Workplace mistreatment and mental health in female surgeons in Pakistan.

BACKGROUND: Despite workplace mistreatment, which includes harassment, bullying and gender discrimination(GD)/bias, being serious problems for female surgeons, there are limited data from lower-middle-income countries like Pakistan. This study explored harassment and GD/bias experienced by female surgeons in Pakistan, and the effects of these experiences on mental health and well-being. METHODS: A nationwide survey was conducted between July and September 2019 in collaboration with the Association of Women Surgeons of Pakistan, an organization consisting of female surgeons and trainees in Pakistan. An anonymous online survey was emailed directly, disseminated via social media platforms (such as Facebook, Twitter and Instagram), and sent to surgical programmes in Pakistan. RESULTS: A total of 146 women surgeons responded to the survey; 67.1 per cent were trainees and the rest attending surgeons. Overall, 57.5 per cent of surgeons reported experiencing harassment, most common being verbal (64.0 per cent) and mental (45.9 per cent), but this mostly went unreported (91.5 per cent). On multivariable analysis adjusted for age and specialty, workplace harassment (odds ratio 2.02 (95 per cent c.i. 1.09 to 4.45)) and bullying (odds ratio 5.14 (95 per cent c.i. 2.00-13.17)) were significantly associated with severe self-perceived burnout, while having a support system was protective against feelings of depression (odds ratio 0.35 (95 per cent c.i. 0.16 to 0.74)). The overwhelming majority (91.3 per cent) believed that more institutional support groups were needed to help surgeons with stress reduction (78.8 per cent), receiving mentorship (74.7 per cent) and work-life balance (67.8 per cent). CONCLUSION: Workplace mistreatment, in particular harassment and bullying, has a damaging impact on the mental well-being of female surgeons, particularly trainees. The absence of support groups in Pakistan should be urgently addressed so that surgeons, especially trainees, may cope better with potentially harmful workplace stressors.

Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease. There are a limited number of therapeutic options available for the treatment of AD. Curcuminoids (a mixture of bisdemethoxycurcumin, demethoxycurcumin and curcumin) is the main chemical constituent found in turmeric, a well known curry spice, having potential in the treatment of AD. The objective of this study was to investigate the effects of curcuminoid mixture and individual constituents on spatial learning and memory in an amyloid-beta (Abeta) peptide-infused rat model of AD and on the expression of PSD-95, synaptophysin and camkIV. Curcuminoid mixture showed a memory-enhancing effect in rats displaying AD-like neuronal loss only at 30 mg/kg, whereas individual components were effective at 3-30 mg/kg. A shorter duration treatment with test compounds showed that the curcuminoid mixture and bisdemethoxycurcumin increased PSD-95 expression in the hippocampus at 3-30 mg/kg, with maximum effect at a lower dose (3 mg/kg) with respective values of 470.5 and 587.9%. However, after a longer duration treatment, two other compounds (demethoxycurcumin and curcumin) also increased PSD-95 to 331.7 and 226.2% respectively at 30 mg/kg. When studied for their effect on synaptophysin in the hippocampus after the longer duration treatment, the curcuminoid mixture and all three individual constituents increased synaptophysin expression. Of these, demethoxycurcumin was the most effective showing a 350.1% increase (P<0.01) at 30 mg/kg compared to the neurotoxin group. When studied for their effect on camkIV expression after longer treatment in the hippocampus, only demethoxycurcumin at 30 mg/kg increased levels to 421.2%. These compounds salvaged PSD-95, synaptophysin and camkIV expression levels in the hippocampus in the rat AD model, which suggests multiple target sites with the potential of curcuminoids in spatial memory enhancing and disease modifying in AD.

Association of cerebral arteriovenous malformations and spontaneous occlusion of major feeding arteries: clinical and therapeutic implications.

OBJECTIVE: The spontaneous occlusion of a cerebral arteriovenous malformation (AVM) occurs rarely. Occlusion of a parent artery feeding the AVM is even more rare, and its incidence is unknown. We undertook this study to determine the incidence of occlusion of a major artery feeding an AVM and to recommend a management strategy for such an AVM. METHODS: We identified AVMs associated with an occluded artery by performing a retrospective angiographic analysis of 500 patients with AVMs who presented to Henry Ford Hospital from 1976 to 1998. RESULTS: A review of the angiograms revealed that 7 (1.4%) of 500 patients with an AVM had occlusion of one or more major arteries feeding the nidus. In four patients, an internal carotid artery and its bifurcation were occluded; in two patients, the M1 segment of the middle cerebral artery was occluded, and in one patient, a vertebral artery was occluded. Pial collaterals and/or a moyamoya pattern of anastomoses developed in all patients, with the exception of one who had vertebral artery occlusion. Five patients underwent definitive treatment: one received radiosurgery, and four underwent surgical excision. One of the surgically treated patients died of complications from excessive blood loss and coagulopathy, but the other three had no postoperative complications. CONCLUSION: The occlusion of a major artery feeding an AVM occurs rarely (1.4%). These AVMs are moderate to large in size (>3 cm). To prevent collateral flow-related complications of cortical "steal" and hemorrhage, as well as the usual risk of hemorrhage from the AVM itself, surgical management should be considered for these AVMs.

