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Congenital Muscular Dystrophy (CMD) is a group of genetic disorders characterized by progressive loss of muscle strength and integrity. Merosin deficient congenital muscular dystrophy type 1A (MDC1A) is a common form of this disorder. Children affected with MDC1A suffer from early onset severe hypotonia and weakness with significant motor milestone delay. Often they do not achieve independent ambulation and die in the second or third decade. Despite extensive advances in diagnosis, cellular and molecular understanding, MDC1A remains a disease without a cure or any proven therapeutic option to relieve or slow disease progression. Our experimental data suggest that treatment with Losartan, an Angiotensin II type I receptor antagonist, results in significant clinical improvements and amelioration of fibrosis in the dy2J/dy2J mouse model of CMD through inhibition of TGFβ and MAPK signaling. We further examined Losartan’s effect on the cellular network, focusing on NFκB signaling. Previous studies suggested a role of NFκB in promoting muscle inflammation, necrosis and degeneration in Duchenne muscular dystrophy patients and animal models. Contrary to this, here we show that Losartan’s beneficial effect in the dy2J/dy2J of CMD is associated with NFκB signaling up-regulation manifested by enhanced serum TNFα level, decreased IκB-β protein level (NFκB inhibitor) and P65 accumulation in gastrocnemius nuclei of the dy2J/dy2J mice. A more in-depth investigation revealed that Losartan induced a modification in the NFκB gene expression towards pro-survival profile as cIAP2, TRAF2 and FTH mRNA levels were markedly increased following treatment. Losartan also induced the expression of anti-apoptotic BCl2 protein and down-regulated the expression of pro-apoptotic caspase 3 protein. Our study indicates that in the dy2J/dy2J mice of CMD, Losartan treatment resulted in NFκB activation with shifting from apoptosis/damage targeting pathway to a profile favoring cell survival. [Copyright &y& Elsevier]

The dy2J/dy2J mouse model of lamininα2-deficient congenital muscular dystrophy (MDC1A) has prominent peripheral neuropathy with slowed conduction. The conduction slowing may be due to reduced myelinated axon number, diameter, and atypical Schwann cell ensheathement/amyelination with aberrant basal lamina, nodal gap shortening, and decreased axon membrane excitability. Although no inflammatory mechanism was identified in dy2J/dy2J neuropathy, other genetically mediated neuropathies show low-grade inflammation and immune pathways play a pathological role. The immune modulating agent, Glatiramer acetate (GA) improves dy2J/dy2J mouse mobility and hind limb muscle strength, and shows significant beneficial effect in the neuropathy of experimental autoimmune neuritis (EAN). GA mechanisms of action from experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis studies are at various levels of the immune response (skewing T-cells from pro- to anti-inflammatory pathways) and generating neuroprotective activity (brain derived neurotrophic factor BDNF, anti-inflammatory cytokines). Because of GA’s beneficial effect in the dy2J/dy2J mouse model we evaluated it’s effect on dy2J/dy2J peripheral neuropathy motor conduction. Homozygous dy2J/dy2J and control mice were treated with GA or placebo for 12weeks from 6weeks of age. Outcome measures included sciatic-posterior tibial motor nerve conduction parameters (NCV, distal latency, and CMAP amplitude, area and dispersion) at 18weeks. GA treated dy2J/dy2J mice showed significantly improved average sciatic-posterior tibial nerve motor conduction velocity 50.35±2.9m/s versus untreated dy2J/dy2J 34.49±2.14m/s (p <0.001), WT controls 63.04±2.33m/s. Glatiramer acetate significantly improved motor nerve conduction velocity (NCV) in the dy2 J/dy2J mouse model of congenital muscular dystrophy. [ABSTRACT FROM AUTHOR]

