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Concept: Pathology

653

 To determine whether patient outcomes differ between general internists who graduated from a medical school outside the United States and those who graduated from a US medical school.

Concepts: Pathology, United States, Physician, Neurology, High school, Pediatrics, Medical school, Internal medicine

431

In retired professional association football (soccer) players with a past history of repetitive head impacts, chronic traumatic encephalopathy (CTE) is a potential neurodegenerative cause of dementia and motor impairments. From 1980 to 2010, 14 retired footballers with dementia were followed up regularly until death. Their clinical data, playing career, and concussion history were prospectively collected. Next-of-kin provided consent for six to have post-mortem brain examination. Of the 14 male participants, 13 were professional and 1 was a committed amateur. All were skilled headers of the ball and had played football for an average of 26 years. Concussion rate was limited in six cases to one episode each during their careers. All cases developed progressive cognitive impairment with an average age at onset of 63.6 years and disease duration of 10 years. Neuropathological examination revealed septal abnormalities in all six post-mortem cases, supportive of a history of chronic repetitive head impacts. Four cases had pathologically confirmed CTE; concomitant pathologies included Alzheimer’s disease (N = 6), TDP-43 (N = 6), cerebral amyloid angiopathy (N = 5), hippocampal sclerosis (N = 2), corticobasal degeneration (N = 1), dementia with Lewy bodies (N = 1), and vascular pathology (N = 1); and all would have contributed synergistically to the clinical manifestations. The pathological diagnosis of CTE was established in four individuals according to the latest consensus diagnostic criteria. This finding is probably related to their past prolonged exposure to repetitive head impacts from head-to-player collisions and heading the ball thousands of time throughout their careers. Alzheimer’s disease and TDP-43 pathologies are common concomitant findings in CTE, both of which are increasingly considered as part of the CTE pathological entity in older individuals. Association football is the most popular sport in the world and the potential link between repetitive head impacts from playing football and CTE as indicated from our findings is of considerable public health interest. Clearly, a definitive link cannot be established in this clinico-pathological series, but our findings support the need for further systematic investigation, including large-scale case-control studies to identify at risk groups of footballers which will justify for the implementation of protective strategies.

Concepts: Alzheimer's disease, Pathology, Parkinson's disease, Dementia, Lewy body, Autopsy, Cerebral amyloid angiopathy, Football

194

On 9 June 2008, the UK’s largest mass stranding event (MSE) of short-beaked common dolphins (Delphinus delphis) occurred in Falmouth Bay, Cornwall. At least 26 dolphins died, and a similar number was refloated/herded back to sea. On necropsy, all dolphins were in good nutritive status with empty stomachs and no evidence of known infectious disease or acute physical injury. Auditory tissues were grossly normal (26/26) but had microscopic haemorrhages (5/5) and mild otitis media (1/5) in the freshest cases. Five lactating adult dolphins, one immature male, and one immature female tested were free of harmful algal toxins and had low chemical pollutant levels. Pathological evidence of mud/seawater inhalation (11/26), local tide cycle, and the relative lack of renal myoglobinuria (26/26) suggested MSE onset on a rising tide between 06∶30 and 08∶21 hrs (9 June). Potential causes excluded or considered highly unlikely included infectious disease, gas/fat embolism, boat strike, by-catch, predator attack, foraging unusually close to shore, chemical or algal toxin exposure, abnormal weather/climatic conditions, and high-intensity acoustic inputs from seismic airgun arrays or natural sources (e.g., earthquakes). International naval exercises did occur in close proximity to the MSE with the most intense part of the exercises (including mid-frequency sonars) occurring four days before the MSE and resuming with helicopter exercises on the morning of the MSE. The MSE may therefore have been a “two-stage process” where a group of normally pelagic dolphins entered Falmouth Bay and, after 3-4 days in/around the Bay, a second acoustic/disturbance event occurred causing them to strand en masse. This spatial and temporal association with the MSE, previous associations between naval activities and cetacean MSEs, and an absence of other identifiable factors known to cause cetacean MSEs, indicates naval activity to be the most probable cause of the Falmouth Bay MSE.