Role of extracellular matrix in tumor invasion: migration of glioma cells along fibronectin-positive mesenchymal cell processes.

OBJECTIVE: The major morbidity of glioma lies in its infiltrative growth. One of the major patterns of this invasive growth is the formation of Scherer's secondary structures associated with the blood vessels and the leptomeninges. To better understand the role of extracellular matrix (ECM) in glioma invasion, we investigated in vitro the interaction between glioma cells and the meningeal mesenchymal tissue from the brain. As an aid to this study, ECM in glioma cell line spheroids was compared with that in primary fetal brain aggregates. METHODS: To study the expression of ECM, four glioma cell lines (U-87 MG, U-251 MG, AN1/lac-z, and HF-66) and primary cells from fetal rat brain were grown as spheroids and monolayers. To sudy the role of ECM in glioma invasion, spheroids from the glioma cell lines were grown over established cultures of fetal meningeal and mesenchymal tissue. Expression of fibronectin, laminin, tenascin, collagen VI, and chondroitin sulfate proteoglycan was studied by immunofluorescence. RESULTS: Expression of ECM by the spheroids was variable. U-87 MG expressed most of the ECM components robustly, whereas AN1/lac-z expressed them all weakly. Fetal rat brain aggregates produced minimal ECM. In cocultures of glioma spheroids and fetal meningeal mesenchymal tissue, individual cells from the glioma spheroids that expressed least fibronectin (AN1/lac-z and U-251 MG) migrated along the fibronectin-positive mesenchymal cells in the culture dish. Cells from the other two lines (U-87 MG and HF-66) that expressed fibronectin strongly did not demonstrate such behavior. None of the other ECM components showed a similar association; mesenchymal cells did not express laminin as strongly as fibronectin, and glioma cells were not observed to align with the laminin-positive structures. CONCLUSION: This study suggests that fibronectin may play a key role in intracerebral invasion of glioma cells.

Neurocytoma in the cerebellum. Case report.

A neurocytoma is a central nervous system tumor composed of small cells with features of neuronal differentiation; it typically occurs in the periventricular region, close to the septum pellucidum and the foramen of Monro. In this article, the authors report the case of a neurocytoma located in the cerebellum, which to their knowledge is the first reported case of its kind. The finding of a neurocytoma at a nonclassic location refutes the theory that this tumor has its origins in subependymal progenitor cells, unless an ectopic location of progenitor cells is invoked to explain the occurrence of a neurocytoma away from the ventricles. On the basis of this case, the authors suggest that neurocytomas should be added to the differential diagnosis of mass lesions in the supratentorial intraventricular regions as well as in the posterior fossa.

Metastasis in meningioma.

Meningioma is a neoplastic growth originating from the leptomeninges. Although meningiomas are usually benign, malignant meningiomas with distant metastases occur infrequently. There is little precise information in the literature regarding the frequency of metastases in meningiomas; their incidence has been vaguely reported to be less than 1 per 1,000. Furthermore, most of the previous studies have also included haemangiopericytomas which most recent authorities do not consider meningiomas. In our experience with the management of 396 meningiomas over the past 18 years, 7 meningiomas were classified as malignant by defined histological criteria. After initially presenting as solitary intracranial neoplasms, three of the malignant meningiomas metastasized to extracranial tissues. Collectively, the metastases involved the vertebral bodies, liver, pelvis, long bones, and the spinal cord. This confers an incidence of metastasis of 0.76% when considering all the meningiomas, and an incidence of approximately 43% when considering only malignant meningioma; both percentages are significantly higher than reported previously. This high incidence of metastasis in the malignant meningioma indicates a worse prognosis than formerly assessed and also characterized the malignant meningioma as a primary central nervous system neoplasm with one of the highest rates of metastasis. In addition, when malignant meningioma is classified by following strict criteria, the risk of metastasis in the ensuing clinical course can be predicted with a higher reliability.

Constitutive Alzheimer's-type tau epitopes in a neuritogenic rat CNS cell line.