The choroid plexus (ChP) is a vital brain barrier and source of cerebrospinal fluid (CSF). Here, we use longitudinal two-photon imaging in awake mice and single-cell transcriptomics to elucidate the mechanisms of ChP regulation of brain inflammation. We used intracerebroventricular injections of lipopolysaccharides (LPS) to model meningitis in mice and observed that neutrophils and monocytes accumulated in the ChP stroma and surged across the epithelial barrier into the CSF. Bi-directional recruitment of monocytes from the periphery and, unexpectedly, macrophages from the CSF to the ChP helped eliminate neutrophils and repair the barrier. Transcriptomic analyses detailed the molecular steps accompanying this process and revealed that ChP epithelial cells transiently specialize to nurture immune cells, coordinating their recruitment, survival, and differentiation as well as regulation of the tight junctions that control the permeability of the ChP brain barrier. Collectively, we provide a mechanistic understanding and a comprehensive roadmap of neuroinflammation at the ChP brain barrier., Competing Interests: Declaration of interests J.O.-M. reports compensation for consulting services with Cellarity, Tessel Biosciences, and Radera Biotherapeutics. J.C. has been an employee of Dyne Therapeutics since April 2021. Her contributions to this manuscript were made when she was employed by Boston Children’s Hospital., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Located in each brain ventricle, choroid plexus (ChP) tissue forms a blood-CSF barrier and produces cerebrospinal fluid (CSF) and other supportive factors. Sheets of ChP epithelial cells enclose a vascularized stroma of mesenchymal, immune, and neuron/glia-like cells. Burgeoning ChP studies are revealing its complex set of functions across the lifespan. To view this SnapShot, open or download the PDF., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress-CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Several secreted factors have been identified as drivers of cerebral vasculature development and inducers of blood-brain barrier (BBB) differentiation. Vascular endothelial growth factor A (VEGF-A) is central for driving cerebral angiogenesis and Wnt family factors (Wnt7a, Wnt7b and norrin) are central for induction and maintenance of barrier properties. Expressed by developing neural tissue (neuron and glia progenitors), they influence the formation of central nervous system (CNS) vascular networks. Another type of factors are tissue-specific paracrine factors produced by endothelial cells (ECs), also known as 'angiocrine' factors, that provide instructive signals to regulate homeostatic and regenerative processes. Very little is known about CNS angiocrine factors and their role in BBB development. Angiomodulin (AGM) was reported to be expressed by developing vasculature and by pathological tumor vasculature. Here we investigated AGM in the developing CNS and its function as a potential BBB inducer., Methods: We analyzed microarray data to identify potential angiocrine factors specifically expressed at early stages of barrier formation. We then tested AGM expression with immunofluorescence and real-time PCR in various organs during development, post-natal and in adults. Permeability induction with recombinant proteins (Miles assay) was used to test potential interaction of AGM with VEGF-A., Results: Several angiocrine factors are differentially expressed by CNS ECs and AGM is a prominent CNS-specific angiocrine candidate. Contrary to previous reports, we found that AGM protein expression is specific to developing CNS endothelium and not to highly angiogenic developing vasculature in general. In skin vasculature we found that AGM antagonizes VEGF-A-induced vascular hyperpermeability. Finally, CNS AGM expression is not specific to BBB vasculature and AGM is highly expressed in non-BBB choroid-plexus vasculature., Conclusions: We propose AGM as a developmental CNS vascular-specific marker. AGM is not a pan-endothelial marker, nor a general marker for developing angiogenic vasculature. Thus, AGM induction in the developing CNS might be distinct from its induction in pathology. While AGM is able to antagonize VEGF-A-induced vascular hyperpermeability in the skin, its high expression levels in non-BBB CNS vasculature does not support its potential role as a BBB inducer. Further investigation including loss-of-function approaches might elucidate AGM function in the developing CNS.

