Gender equity of authorship in pulmonary medicine over the past decade.

BACKGROUND: Gender disparity in authorship broadly persists in medical literature, little is known about female authorship within pulmonary medicine. METHODS: A bibliometric analysis of publications from 2012 to 2021 in 12 journals with the highest impact in pulmonary medicine was conducted. Only original research and review articles were included. Names of the first and last authors were extracted and their genders were identified using the Gender-API web. Female authorship was described by overall distribution and distribution by country/region/continent and journal. We compared the article citations by gender combinations, evaluated the trend in female authorship, and forecasted when parity for first and last authorship would be reached. We also conducted a systematic review of female authorship in clinical medicine. RESULTS: 14,875 articles were included, and the overall percentage of female first authors was higher than last authors (37.0% vs 22.2%, p<0.001). Asia had the lowest percentage of female first (27.6%) and last (15.2%) authors. The percentages of female first and last authors increased slightly over time, except for a rapid increase in the COVID-19 pandemic periods. Parity was predicted in 2046 for the first authors and 2059 for the last authors. Articles with male authors were cited more than articles with female authors. However, male-male collaborations significantly decreased, whereas female-female collaborations significantly increased. CONCLUSIONS: Despite the slow improvement in female authorship over the past decade, there is still a substantial gender disparity in female first and last authorship in high-impact medical journals in pulmonary medicine.

Hyperhomocysteinemia exacerbates Alzheimer's disease pathology by way of the ß-amyloid fibrinogen interaction.

UNLABELLED: Essentials Evidence suggests a comorbidity between hyperhomocysteinemia (HHC) and Alzheimer's disease (AD). Homocysteine (HC) could affect the ß-amyloid (Aß)-fibrinogen interaction in AD pathology. AD patients with concomitant HHC have increased fibrin and Aß deposits in their brains. HC contributes to AD pathology via the Aß-fibrinogen interaction. SUMMARY: Background Accumulating clinical evidence suggests that hyperhomocysteinemia (HHC) is correlated with Alzheimer's disease (AD) and vascular dementia. Objective This study was carried out to elucidate the specific role of elevated homocysteine (HC) levels in AD pathophysiology. Methods Immunohistochemistry was used to examine ß-amyloid (Aß) deposition along blood vessels, also known as cerebral amyloid angiopathy (CAA), fibrin(ogen) deposition, and their correlation to each other in the brains of AD patients with and without HHC. To study AD-HHC co-morbidity in detail, an AD mouse model was administered a high methionine diet for several months. Parenchymal Aß plaques, CAA-positive vessels and fibrin deposits were then assessed by immunohistochemistry at different stages of AD progression. Memory deficits were evaluated with contextual fear conditioning and the Barnes maze. Additionally, the effect of HC and its metabolite, homocysteine thiolactone (HCTL), on the Aß-fibrinogen interaction was analyzed by pull-down, ELISA and fibrin clot formation and fibrinolysis assays in vitro. Results We found increased fibrin(ogen) levels and Aß deposits in the blood vessels and brain parenchyma of AD patients with HHC. We demonstrate that HC and HCTL enhance the interaction between fibrinogen and Aß, promote the formation of tighter fibrin clots and delay clot fibrinolysis. Additionally, we show that diet-induced HHC in an AD mouse model leads to severe CAA and parenchymal Aß deposition, as well as significant impairments in learning and memory. Conclusions These findings suggest that elevated levels of plasma HC/HCTL contribute to AD pathology via the Aß-fibrin(ogen) interaction.

The Alzheimer's disease peptide ß-amyloid promotes thrombin generation through activation of coagulation factor XII.

