Current status of preoperative endoscopic biliary drainage for distal and hilar biliary obstruction.

The purpose of preoperative biliary drainage (PBD) is to reduce complications during the perioperative period. The extrahepatic bile duct comprises distal and hilar bile ducts and assessing the need for PBD must be considered separately for each duct, as surgical procedures and morbidities vary. The representative disease-causing distal bile duct obstruction is pancreatic cancer. A randomized controlled trial has revealed that PBD carries the risk of recurrent cholangitis and pancreatitis before surgery, thus eliminating the need for PBD when early surgery is feasible. However, neoadjuvant therapy has seen a rise in recent years, resulting in longer preoperative waiting periods and an increased demand for PBD. In such cases, metal stents are preferable to plastic stents due to their lower stent occlusion rates. When endoscopic transpapillary biliary drainage (EBD) is not viable, endoscopic ultrasound-guided biliary drainage may be a suitable substitute. In the hilar bile duct, the representative disease-causing obstruction is hilar cholangiocarcinoma. PBD's necessity has long been a subject of contention. In spite of earlier criticisms of routine PBD, recent views have emerged recommending PBD, particularly when major hepatectomy is required, to prevent postoperative liver failure. Given the risk of tumor seeding associated with percutaneous transhepatic biliary drainage, EBD is preferable. Nevertheless, as its shortcomings involve recurrent cholangitis until surgery due to stent or tube obstruction, it is necessary to seek out novel approaches to circumvent complications. In this review we summarize the current evidence for PBD in patients with distal and hilar biliary obstruction.

Histopathological and immunohistochemical features of proliferative lesions in the pituitary pars distalis of rats.

Pituitary proliferative lesions derived from the endocrine cells of the pars distalis are frequently encountered and adenomas/carcinomas are a common cause of death in standard 2-year carcinogenicity studies using various rat strains, especially Sprague-Dawley. This report describes the immunohistochemical characteristics of pituitary tumors derived from the pars distalis in rats. Prolactin (PRL)-containing tumors are the most common, with PRL/growth hormone (GH) dual positive tumor masses (PRL/GH co-positive tumor masses) being more prevalent than only PRL-positive tumor masses (PRL single-positive tumor masses). GH-containing tumors are relatively numerous and many of these are also PRL/GH co-positive tumor masses. TSH-containing tumors are common in females. PRL-containing tumors have been shown to increase the incidence of hyperlactation in males and mammary adenomas/adenocarcinomas in females, suggesting that these masses are functional tumors.

Morphological analyses of nephrin expression in progressive glomerulonephropathy of common marmosets.

In this study, we focused on nephrin, one of the key molecules within the slit diaphragm of podocytes, as although there have been reports on its expression in humans and rats, their presence in common marmosets has not been reported. We investigated nephrin expression and changes in glomeruli, depending on the development of spontaneous progressive glomerulonephropathy in common marmosets. Nineteen common marmosets at two to ten years of age were evaluated. The kidney was examined by microscopy with hematoxylin and eosin and immunohistochemical staining for nephrin. The lesions were classified into three grades according to a renal lesion grading system reported previously. The nephrin-positive area was measured by morphometric analysis, and the nephrin-positive ratio was calculated. Nephrin expression was observed along the glomerular capillary loop in a continuous linear pattern in renal lesion grades 0 to 2 and either discontinuous linear or coarse granular pattern in grade 3. Nephrin expression tended to decrease significantly depending on the grade of renal lesions. Alteration in nephrin expression has been suggested to play an important role in the progression of renal lesions.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Non-proliferative and Proliferative Lesions of the Non-human Primate (M. fascicularis).

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

Immunohistochemical Characteristics of Thymomas and Hyperplastic Lesions in Wistar Hannover Rats.