The central nervous system manifestations of systemic lupus erythematosus (SLE) remain poorly understood. Given the well-defined role of autoantibodies in other lupus manifestations, extensive work has gone into the identification of neuropathic autoantibodies. However, attempts to translate these findings to patients with SLE have yielded mixed results. We used the MRL/MpJ-Faslpr/lpr mouse, a well-established, spontaneous model of SLE, to establish the immune effectors responsible for brain disease. Transcriptomic analysis of the MRL/MpJ-Faslpr/lpr choroid plexus revealed an expression signature driving tertiary lymphoid structure formation, including chemokines related to stromal reorganization and lymphocyte compartmentalization. Additionally, transcriptional profiles indicated various stages of lymphocyte activation and germinal center formation. The extensive choroid plexus infiltrate present in MRL/MpJ-Faslpr/lpr mice with overt neurobehavioral deficits included locally proliferating B and T cells, intercellular interactions between lymphocytes and antigen-presenting cells, as well as evidence for in situ somatic hypermutation and class switch recombination. Furthermore, the choroid plexus was a site for trafficking lymphocytes into the brain. Finally, histological evaluation in human lupus patients with neuropsychiatric manifestations revealed increased leukocyte migration through the choroid plexus. These studies identify a potential new pathway underlying neuropsychiatric lupus and support tertiary lymphoid structure formation in the choroid plexus as a novel mechanism of brain-immune interfacing.

Diabetes mellitus (DM) significantly increases susceptibility to central nervous system (CNS) pathologies, including stroke, vascular dementia, cognitive deficits and Alzheimer's disease. Previous studies (mostly using the streptozotocin model) suggested that blood-brain barrier (BBB) disruption is involved in these conditions. Here, we examined the integrity of brain capillaries and BBB permeability in Lepr db/db obesity-related diabetic mice. Surprisingly, significant BBB leakage was observed only in young mice at the pre-hyperglycemic stage. Thorough examination of barrier permeability at later diabetic stages showed no evidence for significant BBB leakage during the hyperglycemic state. Electron microscopy imaging of mice with short-term hyperglycaemia supported normal BBB permeability but indicated other stress-related changes in capillary ultrastructure, such as mitochondrial degeneration. Based on our study with this mouse genetic model of obesity-related DM, we suggest that previously reported hyperglycaemia-induced BBB leakage is most likely not the underlying mechanism of DM-related CNS pathologies. Finally we propose that BBB hyper-permeability might be an early and transient phenomenon while stress-related endothelial pathologies do correlate with a short-term diabetic state.

The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/fas lpr/lpr ). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we found that abnormal function of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus underlies brain exposure to neuropathic antibodies. Considerable intrathecal lymphocyte infiltration likely occurs through the BCSFB, accompanied by epithelial hyper-permeability to antibodies. Our results challenge the commonly held view of BBB disruption in NPSLE, supporting a shift in focus to BCSFB dysfunction as a causative factor in the disease., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Experts have previously postulated a linkage between lupus associated vascular pathology and abnormal brain barriers in the immunopathogenesis of neuropsychiatric lupus. Nevertheless, there are some discrepancies between the experimental evidence, or its interpretation, and the working hypotheses prevalent in this field; specifically, that a primary contributor to neuropsychiatric disease in lupus is permeabilization of the blood brain barrier. In this commonly held view, any contribution of the other known brain barriers, including the blood-cerebrospinal fluid and meningeal barriers, is mostly excluded from the discussion. In this review we will shed light on some of the blood brain barrier hypotheses and try to trace their roots. In addition, we will suggest new research directions to allow for confirmation of alternative interpretations of the experimental evidence linking the pathology of intra-cerebral vasculature to the pathogenesis of neuropsychiatric lupus., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Depression and anxiety have been inconsistently associated with diabetes. Sex differences in the biological and behavioral correlates of these forms of distress could partially explain these inconsistencies. We investigated sex-specific associations between depression/anxiety symptoms and diabetes in two separate samples., Methods: The First National Health and Nutrition Examination Survey enrolled 3233 participants aged 25 to 74 years from 1971 to 1974. Depression and anxiety symptoms were measured via General Well Being schedule subscales. Incident diabetes for 17 years was defined by the following: a) death certificate, b) participant self-report, or c) health care facility discharge. The Detroit Neighborhood Health Study enrolled 1054 participants 18 years or older from 2008 to 2010. The Patient Health Questionnaire-9 and Generalized Anxiety Disorder-7 assessed depression and anxiety. Participants' self-reported physician-diagnosed prevalent diabetes., Results: In the First National Health and Nutrition Examination Survey, the risk ratio (RR; 95% confidence interval) for incident diabetes among men with high versus low anxiety symptoms was 0.85 (0.56-1.29) and that among women was 2.19 (1.17-4.09; p for interaction = .005). RRs comparing high versus low depressive symptoms for men and women were 0.69 (0.43-1.100) and 2.11 (1.06-4.19); p for interaction = .007. In the Detroit Neighborhood Health Study, the RRs for prevalent diabetes comparing those with high versus low anxiety symptoms were 0.24 (0.02-2.42) for men and 1.62 (0.61-4.32) for women (p for interaction = < .001), whereas RRs for depression were 1.30 (0.46-3.68) for men and 2.32 (1.10-4.89) for women (p for interaction = .16)., Conclusions: In two separate samples, depressive symptoms were related to increased diabetes risk among women but not men. Although less robust, findings for anxiety were differentially associated with diabetes by sex.

