Chronic Inflammatory Cell Infiltration Research Articles

PD-L1 EXPRESSION IN ORAL DYSPLASIA: A PILOT STUDY

<h3>Background</h3> Immune checkpoint inhibitor therapy has a recognized role in oral squamous cell carcinoma (OSCC). Assessment of programmed death-ligand 1 (PD-L1) expression by immunohistochemistry by a trained histopathologist is the current standard method of stratifying patients for immunotherapy. However, to date, limited work has been undertaken on PD-L1 expression in oral dysplastic lesions (ODLs). <h3>Methods and Objective</h3> The principal aims of this study were to assess the expression of PD-L1 in ODL and OSCC using a clinically validated, companion diagnostic antibody (Dako 22C3 PharmDx) and to construct a comprehensive clinicopathologic database of OSCC and ODL. PD-L1 immunohistochemistry was assessed using the combined positive score (CPS) method by a trained histopathologist. In select cases, CD3 and CD8 expression were also assessed in lymphocytes. Statistical analysis was performed using Fisher exact and Pearson chi-square tests. <h3>Results</h3> The majority of OSCC cases tested were positive for PD-L1 using the CPS method (63%; 19/30). PD-L1 expression had a positive association with lymph node metastasis but this was not statistically significant (<i>P</i> > .05). In contrast, a smaller proportion of ODLs were positive for PD-L1 (20%; 4/20), all of which were severely dysplastic. Interestingly, PD-L1 in ODL expression was associated with the presence of a dense chronic inflammatory cell infiltrate. <h3>Conclusions</h3> Evaluating PD-L1 expression using CPS could identify patients with OSCC who may respond to immune checkpoint inhibitors. We have observed PD-L1 expression in a small number of severe ODLs, the significance of which is uncertain at present. Replication in larger patient cohorts is recommended for validation.

Pathology, bacteriology and molecular studies on caseous lymphadenitis in Camelus dromedarius in the Emirate of Abu Dhabi, UAE, 2015-2020.

Caseous lymphadenitis (CLA) or pseudotuberculosis is a chronic zoonotic bacterial disease caused by Corynebacterium pseudotuberculosis, which affects livestock and humans. This study aimed to describe the pathology, bacteriology and confirm the identity of the pathogen by 16S rRNA gene sequencing in Camelus dromedarius. A total of 12 camels with suspected CLA in three regions of Abu Dhabi Emirate (Abu Dhabi, Al Ain and Al Dhafra), United Arab Emirate (UAE) were subjected to clinical and postmortem examinations from January 2015 to December 2020. Clinically, camels were emaciated and showed the presence of external caseous abscesses suggestive of CLA. Postmortem examination showed multiple abscesses of variable sizes with caseous material encapsulated by fibrous tissue in the liver, lungs, muscle, and lymph nodes. Following clinical and postmortem examination, blood, pus and different tissue samples were collected for subsequent analysis. Histopathological examination of all organs stained with Hematoxylin and Eosin (H&E) indicated a central caseo-necrotic core that was admixed with bacterial colonies and infiltration of chronic inflammatory cells, surrounded by a pyogenic membrane, and an outer fibrous connective tissue capsule. Bacterial culture identified the isolates of Corynebacterium pseudotuberculosis biotype ovis strain, and these isolates were shown to be sensitive to all antibiotics tested (penicillin, ampicillin, Co-trimoxazole, enrofloxacin and tetracycline). Moreover, the identity of the isolates was confirmed by partial sequencing of the 16S rRNA gene which showed a 100% identity to Corynebacterium pseudotuberculosis. Phylogenetic analysis based on 16S rRNA gene sequence clearly differentiates Corynebacterium pseudotuberculosis from other species of Corynebacterium. Briefly, this study provided the basic information for infection of Corynebacterium pseudotuberculosis in Camels and will help in controlling of this pathogen in the region.

MO048PATHOGENIC VARIANTS IN CHLORIDE VOLTAGE-GATED CHANNEL 5 (CLCN5), ASSOCIATED WITH DENT DISEASE TYPE 1, SHOULD BE CONSIDERED IN END-STAGE KIDNEY DISEASE OF UNKNOWN AETIOLOGY

