containing plasmid pMC1403, constitutively expresses a tetA fragment-beta-galactosidase fusion protein. If a multicopy runaway replication plasmid, pMOBglII-16 that includes a 2.7-kb BglII DNA fragment from Tnl10 that provides tetR protein is present along with pTB-1, the expression of beta-galactosidase is reduced eightfold. Tetracycline acts as an inducer of the system and restores the level of beta-galactosidase activity measured in transformants containing pTB-1 alone. Plasmid mutants unable to produce active tetR protein are ineffective in reducing expression. Escherichia coli carrying plasmids that express both tetA protein and tetR protein show an increase in the tetracycline resistance level after incubation with the drug. The observations are consistent with the previously proposed mechanism of regulation of tetracycline resistance in Tn10.

DNA Transposable Elements↗

PubMed1995

Analysis of severe photoreceptor loss and Morris water-maze performance in aged rats.

In a study of aging and memory in 25-27-month-old albino rats, performance on a Morris water maze was found to be dependent on the structural integrity of the retina. Generally, as expected, 'learners' had intact retinas, while 'non-learners' had retinas with severe photoreceptor loss and a non-continuous outer nuclear layer, consisting of scattered cell nuclei. However, contrary to this general correlation between learning ability and photoreceptor presence, some learners had severely degenerated retinas and occasionally, non-learners had photoreceptor populations that apparently were comparable to those of learners. Rat retinas from these unpredictable, borderline response categories were examined histopathologically and morphometrically with the purpose of determining the minimal number of photoreceptors (PRs) necessary for animals to be rated as learners on the Morris water maze. However, among these severely damaged retinas of borderline groups, total number of surviving photoreceptors did not vary significantly among the learner, ambiguous or marginal and non-learner groups. The population of surviving PRs in learners was as low as 0.04% and in non-learners as high as 0.4%, as compared to that of young, adult rats. Therefore, borderline learners and non-learners had overlapping surviving PR numbers and the results did not clarify the response difference between these groups in the Morris water maze. It is suggested that the pattern of surviving PRs over the retinal surface, as well as the ratio of surviving rods to cones and their connectivity with other retinal neurons, may be related to the residual function of degenerated retinas of learner rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed2026

Unbiased Spatial Proteomics Uncovers Hepatic in Situ Regulation in Alcohol-Associated Hepatitis.

Alcohol-associated hepatitis (AH) is an acute inflammatory form of alcohol-associated liver disease. Previous studies have explored molecular mechanisms associated with AH pathogenesis through bulk liver tissue analysis; however, the heterogeneity of liver tissue and hence the spatial regulation within the AH liver microenvironment remained unaddressed. Here, an unbiased spatial proteomics analysis on the pathologic regions (PRs) of AH liver tissue is presented, including immune cell infiltration foci, lipid droplets, chicken-wire fibrosis, and fibrotic bands. Through combining a highly efficient nanodroplet processing in one pot for trace samples platform with ultrasensitive liquid chromatography-mass spectrometry, this study identified and quantified a total of 5186 unique proteins from PRs isolated in 200-μm-long × 200-μm-wide × 10-μm-thick areas. This in-depth spatial proteome coverage allowed us to discover mechanistic regulations within individual PRs, including compromised resolution of inflammation with infiltrated neutrophils at infiltration foci, increase of mitochondrial and peroxisomal fatty acid β-oxidation at lipid droplets, and differential cellular and extracellular regulations between chicken-wire fibrosis and fibrotic bands. Overall, this study demonstrated a new capability for AH research, revealed the significance of understanding spatial regulation within AH liver tissue, and further facilitated the development of therapeutic strategies at high resolution.

Proteomics↗

PubMed2005

Platelets can neutralize hydrogen peroxide in an acute toxicity model with cells involved in granulation tissue formation.

Platelets play a key role in the replacement of the blood clot with granulation tissue during the early steps of bone regeneration. We hypothesized that activated platelets can neutralize locally produced reactive oxygen species, thereby protecting cells involved in granulation tissue formation. The potential of platelet-released supernatant (PRS) to neutralize hydrogen peroxide (H(2)O(2)) was tested in an acute toxicity model with osteogenic, inflammatory, and endothelial cells. In the human fetal osteoblastic cell line 1.19 (hFOB), considerable morphological changes, cell shedding, and dysfunction of the respiratory chain were observed when cells were exposed to 3 mM H(2)O(2). Caspase-3 and poly-(ADP-ribose)-polymerase were not activated, suggesting that cell death occurred by necrosis. Preincubation of osteogenic cells, leukocytes, or endothelial cells with PRS decreased the acute toxicity of H(2)O(2). The capacity of platelets to release H(2)O(2)-detoxifying activity was retained for up to 72 h. Aminotriazole, an inhibitor of catalase, decreased the cytoprotective activity of PRS, whereas blocking of glutathione peroxidase by mercaptosuccinate had no effect. These results suggest that platelet-released catalase can rapidly neutralize cytotoxic amounts of H(2)O(2), a process that may play a role during the early stages of bone regeneration.