Background: While a handful of studies have assessed cognition in kidney transplant (TX) recipients, the neuropsychological presentation of this population is not yet clear. Kidney transplantation typically leads to improvement of metabolic factors associated with chronic kidney disease (CKD). However, comorbid diseases independently linked with cognitive compromise often persist, and for this reason, cognitive difficulties may still be present following transplantation., Methods: In this cross-sectional study, we assessed cognition in 42 kidney TX recipients, 45 outpatients with pre-dialysis CKD and 49 healthy controls using measures of verbal learning and memory and executive functioning., Results: Findings indicated that TX and CKD patients demonstrated significantly worse verbal learning and memory in comparison to controls. While both CKD and TX patients exhibited significantly worse performance than controls on a response inhibition measure, only CKD patients performed significantly worse on a set-shifting task., Conclusions: Results suggest that, in comparison to controls, verbal memory and executive functioning skills are worse in both CKD and TX patients. Further research is needed to determine the etiology and extent of cognitive compromise, as well as to assess the clinical implications of these findings.

Reductions in everyday problem solving (EPS) are often reported in older age, although the underlying mechanisms remain unclear. The authors examined the role of 2 variables predicted to mediate (neuropsychological abilities and health status) or moderate (health status) the relationship between age and EPS performance. Toward these ends, they compared EPS and neuropsychological performance in 50 functionally independent adults with chronic kidney disease (CKD) and 64 control participants matched on age and education. Both older age and CKD were associated with worse performance on measures of EPS and memory/executive abilities. Neuropsychological abilities were positively associated with EPS performance. In both the full sample and control participants only, memory/executive functioning mediated the association between presence of chronic illness and EPS. Furthermore, memory/executive functioning partially mediated the link between age and EPS. Findings indicate that relations among age, health status, and EPS are not straightforward. Although performance on neuropsychological measures appeared to underlie EPS declines in chronic illness, increasing age remained independently associated with reduced EPS. The authors discuss implications for models of adult developmental changes in everyday cognition., ((PsycINFO Database Record (c) 2007 APA, all rights reserved).)

We compared aspects of verbal memory and executive functioning in 51 community-dwelling persons with chronic kidney disease (CKD) and 55 healthy controls matched on age and education. Depressive symptoms were assessed with the Centre for Epidemiological Studies-Depression Scale (CES-D), and illness variables included glomerular filtration rate (GFR) and hemoglobin. Findings indicate that persons with CKD exhibited poorer performance on measures of memory (CVLT-II) and executive functioning (DKEFS Trailmaking Test B and Color-Word Interference Tests) in comparison with healthy controls. Furthermore, performance decrements were magnified in older CKD participants on measures of verbal memory and inhibition. Nearly half of CKD participants aged 61 and older exhibited significant impairments in verbal memory and inhibition in comparison to matched controls. Cognitive performance in CKD was not associated with measures of illness severity. The differences observed were not accounted for by depressive symptoms, which were only weakly associated with cognitive performance, and negatively associated with age. Findings highlight the need for further exploration of the etiologies and functional consequences of the neuropsychological presentation of CKD.

