Update on pathogenesis and diagnosis flow of normoalbuminuric diabetes with renal insufficiency

In recent decades, the prevalence of diabetic kidney disease has remained stable and appears to be a wide heterogeneity. Normoalbuminuric diabetes with renal insufficiency, which is characterized by a decline in the glomerular filtration rate in the absence of albuminuria, has been identified as an albuminuria-independent phenotype of diabetic kidney disease. Epidemiological data demonstrate that normoalbuminuric phenotype is prevalent. Compared to albuminuric phenotype, normoalbuminuric phenotype has distinct clinical characteristics and a wide heterogeneity of pathological features. Currently, the pathogenesis of normoalbuminuric phenotype remains unclear. Additionally, the flow of diagnosing normoalbuminuric phenotype is not perfect. In this article, we review the latest studies addressing the epidemiology, clinical characteristics, and pathology of normoalbuminuric phenotype. Based on the studies of clinical features and renal histopathologic changes, we attempt to propose an underlying pathogenesis model and a flow chart for diagnosing normoalbuminuric phenotype.

Impacts of CAD/CAM Metallic Materials on Trace Metals and Biocompatibilities: An in vivo Study in Beagle Dogs

CAD/CAM (computer-aided design and computer-aided manufacturing) technology has been widely applied in clinical dentistry, but the material safety remains a concern. To investigate the impacts of CAD/CAM metallic materials on trace metals and biocompatibilities, selective laser melted (SLM) cobalt-chromium (Co-Cr) alloys and computer numeric controlled milled (CNC milled) commercially pure titanium (CP-Ti) were placed on the maxilla of beagle dogs for 6 months. The trace metals in the oral mucosa, blood, liver, kidney, and hair were then determined by inductively coupled plasma mass spectrometry (ICP-MS). The histopathologic changes and biocompatibilities of tissues were examined by hematoxylin and eosin (H&E) staining, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling (TUNEL) method, immunohistochemistry (IHC) assay, Western blot analysis, and liver and kidney function tests. Our results showed that trace metals released from these two CAD/CAM metallic materials accumulated transiently in the oral mucosa and whole blood. The trace metals released from SLM Co-Cr alloys could also transiently accumulate in the plasm and hair. In addition, these two CAD/CAM metallic materials both induced apoptosis and histopathologic changes in the oral mucosa, with SLM Co-Cr alloys inducing a higher level of apoptosis. In contrast, both materials did not exert autophagic effects on the oral mucosa or affect the trace metals, functions, or biocompatibilities of the liver and kidney. Therefore, this study suggests that CAD/CAM metallic materials should be selected carefully, especially in patients with metal- and apoptosis-related diseases, and CNC-milled CP-Ti can be recommended to patients on account of its better biocompatibility and safety.

Tamoxifen administration induces histopathologic changes within the lungs of Cre-recombinase-negative mice: A case report

Tamoxifen is commonly used as a cancer treatment in humans and for inducing genetic alterations using Cre-lox mouse models in the research setting. However, the extent of tamoxifen off-target effects in animal research is underappreciated. Here, we report significant changes in cellular infiltration in Cre-recombinase-negative mice treated with tamoxifen intraperitoneally. These changes were noted in the lungs, which were characterized by the presence of alveolitis, vasculitis, and pleuritis. Despite significant immunological changes in response to tamoxifen treatment, clinical symptoms were not observed. This study provides a cautionary note that tamoxifen treatment alone leads to histologic alterations that may obscure research interpretations and further highlights the need for the development of alternative mouse models for inducible Cre-mediated deletion.

The Diagnostic Yield of Cone-Beam Computed Tomography for Degenerative Changes of the Temporomandibular Joint in Dogs

Degenerative changes of the temporomandibular joint (DTMJ) may be diagnosed via cone - beam computed tomography (CBCT). However, despite advancement in CBCT imaging, correlation of DTMJ features identified on CBCT with gross and histological findings is currently limited. This study aimed to correlate CBCT findings of DTMJ of dogs with gross and histopathologic changes. Temporomandibular joints (TMJ) (n = 38) from fresh cadaver heads of asymptomatic dogs (n = 19) were examined radiologically, macroscopically, and microscopically. Association of CBCT - detected DTMJ changes with gross and histological findings were statistically evaluated via kappa statistics and ordinal logistic mixed-effects models. The radiological changes observed on CBCT included joint space narrowing, subchondral/cortical bone changes (i.e., erosions or lysis), osteophytes, and subchondral bone sclerosis. Upon macroscopic evaluation, the majority of examined specimens had mild changes with cartilage defects and osteophytes affecting <10% of the total articular surface area. Histopathologic changes comprised splitting and degeneration of the fibrous cartilage layers, subchondral bone exposure, subchondral bone sclerosis, focal subchondral bone lysis, and occasional cell death. Subchondral sclerosis was the most prevalent finding radiologically and histologically with a fair to excellent agreement. Importantly, the more severe the TMJ degenerative changes, the higher the agreement between CBCT and histology. Based on the correlative results of statistical analysis, CBCT was found to be a suitable modality to evaluate DTMJ.