Paired helical filaments (PHFs) of Alzheimer's disease (AD) largely comprise hyperphosphorylated forms of the cytoskeletal protein tau. AD-type tau phosphoepitopes, detected by various monoclonal antibodies, are absent from normal adult neurons, but recent studies have shown that their expression may contribute to neuritogenesis and axon differentiation in the developing nervous system. Therefore, we have examined a brain nerve cell line that is spontaneously neuritogenic for possible expression of AD-type tau epitopes. The neuritogenic rat brain cell line B103 was found to constitutively produce two-AD related epitopes of tau, detected by cellular immunofluorescence studies with the PHF-1 and Alz-50 monoclonal antibodies. Biochemical studies showed that the antibodies bound to proteins within the molecular, weight range expected for phosphorylated tau isoforms. Further verification was established by use of tau antisense oligomers, which eliminated cellular immunofluorescence due to the AD-related monoclonals and polyclonal anti-tau but did not eliminate fluorescence due to anti-tubulin. Cells treated with tau antisense were not neurite-free. Neurites that remained, however, were abnormal, generally short and wavy in appearance. Cellular distribution of the tau epitopes was found to be particularly interesting. Alz-50 recognized only cytoplasmic tau whereas PHF-1 recognized nuclear tau as well as cytoplasmic. Thus, the two epitopes, are morphologically segregated within the cell. Because subcellular segregation of tau is compromised in Alzheimer's disease, mechanisms that segregate AD-type phosphotau epitopes in B103 cells may have relevance to this neurodegenerative disorder.

Particulate forms of APP in the extracellular milieu of cultured cells.

The principle externalized forms of amyloid precursor protein (APP) are soluble and well-characterized, but some evidence has suggested the additional presence of externalized APP in a nonsoluble form. To further assess this possibility, the current study has applied high resolution microscopy protocols in addition to immunoprecipitation to characterize externalized APP in three commonly used cell culture models (SH-SY5Y human neuroblastoma cells, fetal rat brain cells, and HEK 293 human embryonic kidney cells). Confocal immunofluorescence microscopy, using an antiserum against the c-terminal domain of APP, showed typical cell-associated APP, but hot spots of APP also were evident in cell-free areas, apparently associated with the culture substrata. These hot-spots were examined for evidence of cellular deterioration by whole mount transmission electron microscopy. Neither cell debris nor disrupted cells were present. Instead, the hot spots of substratum-bound APP comprised discrete microparticles, approximately 50-100 nm across. These microparticles also could be found near cells and in some cases were attached to cell surface fibrils. Substratum-bound APP also could be found clustered within the extracellular matrix made by primary cell cultures. Occurrence of APP in extracellular microparticles was verified by centrifugation-immunoprecipitation analysis of media conditioned by APP-transfected cells. Radiolabeling data showed that particulate APP was from metabolically active cells. Metabolic labeling of particle-associated APP, as well as the absence of cellular debris near the APP-containing particles, suggests that the occurrence of nonsoluble APP in the extracellular milieu derives from a physiologically active process.

Phosphorylated tau epitope of Alzheimer's disease is coupled to axon development in the avian central nervous system.

The monoclonal antibody PHF-1 recognizes phosphorylated tau isoforms present in paired helical filaments of Alzheimer's disease. We have found that PHF-1 immunoreactivity is present in chick brain, which expresses three major PHF-1-reactive proteins at the same molecular weights seen in humans. The developmental pattern of expression suggests a functional role in differentiation, rather than in programmed nerve cell death. Expression of PHF-1 immunoreactivity in developing retina was highly cell selective, showing robust staining of ganglion cells, the only long-axon neuron of the seven major retina cell types. The majority of ganglion cells were PHF-1 positive. The developmental window of expression extended at least from E6 through P0, well outside the period of embryonic ganglion cell death. Mature cells did not show PHF-1 immunoreactivity. In the embryo, staining was particularly robust in ganglion cell axons (optic fiber layer), and association of PHF-1 reactivity with axonal tracts also was seen in developing forebrain. PHF-1 polarization occurred at ages when staining with polyclonal anti-tau did not show axonal selectivity. Similarly, in cell cultures, PHF-1 immunoreactivity became localized to single neurites, but polyclonal anti-tau did not. These results indicate that, rather than being associated with cell degeneration, PHF-1 immunoreactivity in the developing nervous system is associated with early stages of axon formation, both in vivo and in vitro. Therefore, expression of PHF-1 immunoreactive proteins in Alzheimer's disease suggests that paired helical filament formation might be triggered by mechanisms related to axon regeneration.