An 80-year-old male with a distant 10 pack-years smoking history and squamous cell carcinoma (SCCA) of the scalp diagnosed 15 years ago presented with a new right nasal bulbar conjunctival lesion ...found to be invasive SCCA. The patient was started on interferon alfa-2b for 5 months until there was no evidence of residual disease. During a follow-up visit 10 months after diagnosis and during routine ophthalmic follow-up, an enlarged right submandibular lymph node was found through neck palpation and revealed to be SCCA without extranodal extension. The lesion was likely to have metastasized from his right conjunctival squamous cell carcinoma (CSCCA). Regional lymph nodes are a commonplace of metastasis for CSCCA making neck palpation a reasonable and recommended part of clinical examination to monitor for metastasis. This is the first known case of identifying regional metastasis of CSCCA through neck palpation.
Background Activating variants in platelet-derived growth factor receptor beta (PDGFRB), including a variant we have previously described (p.Tyr562Cys g.149505130T>C GRCh37/hg19; c.1685A>G), are ...associated with development of multiorgan pathology, including aneurysm formation. To investigate the association between the allele fraction genotype and histopathologic phenotype, we performed an expanded evaluation of post-mortem normal and aneurysmal tissue specimens from the previously published index patient. Methods and Results Following death due to diffuse subarachnoid hemorrhage in a patient with mosaic expression of the above PDGFRB variant, specimens from the intracranial, coronary, radial and aortic arteries were harvested. DNA was extracted and alternate allele fractions (AAF) of
were determined using digital droplet PCR. Radiographic and histopathologic findings, together with genotype expression of
were then correlated in aneurysmal tissue and compared to non-aneurysmal tissue. The
variant was identified in the vertebral artery, basilar artery, and P1 segment aneurysms (AAF: 28.7%, 16.4%, and 17.8%, respectively). It was also identified in the coronary and radial artery aneurysms (AAF: 22.3% and 20.6%, respectively). In phenotypically normal intracranial and coronary artery tissues, the
variant was not present. The
variant was absent from lymphocyte DNA and normal tissue, confirming it to be a non-germline somatic variant. Primary cell cultures from a radial artery aneurysm localized the
variant to CD31-, non-endothelial cells. Conclusions Constitutive expression of PDGFRB within the arterial wall is associated with the development of human fusiform aneurysms. The role of targeted therapy with tyrosine kinase inhibitors in fusiform aneurysms with
mutations should be further studied.
Generally, studies of gadolinium (Gd) deposition in humans measure concentration by analyzing formalin fixed postmortem tissue. However, the effect of formalin fixation on measured Gd concentration ...has not been well investigated.
To evaluate the effect of fixation by comparing Gd concentration in fresh versus formalin-fixed postmortem human tissues.
Fresh samples of bone and skin were collected from autopsy cases with previous exposure to Gd-based contrast agents (GBCAs). The type of GBCA administered, dose, and estimated glomerular filtration rate were recorded. Each tissue sample was cut into three aliquots. Paired samples were stored fresh frozen while the remaining two were stored in 10% neutral buffered formalin for one and three months, respectively. Gd concentration was measured using ICP-MS.
Of 18 autopsy cases studied, 12 were exposed to only macrocyclic GBCA, one to only linear agents, and five received both macrocyclic and linear agents. On average, Gd concentration for bone decreased 30.7% after one month of fixation (
= 0.043) compared to non-fixed values. There was minimal, if any, change in concentration between one and three months (average decrease 1.5%;
= 0.89). The findings were numerically similar for skin tissue with an average decrease of 36.9% after one month (
= 0.11) and 6.0% (
= 0.73) between one and three months.
Formalin fixation appears to decrease Gd concentration in bone and skin by approximately 30%-40% on average. The largest decrease occurs within the first 30 days of fixation followed by a considerably smaller decrease at 60 days.