Despite the acceptance of evolutionary theory in the biological and social sciences, typological thinking--the belief that individual differences diverge around an underlying type or essence--has persisted. The most egregious example is J. H. Langdon Down's "ethnological classification of idiocy," taken seriously in the field for almost 80 years after its origin in 1866. Past and present controversies over the definition of mental retardation have turned on an unacknowledged typological axis. Some contemporary research on Down syndrome indicates that the allure of typology is still an obstacle to the appreciation of individual differences and human dignity in the field of mental retardation.

Objective: To determine whether psychosocial difficulties are more prevalent among ambulatory patients using the ED for nonemergent complaints as compared with ambulatory patients having emergent complaints., Methods: A survey of noncritical ED patients was performed using anonymous questionnaires addressing psychosocial difficulties: psychiatric illness, educational level, homelessness, alcohol and/or drug dependency (CAGE and DAST surveys), and depression (DSM-III criteria). Three independent physicians ranked each patient's chief complaint as either emergent or appropriate for primary care. The majority ranking was used to determine whether the complaint was emergent. Groups with and without specific psychosocial difficulties were compared for their proportion of emergent vs primary care complaints., Results: Of 700 patients, 367 (52%) met criteria for > or = 1 psychosocial difficulty [acute psychosis-36 (5%), illiteracy-139 (20%), homelessness-45 (6%), alcohol dependency-111 (16%), drug dependency-66 (9%), and depression-130 (19%)]. There were 379 (54%) ED visits considered emergent. Patient groups with vs without > or = 1 psychosocial difficulty had similar rates of emergent visits (58% vs 50%, p = 0.04). Emergent visit rates also were similar for subgroups with vs without specific psychosocial difficulties: psychosis (56% vs 54%, p = 1.00) illiteracy (58% vs 53%, p = 0.89), homelessness (62% vs 54%, p = 0.33), alcohol dependency (62% vs 53%, p = 0.08), drug dependency (59% vs 54%, p = 0.47), or depression (58% vs 53%, p = 0.42)., Conclusion: Psychosocial difficulties are common among ED patients; however, emergent complaints are just as common in these patients as they are in those without psychosocial difficulties.

Objective: To determine the nature of strokes complicating cardiac surgery., Design: A medical record review was undertaken of all patients who underwent cardiac surgery (either coronary bypass, valvular surgery, or both) between January 1990 and July 1995. Univariate and multivariate analyses were done using odds ratios (ORs) and logistic regression., Results: A total of 2211 patients underwent cardiac surgery. A total of 44 patients (2%) had postoperative strokes. They were compared with 104 surgical controls. Univariate analysis revealed that the patients with stroke were significantly older and had significantly higher rates of transient ischemic attack, congestive heart failure, and peripheral vascular disease by history. A multivariate logistic regression revealed the significant variables associated with stroke were congestive heart failure (OR, 6.8) and transient ischemic attack (OR, 1.2). Analyses of surgical variables revealed that bypass pump time of more than 120 minutes (OR, 1.40) was the only significant predictor. The majority of strokes (61%) had occurred by postoperative day 2, but 39% occurred between postoperative days 3 to 9. Hemispheric syndromes occurred in 70%, brain stem and cerebellar syndromes in 14%, and lacunar syndromes in 16%. Computed tomographic scans revealed that 29 patients had new infarcts, of which 20 (69%) were territorial, 5 (17%) were small deep, and 4 (14%) were border zone. Hemorrhagic infarction was found in 2 cases (5%). One patient (2.5%) had a cardiorespiratory arrest while undergoing computed tomography. Discharge disposition was good in 88% of patients with stroke (12% with poor outcomes) vs 97% of controls with good outcomes (3% with poor outcomes) (P = .04)., Conclusions: Strokes may be delayed following cardiac surgery perhaps because of ongoing risk of embolism or a hypercoagulable state. A surprisingly high proportion of patients have lacunar syndromes or small-deep infarcts shown on computed tomography. Early computed tomographic imaging may be useful to exclude hemorrhage if anticoagulation is considered, but is not without risk in these potentially unstable patients. Greater understanding of risk factors for stroke, timing, and subtypes may ultimately allow identification of patients at particularly high risk for perioperative stroke.