Abstract Background and Aims Hemizygous variants in chloride voltage-gated channel 5 (CLCN5) on chromosome Xp11.22 cause Dent disease type 1, characterised by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. We describe a truncating pathogenic variant in two brothers presenting with end-stage kidney disease (ESKD) and no evidence of nephrolithiasis or nephrocalcinosis. Method Two white British brothers presented to a different regional centre over 20 years ago with ESKD of unknown aetiology. The UK 100,000 Genomes Project provided a unique opportunity to make a molecular diagnosis using whole-genome sequencing linked to clinical records. Results The older brother presented with ESKD aged 23 with bilateral small kidneys and no evidence of nephrolithiasis or nephrocalcinosis on ultrasound. He had various musculoskeletal pains, 'cutaneous ectopic calcification' and secondary hyperparathyroidism, all of which improved post parathyroidectomy. Investigation of his 17-year-old brother for consideration of kidney transplant donation revealed progressive chronic kidney disease (CKD), microscopic haematuria, proteinuria (3g/24hours) and hypokalaemia. There was no nephrocalcinosis or renal calculi on ultrasound or cystoscopy. Renal biopsy showed tubulointerstitial changes with patchy fibrosis and marked chronic inflammatory cell infiltrates. He had a history of enuresis, polydipsia, delayed bone age and general developmental delay. ESKD by the age of 22 was complicated by hypertension and hyperparathyroidism requiring parathyroidectomy. Right knee pain with 'unusual osteochondral abnormality' on MRI resulted in a supracondylar femoral osteotomy. Early serum and urine biochemistry results were not available. A hemizygous nonsense variant p.Arg417Ter in CLCN5 was identified by whole-genome sequencing via the 100,000 Genomes Project. Sanger sequencing at the Wessex Regional Genetics Laboratory confirmed this. This variant was predicted to be protein-truncating, was absent in the genome aggregation database (gnomAD) and equivalent to a variant associated with Dent disease in other patients therefore classified as a class 5 pathogenic variant according to ACMG guidelines. Three male children with Dent disease have previously been reported with the pathogenic variant p.Arg347Ter. A seven and a twelve year old from two different families in Japan had microscopic haematuria, proteinuria, elevated β2-microglobulin and normal renal function. The twelve-year-old had mild hypercalciuria, but neither had a history of nephrolithiasis or nephrocalcinosis. A four-year-old Turkish boy manifested hypophosphataemia, nephrolithiasis and nephrocalcinosis. Unusually for Dent disease, he also had hypokalaemic hypochloraemic metabolic alkalosis and hyper-reninaemic hyperaldosteronism more characteristic of Bartter syndrome, but with elevated β2-microglobulin more typical of Dent disease. None of these cases had CKD but were all reported at a very young age. Conclusion Approximately 15% of patients with ESKD in Europe have an unknown aetiology. Dent disease has a variable phenotype and screening of patients for low molecular weight proteinuria such as β2-microglobulin is not routinely performed. Dent disease type 1 should be considered in patients presenting with unexplained renal failure even without typical clinical features.

P395 Impact of mirikizumab therapy on histologic measures of intestinal inflammation in a Phase 2 study of patients with moderately to severely active Crohn’s disease

Abstract Background Mirikizumab (miri), a p19-directed IL-23 antibody, demonstrated efficacy and was well-tolerated in a phase 2 randomized clinical trial (NCT02891226) in patients with Crohn’s disease (CD). The histologic results at Week (W)12 induction and W52 maintenance are presented here. Methods Patients were randomized 2:1:1:2 across 4 treatment arms (PBO, 200, 600, 1000mg miri) administered intravenously (IV) every four weeks (Q4W) at Weeks 0, 4, and 8. Patients who received miri and achieved ≥1 point improvement from baseline (BL) at W12 in Simple Endoscopic Score for Crohn’s Disease (SES-CD) were re-randomized 1:1 into double-blind maintenance to continue their IV dose assignment Q4W (IV/IV) or to 300mg miri SC Q4W (IV/SC); maintenance IV arms were pooled for analysis. W12 non-improvers and all induction PBO patients received 1000mg miri Q4W from W12 through W52. Biopsies from terminal ileum and 4 colonic segments (ascending, transverse, descending, rectum) were obtained during endoscopy at W0, 12 and 52 and scored blind to treatment and response status. Ileum and colon scores were reported separately. Colon scores were derived from the sum of the 4 colonic segments, and total intestine scores from the 4 colonic segments plus ileum. Endpoints were defined post-hoc but prior to performing the analyses and only included patients with active histologic disease at BL (see Table). Histologic response was defined as: a) absence of neutrophils in lamina epithelialis, and absence of epithelial damage, erosions and ulceration or b) decrease of either RHI or GHAS ≥50% from BL. Histologic remission was defined as absence of mucosal neutrophils, epithelial damage, erosions, and ulceration. Deep histologic remission was defined as histologic remission combined with absence of chronic inflammatory cell infiltration of the lamina propria. For assessment of total intestine inflammation, the criteria for response, remission or deep remission must have been met in all 5 bowel segments. Results At W12, histologic response and remission were significantly higher in all segments of the 1000mg group versus PBO (response: ileum p&amp;lt;0.01, total intestine p&amp;lt;0.01, colon p&amp;lt;0.05; remission: ileum p&amp;lt;0.05, colon p&amp;lt;0.05, total intestine p&amp;lt;0.01). Among the W12 improvers, both histologic response and histologic remission at W52 were similar in ileum and colon in the IV/IV group, but lower in ileum than colon in the IV/SC group. All but 2 patients with remission at W52 were in deep histologic remission. Conclusion Patients treated with miri achieved and sustained histologic response and remission over 52 weeks of treatment. Among patients with W52 histologic remission, all but 2 patients achieved deep remission.