Previously, we investigated the higher incidence of hyperplastic lesions and thymomas and histopathological resemblance of cortex-medullary structures between thymomas and normal thymuses in Wistar Hannover (WH) rats. Thymomas had pale-staining cell foci (PA) similar to medulla but without lymphocytes. Here, we focused on the differences in cytokeratin (CK) expression in the thymic epithelia of the cortex and medulla and compared the structures of thymomas and normal thymuses. Thymomas, hyperplastic lesions, and normal thymuses obtained from background studies of WH rats were stained with antibodies against CK14, CK18, and CD20. In normal thymuses, the epithelial cells were positive for CK14 in the medulla and subcapsular area and for CK18 in the cortex, B-cells were positive for CD20 in the medulla. In thymomas, the epithelial cells were positive for CK14 in the medullary differentiation (MD) areas and for CK18 in the cortex-like lymphocyte rich and PA, and B-cells were positive for CD20 in the MD areas.

A spontaneous middle ear adenocarcinoma characterized by abundant eosinophilic matrix in a young male Crl:CD(SD) rat.

A mass was detected in the right tympanic cavity of a 15-week-old male Crl:CD(SD) rat. Histological examination revealed papillary or tubular proliferations of epithelial cells including ciliated cells that produce mucus and have an abundant eosinophilic matrix. The malignancy of this tumor was revealed by its destructive proliferation, cellular polymorphism, and high proliferative activity. The tumor was diagnosed as a middle ear adenocarcinoma due to its location and histological characteristics. This is the first report of a middle ear adenocarcinoma in rats and the first middle ear tumor accompanied by eosinophilic matrix observed in either humans or animals. The eosinophilic matrix was positive for periodic acid-Schiff and periodic acid-silver methenamine stains and for laminin and collagen Type IV, immunohistochemically, but negative for Congo red, which suggested that this matrix was a basement membrane substance.

Spontaneous globule leukocyte tumor accompanied by inflammatory cells in a Wistar Hannover rat.

We encountered hematolymphoid neoplastic lesions in the form of many nodules in the spleen and liver in a 110-week-old male Wistar Hannover rat (Crl:WI (Han)). The lesions contained atypical proliferative cells, eosinophils, lymphocytes, and macrophages. The proliferative cells comprised various atypical cell types with or without cytoplasmic eosinophilic granules. The granules were positively stained using periodic acid-Schiff and elastase stains, were bluish purple using phosphotungstic acid and hematoxylin, and showed no metachromasia using toluidine blue. In immunohistochemical staining, the proliferative cells with or without granules were positive for granzyme B, rat mast cell protease II, and Ki67. Electron microscopic examination revealed that single to multiple high-density granules of variable size were covered by a membrane. These findings led to a diagnosis of globule leukocyte tumor. The accompaniment of this tumor by inflammatory cells is likely evoked by mast cell-like active mediators contained in the granules of the globule leukocytes.

Relationship Between Immunoglobulin Deposition and Early Lesions of Progressive Glomerulonephropathy in Young Common Marmosets.

The authors previously investigated progressive glomerulonephropathy in 2- to 11-year-old common marmosets and characterized age-related changes of the renal glomeruli and development of tubulointerstitial lesions. In this study, immunoglobulin deposition and ultrastructural changes of the glomeruli were investigated in 5 young marmosets from 6 months to 3 years of age with pre-onset or early glomerulonephropathy. In all animals, the foot processes of podocytes were effaced, and IgM was deposited into the glomeruli. In glomeruli without glomerular basement membrane (GBM) alteration, IgM was the only immunoglobulin type deposited in the glomeruli. In cases with more advanced lesions of reticulation and thickening of GBM, IgA and IgG deposits were also observed. Therefore, the authors conclude that IgM may be the primary or earliest immunoglobulin deposited in this nephropathy, whereas IgA and IgG deposition may be connected to the progression of the glomerular lesions. IgM deposition and foot process effacement of podocytes occur early in the life of affected marmosets.

Morphological and immunohistochemical diversity of endometrial stromal sarcoma in rats.