UNLABELLED: Essentials How the Alzheimer's disease (AD) peptide ß-amyloid (Aß) disrupts neuronal function in the disease is unclear. Factor (F) XII initiates blood clotting via FXI, and thrombosis has been implicated in AD. Aß triggers FXII-dependent FXI and thrombin activation, evidence of which is seen in AD plasma. Aß-triggered clotting could contribute to neuronal dysfunction in AD and be a novel therapeutic target. SUMMARY: Background ß-Amyloid (Aß) is a key pathologic element in Alzheimer's disease (AD), but the mechanisms by which it disrupts neuronal function in vivo are not completely understood. AD is characterized by a prothrombotic state, which could contribute to neuronal dysfunction by affecting cerebral blood flow and inducing inflammation. The plasma protein factor XII triggers clot formation via the intrinsic coagulation cascade, and has been implicated in thrombosis. Objectives To investigate the potential for Aß to contribute to a prothrombotic state. Methods and results We show that Aß activates FXII, resulting in FXI activation and thrombin generation in human plasma, thereby establishing Aß as a possible driver of prothrombotic states. We provide evidence for this process in AD by demonstrating decreased levels of FXI and its inhibitor C1 esterase inhibitor in AD patient plasma, suggesting chronic activation, inhibition and clearance of FXI in AD. Activation of the intrinsic coagulation pathway in AD is further supported by elevated fibrin levels in AD patient plasma. Conclusions The ability of Aß to promote coagulation via the FXII-driven contact system identifies new mechanisms by which it could contribute to neuronal dysfunction and suggests potential new therapeutic targets in AD.

Mucopolysaccharidosis VII in a Cat Caused by 2 Adjacent Missense Mutations in the GUSB Gene.

BACKGROUND: Mucopolysaccharidoses (MPS) are common lysosomal storage disorders causing typically progressive skeletal and ocular abnormalities. OBJECTIVES: To describe the clinic features, metabolic profile and a unique mutation in a domestic shorthair (DSH) kitten with MPS VII. ANIMALS: Affected kitten and 80 healthy cats. METHODS: Serum lysosomal enzyme activities and urinary glycosaminoglycan (GAG) accumulation were assessed. Exons of the ß-glucuronidase gene (GUSB) were sequenced from genomic DNA and genotyping was conducted. RESULTS: A 3-month-old DSH cat was presented for stunted growth, paresis, facial dysmorphia, multiple skeletal deformities, and corneal opacities. Evaluation of blood smears disclosed metachromatic granules in leukocytes and a urinary mucopolysaccharide spot test was positive. The proband had no GUSB activity but normal or increased activities for other lysosomal enzymes. Sequencing of the GUSB gene from the proband and comparison to the sequence of 2 healthy cats and the published feline genome sequence demonstrated 2 unique single base transitions (c.1421T>G and c.1424C>T) in exon 9, altering 2 adjacent codons (p.Ser475Ala and p.Arg476Trp). These amino acid changes are in a highly conserved domain of the GUSB protein and nontolerable to maintain function. Moreover, the p.Arg476Trp mutation previously has been identified in human patients. None of the other clinically healthy cats had these mutations. CONCLUSIONS AND CLINIC IMPORTANCE: The diagnostic approach to MPS disorders is delineated. This is only the second mutation known to cause MPS VII in cats. Similarly, 2 different mutations have been described in MPS VII dogs, thereby showing the molecular heterogeneity of MPS VII in companion animals.

Plasmin deficiency leads to fibrin accumulation and a compromised inflammatory response in the mouse brain.

BACKGROUND: Excess fibrin in blood vessels is cleared by plasmin, the key proteolytic enzyme in fibrinolysis. Neurological disorders and head trauma can result in the disruption of the neurovasculature and the entry of fibrin and other blood components into the brain, which may contribute to further neurological dysfunction. OBJECTIVES: While chronic fibrin deposition is often implicated in neurological disorders, the pathological contributions attributable specifically to fibrin have been difficult to ascertain. An animal model that spontaneously acquires fibrin deposits could allow researchers to better understand the impact of fibrin in neurological disorders. METHODS: Brains of plasminogen (plg)- and tissue plasminogen activator (tPA)-deficient mice were examined and characterized with regard to fibrin accumulation, vascular and neuronal health, and inflammation. Furthermore, the inflammatory response following intrahippocampal lipopolysaccharide (LPS) injection was compared between plg(-/-) and wild type (WT) mice. RESULTS AND CONCLUSIONS: Both plg(-/-) and tPA(-/-) mice exhibited brain parenchymal fibrin deposits that appear to result from reduced neurovascular integrity. Markers of neuronal health and inflammation were not significantly affected by proximity to the vascular lesions. A compromised neuroinflammatory response was also observed in plg(-/-) compared to WT mice following intrahippocampal LPS injection. These results demonstrate that fibrin does not affect neuronal health in the absence of inflammation and suggest that plasmin may be necessary for a normal neuroinflammatory response in the mouse CNS.