Nodular fasciitis of the breast: a clinicopathological and genetic analysis of seven cases

Objective: To investigate the clinicopathological and genetic features of nodular fasciitis of the breast (NFB). Methods: The clinical and histologic features of seven NFBs were retrospectively reviewed. Immunohistochemistry, fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) were performed. Results: All the seven patients were female, with a mean age of 36 years (range from 15 to 51 years). The duration of the lesion ranged from 10 days to 2 years. There was no history of trauma for all patients. The lesions occurred in the upper quadrant (4 cases), the lower quadrant (2 cases) and the axillary tail region (1 case). The maximum diameter was 1.0-3.5 cm. All cases showed similar morphology as nodular fasciitis occurring elsewhere in the body. They were composed of plump spindle cells arranged in short bundles or fascicles within a loose collagenous/myxoid stroma. Erythrocyte extravasation, mixed chronic inflammatory cells infiltration and microcystic changes were typically seen. Mitoses were present, with no atypical mitoses observed. The spindle cells were positive for smooth muscleactin(SMA, 6/6), CD10(2/3), and negative for desmin, β-catenin, CD34, CKpan, EMA, S-100, p63 and ALK-1.The Ki-67 index were 5%-15%. USP6 gene rearrangement was found in six cases and MYH9-USP6 gene fusion in two cases. Local resection was performed in six cases. Spontaneous regression was observed in one case. Follow-up of all seven cases revealed no recurrence or metastasis. Conclusions: Although rare, NFB can mimic breast cancer clinically, radiologically and histologically. It should be always considered in the differential diagnosis for the spindle cell proliferations of the breast. A diagnosis of NFB can be achieved basing on the typical clinicopathological presentation. FISH detection of USP6 gene rearrangement in challenging cases is of great value.

Differentiating Recurrent Thyroiditis From Graves’ Disease on a Background of Lithium Use

A 26-year-old female presented with severe thyrotoxic symptoms 4 months post-partum following an uncomplicated pregnancy; investigations showed a FT4 39.4 pmol/L (n 12 – 22 pmol/L), FT3 8 pmol/L (n 3.1 – 6.8 pmol/L), FT4:FT3 ratio 4.9, TSH <0.02 mU/L (n 0.27 – 4.2 mU/L), TSH receptor antibody (TRAb) < 0.9 IU/L (n < 0.9 IU/L) with normal blood flow on ultrasound doppler and a low (0.2%) Tc99 uptake isotope scan suggesting thyroiditis. 2 years previously she had an episode of thyroiditis (investigations showed FT4 31.2 pmol/L, FT3 7 pmol/L, FT4:FT3 ratio 4.4, TSH <0.02 mU/L and imaging showed low (0.4%) Tc99 uptake) when on lithium 1gm/day for more than a year to treat bipolar disorder.On recurrence, despite compliant treatment with Propranolol and Prednisolone 30mg once daily, thyroid function deteriorated and 2 months later repeat thyroid function testing showed a FT4 > 100 pmol/L, FT3 30.2 pmol/L, FT4:FT3 ratio 3.3 and TSH < 0.02 mU/L. A repeat Tc99 uptake scan showed increased uptake at 13% and ultrasound showed a very vascular bulky thyroid gland. These investigations were suggestive of either a rebound hyperthyroidism (post-thyroiditis) or Graves’ disease. At this stage, TRAb titers were repeated and were now elevated at 4.5 IU/L therefore carbimazole 40mg daily was started. Due to the severity of symptoms, she underwent urgent thyroidectomy. Histopathology showed features of diffuse hyperplasia of the thyroid gland with variably sized follicles lined by cuboidal epithelial cells and a mild patchy chronic inflammatory cell infiltrate in the stroma. Post thyroidectomy she is stable on L-thyroxine therapy.Points for discussion:1. Lithium is typically used as a mood stabilizer and as thyroid dysfunction is known to exacerbate mood disturbances it is vital that patients are appropriately screened, monitored and treatment is commenced promptly for thyroid disease.2. Lithium can increase clinical manifestations of thyroid autoimmunity and may influence thyrotoxicosis either due to thyroiditis or Graves’ disease. Differentiating these etiologies is important from the treatment perspective.3. FT4:FT3 ratios, TSH receptor antibodies, Tc99 uptake scans and ultrasound doppler of the thyroid will assist in diagnostic accuracy. However, in certain rare circumstances, during the recovery phase of thyroiditis, the Tc99 scan can demonstrate diffusely increased activity, which is representative of a rebound phenomenon thus posing a diagnostic dilemma.4. Finally, TRAb titers may help differentiate the above, but sometimes may change from undetectable to high suggesting changes in thyroid autoimmunity.