It is widely believed that the eugenics movements was largely responsible for the turn of the century perception that individuals with mental retardation were a social menace. However, that explanation fails to account for the vast corpus of 19th century degeneration theory, which, in the Progressive era, became the lens through which mental retardation was viewed. In this paper I have described the chain of theological and scientific reasoning that led to the linkage of mental retardation with the evolutionary "mark of the beast," a development that not only helped fuel the notorious myth of the "menace of the feeble-minded" but also cast a long shadow into this century.

All members of a large union were invited to participate in a study of potentially adverse effects of asbestos exposure. Clinical findings among 1,117 workers (90% of those eligible for examination) are presented in this study. Cough was much less common among those without a history of cigarette smoking, although duration from onset of employment did not appreciably affect the prevalence of cough among the smokers. Rhonchi present among nonsmokers were limited in extent, but were marked and diffuse among cigarette smokers. Although dyspnea was as prevalent among nonsmokers as in smokers forty years and more after onset of exposure, it was relatively uncommon and found only among smokers when examined shortly after onset of exposure. Cigarette smoking had less influence on the prevalence of râles among asbestos workers; both smokers and nonsmokers showed this finding when examined 30 years and more after onset of asbestos exposure. Analysis of powerhouse work experience and mask use as possible confounders indicated no difference in prevalence of these characteristics between the smokers and nonsmokers.

The relative analgesic efficacy of zomepirac sodium 100 mg and fenoprofen calcium 200 mg was evaluated in patients with pain due to surgical removal of dental impactions. This is the first study to make a direct comparison of their effectiveness. This study is especially important since zomepirac sodium was recently removed from the market as an analgesic for acute pain. Zomepirac sodium was extremely popular among clinicians and was considered the most effective of the peripherally acting analgesics. Patients were requested to take a single dose of study medication when they had moderate to severe pain. The study medications were identical in appearance and randomly allocated under double-blind conditions. The medication was evaluated over the next 4 hours according to subjective analgesic measurement scales. The primary measures of efficacy included total pain relief ( TOTPAR ), sum pain intensity difference ( SPID ), overall evaluation, and time to remedication . Of the 136 patients entered, 117 were included in the efficacy analysis. Both active agents demonstrated marked superiority to placebo (p less than 0.001) for all efficacy measures but were inseparable from each other. The mean analgesic efficacy values for both zomepirac sodium and fenoprofen calcium were almost identical. The nineteen subjects who reported side effects were evenly distributed among the three groups. No serious side effects occurred. The results of this study indicate that fenoprofen calcium 200 mg and zomepirac sodium 100 mg are equally efficacious, with similar onset, peak, and total analgesic effects.