The GluK4 kainate receptor subunit regulates memory, mood, and excitotoxic neurodegeneration.

Though the GluK4 kainate receptor subunit shows limited homology and a restricted expression pattern relative to other kainate receptor subunits, its ablation results in distinct behavioral and molecular phenotypes. GluK4 knockout mice demonstrated impairments in memory acquisition and recall in a Morris water maze test, suggesting a previously unreported role for kainate receptors in spatial memory. GluK4 knockout mice also showed marked hyperactivity and impaired pre-pulse inhibition, thereby mirroring two of the hallmark endophenotypes of patients with schizophrenia and bipolar disorder. Furthermore, we found that GluK4 is a key mediator of excitotoxic neurodegeneration: GluK4 knockout mice showed robust neuroprotection in the CA3 region of the hippocampus following intrahippocampal injection of kainate and widespread neuroprotection throughout the hippocampus following hypoxia-ischemia. Biochemical analysis of kainate- or sham-treated wild-type and GluK4 knockout hippocampal tissue suggests that GluK4 may act through the JNK pathway to regulate the molecular cascades that lead to excitotoxicity. Together, our findings suggest that GluK4 may be relevant to the understanding and treatment of human neuropsychiatric and neurodegenerative disorders.

Facilitators and barriers to teamworking and patient centeredness in multidisciplinary cancer teams: findings of a national study.

BACKGROUND: Multidisciplinary teams (MDTs) are the standard means of making clinical decisions in surgical oncology. The aim of this study was to explore the views of MDT members regarding contribution to the MDT, representation of patients' views, and dealing with disagreements in MDT meetings-issues that affect clinical decision making, but have not previously been addressed. METHODS: Responses to open questions from a 2009 national survey of MDT members about effective MDT working in the United Kingdom were analyzed for content. Emergent themes were identified and tabulated, and verbatim quotes were extracted to validate and illustrate themes. RESULTS: Free-text responses from 1,636 MDT members were analyzed. Key themes were: (1) the importance of nontechnical skills, organizational support, and good relationships between team members for effective teamworking; (2) recording of disagreements (potentially sharing them with patients) and the importance of patient-centered information in relation to team decision making; (3) the central role of clinical nurse specialists as the patient's advocates, complementing the role of physicians in relation to patient centeredness. CONCLUSIONS: Developing team members' nontechnical skills and providing organizational support are necessary to help ensure that MDTs are delivering high-quality, patient-centered care. Recording dissent in decision making within the MDT is an important element, which should be defined further. The question of how best to represent the patient in MDT meetings also requires further exploration.

Allo-SCT for high-risk AML-CR1 in the molecular era: impact of FLT3/ITD outweighs the conventional markers.

Seventy-nine patients with AML in CR1 received allo-SCT between May 2006 and May 2011, and the prognostic impact of FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutation was evaluated in the context of other clinical prognostic factors. Patients with FLT3/ITD + AML had significantly inferior DFS (2-year DFS: 19% vs 64%, P = 0.0027), increased risk of relapse (1-year: 59% vs 19%, P = 0.01), and a trend towards decreased OS (P = 0.08) compared with patients without FLT3/ITD. Multivariate analysis confirmed FLT3/ITD + independently predicted a shorter DFS (HR, 3.0; 95% CI), 1.4-6.5; P = 0.01) and increased risk of relapse (HR, 4.9; 95% CI, 2.0-12.3, P = 0.01). Time to relapse in patients with FLT3/ITD + was short with 100-day cumulative risk of 45% (95% CI, 33-57). Our data suggest that the poor prognostic implication of FLT3/ITD positivity remains even after early allo-SCT in patients with FLT3/ITD + AML, and patients remain at high risk of early relapse. FLT3/ITD positivity also outweighs other conventional prognostic markers in predicting relapse.

Survey of pathogens in hatchery Chinook salmon with different out-migration histories through the Snake and Columbia rivers.