Preventive and therapeutic effects and mechanism of Xiaoer Feike Granules on chronic bronchitis induced by lipopolysaccharide in rats

The aim of this paper was to investigate the preventive and therapeutic effects of Xiaoer Feike Granules(XEFK) on chronic bronchitis in rats and its mechanism. Except for 10 rats in the blank group, the remaining 50 of the 60 SD rats were used to establish a model of chronic bronchitis induced by LPS. On the 22 nd day, the model rats were randomly divided into 5 groups according to their body weight, and administrated with purified water, Keteling Capsules 0.11 g·kg~(-1), XEFK 3.2, 1.6 and 0.8 g·kg~(-1)(the dosing concentrations were 0.32, 0.16, 0.08 g·mL~(-1), respectively). These rats took the corresponding drug orally once a day, for consecutive 21 days. The rats were anesthetized 1 hour after the last administration, and the lavage bronchus and alveoli were collected. Then, after the fixation of the smear, neutrophils were counted microscopically, and the contents of glutathione peroxidase(GSH-Px), superoxide dismutase(SOD) and malondialdehyde(MDA) in the bronchoalveolar lavage fluid(BALF) were detected by colorimetric method. Flow cytometry was used to detect the content changes of T cell subsets CD4~+, CD8~+, CD4~+/CD8~(+ )in serum. Hemorheology related indexes were detected by automatic hemorheology. Enzyme-linked immunosorbent assay(ELISA) was used to detect the contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), IL-2, IL-6 and IL-10 in serum. The expression of TNF-α and IL-10 mRNA in lung was detected by Real-time quantitative PCR(RT-qPCR). HE staining was used to observe the pathological changes in the bronchitis tissues. Compared with the model group, XEFK high and medium dose groups could significantly reduce the contents of neutrophils and MDA in bronchial lavage fluid, and increase the activities of GSH-Px and SOD in BALF, and repair the chronic inflammatory cell infiltration and lymphoid tissue hyperplasia in the bronchial mucosal layer and submucosal layer. The high-dose group could reduce the plasma viscosity of rats, but there was no statistical difference in other hemorheological indexes. CD4~+, CD8~+, CD4~+/CD8~+, IL-2 and IL-10 contents in each dose group were significantly increased, and TNF-α, IL-1β and IL-6 contents were significantly decreased in serum. Each dose group could significantly down-regulate the expression level of TNF-α mRNA in the lung and increase the expression of IL-10 mRNA. XEFK could reduce lipid peroxidation, increase the content of peripheral blood T cell subsets, regulate the release and secretion of inflammatory factors, and repair the morphological and pathological changes of bronchial tissue. Its mechanism might be related to the improvement of inflammatory response and the enhancement of immune function.

Clinical application of negative-pressure wound therapy in uncomplicated cardiac pacemaker pocket infection

Objective: To investigate the feasibility of negative-pressure wound therapy (NPWT) in the treatment of uncomplicated cardiac pacemaker pocket infection. Methods: From January 2013 to March 2020, 35 patients with uncomplicated cardiac pacemaker pocket infection were admitted to the Department of Cardiology of Peking University First Hospital, including 21 males and 14 females, aged 27 to 84 years. The retrospective cohort study was conducted. After a complete debridement followed by continuous NPWT (with negative pressure of -16.67 kPa), the pulse-generator was inserted into the new pocket between the musculus pectoralis major and pectoralis minor. Pressure drainage tube was put into the old pocket space. NPWT with the same mode was used again for 5 to 7 days after the wound was closed. The removed pocket tissue of patients was observed with hematoxylin-eosin staining. The wound healing on 10 to 12 days after the operation of pacemaker replacement was observed, and the recurrence of infection was observed during 6 to 42 months follow-up after operation. Results: The fibrous sac wall was observed in pocket tissue of the patients, and the tissue was partially covered with stratified epithelium, with many chronic inflammatory cells infiltration. Multinucleated giant cell reaction was observed in the tissue of some patients. Ten to twelve days after the operation of pacemaker replacement, 35 patients had good wound healing, and sutures were removed. After 6 to 42 months follow-up after operation, 31 patients were cured with no recurrence of infection and the wounds were well-healed; 4 patients who had recurrent infection received whole system of pacemaker removal after the operation. Conclusions: On the premise of complete debridement, NPWT is an alternative treatment for patients with uncomplicated cardiac pacemaker pocket infection.