Concepts: Disease, Infectious disease, Causality, Pathology, Infection, Toxin, Dolphin, Porpoise

181

It has been shown that caloric restriction (CR) delays aging and possibly delays the development of Alzheimer’s disease (AD). We conjecture that the mechanism may involve interoceptive cues, rather than reduced energy intake per se. We determined that hunger alone, induced by a ghrelin agonist, reduces AD pathology and improves cognition in the APP-SwDI mouse model of AD. Long-term treatment with a ghrelin agonist was sufficient to improve the performance in the water maze. The treatment also reduced levels of amyloid beta (Aβ) and inflammation (microglial activation) at 6 months of age compared to the control group, similar to the effect of CR. Thus, a hunger-inducing drug attenuates AD pathology, in the absence of CR, and the neuroendocrine aspects of hunger also prevent age-related cognitive decline.

Concepts: Alzheimer's disease, Senescence, Pathology, Cognition, Amyloid, Memory, Beta amyloid, Inclusion body myositis

172

A progressive increase in the incidence of thyroid cancer (TC) has been reported over the last few decades. This either reflects the increased number of newly discovered and accurately selected thyroid nodules with more sensitive technologies and a relative more potent carcinogenic effect of pathogenetic factors in malignant, but not benign nodules. This observational time-trend study addresses this issue by analysing the proportion of TC within 8411 consecutive thyroid nodule (TN) patients evaluated in Pisa by the same pathology Department and individual clinician over a four-decade period. From 1972 to 1979 surgery was used to detect TC among the TN patients: 1140 TN patients were operated on and 35 cancers were detected (3.1% of all the TN patients). Subsequently, needle aspiration techniques were used to select TN for surgery. From 1980 to 1992, 5403 TN patients were examined, 483 were selected for surgery, and 150 cancers were found (2.8% of all the TN patients). From 1993 to 2010, 1568 TN patients were examined, 143 were selected for surgery, and 46 cancers were found (2.9% of all the TN patients). Therefore, in the University Hospital of Pisa, and independent of preoperative TN selection protocols, these proportions of TN eventually found to harbor TC remained statistically unchanged over 40 years (p = 0.810). This finding suggests that pathogenic risk factors and more sensitive diagnostic technologies did not differentially affect the incidence of TN and TC.

Concepts: Epidemiology, Cancer, Oncology, Pathology, Hospital, Needle aspiration biopsy, Selection, Carcinogen

171

Cryptococcosis is the leading invasive fungal infection in the world today. Over the past century, the causative agents, Cryptococcus neoformans and Cryptococcus gattii, have risen from the status of medical curiosities to common but life-threatening central nervous system pathogens. In an elegant experimental pathobiology study of these two organisms carried out by Ngamskulrungroj et al., there are three matters that merit further discussion. First is the question of whether there is a variable specific pathobiology for each yeast strain. Does it make biological and clinical sense to designate C. neoformans and C. gattii as two separate species? Second is the matter of how the organisms differ pathologically at the site of infection. Finally, there is the possibility that the human immune system responds differently to each species. Although no single study can provide definitive mechanistic answers to the important questions, this experimental pathology study and its discussion clearly frame the issues to be dissected.

Concepts: AIDS, Immune system, Nervous system, Bacteria, Biology, Pathology, Cryptococcus neoformans, Basidiomycota

169

Since their discovery in 1971, the polyomaviruses JC (JCPyV) and BK (BKPyV), isolated from patients with progressive multifocal leukoencephalopathy and polyomavirus-associated nephropathy, respectively, remained for decades as the only known members of the Polyomaviridae family of viruses of human origin. Over the past five years, the application of new genomic amplification technologies has facilitated the discovery of several novel human polyomaviruses (HPyVs), bringing the present number to 10. These HPyVs share many fundamental features in common such as genome size and organization. Infection by all HPyVs is widespread in the human population, but they show important differences in their tissue tropism and association with disease. Much remains unknown about these new viruses. In this review, we discuss the problems associated with studying HPyVs, such as the lack of culture systems for the new viruses and the gaps in our basic understanding of their biology. We summarize what is known so far about their distribution, life cycle, tissue tropism, their associated pathologies (if any), and future research directions in the field.

