Purpose MD–PhD training programs provide an integrated approach for training physician–scientists. The goal of this study was to characterize the career path taken by MD–PhD program alumni during the past 40 years and identify trends that affect their success. Method In 2007–early 2008, 24 programs enrolling 43% of current trainees and representing half of the National Institutes of Health-funded MD–PhD training programs submitted anonymous data on 5,969 current and former trainees. Results The average program enrolled 90 trainees, required 8.0 years to complete, and had an attrition rate of 10%. Nearly all (95%) of those who graduated entered residencies. Most (81%) were employed in academia, research institutes, or industry; 16% were in private practice. Of those in academia, 82% were doing research and at least 61% had identifiable research funding. Whereas two-thirds devoted more than 50% effort to research, only 39% devoted more than 75% effort. Many with laboratory-based PhDs reported doing clinical, as well as basic and translational, research. Emerging trends include decreasing numbers of graduates who forego residencies or hold primary appointments in nonclinical departments, increasing time to graduation, and expanding residency choices that include disciplines historically associated with clinical practice rather than research. Conclusions Most MD–PhD program graduates follow career paths generally consistent with their training as physician–scientists. However, the range of their professional options is broad. Further thought should be given to designing their training to anticipate their career choices and maximize their likelihood of success as investigators.

HIV-infected patients carrying the Hp 2-2 phenotype show a worse prognosis, which is reflected by a more rapid rate of viral replication (in the absence of antiviral treatment). They also accumulate more iron and oxidize more vitamin C, suggesting that less efficient protection against haemoglobin/iron-driven oxidative stress may be a direct mechanism for stimulating viral replication.

A major concern associated with ZIKV infection is the increased incidence of microcephaly with frequent calcifications in infants born from infected mothers. To date, postmortem analysis of the central nervous system (CNS) in congenital infection is limited to individual reports or small series. We report a comprehensive neuropathological study in ten newborn babies infected with ZIKV during pregnancy, including the spinal cords and dorsal root ganglia (DRG), and also muscle, pituitaries, eye, systemic organs, and placentas. Using in situ hybridization (ISH) and electron microscopy, we investigated the role of direct viral infection in the pathogenesis of the lesions. Nine women had Zika symptoms between the 4th and 18th and one in the 28th gestational week. Two babies were born at 32, one at 34 and 36 weeks each and six at term. The cephalic perimeter was reduced in four, and normal or enlarged in six patients, although the brain weights were lower than expected. All had arthrogryposis, except the patient infected at 28 weeks gestation. We defined three patterns of CNS lesions, with different patterns of destructive, calcification, hypoplasia, and migration disturbances. Ventriculomegaly was severe in the first pattern due to midbrain damage with aqueduct stenosis/distortion. The second pattern had small brains and mild/moderate (ex-vacuo) ventriculomegaly. The third pattern, a well-formed brain with mild calcification, coincided with late infection. The absence of descending fibres resulted in hypoplastic basis pontis, pyramids, and cortico-spinal tracts. Spinal motor cell loss explained the intrauterine akinesia, arthrogryposis, and neurogenic muscle atrophy. DRG, dorsal nerve roots, and columns were normal. Lympho-histiocytic inflammation was mild. ISH showed meningeal, germinal matrix, and neocortical infection, consistent with neural progenitors death leading to proliferation and migration disorders. A secondary ischemic process may explain the destructive lesions. In conclusion, we characterized the destructive and malformative consequences of ZIKV in the nervous system, as reflected in the topography and severity of lesions, anatomic localization of the virus, and timing of infection during gestation. Our findings indicate a developmental vulnerability of the immature CNS, and shed light on possible mechanisms of brain injury of this newly recognized public health threat.

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During the past two decades, there has been a tremendous expansion of knowledge regarding the neurobiological effects of substance abuse and how these effects impact behavior. At the same time, there has been a profound change in our understanding of the way in which the central nervous system responds to noxious stimuli. Most often referred to as the innate immune response (IIR), this defense mechanism is activated by a number of agents (toxic, microbial, ischemic) and has been implicated in the progression of a number of neurodegenerative diseases. We review evidence that psychostimulants of abuse (cocaine, methamphetamine, ecstasy) are associated with activation of the IIR. We first present background on what is currently known about the IIR including some of the cellular elements involved (microglia, astrocytes, vascular endothelial cells), key receptor pathways, and primary inflammatory cytokines (IL-1β, IL-6, TNF-α). We then present a variety of protein and gene expression data taken from animal studies that show increased expression of various components of the IIR following acute or repeated psychostimulant administration. Collectively the data indicate an association of psychostimulant use with IIR activation in the brain even at exposures not traditionally associated with neurotoxicity. Thus, the gradually escalating deleterious effects of psychostimulant use could in part involve neuroinflammatory mechanisms. Finally, we offer one hypothesis of a possible mechanism by which psychostimulants result in IIR activation and discuss the potential therapeutic implications of these findings for treatment of the recovering addict.

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Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and interferon-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses.

Inflammation and airway remodeling occur in a variety of airway diseases. Modeling aspects of the inflammatory and fibrotic processes following repeated exposure to particulate matter may provide insights into a spectrum of airway diseases, as well as prevention/treatment strategies. An agent-based model (ABM) was created to examine the response of an abstracted population of inflammatory cells (nominally macrophages, but possibly including other inflammatory cells such as lymphocytes) and cells involved in remodeling (nominally fibroblasts) to particulate exposure. The model focused on a limited number of relevant interactions, specifically those among macrophages, fibroblasts, a pro-inflammatory cytokine (TNF-α), an anti-inflammatory cytokine (TGF-β1), collagen deposition, and tissue damage. The model yielded three distinct states that were equated with (1) self-resolving inflammation and a return to baseline, (2) a pro-inflammatory process of localized tissue damage and fibrosis, and (3) elevated pro- and anti-inflammatory cytokines, persistent tissue damage, and fibrosis outcomes. Experimental results consistent with these predicted states were observed in histology sections of lung tissue from mice exposed to particulate matter. Systematic in silico studies suggested that the development of each state depended primarily upon the degree and duration of exposure. Thus, a relatively simple ABM resulted in several, biologically feasible, emergent states, suggesting that the model captures certain salient features of inflammation following exposure of the lung to particulate matter. This ABM may hold future utility in the setting of airway disease resulting from inflammation and fibrosis following particulate exposure.