Clinicopathological features of inflammatory myofibroblastic tumor

Objective: To investigate the clinicopathological diagnosis and differential diagnosis of inflammatory myofibroblastic tumor (IMT). Methods: Thirty-two cases of IMT collected at the People's Hospital of Jiangsu Province from May 2010 to May 2020 were evaluated for their clinical, histologic, immunohistochemical and genomic features, and relevant literature was reviewed. Results: There were 19 male and 13 female patients, with age ranging from 5 to 65 years (mean, 37 years). The tumors were located in the lung and mediastinum (10 cases), gastrointestinal tract and mesentery/omentum (12 cases), urinary bladder (5 cases), head and neck (3 cases), somatic soft tissue (1 case), and retroperitoneum (1 case). Four cases of epithelioid inflammatory myofibroblastic sarcoma (EIMS) were all located intra-abdominally. Histologically, the tumor cells were myofibroblasts and fibroblasts arranged in predominantly fusiform pattern, with variably edematous to myxoid background or sclerotic collagenized stroma, and variably mixed chronic or acute inflammatory cells infiltration. EIMS were composed mainly of epithelioid tumor cells, with myxoid stroma and numerous neutrophils. Immunohistochemically, the tumor cells expressed cytoplasmic ALK (25/32, 78%), whereas the four EIMS showed nuclear membrane ALK staining pattern. The tumor cells also expressed CKpan (8/19), SMA (24/32, 75%) and desmin (12/32, 38%); all four EIMS also showed strong positivity for desmin. Fluorescence in situ hybridization (FISH) for ALK gene rearrangement showed split apart signals in 12 of 15 cases, most commonly with atypical signals. Next-generation sequencing (NGS) was performed in three tumors and showed that one case of lower leg IMT harbored a novel CLIP2-ALK fusion, and two cases of EIMS harbored RANBP2-ALK fusion. Follow-up data were available in 29 patients. Twenty-two patients were alive with no evidence of tumor, four patients had tumor recurrences (three patients were treated with crizotinib and were alive with tumor), and three patients died of the disease (including two patients with EIMS). Conclusions: IMTs show a wide morphologic spectrum, and should be differentiated form a variety of benign or malignant tumors. Immunohistochemistry (ALKp80, ALKD5F3) and FISH (ALK break-apart probe) could assist the diagnosis of IMT, with NGS recommended for the atypical cases.

Entelon (vitis vinifera seed extract) reduces degenerative changes in bovine pericardium valve leaflet in a dog intravascular implant model.

Inflammation and calcification are major factors responsible for degeneration of bioprosthetic valve and other substitute heart valve implantations. The objective of this study was to evaluate the anti-inflammatory and anti-calcification effects of Entelon150® (consisting of grape-seed extract) in a beagle dog model of intravascular bovine pericardium implantation. In total, 8 healthy male beagle dogs were implanted with a bovine pericardium bilaterally in the external jugular veins and divided into two groups. Animals in the Entelon150® group (n = 4) were treated with 150 mg of Entelon150® twice daily for six weeks after surgery. The negative control (NC) group (n = 4) was treated with 5 ml of saline using the same method. After six weeks, we measured the calcium content, performed histological examination, and performed molecular analysis. The calcium content of implanted tissue in the Entelon150® group (0.56±0.14 mg/g) was significantly lower than that in the NC group (1.48±0.57 mg/g) (p < 0.05). Histopathological examination showed that infiltration of chronic inflammatory cells, such as fibroblasts and macrophages, occurred around the graft in all groups; however, the inflammation level of the implanted tissue in the Entelon150® group was s lower than that in the NC group. Both immunohistochemical and western blot analyses revealed that bone morphogenetic protein 2 expression was significantly attenuated in the Entelon150® group. Our results indicate that Entelon150® significantly attenuates post-implantation inflammation and degenerative calcification of the bovine pericardium in dogs. Therefore, Entelon150® may increase the longevity of the bovine pericardium after intravascular implantation.

Clinicopathological features and post-resection outcomes of inflammatory pseudotumor of the liver.

Backgrounds/AimsHepatic inflammatory pseudotumor (HIPT) is a rare disease characterized by chronic infiltration of inflammatory cells and area of fibrosis. The objective of this retrospective observational study was to investigate clinicopathological features and outcomes of patients who underwent hepatic resection (HR) for HIPT.MethodsFrom 2009 to 2018, seven patients with HIPT underwent HR, accounting for 0.06% of 11,979 adults who underwent HR at our center.ResultsThese seven patients included five men and two women. Their mean age was 62.3±11.6 years. In four patients with hepatitis B virus (HBV)-associated liver cirrhosis or chronic hepatitis, liver masses were suspected of hepatocellular carcinoma (HCC) or combined HCC-cholangiocarcinoma based on imaging studies. In three patients without HBV infection, two patients were suspected of HCC, for whom liver biopsy was not performed. One patient was suspected of liver abscess or HIPT, for whom percutaneous liver biopsy was performed and the mass was diagnosed with HIPT. However, this patient underwent HR owing to abdominal pain. No patient presented with abnormally elevated levels of alpha-fetoprotein, protein induced by vitamin K absence or antagonist-II, or CA19-9. During a mean follow-up period of 76.4±34.8 months, no patient experienced recurrence of HIPT.ConclusionsHIPT, a rare form of liver disease, is often misdiagnosed as malignant liver tumor. Active histological diagnosis is warranted for patients with suspected HIPT to avoid unnecessary operation. HR can be indicated in case of diagnostic ambiguity of HIPT or under a clinical diagnosis of malignant liver tumor.