Blood Platelets↗

PubMed2026

Effectiveness of peer recovery support services for substance use disorders: A systematic review of healthcare utilization, behavioral health, and engagement outcomes.

BACKGROUND: Peer recovery support services (PRS) delivered by individuals with lived experience of substance use, are increasingly incorporated into substance use disorder (SUD) care systems to improve care engagement, reduce acute care use, and support recovery. However, existing systematic reviews have focused on substance use outcomes, with limited attention to healthcare utilization, psychosocial functioning, and outcomes across settings, and populations. METHODS: This systematic review, registered in PROSPERO (CRD42023469279), synthesized peer-reviewed studies from 2003 to 2026 evaluating PRS for individuals with alcohol or drug-related SUD. Using MEDLINE, Embase, PsycINFO, and CINAHL, the review included 53 studies primarily conducted in high-income countries that reported quantitative outcomes across substance use, healthcare utilization, behavioral health, and treatment engagement. Risk of bias was assessed using Cochrane RoB 2, ROBINS-I, and ROBINS-E tools. RESULTS: Overall, evidence was most favorable for selected treatment-linkage and engagement outcomes, whereas findings for substance use, emergency department use, hospitalization, overdose, and mortality were inconsistent. Uncontrolled longitudinal studies frequently reported improvements in depression and anxiety, but no randomized trials evaluated these outcomes, limiting causal inference. Exploratory cross-study patterns suggested that sustained navigation, practical assistance, and repeated peer contact were more often present in programs reporting favorable outcomes; however, these components were not independently evaluated. Substantial heterogeneity, frequent multicomponent interventions, high risk of bias in many nonrandomized studies, and limited long-term and economic data constrain conclusions. CONCLUSIONS: Findings support the promise of PRS while underscoring the need for more rigorous comparative studies, cost-effectiveness data, and further research in low- and middle-income countries.

Humans↗

PubMed2005

Ganirelix acetate use in normal- and poor-prognosis patients and the impact of estradiol patterns.

OBJECTIVE: To evaluate cycle outcomes in patients with either poor or normal prognosis undergoing IVF treatment with a GnRH antagonist (ganirelix acetate) for LH suppression. DESIGN: Nonrandomized, noncontrolled, retrospective review. PATIENT(S): 204 patients, aged 23-41 years, undergoing IVF. INTERVENTION(S): Patients completed 225 consecutive cycles of IVF with a GnRH antagonist (Antagon; Organon, Roseland, NJ) for LH surge prevention. Sixty cycles were conducted in patients with a known poor prognosis, whereas 165 were conducted in patients with a normal IVF prognosis. MAIN OUTCOME MEASURE(S): Pregnancy rate (PR), for the series as a whole and according to prognosis, and serum E2 patterns. RESULT(S): The PR per initiated cycle for the series as a whole was 33.3%. The pregnancy rate was 42.1% per ET for the entire series, with a cycle cancellation rate of 21%. When evaluated by prognosis, the poor-prognosis patients had PRs of 8.3% per attempt and 15% per transfer, whereas the normal-prognosis patients had PRs of 40% per attempt and 45% per transfer. Pregnancy rate did not vary by E2 pattern (drop, plateau, or rise). Oral contraceptive pretreatment was noted to be associated with high cancellation rates in the group of known poor responders, whereas for the group as a whole, cycle outcome was unaffected by the use of oral contraceptives. CONCLUSION(S): Use of GnRH antagonists in patients with an a priori poor IVF prognosis results in predictably poor outcomes. Patients without factors predicting poor outcome have acceptable PRs. The pattern of E2 rise immediately after initiation of GnRH antagonists does not predict cycle outcome. Oral contraceptives can be successfully used to schedule antagonist-based IVF cycles but might increase the risk of cycle cancellation in some patient populations.

Adult↗

PubMed2007

Effect of embryo quality on pregnancy outcome following single embryo transfer in women with a diminished egg reserve.

