Coverage of education and training of traumatic brain injury-induced growth hormone deficiency in US residency and fellowship programs: a cross-sectional study.

BACKGROUND: Hypopituitarism, including growth hormone deficiency (GHD), is a common sequela of traumatic brain injury (TBI). This study explored the coverage of education and training of TBI-induced hypopituitarism in general and GHD in particular, in postgraduate program curricula to identify knowledge gaps and opportunities. METHODS: An online survey and qualitative interviews (focus groups) were conducted among endocrinology, neurology, and physiatry postgraduate program directors in the United States (US). The study received an IRB exemption. RESULTS: A total of 419 fellowship and residency programs were invited to participate; 60 program directors completed the survey and 11 of these participated in the focus groups. About half of the respondents considered TBI-induced hypopituitarism important or fairly important to include in the curriculum, and nearly two-thirds considered it an appropriate training component. Neurology program directors considered education regarding hypopituitarism following TBI less important and relevant for their curricula compared with endocrinology and physiatry program directors. About half (53%) of the programs responded that they included TBI-induced pituitary disorders in their curricula. About two-thirds (68%) of endocrinology programs, compared with only one-quarter (25%) of neurology programs, covered TBI-induced pituitary disorders. Respondents identified multiple barriers to expanding hypopituitarism following TBI in the curriculum, including the rarity of condition and lack of time/room in the curriculum. Respondents reported that consensus clinical guidelines and the availability of more data on TBI-induced hypopituitarism, including GHD, would greatly impact the development of educational curricula on this topic. CONCLUSIONS: To improve the management of TBI-induced hypopituitarism, education and training should be expanded in US fellowship and residency programs to prepare trainees to effectively screen, diagnose, and treat TBI-induced hypopituitarism, including GHD.

A traumatic brain injury (TBI) can occur with a sudden blow to the head or the body. Most people recover from TBI within weeks, but the injury can cause long-term effects by reducing the body's production of growth hormone (GH), which can interfere with daily activities and impair quality of life. This study explored education and training of doctors in the US to identify gaps in knowledge about GH deficiency and opportunities for improvement. Online survey and interviews (focus groups) were conducted among directors of 3 postgraduate (after medical school) training programs: endocrinology, neurology, and physiatry (the diagnosis, prevention, and treatment of all types of impairment related to the brain, nerves, bones, and muscles).A total of 60 program directors completed the survey and 11 of these participated in the focus groups. About half of the respondents felt education about GH deficiency caused by TBI is important, and nearly two-thirds thought it was appropriate to include in medical training. Half of the programs said that hormone disorders caused by TBI were currently included in their training. Respondents identified multiple barriers to expanding education on this topic in training programs. The main barriers were that the condition is thought to be uncommon and not having time for more training. Respondents thought that clinical guidelines and availability of more information on the condition would greatly impact the development of training about GH deficiency after TBI.To improve the management of GH deficiency caused by TBI, education and training should be expanded to prepare doctors in training to be better able to screen, diagnose, and treat GH deficiency caused by TBI.

HIV-infected microglia mediate cathepsin B-induced neurotoxicity.

HIV-1-infected mononuclear phagocytes release soluble factors that affect the homeostasis in tissue. HIV-1 can prompt metabolic encephalopathy with the addition of neuronal dysfunction and apoptosis. Recently, we reported that HIV-1 enhances the expression and secretion of bioactive cathepsin B in monocyte-derived macrophages, ultimately contributing to neuronal apoptosis. In this research, we asked if microglia respond to HIV infection similarly by modifying the expression, secretion, and neurotoxic potential of cathepsin B and determined the in vivo relevance of these findings. HIV-1ADA-infected human primary microglia and CHME-5 microglia cell line were assessed for expression and activity of cathepsin B, its inhibitors, cystatins B and C, and the neurotoxicity associated with these changes. Human primary neurons were exposed to supernatants from HIV-infected and uninfected microglia in the presence of cathepsin B inhibitors and apoptosis was assessed by TUNEL. Microglial expression of cathepsin B was validated in brain tissue from HIV encephalitis (HIVE) patients. HIV-infected microglia secreted significantly greater levels of cathepsin B, cystatin B, and cystatin C compared to uninfected cells. Increased apoptosis was observed in neurons exposed to supernatants from HIV-1 infected microglia at day 12 post-infection. The cathepsin B inhibitor CA-074 and cathepsin B antibody prevented neuronal apoptosis. Increased microglia-derived cathepsin B, cystatin B, and cystatin C and caspase-3+ neurons were detected in HIVE brains compared to controls. Our results suggest that HIV-1-induced cathepsin B production in microglia contributes to neuronal apoptosis and may be an important factor in neuronal death associated with HIVE.

Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count.

Several studies report associations between the particularly interesting new cysteine histidine-rich (PINCH) protein and HIV-associated CNS disease. PINCH is detected in the CSF of HIV patients, and changes in levels during disease may be indicative of changes in disease status over time. PINCH binds hyperphosphorylated Tau (hpTau) in the brain and CSF, but little is known about the relevance of these interactions to HIV CNS disease. In this study, PINCH and hpTau levels were assessed in three separate CSF samples collected longitudinally from 20 HIV+ participants before and after initiating antiretroviral therapy or before and after a change in the treatment regimen. The intervals were approximately 1 (T2) and 3-7 (T3) months from the initial visit (baseline, T1). Correlational analyses were conducted for CSF levels of PINCH and hpTau and other variables including blood CD4 T-cell count, plasma and CSF viral burden, CSF neopterin, white blood cell (WBC) count, and antiretroviral CNS penetration effectiveness (CPE). Values for PINCH and hpTau were determined for each patient by calculating the fold changes between the second (T2) and third measurements (T3) from the baseline measurement (T1). Statistical analyses showed that the fold changes in CSF PINCH protein from T1 to T2 were significantly higher in participants with CD4 counts >200 cells/mm(3) at T2 compared to those with CD4 counts <200 cells/mm(3) at T2. This trend persisted irrespective of plasma or CSF viral burden or antiretroviral therapy CPE scores. The fold changes in PINCH levels between T1 and T2, and T1 and T3 were highly correlated to the fold changes in hpTau at T2/T1 and T3/T1 (correlation coefficient = 0.69, p < 0.001; correlation coefficient = 0.83, p < 0.0001, respectively). In conclusion, in these HIV participants, changes in CSF levels of PINCH appear to correlate with changes in blood CD4 count and with changes in CSF hpTau levels, but not with plasma or CSF viral burden, neopterin, WBC, or antiretroviral regimen CPE.

Micro-computed tomography assessment of vertebral column defects in retinoic acid-induced rat model of myelomeningocele.

BACKGROUND: Myelomeningocele (MMC) is a common congenital malformation and the most severe form of spina bifida characterized by the protrusion of spinal cord and meninges through the spinal defect. Our objective was to improve the assessment of congenital vertebral defects in animal models of MMC using three-dimensional high resolution micro-computed tomography (micro-CT) imaging and quantitative digital analyses methods. METHODS: Lumbosacral MMC was induced in fetal rats by exposure of pregnant mothers at embryonic day 10 (E10) to all-trans retinoic acid, and rats were examined at term (embryonic day 22). The axial skeleton was examined in an MMC model for the first time using ex vivo micro-CT at 10 µm voxel resolution to allow high resolution two-dimensional and three-dimensional characterization of anomalies in lumbosacral vertebrae, and quantitative assessment of distances between dorsal vertebral arches in lumbosacral regions in MMC rats, compared with normal controls. RESULTS: We observed, in detail, skeletal defects in lumbosacral vertebra of MMC rats, including in the morphology of individual dorsal vertebral arches. Use of high resolution micro-CT has also enabled us to identify the delayed (nonfused) or absent ossification in vertebral bodies, increased fusion of adjacent lateral vertebral elements, and quantify the extent of dorsal arch widening. Distances between dorsal vertebral arches showed statistically significant increases from L5 through S4 in MMC rats, compared with normal controls. CONCLUSION: High-resolution micro-CT combined with digital quantification methods is a powerful technique ideally suited for precise assessment of complex congenital skeletal abnormalities such as examined in this rodent model of MMC.

Dysregulation of PINCH signaling in mesial temporal epilepsy.