This study utilized laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to quantify gadolinium in the hair of autopsy cases that had received gadolinium-based contrast agents ...(GBCAs) before death. Consecutive autopsy cases were reviewed for GBCA injections and subjects who received a single type of GBCA in the year before death were included. Hair samples were analyzed using LA-ICP-MS as a line scan technique and parameters were optimized to maximize instrument sensitivity, accuracy, and precision. Linear regression analyses between hair measures and gadolinium dose were executed. LA-ICP-MS analysis produced a time-resolved record of GCBA exposure, with the position of the gadolinium peak maxima along the hair shaft providing a good estimate for the day that GBCA injection occurred (
R
2
= 0.46;
p
= 0.0022); however, substantial within and between subject variation in the position of the GBCA peak was observed. Average area under the curve for gadolinium peaks in the hair samples was a better predictor of gadolinium dose (
R
2
= 0.41;
p
= 0.0046), compared to the average of peak maxima concentration. Correlation between area under the curve and dose suggests that LA-ICP-MS analysis of hair may be an effective method to evaluate gadolinium levels in subjects in vivo after exposure to GBCAs. This study demonstrates that analysis of human hair using techniques with high spatial resolution such as LA-ICP-MS has excellent potential to reveal time-dependent signatures of past exposures.
Local immune activation at mucosal surfaces, mediated by mucosal lymphoid tissues, is vital for effective immune responses against pathogens. While pathogens like severe acute respiratory syndrome ...coronavirus 2 (SARS-CoV-2) can spread to multiple organs, patients with coronavirus disease 2019 (COVID-19) primarily experience inflammation and damage in their lungs. To investigate this apparent organ-specific immune response, we develop an analytical framework that recognizes the significance of mucosal lymphoid tissues. This framework combines histology, immunofluorescence, spatial transcript profiling, and mathematical modeling to identify cellular and gene expression differences between the lymphoid tissues of the lung and the gut and predict the determinants of those differences. Our findings indicate that mucosal lymphoid tissues are pivotal in organ-specific immune response to SARS-CoV-2, mediating local inflammation and tissue damage and contributing to immune dysfunction. The framework developed here has potential utility in the study of long COVID and may streamline biomarker discovery and treatment design for diseases with differential pathologies at the organ level.
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•Mucosal lymphoid tissues drive organ-specific response during SARS-CoV-2 infection•Injury signature is enriched in the lymphoid tissues of the lung relative to the gut•Lung lymphoid tissues harbor increased inflammatory macrophages during infection•Absence of activated dendritic cells in those tissues suggests immune dysfunction
Ng et al. investigate the role of mucosal lymphoid tissues in SARS-CoV-2 infection, uncovering distinct immune responses in the lung versus the gut. Lung lymphoid tissues exhibit elevated inflammatory macrophages, diminished activated dendritic cells, and amplified injury signatures, underscoring their pivotal role in organ-specific infection response.
Twins have an increased risk for congenital malformations and disruptions, including defects in brain morphogenesis. We analyzed data on brain imaging, zygosity, sex, and fetal demise in 56 proband ...twins and 7 less affected co‐twins with abnormal brain imaging and compared them to population‐based data and to a literature series. We separated our series into malformations of cortical development (MCD, N = 39), cerebellar malformations without MCD (N = 13), and brain disruptions (N = 11). The MCD group included 37/39 (95%) with polymicrogyria (PMG), 8/39 (21%) with pia‐ependymal clefts (schizencephaly), and 15/39 (38%) with periventricular nodular heterotopia (PNH) including 2 with PNH but not PMG. Cerebellar malformations were found in 19 individuals including 13 with a cerebellar malformation only and another 6 with cerebellar malformation and MCD. The pattern varied from diffuse cerebellar hypoplasia to classic Dandy–Walker malformation. Brain disruptions were seen in 11 individuals with hydranencephaly, porencephaly, or white matter loss without cysts. Our series included an expected statistically significant excess of monozygotic (MZ) twin pairs (22/41 MZ, 54%) compared to population data (482/1448 MZ, 33.3%; p = .0110), and an unexpected statistically significant excess of dizygotic (DZ) twins (19/41, 46%) compared to the literature cohort (1/46 DZ, 2%; p < .0001. Recurrent association with twin–twin transfusion syndrome, intrauterine growth retardation, and other prenatal factors support disruption of vascular perfusion as the most likely unifying cause.
Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced 18F-fluorodeoxyglucose (FDG) uptake.
The ...goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans.
These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.