To clarify the histopathological characteristics of rat endometrial stromal sarcoma (ESS), we morphologically reviewed 12 malignant uterine tumors protruding into the lumen in previous rat carcinogenicity studies. The 12 cases were classified into the following 6 types based on their morphological features: spindle cell and collagen rich type, pleomorphic/spindle cell and compact type, decidual alteration type, histiocytic and multinucleated giant cell mixture type, Antoni A-type schwannoma type, and Antoni B-type schwannoma type. Immunohistochemically, tumor cells in all cases exhibited focal or diffuse positive reactions for vimentin, and 11 of the 12 cases were positive for S-100. Interestingly, 9 cases were positive for desmin or αSMA, indicating tumor cells expressing smooth muscle properties. Both Antoni A- and B-type schwannoma types showed low reactions for both muscle markers. Positive results for estrogen receptor α in the 11 cases suggested that they were derived from endometrial stromal cells. On the basis of their immunohistochemical profiles, they were considered to be derived from endometrial stromal cells while they showed morphological variation. The detection of a basement membrane surrounding tumor cells might not be a definitive indicator for differential diagnosis of ESS from malignant schwannoma. In conclusion, ESS could exhibit wide morphological and immunohistochemical variation including features of schwannoma or smooth muscle tumor.

Spontaneous Age-related Lesions of the Kidney Fornices in Sprague-Dawley Rats.

The upper portion of the rat kidney pelvis has specialized anatomic structures referred to as fornices. Fornices have a role in urine concentration. Spontaneous lesions including mineralization, epithelial hyperplasia, and inflammatory cell infiltration may occur in the area of the fornices. However, little information regarding specific historical control data or the spontaneous development of these findings in male and female fornices is known. Understanding spontaneous age-related lesions in the area of the fornices versus other portions of the kidney pelvis may be relevant in the identification of test article-induced changes. A retrospective study was conducted of male and female Sprague-Dawley rat kidney fornices over several time points to determine the incidence and severity of mineralization, epithelial hyperplasia, and inflammatory cell infiltration. Based on this investigation, these lesions appeared to increase over time and, in general, occurred earlier and with a greater incidence in females. Regarding those chemicals that may result in lesions of the kidney pelvis, it may be important for pathologists to separately diagnose lesions of the fornices from other portions of the kidney pelvis to help differentiate between any spontaneous age-related and induced changes.

Zinc regulates expression of IL-23 p19 mRNA via activation of eIF2α/ATF4 axis in HAPI cells.

Zinc (Zn(2+)) is considered to be one of the factors aggravating brain damage after cerebral ischemia. Since Zn(2+) activates microglia, immune cells in the brain, this metal is proposed to modulate neuroinflammatory responses in the post-ischemic brain. Interleukin (IL)-23 is a heterodimeric cytokine composed of the p19 subunit unique to IL-23 and the p40 subunit common to IL-12. IL-23 has been shown to play a critical role in the progression of ischemic brain injury. However, whether Zn(2+) participates in the expression of IL-23 in microglia remains unknown. In this study, we examined the effect of Zn(2+) on IL-23 p19 mRNA expression using rat immortalized microglia HAPI cells. Exposure to Zn(2+) dose- and time-dependently induced the expression of IL-23 p19 mRNA in HAPI cells. Inhibitors of MAPK and NF-κB pathways failed to suppress this induction. Interestingly, we found that Zn(2+) stimulated the phosphorylation of eIF2α and promoted the nuclear accumulation of activating transcription factor 4 (ATF4). Treatment with salubrinal, an eIF2α dephosphorylation inhibitor, enhanced Zn(2+)-induced ATF4 accumulation and IL-23 p19 mRNA expression. In addition, reporter assay using the IL-23 p19 promoter region revealed that ATF4 directly transactivated IL-23 p19 promoter and that dominant-negative ATF4 suppressed Zn(2+)-induced activation of IL-23 p19 promoter. Taken together, these findings suggest that Zn(2+) up-regulates expression of the IL-23 p19 gene via the eIF2α/ATF4 axis in HAPI cells.

Spontaneous and bilateral necrosis of the femoral head in a young experimental beagle dog.