OBJECTIVE: To evaluate independently the effect of blastomere number and degree of fragmentation on pregnancy outcome following single ETs in women with a decreased egg reserve. DESIGN: Retrospective cohort analysis. SETTING: In vitro fertilization center of a university-based practice. PATIENT(S): Women having a single ET related to a decreased egg reserve. A requirement for inclusion was a day 3 serum FSH >12 mIU/mL and < or =3 antral follicles on ultrasound. INTERVENTION(S): Patients received no or minimal stimulation with gonadotropins. MAIN OUTCOME MEASURE(S): Pregnancy rates (PRs) following single ETs were evaluated according to blastomere number (group 1, < or =4 cells; group 2, 5 cells; group 3, 6 cells; group 4, 7 cells; and group 5, > or =8 cells) and fragmentation index (A, no fragmentation; B, 1-25% fragmentation; and C, >25% fragmentation). Embryo transfers and morphologic evaluation were performed on day 3. RESULT(S): The clinical and delivered PRs according to blastomere number showed that 6-8-cell embryos were six times more likely to implant than 4-5-cell embryos (6.6% versus 40.4% clinical). Degree of fragmentation did not predict outcome nearly as well as blastomere number. The overall clinical and delivered PRs per transfer were 27.8% and 24.1%, respectively, and were 14.8% and 12.8% per retrieval, respectively, and were 9.0% and 7.3% per initiated cycle, respectively. CONCLUSION(S): Six, seven, or eight-cell embryos have equal chances of implanting in women with day 3 elevated serum FSH. The key finding is that these embryos do better than those with <6 blastomeres. These data may be helpful in women with a diminished ovarian reserve in attempting IVF with their own eggs or when choosing donor oocytes.

Adult↗

PubMed2006

A rudimentary epiglottis associated with Pierre Robin sequence.

Epiglottis anomaly associated with Pierre Robin sequence (PRS) is a rare occurrence. To the knowledge of the authors, this is the first reported case of epiglottic anomaly associated with PRS. Doctors should remain aware of this atypical presentation in a PRS patient, and the presented case highlights the clinical challenges that must be met to ensure effective treatment of the defect in terms of compromised respiration, swallowing and feeding.

Arytenoid Cartilage↗

PubMed2006

CD7 expression predicts poor disease free survival and post-remission survival in patients with acute myeloid leukemia and normal karyotype.

AML patients with normal karyotype comprise the largest subgroup ( approximately 50%) but have a highly heterogeneous clinical course. By multi-parameter flow cytometry we analyzed CD7 expression along with other phenotypic markers in 185 patients with normal-karyotype AML. CD7 was expressed in 68 (37%) patients. CD7 expression was associated with younger age (P=0.024) but not with sex, WBC count, or extramedullary disease. Patients expressing CD7 had significant shorter disease free (DFS) and post-remission survivals (PRS) than patients without CD7 (DFS of 12 months versus 42 months, P=0.005; PRS of 15 months versus 33 months, P=0.013). We also found that expression of CD34 or HLA-DR was associated with lower CR rate (P=0.0007 and P=0.019, respectively) but did not affect DFS or OS. Furthermore, as for all AML patients, we demonstrated that in the normal karyotypic subgroup, patients with higher WBC counts (>50) and older age (>60 years) had lower CR rate (P=0.003 and P=0.0157, respectively) and shorter OS (P</=0.001 and P=0.007, respectively). Multivariate analysis of age, WBC, CD34, HLA-DR and CD7 showed that CD7 expression was an independent risk factor for DFS (P=0.01) and PRS (P=0.02).

Acute Disease↗

PubMed2004

Functional analysis of HIV-1 vif genes derived from Japanese long-term nonprogressors and progressors for AIDS.

We analyzed the function of human immunodeficiency virus type 1 (HIV-1) vif gene from Japanese long-term nonprogressors (LTNPRs) and progressors (PRs) for acquired immunodeficiency syndrome (AIDS). We constructed a basic HIV-1 infectious clone, which facilitated the incorporation and evaluation of vif from infected individuals. Proviral reporter clones carrying vif from six Japanese LTNPRs and seven PRs were then generated and their in vitro growth kinetics were analyzed. The vif clones, which could confer infectivity on reporter viruses, were considered active, and the ratio of the active clones to the number of clones examined per individual was determined. For the majority of LTNPRs, there was no correlation between presence or absence of functional vif with long-term nonprogression for AIDS. There was one exception in which all the clones examined had inactive vif, suggesting a probable association of inactive vif with the nonprogression. All PRs with high viral load had a high ratio of active vif clones. Our results suggest that the presence of functional vif would influence HIV-1 infectivity and disease progression in infected individuals.

Amino Acid Sequence↗

PubMed2005

Acute stress-induced hypersensitivity to colonic distension depends upon increase in paracellular permeability: role of myosin light chain kinase.