IFI16 contributes to the pathogenesis of abdominal aortic aneurysm by regulating the caspase-1/IL-1β/MCPIP1 pathway

AimsAbdominal aortic aneurysm (AAA) is a multi-factorial progressive vascular disease characterized by chronic inflammatory cell infiltration. We investigated the roles played by IFI16 and ASC inflammasomes in AAA development and progression. Materials and methodsWestern blot and qRT-PCR studies were performed to analyze the expression of relative genes in AAA specimens and mouse vascular smooth muscle cells (VSMCs). The apoptosis rates and ROS levels of VSMCs were assessed by flow cytometry. Transwell assays were performed to analyze the migration ability of VSMCs. The levels of MCP-1, IL-1β, and IL-6 in the supernatants of cultured VSMCs were analyzed by ELISA. Key findingsIncreased levels of IFI16 expression were found in AAA specimens and Ang-II-treated VSMCs. IFI16 and ASC silencing suppressed the apoptosis and migration ability of VSMCs undergoing Ang-II treatment, reduced elasticity damage to the aortic wall, and decreased the levels of MMP expression. The effect of IFI16 knockdown in Ang-II-induced VSMCs was reversed by MCPIP1 overexpression. SignificanceOur data suggest that an up-regulation of IFI16 and ASC expression might promote the apoptosis of VSMCs, enhance the inflammatory response, and impairs vascular wall elasticity via a MCPIP1-related mechanism. The inflammasome components IFI16 and ASC might be involved in AAA progression and serve as target molecules for diagnosing and treating AAA.

First record of the nematode, Huffmanela sp. infecting the broomtail wrasse (Cheilinus lunulatus) from Egypt.

A total of 385 Red Sea coral reef fish representing three species; Broom tail wrasse (Cheilinus lunulatus), Blacktip grouper (Epinephelus fasciatus) and Rabbit fish (Siganus sp.). were examined for the presence of nematode Huffmanela species. The eggs of Huffmanela species were isolated and identified only from the C. lunulatus. The total prevalence of Huffmanela sp. infestation were 69.5%. The highest prevalence was observed in winter and the lowest in spring and summer. The prevalence was increased in correlation with fish body weight. Fully developed eggs of Huffmanela species were dark brown embryonated, elongated, with slightly protruding plugs. A high density of Huffmanela sp. eggs with different developmental stages packed the epithelial layer of the gas bladder. The surrounding tissue of gas bladder was hemorrhagic and sometimes necrotic associated with chronic inflammatory cell infiltration. This is the first record of Huffmanela species infestation in Broom tail wrasse C. lunulatus, Red Sea coral reef fishes.

Vulval acne: a case series describing clinical features and management.

Intermittent inflammation of the vulval pilosebaceous units is common and usually self-limiting, but some patients experience recurrent and more troublesome symptoms. There is a scarcity of information on this problem. We describe the clinical and histological features in these patients and the response to treatment. A retrospective, observational study of 16 patients with this phenomenon of recurrent, protracted folliculocentric inflammation of the vulval pilosebaceous unit was performed. Details on the clinical features, histology and response to treatment were collected. Mean age at presentation was 32years (range 21-45). All patients reported recurrent painful papules and pustules on the labia majora and labia minora. Nine patients reported a cyclical pattern to the development of lesions, with premenstrual exacerbation being most common. Histological examination of these lesions showed a folliculocentric microabscess formation surrounded by an acute and chronic inflammatory cell infiltrate, with a focal foreign-body granulomatous reaction. All our patients responded well to tetracycline, antiandrogenic or retinoid therapy. We propose the term 'vulval acne' for this condition and propose a stepwise approach to its management. We hope to highlight this as a common but underreported entity.

Chemical exposure-induced systemic fibrosing disorders: Novel insights into systemic sclerosis etiology and pathogenesis

Numerous drugs and chemical substances are capable of inducing exaggerated tissue fibrotic responses. The vast majority of these agents cause localized fibrotic tissue reactions or fibrosis confined to specific organs. Although much less frequent, chemically-induced systemic fibrotic disorders have been described, sometimes occurring as temporally confined outbreaks. These include the Toxic Oil Syndrome (TOS), the Eosinophilia-Myalgia Syndrome (EMS), and Nephrogenic Systemic Fibrosis (NSF). Although each of these disorders displays some unique characteristics, they all share crucial features with Systemic Sclerosis (SSc), the prototypic idiopathic systemic fibrotic disease, including vasculopathy, chronic inflammatory cell infiltration of affected tissues, and cutaneous and visceral tissue fibrosis. The study of the mechanisms and molecular alterations involved in the development of the chemically-induced systemic fibrotic disorders has provided valuable clues that may allow elucidation of SSc etiology and pathogenesis. Here, we review relevant aspects of the TOS, EMS, and NSF epidemic outbreaks of chemically-induced systemic fibrosing disorders that provide strong support to the hypothesis that SSc is caused by a toxic or biological agent that following its internalization by endothelial cells induces in genetically predisposed individuals a series of molecular alterations that result in the development of SSc clinical and pathological alterations.