Mounting evidence suggests that inflammation is important in epileptogenesis. Particularly Interesting New Cysteine Histidine-rich (PINCH) protein is a highly conserved, LIM-domain protein known to interact with hyperphosphorylated Tau. We assessed PINCH expression in resected epileptogenic human hippocampi and further explored the relationships among PINCH, hpTau and associated kinases. Resected hippocampal tissue from 7 patients with mesial temporal lobe epilepsy (MTLE) was assessed by Western analyses to measure levels of PINCH and hyperphosphorylated Tau, as well as changes in phosphorylation levels of associated kinases AKT and GSK3ß in comparison to normal control tissue. Immunolabeling was also conducted to evaluate PINCH and hpTau patterns of expression, co-localization and cell-type specific expression. Hippocampal PINCH was increased by 2.6 fold in the epilepsy cases over controls and hpTau was increased 10 fold over control. Decreased phospho-AKT and phospho-GSK3ß in epilepsy tissue suggested involvement of this pathway in MTLE. PINCH and hpTau co-localized in some neurons in MTLE tissue. While PINCH was expressed by both neurons and astrocytes in MTLE tissue, hpTau was extracellular or associated with neurons. PINCH was absent from the serum of control subjects but readily detectable from the serum of patients with chronic epilepsy. Our study describes the expression of PINCH and points to AKT/GSK3ß signaling dysregulation as a possible pathway in hpTau formation in MTLE. In view of the interactions between hpTau and PINCH, understanding the role of PINCH in MTLE may provide increased understanding of mechanisms leading to inflammation and MTLE epileptogenesis and a potential biomarker for drug-resistant epilepsy.

Expression of Signaling Molecules in Progressive Multifocal Leukoencephalopathy.

INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a debilitating demyelinating disease of the CNS caused by the infection and destruction of glial cells by JC virus (JCV) and is an AIDS-defining disease. Infection with JCV is common and most people acquire antibodies early in life. After initial infection, JCV remains in an asymptomatic persistent state and can be detected by PCR in many tissues including brain. A major question in PML pathogenesis is how the virus reactivates from persistence in HIV-1/AIDS. Our studies with primary cultures of glial cells have implicated transcription factors NF-κB and NFAT4, which bind to a unique site in the JCV noncoding control region and stimulate viral gene expression. Furthermore, these transcription factors are controlled by pathways downstream of proinflammatory cytokines, e.g., TNF-α activates NF-κB and stimulates JCV transcription. OBJECTIVES: We hypothesize that HIV-1/PML initiation may involve reactivation of JCV by cytokine disturbances in the brain such as occur in HIV-1/AIDS. In this study, the objective was to evaluate HIV-1/PML clinical samples for expression of TNF-α and its receptors and subcellular localization of NF-κB p65 and NFAT4 compared to non-PML controls. METHODS: We evaluated HIV-1/PML clinical samples and non-PML controls for expression of TNF-α and its receptors and subcellular localization of NF-κB p65 and NFAT4 using Western blot and immunohistochemistry. RESULTS: Consistent with our hypothesis, compared to non-PML controls, HIV-1/PML tissue has high levels of TNF-α and TNFR1 expression and NF-κB and NFAT4 were preferentially localized to the nucleus. CONCLUSION: The involvement of TNF-α/NF-κB/NFAT4 signaling in JCV regulation that we reported from experiments in cultured human glial cells may be clinically relevant in PML.

PINCH in the cellular stress response to tau-hyperphosphorylation.

Particularly interesting new cysteine- histidine- rich protein (PINCH) is an adaptor protein that our data have shown is required for neurite extension under stressful conditions. Our previous studies also report that PINCH is recalled by neurons showing decreased levels of synaptodendritic signaling proteins such as MAP2 or synaptophysin in the brains of human immunodeficiency virus (HIV) patients. The current study addressed potential role(s) for PINCH in neurodegenerative diseases. Mass spectrometry predicted the interaction of PINCH with Tau and with members of the heat shock response. Our in vitro data confirmed that PINCH binds to hyperphosphorylated (hp) Tau and to E3 ubiquitin ligase, carboxy-terminus of heat shock-70 interacting protein. Silencing PINCH prior to induction of hp-Tau resulted in more efficient clearance of accumulating hp-Tau, suggesting that PINCH may play a role in stabilizing hp-Tau. Accumulation of hp-Tau is implicated in more than 20 neuropathological diseases including Alzheimer's disease (AD), frontotemporal dementia (FTD), and human immunodeficiency virus encephalitis (HIVE). Analyses of brain tissues from HIVE, AD and FTD patients showed that PINCH is increased and binds to hp-Tau. These studies address a new mechanism by which AD and HIV may intersect and identify PINCH as a contributing factor to the accumulation of hyperphosphorylated Tau.