The operation of the Federal Columbia River Power System (FCRPS) has negatively affected threatened and endangered salmonid populations in the Pacific Northwest. Barging Snake River spring Chinook salmon Oncorhynchus tshawytscha through the FCRPS is one effort to mitigate the effect of the hydrosystem on juvenile salmon out-migration. However, little is known about the occurrence and transmission of infectious agents in barged juvenile salmon relative to juvenile salmon that remain in-river to navigate to the ocean. We conducted a survey of hatchery-reared spring Chinook salmon at various points along their out-migration path as they left their natal hatcheries and either migrated in-river or were barged through the FCRPS. Salmon kidneys were screened by polymerase chain reaction for nine pathogens and one family of water molds. Eight pathogens were detected; the most prevalent were Renibacterium salmoninarum and infectious hematopoietic necrosis virus. Species in the family Saprolegniaceae were also commonly detected. Pathogen prevalence was significantly greater in fish that were barged through the FCRPS than in fish left to out-migrate in-river. These results suggest that the transmission of infectious agents to susceptible juvenile salmon occurs during the barging process. Therefore, management activities that reduce pathogen exposure during barging may increase the survival of juvenile Chinook salmon after they are released.

Fibrinogen, a possible key player in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by progressive loss of cognitive function and subsequent death. Since the first case of this disease was diagnosed one century ago, much effort has been dedicated to find a cure. However, even though progress has been made in the knowledge of the pathogenesis of this disease, an effective treatment has not been found. Therefore, new approaches are needed urgently. AD patients have an abnormal cerebral vasculature and brain hypoperfusion, and a large body of research, including some from our lab, implicates cerebrovascular dysfunction as a contributing factor to AD. Reducing fibrinogen, a circulating protein critical in hemostasis, provides a significant decrease in the neurovascular damage, blood-brain barrier permeability and neuroinflammation present in AD. These studies implicate fibrinogen as a possible contributor to AD.

Stress-induced spine loss in the medial amygdala is mediated by tissue-plasminogen activator.

The amygdala, which exerts a regulatory influence on the stress response, is itself affected by stress. It has been reported that the serine protease tissue-plasminogen activator (tPA), a key mediator of spine plasticity, is required for stress-induced facilitation of anxiety-like behavior. Importantly, tPA is also involved in stress-induced activation of molecular signals that have the potential to contribute to neuronal remodeling in the medial amygdala (MeA). However, little is known about the precise nature of, and specific role played by tPA in, stress-induced structural plasticity in the MeA. Hence, we compared the impact of chronic restraint stress on spine density of medium spiny stellate neurons in MeA in wild-type mice with mice in which the tPA gene is disrupted (tPA-/-). In wild-type mice, chronic stress caused significant reduction in MeA spine density, which was in contrast to enhanced spine density in the neighboring basolateral amygdala (BLA). Strikingly, tPA-/- mice exhibited significant attenuation of stress-induced spine retraction in the MeA, but BLA spinogenesis was not affected. Therefore, tPA-dependence of stress-induced modulation in spine density was restricted to the MeA. Further, MeA neurons in tPA-/- mice, even when challenged with repeated stress, were able to maintain levels of spine density that were comparable to that of wild-type mice without stress. Our findings provide novel evidence for a permissive role for tPA in amygdalar spine plasticity elicited by behavioral stress.

Tissue plasminogen activator in the bed nucleus of stria terminalis regulates acoustic startle.

The bed nucleus of stria terminalis is a basal forebrain region involved in regulation of hormonal and behavioral responses to stress. In this report we demonstrate that bed nucleus of stria terminalis has a high and localized expression of tissue plasminogen activator, a serine protease with neuromodulatory properties and implicated in neuronal plasticity. Tissue plasminogen activator activity in the bed nucleus of stria terminalis is transiently increased in response to acute restraint stress or i.c.v. administration of a major stress mediator, corticotropin-releasing factor. We show that tissue plasminogen activator is important in bed nucleus of stria terminalis function using two criteria: 1, Neuronal activation in this region as measured by c-fos induction is reduced in tissue plasminogen activator-deficient mice; and 2, a bed nucleus of stria terminalis-dependent behavior, potentiation of acoustic startle by corticotropin-releasing factor, is attenuated in tissue plasminogen activator-deficient mice. These studies identify a novel site of tissue plasminogen activator expression in the mouse brain and demonstrate a functional role for this protease in the bed nucleus of stria terminalis.