Concepts: Human genome, Biology, Virus, Genome, Pathology, Progressive multifocal leukoencephalopathy, JC virus, Polyomavirus

169

INTRODUCTION: Although palsy of the long thoracic nerve is the classical pathogenesis of winging scapula, it may also be caused by osteochondroma. This rare etiopathology has previously been described in pediatric patients, but it is seldom observed in adults. CASE PRESENTATION: We describe three cases of static scapular winging with pain on movement. Case 1 is a Caucasian woman aged 35 years with a wing-like prominence of the medial margin of her right scapula due to an osteochondroma originating from the ventral omoplate. Histopathological evaluation after surgical resection confirmed the diagnosis. The postoperative course was unremarkable without signs of recurrence on examination at 2 years. Case 2 is a Caucasian woman aged 39 years with painful scapula alata and neuralgic pain projected along the left ribcage caused by an osteochondroma of the left scapula with contact to the 2nd and 3rd rib. Following surgical resection, the neuropathic pain continued, demanding neurolysis of the 3rd and 4th intercostal nerve after 8 months. The patient was free of symptoms 2 years after neurolysis. Case 3 is a Caucasian woman aged 48 years with scapular winging due to a large exostosis of the left ventral scapular surface with a broad cartilaginous cap and a large pseudobursa. Following exclusion of malignancy by an incisional biopsy, exostosis and pseudobursa were resected. The patient had an unremarkable postoperative course without signs of recurrence 1 year postoperatively. Based on these cases, we developed an algorithm for the diagnostic evaluation and therapeutic management of scapula alata due to osteochondroma. CONCLUSIONS: Orthopedic surgeons should be aware of this uncommon condition in the differential diagnosis of winged scapula not only in children, but also in adult patients.

Concepts: Medical terms, Pathology, Physician, Pain, Scapula, Serratus anterior muscle, Winged scapula, Long thoracic nerve

168

BACKGROUND: Pathologic studies played an important role in evaluating patients with Alport syndrome besides genotyping. Difficulties still exist in diagnosing Alport syndrome (AS), and misdiagnosis is a not-so-rare event, even in adult patient evaluated with renal biopsy. METHODS: We used nested case–control study to investigate 52 patients previously misdiagnosed and 52 patients initially diagnosed in the China Alport Syndrome Treatments and Outcomes Registry e-system. RESULTS: We found mesangial proliferative glomerulonephritis (MsPGN, 26.9%) and focal and segmental glomerulosclerosis (FSGS, 19.2%) were the most common misdiagnosis. FSGS was the most frequent misdiagnosis in female X-linked AS (fXLAS) patients (34.8%), and MsPGN in male X-linked AS (mXLAS) patients (41.2%). Previous misdiagnosed mXLAS patients (13/17, 76.5%) and autosomal recessive AS (ARAS) patients (8/12, 66.7%) were corrected after a second renal biopsy. While misdiagnosed fXLAS patients (18/23, 78.3%) were corrected after a family member diagnosed (34.8%) or after rechecking electronic microscopy and/or collagen-IV alpha-chains immunofluresence study (COL-IF) (43.5%) during follow-up. With COL-IF as an additional criterion for AS diagnosis, we found that patients with less than 3 criteria reached have increased risk of misdiagnosis (3.29-fold for all misdiagnosed AS patients and 3.90-fold for fXLAS patients). CONCLUSION: We emphasize timely and careful study of electronic microscopy and COL-IF in pathologic evaluation of AS patients. With renal and/or skin COL-IF as additional criterion, 3 diagnosis criteria reached are the cutoff for diagnosing AS pathologically.

Concepts: Medical terms, Diagnosis, Pathology, Medical diagnosis, Glomerulonephritis, Sex linkage, Dominance, Alport syndrome

167

Formalin fixation is a mainstay of modern histopathologic analysis, yet the practice is poorly standardized and a significant potential source of preanalytical errors. Concerns of workflow and turnaround time drive interest in developing shorter fixation protocols, but rapid protocols can lead to poor histomorphology or inadequate downstream assay results. Additionally, assays such as immunohistochemistry for phosphorylated epitopes have historically been challenging in the context of formalin-fixed tissue, indicating that there may be room for improvement in this process that is fundamental to the practice of anatomic pathology. With these issues in mind, we studied basic formalin biochemistry to develop a novel formalin fixation protocol that involves a pre-incubation in subambient temperature formalin prior to a brief exposure to heated formalin. This new protocol is more rapid than standard protocols yet preserves histomorphology and yields tissue that is compatible with an expanded set of downstream clinical and research assays, including immunohistochemistry for phosphorylated epitopes.

Concepts: Biology, Pathology, Anatomical pathology, Histology, Histopathology, Greek loanwords, Immunohistochemistry, Formaldehyde