Hypersensitivity to rectal or colonic distension characterizes most patients with IBS and increased gut permeability has been described in post-dysenteric IBS patients. However, no link has been established between these two events. The aim of this study was to determine (i) whether chemical blockade of stress-induced increase of colonic paracellular permeability by 2,4,6 triaminopyrimidine (TAP) affects the concomitant hypersensitivity to colonic distension, (ii) the role of epithelial cell contraction in the stress-induced increased permeability and hyperalgesia, using a myosin light chain kinase inhibitor (ML-7). The effect of acute partial restraint stress (PRS) on visceral sensitivity to colorectal distension (RD) was assessed by abdominal muscle electromyography. Colonic paracellular permeability was determined by measuring percentage of urinary 51Cr-EDTA recovery after intracolonic infusion. The effect of stress on both parameters was evaluated after TAP, ML-7 or vehicle pretreated animals. PRS significantly increased colonic paracellular permeability and the number of spike bursts for all volumes of RD applied compared to sham. TAP suppressed the stress-induced increase of colonic paracellular permeability and sensitivity to colonic distension. Similarly, ML-7 blocked the stress-induced increase of colonic paracellular permeability and sensitivity. Neither ML-7 nor TAP had any effect on both permeability and sensitivity in absence of stress. The increase of colonic permeability induced by PRS results from epithelial cell cytoskeleton contraction through myosin light chain kinase activation and this increase is responsible for stress-induced rectal hypersensitivity.

Action Potentials↗

PubMed2004

Successful management of a neonate with Pierre-Robin syndrome and severe upper airway obstruction by long term placement of a laryngeal mask airway.

The severity of airway obstruction varies in infants with Pierre-Robin syndrome (PRS). Some have severe upper airway obstruction that results in respiratory failure and even death. We report a case of neonate with isolated PRS who had a severe airway obstruction and respiratory failure after birth. She had complications of bilateral pneumothorax, subcutaneous emphysema, and hypoxaemia due to difficult tracheal intubation. Respiratory failure recurred immediately after extubation; she was resuscitated by inserting a laryngeal mask airway. The laryngeal mask airway was left inserted for 6 days. It was successful in this patient and eliminated the need for invasive surgical procedures. In conclusion, the relatively long term use of a laryngeal mask airway, which has not been reported before, could be an alternative therapy for patients with PRS with airway obstruction.

Airway Obstruction↗

PubMed2025

Polygenic risk scores for rheumatoid arthritis and idiopathic pulmonary fibrosis and associations with RA, interstitial lung abnormalities, and quantitative interstitial abnormalities among smokers.

OBJECTIVE: Genome-wide association studies (GWAS) facilitate construction of polygenic risk scores (PRSs) for rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). We investigated associations of RA and IPF PRSs with RA and high-resolution chest computed tomography (HRCT) parenchymal lung abnormalities. METHODS: Participants in COPDGene, a prospective multicenter cohort of current/former smokers, had chest HRCT at study enrollment. Using genome-wide genotyping, RA and IPF PRSs were constructed using GWAS summary statistics. HRCT imaging underwent visual inspection for interstitial lung abnormalities (ILA) and quantitative CT (QCT) analysis using a machine-learning algorithm that quantified percentage of normal lung, interstitial abnormalities, and emphysema. RA was identified through self-report and DMARD use. We investigated associations of RA and IPF PRSs with RA, ILA, and QCT features using multivariable logistic and linear regression. RESULTS: We analyzed 9,230 COPDGene participants (mean age 59.6 years, 46.4 % female, 67.2 % non-Hispanic White, 32.8 % Black/African American). In non-Hispanic White participants, RA PRS was associated with RA diagnosis (OR 1.32 per unit, 95 %CI 1.18-1.49) but not ILA or QCT features. Among non-Hispanic White participants, IPF PRS was associated with ILA (OR 1.88 per unit, 95 %CI 1.52-2.32) and quantitative interstitial abnormalities (adjusted β=+0.50 % per unit, p = 7.3 × 10-8) but not RA. There were no statistically significant associations among Black/African American participants. CONCLUSIONS: RA and IPF PRSs were associated with their intended phenotypes among non-Hispanic White participants but performed poorly among Black/African American participants. PRS may have future application to risk stratify for RA diagnosis among patients with ILD or for ILD among patients with RA.

Humans↗

PubMed2004

Building a retinal mosaic: cell-fate decision in the fly eye.

Across the animal kingdom, color discrimination is achieved by comparing the outputs of photoreceptor cells (PRs) that have different spectral sensitivities. Much remains to be understood about how the pattern of these different PRs is generated and maintained. The Drosophila eye has long provided a beautiful system for understanding various aspects of retinal-cell differentiation. Recent progress in this field is revealing that a highly ordered series of events, involving cell-cell communication, localized signaling and stochastic choices, creates a complex mosaic of PRs that is reminiscent of the human retina. Notably, several of the factors used in generating the retinal mosaic of the fruitfly have corresponding functions in vertebrates that are likely to have similar roles.

Animals↗