Effect of di-(2-ethylhexyl) phthalate (DEHP) on allergic rhinitis

Allergic rhinitis (AR) is a common chronic inflammatory disease of the upper respiratory tract. Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer and belongs to environmental endocrine disruptors (EDCs). It can be entered the human body which is harmful to health. The relationship between DEHP and AR is still inconclusive. This study aims to investigate the effect of environmental pollutants DEHP on AR. By examining DEHP metabolites in the urine of AR patients and building an AR model. 24 BALB/c mice were used as the study subjects, and ovalbumin (OVA) and DEHP (3 mg/kg/body) were used for intragastric administration. They were divided into control group, DEHP group, OVA group and OVA + DEHP group. Examination, behavioral scoring, inflammatory factor testing, oxidative stress testing, detection of aryl hydrocarbon receptor (AhR) and signaling pathways CYP1A1 and CYP1B1 related proteins and mRNA. The concentrations of 3 metabolites of DEHP (MEHHP, MEOHP, and MEHP) in urine of AR patients were higher. And HE-staining showed that for the control group, many chronic inflammatory cell infiltration and nasal mucosal destruction were observed in the OVA + DEHP group and were more severe than the OVA group. Allergic symptom scores were obtained from sneezing, scratching, number of scratching, and nose flow. The scores of the OVA group and the OVA + DEHP group were higher than 7 points. Serum ELISA and nasal mucosal oxidative stress tests are more serious in the OVA + DEHP group. The expression of AhR protein and its mRNA was increased in the DEHP group, OVA group and OVA + DEHP group. The OVA + DEHP group was more significant in the OVA group and DEHP group. And the mRNAs of the AhR-related signaling pathways CYP1A1 and CYP1B1 were also more prominent in the OVA + DEHP group. DEHP may aggravate its inflammatory response through the AhR pathway closely related to the environment. When combined with OVA, DEHP can further aggravate the OVA-induced nasal inflammatory response and make the nasal cavity have undergone severe changes, and many inflammatory cells have infiltrated. DEHP has shown an adjuvant effect, and the AhR-related signaling pathways CYP1A1 and CYP1B1 may be critical.

CHONDROMA OR CHONDROMATOUS METAPLASIA IN A FIBROUS HYPERPLASIA? A DIAGNOSTIC DILEMMA

Atypical changes of connective tissue to cartilage in the oral cavity is uncommon and constitute a challenging diagnosis. A 69-year- old woman showed a nodular and pedunculated lesion in the alveolar crest of anterior alveolar edentulous upper jaw, normochromic, measuring approximately 1.0 cm. It was noted that the prosthesis had no stability and retention from the bone crest. Panoramic radiograph was performed, which did not show any lesion. Thus, clinical hypothesis of inflammatory fibrous hyperplasia (IFH) was established, and an incisional biopsy was performed under local anesthesia. Microscopic examination revealed cartilaginous tissue with areas resembling hyaline cartilage and fibrocartilage. Chondrocytes were evenly dispersed with no cytologic atypia or significant mitotic activity. Additionally, parakeratinized stratified squamous epithelium and dense fibrous connective tissue with moderate chronic inflammatory cell infiltrate was observed. The histopathologic diagnosis was IFH associated with chondromatous metaplasia. The excision site healed well with no evidence of recurrence. Atypical changes of connective tissue to cartilage in the oral cavity is uncommon and constitute a challenging diagnosis. A 69-year- old woman showed a nodular and pedunculated lesion in the alveolar crest of anterior alveolar edentulous upper jaw, normochromic, measuring approximately 1.0 cm. It was noted that the prosthesis had no stability and retention from the bone crest. Panoramic radiograph was performed, which did not show any lesion. Thus, clinical hypothesis of inflammatory fibrous hyperplasia (IFH) was established, and an incisional biopsy was performed under local anesthesia. Microscopic examination revealed cartilaginous tissue with areas resembling hyaline cartilage and fibrocartilage. Chondrocytes were evenly dispersed with no cytologic atypia or significant mitotic activity. Additionally, parakeratinized stratified squamous epithelium and dense fibrous connective tissue with moderate chronic inflammatory cell infiltrate was observed. The histopathologic diagnosis was IFH associated with chondromatous metaplasia. The excision site healed well with no evidence of recurrence.

Toxicokinetics of Titanium Dioxide (Tio2) Nanoparticles After Intraperitoneal Injection in Male Mice

In the present study, male albino mice were used to estimate the effects of titanium dioxide nanoparticles (TiO2) suspension used in two doses (150, 600 mg/kg) through intraperitoneal route. The results revealed a significant difference (p≤0.05) among the control and experimental groups in all haematological parameters, including a significant increase in White Blood Cell (W.B.C) count, Mean Cell Volume (MCV), Mean Cell Haemoglobin Concentration (MCHC), and Mean Cell Haemoglobin (MCH). Also, the results showed a significant decrease in Red Blood Cell (R.B.C.) count and Haemoglobin (Hb). Biochemical tests included AST and ALT and showed a significant elevation in all exposed groups, while ALP was decreased after fourteen and thirty days of exposure. In the case of kidney function, creatinine was increased in all groups during the experiment, whereas uric acid was increase in many cases and recorded the highest mean value after fourteen days of exposure to the dose of 150mg/kg and after thirty days of exposure to the dose of 600mg/kg. Level of urea was decreased in the fourteen-days and thirty-days treatment groups, while its mean values after using the two doses did not change significantly after one day. Cholesterol level was decreased after thirty days, recording the lowest mean value at 600mg/kg, whereas the level of HDL was significantly (p≤0.05) decreased and that of LDL significantly increased. The study of bioaccumulation demonstrated that the TiO2 NPs are accumulated mainly in the spleen, followed by the liver and kidneys of mice, respectively. Also, the doses used caused histological alterations such as changes in the congested dilated portal tract, with heavy inflammatory cells infiltration and dilated central venule in the liver, along with glomerular congestion, tubular congestion, atrophy, chronic inflammatory cells infiltration, and dilated tubules with flat atrophied lining epithelium in the kidneys. The histologic alterations observed may represent an indication of different degrees of organ injury due to the toxicity of TiO2 NPs, resulting in an inability to deal with accumulated residues from the metabolic and structural disturbances caused by these nanoparticles.