Protective effects and mechanisms of high-dose vitamin C on sepsis-associated cognitive impairment in rats

Sepsis survivors present long-term cognitive deficits. The present study was to investigate the effect of early administration of high-dose vitamin C on cognitive function in septic rats and explore its possible cerebral protective mechanism. Rat sepsis models were established by cecal ligation and puncture (CLP). Ten days after surgery, the Morris water maze test was performed to evaluate the behavior and cognitive function. Histopathologic changes in the hippocampus were evaluated by nissl staining. The inflammatory cytokines, activities of antioxidant enzymes (superoxide dismutase or SOD) and oxidative products (malondialdehyde or MDA) in the serum and hippocampus were tested 24 h after surgery. The activity of matrix metalloproteinase-9 (MMP-9) and expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1(HO-1) in the hippocampus were measured 24 h after surgery. Compared with the sham group in the Morris water maze test, the escape latency of sepsis rats was significantly (P = 0.001) prolonged in the navigation test, whereas the frequency to cross the platform and the time spent in the target quadrant were significantly (P = 0.003) reduced. High-dose vitamin C significantly decreased the escape latency (P = 0.01), but increased the time spent in the target quadrant (P = 0.04) and the frequency to cross the platform (P = 0.19). In the CLP+ saline group, the pyramidal neurons were reduced and distributed sparsely and disorderly, the levels of inflammatory cytokines of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 in the serum and hippocampus were significantly increased (P = 0.000), the blood brain barrier (BBB) permeability in the hippocampus was significantly (P = 0.000) increased, the activities of SOD in the serum and hippocampus were significantly (P = 0.000 and P = 0.03, respectively) diminished while the levels of MDA in the serum and hippocampus were significantly (P = 0.007) increased. High-dose vitamin C mitigated hippocampus histopathologic changes, reduced systemic inflammation and neuroinflammation, attenuated BBB disruption, inhibited oxidative stress in brain tissue, and up-regulated the expression of nuclear and total Nrf2 and HO-1. High-dose vitamin C significantly (P < 0.05) decreased the levels of tumor necrosis factor- (TNF)-α, interleukin-6 (IL-6), MDA in the serum and hippocampus, and the activity of MMP-9 in the hippocampus, but significantly (P < 0.05) increased the levels of SOD, the anti-inflammatory cytokine (IL-10) in the serum and hippocampus, and nuclear and total Nrf2, and HO-1 in the hippocampus. In conclusion, high-dose vitamin C can improve cognition impairment in septic rats, and the possible protective mechanism may be related to inhibition of inflammatory factors, alleviation of oxidative stress, and activation of the Nrf2/HO-1 pathway.

Determining the Role of Natural SARS-CoV-2 Infection in the Death of Ten Domestic Pets

Transmission of SARS-CoV-2, the virus that causes COVID-19, from people to companion animals has been reported globally. Between March 2020 and January 2021, the United States reported 94 companion animals with SARS-CoV-2. While most animals with SARS-CoV-2 have mild illness, 10 animals (5 dogs, 5 cats) died around the time of SARS-CoV-2 diagnosis. In one dog, histopathologic changes suggest SARS-CoV-2 exacerbated a severe chronic respiratory disease and contributed to death. In one cat, SARS-CoV-2 was associated with histopathologic changes suggesting the virus caused clinical signs that resulted in euthanasia. In the remaining eight animals, SARS-CoV-2 infection was an incidental finding (4 dogs, 4 cats). This report provides evidence that in rare circumstances, SARS-CoV-2 can contribute to or cause death in companion animals with underlying conditions.

Histologic findings of the dura mater at the level of the foramen magnum in 121 CKCS with Chiari-like malformation

Background: To describe histopathologic features found in dural biopsies of Cavalier King Charles Spaniels (CKCS) with Chiari-like malformation (CM) and identify any associations between age, duration of clinical signs, syrinx location or syringomyelia (SM) and quality of life (QOL). The medical records of 121 consecutive client owned CKCS with CM and SM, confirmed by whole body magnetic resonance imaging (MRI), that underwent foramen magnum decompression (FMD) with cranioplasty and durectomy with biopsy from 2006 to 2016 were retrospectively reviewed. Dura biopsies were submitted to a board-certified veterinary pathologist for histopathologic interpretation. The chi-square test was used to analyze associations between diagnosis and categorical variables. For continuous measures, the Kruskal-Wallis non-parametric test was used to compare distributions across pathology categories. A result was considered statistically significant at the P<0.05 level of significance. Results: The mean age, duration of pre-surgical clinical signs, and pre-operative QOL (1-5 scale) were 44.27 months, 44.78 weeks, and 2.72 respectively. Syringomyelia was found in the cervical region only in thirty-nice of one hundred twenty-one (32.23%) of dogs, in the cervical and thoracic region only in seventeen of one hundred twenty-one (14.05%) of dogs, and in the cervical, thoracic and lumbar region combined in sixty-five of one hundred twenty-one (53.72%) of dogs. Sixty-six of one hundred twenty-one (54.55%) dural biopsy specimens had histopathology changes; fifty-five (45.45%) did not. Forty-three of one hundred twenty-one (35.54%) dural biopsy specimens had osseous metaplasia, sixteen of one hundred twenty-one (13.22%) had evidence of fibrosis, four of one hundred twenty-one (3.31%) had arachnoid hyperplasia, and three of one hundred twenty-one (2.48%) had evidence of mineralization. Conclusions: The majority of dogs with CM were found to have histopathologic changes in the dura at the time of FMD cranioplasty was performed. These dural changes can be observed in dogs experiencing clinical signs for a time period as short as four weeks prior to presentation. Histopathologic changes were not associated with age, breed, duration of clinical signs, the location of syringomyelia or preoperative QOL. The influence of histopathologic changes on long term prognosis in dogs without dural decompression is unknown since all dogs in this study had dural resection.