•Plasma VEGF-A is chronically elevated in veterans with blast-related mTBI.•Plasma VEGF-A correlates with glucose uptake measured by FDG-PET in cerebellum.•Impaired cognitive inhibition correlates with plasma VEGF-A in blast mTBI veterans.•Chronic vascular disturbances are an important feature of blast-related mTBI.
•We present a case of neutral lipid storage disease with myopathy (NLSDM) caused by a rare variant in PNPLA2 (c.757 + 1G > T).•As the second report in an affected individual this variant is likely ...pathologic.•This variant may be unique to the Hmong population.•Improved genotype–phenotype correlation is necessary to improve diagnosis of neutral lipid storage disease with myopathy.
Neutral lipid storage disease with myopathy is a rare disorder of lipid metabolism caused by variants in the Patatin-Like Phospholipase Domain Containing 2 (PNPLA2) gene. Diagnosis is often delayed due to variable presentations, which is of concern due to increased risk of cardiomyopathy. Better phenotype–genotype characterization is necessary to improve speed and accuracy of diagnosis. Here, we describe a 32-year-old woman of Hmong descent with progressive muscle pain and weakness who had a muscle biopsy with characteristic features of a lipid storage myopathy. Genetic testing revealed a homozygous splice site variant in PNPLA2, c.757 + 1G > T. This case, in combination with the one previously reported case of this PNPLA2 variant, also in a family of Hmong descent, suggests this particular variant may be unique to the Hmong population, a Southeast Asian minority group living in the United States, who immigrated to the United States as refugees after the Vietnam War.
Bacterial and fungal co-infections are reported complications of coronavirus disease 2019 (COVID-19) in critically ill patients but may go unrecognized premortem due to diagnostic limitations. We ...compared the premortem with the postmortem detection of pulmonary co-infections in 55 fatal COVID-19 cases from March 2020 to March 2021. The concordance in the premortem versus the postmortem diagnoses and the pathogen identification were evaluated. Premortem pulmonary co-infections were extracted from medical charts while applying standard diagnostic definitions. Postmortem co-infection was defined by compatible lung histopathology with or without the detection of an organism in tissue by bacterial or fungal staining, or polymerase chain reaction (PCR) with broad-range bacterial and fungal primers. Pulmonary co-infection was detected premortem in significantly fewer cases (15/55, 27%) than were detected postmortem (36/55, 65%;
< 0.0001). Among cases in which co-infection was detected postmortem by histopathology, an organism was identified in 27/36 (75%) of cases.
,
, and
were the most frequently identified bacteria both premortem and postmortem. Invasive pulmonary fungal infection was detected in five cases postmortem, but in no cases premortem. According to the univariate analyses, the patients with undiagnosed pulmonary co-infection had significantly shorter hospital (
= 0.0012) and intensive care unit (
= 0.0006) stays and significantly fewer extra-pulmonary infections (
= 0.0021). Bacterial and fungal pulmonary co-infection are under-recognized complications in critically ill patients with COVID-19.
Aims
In response to concerns regarding resource expenditures required to implement fully the 2012 National Institute on Aging and the Alzheimer's Association (NIA‐AA) Sponsored Guidelines for the ...neuropathological assessment of Alzheimer's disease (AD), we previously developed a sensitive and cost‐reducing condensed protocol (CP) at the University of Washington (UW) Alzheimer's Disease Research Center (ADRC) that consolidated the recommended NIA‐AA protocol into fewer cassettes requiring fewer immunohistochemical stains. The CP was not designed to replace NIA‐AA protocols, but instead to make the NIA‐AA criteria accessible to clinical and forensic neuropathology practices where resources limit full implementation of NIA‐AA guidelines.
Methods and results
In this regard, we developed practical criteria to instigate CP sampling and immunostaining, and applied these criteria in an academic clinical neuropathological practice. During the course of 1 year, 73 cases were sampled using the CP; of those, 53 (72.6%) contained histological features that prompted CP work‐up. We found that the CP resulted in increased identification of AD and Lewy body disease neuropathological changes from what was expected using a clinical history‐driven work‐up alone, while saving approximately $900 per case.
Conclusions
This study demonstrates the feasibility and cost‐savings of the CP applied to a clinical autopsy practice, and highlights potentially unrecognised neurodegenerative disease processes in the general ageing community.
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