Pulp and dentine responses to selective caries excavation: A histological and histobacteriological human study

ObjectiveThe present study investigated the histobacteriological condition of human carious dentine, and the histological response of dental pulps after selective caries excavation to firm dentine and cavity restoration with adhesive procedures. MethodsTwelve vital teeth with medium/deep occlusal caries from 12 patients were scheduled for extraction. The patients gave consent to have caries removed selectively and the cavity restored with adhesive procedures prior to extraction. Caries excavation was achieved using burs and sharp hand excavators until “leathery” or “firm” dentine was encountered. After extraction, the teeth were completely-demineralised, processed for light microscopy, serial-sectioned and stained with haematoxylin and eosin staining for histological examination of dentine characteristics and pulpal responses. Additional sections were stained with Taylor-modified Brown and Brenn technique for histobacteriological examination of bacteria infiltration of the dentinal tubules and dental pulp. ResultsThe 12 teeth showed varying degrees of tertiary dentine formation. Chronic inflammatory cell infiltrates were identified in the pulp of all specimens and appeared as scattered inflammatory cells or exiguous localised accumulations. Capillaries were heavily congested with erythrocytes and polymorphonuclear leukocytes. A large amount of stainable bacteria was observed in the dentine subjacent to the cavity floor in all specimens. ConclusionsThe present study demonstrated that “leathery” or “firm” carious dentine is infected. The remnant bacteria in the dentine provoked subclinical pulpal inflammation over the entire evaluation period. The presence of potentially-arrested caries does not necessarily mean that bacterial infection is absent or under control. Clinical significanceKnowledge on the pulpal response to active caries and the inflammatory responses associated with bacteria ingress into dentine is paramount in helping clinicians make an informed, rational choice based on biologically-robust principles.

A comparative study of "constant volume" animal model and "constant pressure" animal model of intra-abdominal hypertension

To select the animal model more consistent with the pathophysiology of abdominal compartment syndrome (ACS) through the comparative study of the methods of multiple water sacs superimposed compression and gas perfusion. Ten experimental pigs were randomly divided into two groups (n = 5): the "constant volume model" (constant volume model group) and the "constant pressure model" (constant pressure model group) of intra-abdominal hypertension. The models were prepared by the method of water sac superposition and pressurization, and artificial pneumoperitoneum respectively. The abdominal pressures of both groups were 25 mmHg (1 mmHg = 0.133 kPa) and observed for 4 hours. The pressure was measured once an hour for 4 hours and the pressure-time curves of the two groups were drawn respectively. The experimental animals were sacrificed 4 hours after modeling. The heart and lung were harvested, and the histopathological changes were observed by hematoxylin-eosin (HE) staining. Two groups of experimental pigs were successfully modeled. The abdominal pressure gradually increased at 0, 1, 2, 3, 4 hours after operation in the constant volume model group (mmHg: 25.0±0, 27.1±0.2, 29.4±0.1, 30.9±0.2, 33.1±0.1), and there was a positive correlation between the abdominal pressure and time (functional equation: Y1 = 25.102 0+1.996 0X1; R2 = 0.996 2, P = 0.000 1). The abdominal pressure value in the constant pressure model group at 0, 1, 2, 3, 4 hours were maintained 25 mmHg, and there was no linear correlation between the abdominal pressure and time (functional equation: Y2 = 25). HE staining showed that in the constant volume model group, the myocardial fibers were accompanied with hyaline degeneration, significantly reduced transverse lines, part of myocardial fiber atrophy, and visible nuclear aggregation; hemorrhage, chronic inflammatory cell infiltration and inflammatory exudation were found in the lung tissues. In the constant pressure model group, partial atrophy of myocardial fiber, partial hypertrophy, focal hyaline degeneration, disappearance of local striae, hyaline degeneration of myocardial fiber, dilation and congestion of intermyocardial artery were observed. Slight hyperplasia of alveolar epithelium in some areas, heart failure cells, dilation and congestion of bronchi and trachea artery, a large number of red blood cells and uniform light staining substances in lumen were found. After the model was made by the method of multiple water sacs, the pressure of the abdominal cavity continued to increase with the development of the disease, which was in line with the clinical pathological changes of ACS, and was more suitable for making the animal model of the intra-abdominal hypertension.