This report describes the pathological characterizations of a rare case of necrosis of the femoral head that was spontaneous, bilateral, avascular and nontraumatic. A 14-month-old beagle dog was presented with pain in the hind limbs. At necropsy, the articular surface in the bilateral femoral head was markedly irregular. There were no gross abnormalities other than in the hip joints. Microscopically, a wide range of trabecular bone necrosis localized in the subchondral area was observed in both femoral heads. In the right femoral head, fibrosis and proliferative vessels were noted in the subchondral area. The articular cartilage was thickened irregularly, but there was no evidence of cartilage necrosis. The bone marrow adjacent to the affected area showed severe depression. In the metaphysis, atrophic bone marrow, but not bone necrosis, was observed. This was a rare case of spontaneous necrosis of the femoral head in an experimental beagle dog.

Proliferative lesions in thyroid follicular cells of dwarfs derived from Wistar Hannover GALAS rats.

We observed spontaneous dwarfism among Wistar Hannover GALAS rats, caused by primary hypothyroidism. The dwarf (D) rats showed markedly high serum thyroid-stimulating hormone (TSH) values. In this study, we investigated the incidence and histopathological characteristics of the proliferative lesions of the thyroid follicular cells in our D rats. Gross enlargement of thyroid and histological vacuolar change of the thyroid follicular cells with age-related progression suggesting diffuse hypertrophy/hyperplasia were seen in all the D rats. In addition, focal proliferative lesions-namely hyperplasias, activated hyperplasias, adenomas, and adenocarcinomas--were seen in D rats aged over 50 weeks. Taken together, these results suggested that the sustained stimulation of elevated levels of serum TSH caused and enhanced diffuse hypertrophy of thyroid follicular cells and subsequent development of focal proliferative lesions.

Histological characteristics of the regression of corpora lutea in wistar hannover rats: the comparisons with sprague-dawley rats.

We examined the ovaries of 44 Wistar Hannover (RccHan(TM):WIST) (WH) and 30 Sprague-Dawley (SD) rats at 32-weeks of age to determine whether the ovarian structure and formation/regression of the corpora lutea (CLs) differ between the two strains. The average ovary weight was higher in WH rats. The average number of all CLs, including currently formed and previously formed CLs, was higher in WH rats in all cycles; however, no appreciable difference was detected in the number of newly or currently formed CLs between the two strains. CLs regression characterized by degeneration and necrosis of luteal cells began to appear in diestrus in both strains; however, the distribution of degenerated/necrotic cells in CLs differed. Necrotic cells were scattered in SD rats but were focally observed in the center of the CL in WH rats. The reduction in size of previously formed CLs accompanied by regression started about 2 or more stages later in WH rats than in those of SD rats. In conclusion, the higher number of CLs in WH rats is considered to be due to slow CL regression compared with in SD rats.

Corneal mineralization in wistar hannover rats.

We have recently started using Wistar Hannover rats in Japan and are now collecting background data. We have been frequently observing corneal mineralization in Wistar Hannover rats of both the RccHan(TM):WIST and Crl:WI (Han) strains. In this study, details of corneal mineralization in Wistar Hannover rats were histopathologically and ultrastructurally investigated. According to the results, Wistar Hannover rats had a much higher incidence of corneal mineralization compared with Sprague-Dawley rats. The incidence of corneal mineralization was higher in males than females. According to the histological examination, mineral deposits were positive for calcium by von Kossa's method. Furthermore, in response to mineralization, keratocytes probably become active to play an important role against the mineralized substance.

Bacterial pleuritis with thickened mesothelial hyperplasia in a young beagle dog.

A five-month-old male beagle dog suddenly became moribund. Bloody fluid accumulated in the thoracic and abdominal cavities, and soft yellow flecks were floating in the thoracic fluid. The mediastinum and pericardium became dark reddish with villous thickening. Other parietal and pulmonary pleurae were rough, and the organs adhered to each other. Histologically, most mediastinal pleura formed papillary projections covered by a single layer of mesothelial cells. Many macrophages and neutrophils infiltrated the submesothelial connective tissue. At the mediastinum adjacent to the pericardium, cuboidal mesothelial cells proliferated solidly and formed a thick surface stratum. The flecks consisted of gram-negative filamentous or small bacillary (coccoid) bacteria. In the right posterior lobe of the lung, neutrophilic infiltration and a large encapsulated abscess including a bacterial colony were present. We diagnosed this case as "bacterial pleuritis with thickened mesothelial hyperplasia". The cause of the pleuritis might be a chronic pleural infection spread via the lung abscess.