We studied the prevalence of spirometric changes among asbestos insulation workers to investigate when functional abnormalities appear during the course of asbestos employment and the influence of cigarette smoking. Of 1,249 eligible asbestos insulation workers in the New York-New Jersey metropolitan area, 1,117 (89.4%) were examined in the year 1963 to provide baseline pulmonary function status for long-term prospective observation. Forced vital capacity (FVC) was measured in all 1,117 workers and forced expiratory volume in 1 second (FEV1) in 613 workers (55%). Of 353 workers examined in the first 10 years after onset of exposure, 26 (7.4%) had FVC below 70% of predicted, a prevalence similar to that reported in nonexposed general populations. Prevalence increased with time from onset of exposure. Of the 117 workers examined 40 or more years after onset of exposure, 76 (55%) had FVC below 70% of predicted. A similar trend with time was shown for FEV1 and FEV1/FVC. Cigarette smoking had little influence on the prevalence of pure restrictive impairment. Cigarette smokers and non-cigarette smokers had much the same prevalence (28%) of moderate to severe reduction of FVC while the FEV1/FVC was normal. None of the non-cigarette smokers and five of the cigarette smokers had a predominantly obstructive pattern. One non-cigarette smoker and eight cigarette smokers showed reduction of both FVC and FEV1/FVC, consistent with a mixed ventilatory abnormality. The data demonstrate that asbestos alone without the additional effect of cigarette smoking has no measureable effect on the function of the large airways.

To determine the relative analgesic efficacy of ibuprofen 400 mg and acetaminophen 1000 mg, we conducted a single-dose, double-blind, placebo-controlled, randomized clinical trial using a standard assay for analgesic agents, the dental pain model. At regular intervals over 6 hours, 184 patients who had undergone dental impaction surgery rated pain intensity and relief on categorical scales and pain half-gone on a dichotomous nominal scale; a categorical overall evaluation was completed at the end of 6 hours. Both active agents were effective compared to placebo. Ibuprofen 400 mg was more effective than acetaminophen 1000 mg for Sum Pain Intensity Difference (SPID), Total Pain Relief (TOTPAR), sum pain half-gone, and overall evaluation (P less than .05 to P less than .001). The time-effect curves demonstrated a greater peak effect and longer duration of action for ibuprofen 400 mg compared to acetaminophen 1000 mg. Side effects were reported in five ibuprofen patients, 11 acetaminophen-treated patients, and seven placebo patients. Based on the results of this clinical study, we conclude that ibuprofen 400 mg is a safe and more effective analgesic than acetaminophen 1000 mg for patients with acute pain.

A cohort of 820 men in a Paterson, New Jersey, amosite asbestos factory which began work during 1941-1945 was observed from 5 to 40 years after start of work. Most of the cohort had limited duration of work experience (days, weeks, months), though some men worked for several years until the factory closed in 1954. With white males of New Jersey as the control population, Standardized Mortality Ratios (SMRs) of 500 are evident for the cohort for lung cancer and for noninfectious pulmonary diseases (including asbestosis), while being almost 300 for total cancer and about 170 for all causes of death. A statistically significant SMR of almost 200 is seen for colon-rectum cancer. Mesothelioma incidence initially shows a strong relationship with advancing time since onset of exposure and then tails off. The main concern of the study is with dose-response patterns. Response is measured by the mortality for relevant causes of death, while the direct asbestos dosage was measured in two ways. One way was the length of time worked in the factory and the other was the individual's accumulated fiber exposure, calculated by multiplying the aforementioned length of time worked by the estimated fiber exposures associated with the particular job that the worker had in the factory. Whichever measure of dosage is used, it was found that, in general, the lower the dose, the longer it took for adverse mortality to become evident and, also, the smaller the magnitude of that adverse mortality.

A cohort of 1,117 asbestos insulation workers was established in 1963 and has been prospectively followed since then. Chest X-ray abnormalities detected at the initial medical examination, and interpreted according to the International Labour Office Classification of Radiographs of Pneumoconioses are reported in this paper. The prevalence of all radiographic abnormalities (pleural and pulmonary) increased with duration from onset of asbestos exposure. A positive smoking history was associated with a significantly higher prevalence of small irregular opacities indicating interstitial pulmonary fibrosis. Such an association was not found for pleural fibrosis. The possible mechanisms which underlie the effect of smoking on asbestos-induced interstitial fibrosis seem to be of much less importance in the development of pleural fibrosis. Progression of radiographic changes over the 20-year interval 1963-1983 will be separately reported as will the predictive significance of these changes.