Effects of seasonal climatic conditions on the diagnosis of Mycobacterium avium subspecies paratuberculosis in dairy cattle.

Validity of Johne's disease programs and control protocols that rely on established cut points [e.g., specified sample-to-positive (S/P) ratios] for ELISA serological tests depends on interpreted results that are not susceptible to variable test accuracy. It was hypothesized that seasonal variability exists in serological response to Mycobacterium avium subsp. paratuberculosis (MAP) infection. Further, a reciprocal response may occur, resulting in greater risk of fecal shedding in subclinically infected animals. A testing regimen was invoked that included multiple testing of individual adult cows during the 4 seasons. Serum was collected on a cyclic, monthly basis from 3 randomly selected cohorts of dairy cows, and fecal samples were collected from the 20% of cows with the greatest ELISA test S/P ratios. Staggered, quarterly sampling was continued for 1 yr, and at the conclusion, serum was analyzed en masse. The ELISA outcome values (i.e., S/P ratio) were treated both as categorical and continuous variables. The potential lagged effects of temperature-related seasonality on S/P ratio, as well as the potential for a change in test result caused by temperature were assessed. Results for fecal culture were analyzed on a categorical scale and compared with the ELISA results to explore the possibility of reciprocal fecal shedding. No significant seasonal effects on either S/P ratios or the proportion of cows seropositive to MAP were observed. Furthermore, no evidence was found linking temperature-related seasonality to a reciprocal increase in the risk of fecal culture positivity for MAP.

Laminin chain expression suggests that laminin-10 is a major isoform in the mouse hippocampus and is degraded by the tissue plasminogen activator/plasmin protease cascade during excitotoxic injury.

Laminins are important components of the extracellular matrix, and participate in neuronal development, survival and regeneration. The tissue plasminogen activator/plasmin extracellular protease cascade and downstream laminin degradation are implicated in excitotoxin-induced neuronal degeneration. To determine which specific laminin chains are involved, we investigated the expression of laminins in the hippocampus, and the cell types expressing them. Reverse transcription-PCR demonstrated that the messenger RNAs for all laminin chains could be detected in the hippocampus. To determine the localization of laminin chain expression, immunostaining was used. This method showed that alpha5, beta1 and gamma1 are most highly expressed in the neuronal cell layers. Immunoblotting confirmed the hippocampal expression of the chains alpha5, beta1 and gamma1, and RNA in situ hybridization showed a neuronal expression pattern of alpha5, beta1 and gamma1. At early time points following intrahippocampal injection of kainate, alpha5, beta1 and gamma1 chain immunoreactivities were lost. In addition, tissue plasminogen activator-deficient mice, which are resistant to kainate-induced neuronal death, show no significant change in laminins alpha5, beta1 and gamma1 after intrahippocampal kainate injection. Taken together, these results suggest that laminin-10 (alpha5-beta1-gamma1) comprises a major neuronal laminin in the mouse hippocampus, and is degraded before neuronal death during excitotoxic injury by the tissue plasminogen activator/plasmin protease cascade. By identifying a neuronal laminin (laminin-10) that participates in neuronal degeneration after excitotoxic injury, this study clarifies the molecular definition of the extracellular matrix in the hippocampus and further defines a pathway for mechanisms of neuronal death.

Areca nut, energy metabolism and hunger in Asian men.