Vascular smooth muscle lipofuscinosis occurring predominantly in veins of a cynomolgus monkey (Macaca fascicularis).

A 6-year-old male cynomolgus monkey showed chronic wasting. No gross abnormalities were observed in necropsy except for changes secondary to wasting. Microscopic examination revealed pigment granules deposition in systemic smooth muscles. They were observed as brown or basophilic in hematoxylin and eosin stain, and were positive for periodic acid-Schiff, Schmorl and Ziehl-Neelsen. Ultrastructurally, they consisted of residual bodies surrounded with varying amounts of solitary ribosomes. Thus, these granules were considered as lipofuscin. Unlike brown bowel syndrome in humans, the pigment granules were distributed systemically not only in the digestive tract but also in the blood vessels predominantly in the veins. To our knowledge, this is the first report on vascular smooth muscle lipofuscinosis occurring predominantly in the veins of primates.

Novel adsorptive type apheresis device Immunopure for ulcerative colitis from clinical perspectives based on clinical trials: Japan and Europe.

Several adsorptive type devices for ulcerative colitis are used for the induction of remission in patients with active severe disease worldwide. In 2020, the novel apheresis device Immunopure for ulcerative colitis was launched in Japan. Immunopure, like the polyethylene terephthalate column, uses polyarylate, a type of polyester resin, as the adsorbent. Similar to the cellulose acetate column, Immunopure is filled with adsorbent beads and expected to provide ease of use, with minimal risk of column clogging. Immunopure adsorbs leukocytes and platelets, especially activated platelets and platelet-leukocyte aggregates. In this article, the capability of Immunopure is evaluated from clinical perspective based on a clinical trial in Japan/Europe. As a result, Immunopure is comparable to other products in clinical effectiveness and indicated for the treatment of patients with refractory moderate ulcerative colitis, making it highly useful in clinical practice.

New findings concerning eosinophilic substance deposition in mouse nasal septum: sex difference and no increase in seniles.

An eosinophilic substance (ES) is usually observed in the mouse nasal septum. In contrast to textbooks and one report describing ES as amyloid, a previous study by the authors revealed that ES is not amyloid but consists of collagen and an amorphous material. Furthermore, it was suggested that the amorphous material was produced by clear HE-stained nasal gland epithelial cells present at the dorsal portion directly above the vomeronasal organ. In this histological examination, ES deposition showed sex difference (more intense in males than in females). ES increased with age but not in seniles, suggesting that the increase has a limit. In the detailed examination using subserial HE-stained nasal sections, it was revealed that the clear HE-stained nasal glands continued to the vomeronasal glands, which communicated with the lumen of the vomeronasal organ, and the vomeronasal gland epithelial cells contained strongly periodic acid-Schiff (PAS) positive granules, similar to the clear HE-stained nasal gland epithelial cells. ES also deposited in the interstitium of the vomeronasal glands. The results suggested a possibility that ES deposition may be related to vomeronasal organ.

Deposition process of eosinophilic substance in mouse nasal septum.

An eosinophilic substance is usually observed in the mouse nasal septum, and its volume increases with age. In contrast to descriptions in textbooks defining the eosinophilic substance as amyloid, our previous report revealed that the observed eosinophilic substance is not amyloid, but consisted of collagen and an amorphous material. Furthermore, it was suggested that the amorphous material was produced by the clear hematoxylin and eosin (HE)-stained nasal gland epithelial cells. In this study, we investigated the deposition process of the amorphous material produced by nasal gland epithelial cells in the interstitium morphologically. In most cases, the amorphous materials in the clear HE-stained nasal gland epithelial cells accumulated at the basal portion. Collagen fibers surrounding the nasal glands partially disappeared, whereas the amorphous material in contact with the rough endoplasmic reticulum of the nasal gland epithelial cells continued to the amorphous material in the interstitium. These findings suggested that the amorphous material produced by the clear HE-stained nasal gland epithelial cells migrated to the interstitium through the partial opening of the basement membrane.