BACKGROUND: The nut of the Areca catechu palm has long been attributed effects on hunger and the digestive process. OBJECTIVES: The objectives were to assess experimentally effects of areca nut on fasting and postprandial energy metabolism, substrate utilization and hunger. SUBJECTS AND METHODS: Two randomized, placebo-controlled, double-blind studies were undertaken. In study 1, eight Indian men received bioadhesive gels delivering 0, 5, 10 or 20 mg arecoline to the buccal sulcus after an overnight fast. Resting energy expenditure and substrate utilization were determined by ventilated hood calorimetry over 6 h during which hunger was rated on five occasions. In study 2, 15 Indian men received gels delivering 0 or 10 mg arecoline after consuming a 2.5 MJ meal, and the same protocol was then applied as in study 1. RESULTS: Fasting resting energy expenditures exceeded basal metabolic rate (BMR) by 5.4+/-0.8% (Mean+/-SE) after placebo, and 5.1+/-0.7% after 20 mg arecoline, but by 0.9+/-0.8% and 0.7+/-0.5% following 5 mg and 10 mg arecoline, respectively. Carbohydrate (CHO) utilization rates rose after areca nut compared to placebo (F(3,252)= 7.3, p< 0.001). Hunger varied across doses (chi(2) = 10.5, p < 0.02), being lowest after 10 mg and highest after 20 mg, and was influenced by interaction of dose with delta resting energy expenditure. In study 2, areca dose interacted with fat-free mass (FFM) to lower by 5.4+/-11.2% the thermic effect of a meal (F(1,28) = 4.9, p = 0.05), and retarded peak 'digestive-phase' thermogenesis by 60 min (F(1,58) = 5.7, p = 0.02). Postprandial delta CHO utilization was greater (F(1,28) = 4.5, p = 0.05), and hunger was lower (chi:(2) = 3.8, p = 0.05), after areca nut. The areca nut altered relationships of hunger to thermic effects of the meal, and to delta substrate utilization, in ways consistent with appetite suppression. CONCLUSION: Areca nut constituents modulate metabolic signals regulating appetite in man. This concurs with customary belief.

Anthropological perspectives on use of the areca nut.

This paper first reviews the identity of historical and contemporary users of the areca nut. It then considers the reasons given by users for indulging in areca consumption, drawing upon historical, ethnographic and experimental sources of evidence for the effects which users have sought to derive from it. Particularly important is the social context in which consumption occurs, and the social meanings attached to areca use and exchange. Finally, a possible evolutionary hypothesis is postulated to explain the origins of areca use as a form of behaviour indicating reproductive availability. However, diverse culturally explicit reasons underlie usage and what may once have been a sufficient rationale for consumption may no longer justify this pattern of behaviour.

Low-risk persistent gestational trophoblastic disease: outcome after initial treatment with low-dose methotrexate and folinic acid from 1992 to 2000.

PURPOSE: We have simplified the treatment of gestational trophoblastic disease (GTD) in order to reduce the number of patients exposed to potentially carcinogenic chemotherapy. Patients who score 0 to 8 on the Charing Cross scoring system are classified as low-risk and receive methotrexate (MTX) and folinic acid (FA), whereas those who score higher than 8 are classified as high-risk and receive the etoposide, methotrexate, and dactinomycin (EMA)/cyclophosphamide and vincristine (CO) regimen. PATIENTS AND METHODS: Between 1992 and 2000, 485 women with GTD were commenced on MTX/FA at Charing Cross Hospital, London, United Kingdom. If patients developed MTX resistance or toxicity, treatment was altered according to the level of beta human chorionic gonadotropin (hCG). If serum hCG was < or = 100 IU/L, patients received dactinomycin; if hCG was greater than 100 IU/L, patients received EMA/CO. RESULTS: The median duration of follow-up was 4.7 years. Overall survival was 100% and the relapse rate was 3.3% (16 of 485 patients). hCG values normalized in 324 (66.8%) of 485 patients with MTX alone, whereas 161 (33.2%) of 485 patients required a change in treatment, 11 because of MTX toxicity and 150 because of MTX resistance. Sixty-seven patients changed to dactinomycin, of whom 58 achieved normal hCG values, and nine required third-line chemotherapy with EMA/CO. hCG values normalized in 93 (98.9%) of 94 patients who changed directly to EMA/CO from MTX. CONCLUSION: Single-agent dactinomycin has activity in patients with low-risk GTD who develop MTX resistance and whose hCG is low. Simplifying the stratification of GTD into two classes (low- and high-risk) does not compromise overall outcome and may reduce the risk of second tumors.

Tissue plasminogen activator in nervous system function and dysfunction.

The extracellular protease tissue plasminogen activator (tPA) has been implicated in various normal and pathological situations in the mammalian nervous system. The availability of (i) transgenic and knock-out mice in which the expression level of tPA can be widely varied, (ii) in vivo models for studying function and disease, and (iii) culture models for examining cell behavior, has allowed a detailed evaluation of many of these proposed functions. This chapter summarizes the current state of knowledge of possible roles for the tPA/plasminogen system in neuronal function and dysfunction.