Fibrinogen Aα-chain amyloidosis outbreaks in Japanese squirrels (Sciurus lis): a potential disease model.

Fibrinogen Aα-chain amyloidosis is a hereditary systemic amyloidosis characterized by glomerular amyloid depositions, which are derived from the fibrinogen Aα-chain variant in humans. Despite its unique pathology, the pathogenic mechanisms of this disease are only partially understood. This is in part because comparative pathological studies on fibrinogen Aα-chain amyloidosis are currently unavailable as there is a lack of reported cases in animals other than humans. In this study, mass spectrometry-based proteomic analyses of Japanese squirrels (Sciurus lis) that died in five Japanese zoos showed that they developed glomerular-associated fibrinogen Aα-chain amyloidosis with an extremely high incidence rate (29/38 cases, 76.3%). The condition was found to be age-dependent in the Japanese squirrels, with 89% of individuals over 4 years of age affected. Mass spectrometry revealed that the C-terminal region of the fibrinogen Aα-chain was involved in amyloidogenesis in Japanese squirrels as well as humans. No gene variations were identified between amyloid-positive and amyloid-negative squirrels, which contrasted with the available data for humans. The results indicate that fibrinogen Aα-chain amyloidosis is a senile amyloidosis in Japanese squirrels. The results have also provided comparative pathological support that the amyloidogenic C-terminal region of the fibrinogen Aα-chain is involved in the characteristic glomerular pathology, regardless of the animal species. This study elucidates the potential causes of death in Japanese squirrels and will contribute to future comparative pathological studies of fibrinogen Aα-chain amyloidosis. © 2023 The Pathological Society of Great Britain and Ireland.

Cholecystokinin-Induced Duodenogastric Bile Reflux Increases the Severity of Indomethacin-Induced Gastric Antral Ulcers in Re-fed Mice.

BACKGROUND/AIMS: We examined the involvement of cholecystokinin (CCK) in the exacerbation of indomethacin (IND)-induced gastric antral ulcers by gastroparesis caused by atropine or dopamine in mice. METHODS: Male mice were fed for 2 h (re-feeding) following a 22-h fast. Indomethacin (IND; 10 mg/kg, s.c.) was administered after re-feeding; gastric lesions were examined 24 h after IND treatment. In another experiment, mice were fed for 2 h after a 22-h fast, after which the stomachs were removed 1.5 h after the end of the feeding period. Antral lesions, the amount of gastric contents, and the gastric luminal bile acids concentration were measured with or without the administration of the pro- and antimotility drugs CCK-octapeptide (CCK-8), atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, lorglumide (CCK1 receptor antagonist), ondansetron, and haloperidol alone and in combination. RESULTS: IND produced severe lesions only in the gastric antrum in re-fed mice. CCK-8, atropine, dopamine, SR57227 and apomorphine administered just after re-feeding increased bile reflux and worsened IND-induced antral lesions. These effects were significantly prevented by pretreatment with lorglumide. Although atropine and dopamine also increased the amount of gastric content, lorglumide had no effect on the delayed gastric emptying provoked by atropine and dopamine. Both ondansetron and haloperidol significantly inhibited the increase of bile reflux and the exacerbation of antral lesions induced by atropine and dopamine, respectively, but did not affect the effects of CCK-8. CONCLUSIONS: These results suggest that CCK-CCK1 receptor signal increases bile reflux during gastroparesis induced by atropine and dopamine, exacerbating IND-induced antral ulcers.

Gastroparesis Worsens Indomethacin-Induced Gastric Antral Ulcers by Bile Reflux via Activation of 5-HT3 and Dopamine D2 Receptors in Mice.

BACKGROUND/AIMS: We examined the contributions of gastric emptying and duodenogastric bile reflux in the formation of gastric antral ulcers induced by NSAIDs in mice. METHODS: We used the murine re-fed indomethacin (IND) experimental ulcer model. Outcome measures included the appearance of gastric lesions 24 h after IND treatment and the assessment of gastric contents and the concentration of bile acids 1.5 h after re-feeding. The effects of atropine, dopamine, SR57227 (5-HT3 receptor agonist), apomorphine, ondansetron, haloperidol, and dietary taurocholate and cholestyramine were also examined. RESULTS: IND (10 mg/kg, s.c.) induced severe lesions only in the gastric antrum in the re-fed model. The antral lesion index and the amount of food intake during the 2-h refeeding period were positively correlated. Atropine and dopamine delayed gastric emptying, increased bile reflux, and worsened IND-induced antral lesions. SR57227 and apomorphine worsened antral lesions with increased bile reflux. These effects were prevented by the anti-emetic drugs ondansetron and haloperidol, respectively. The anti-emetic drugs markedly decreased the severity of antral lesions and the increase of bile reflux induced by atropine or dopamine without affecting delayed gastric emptying. Antral lesions induced by IND were increased by dietary taurocholate but decreased by the addition of the bile acid sequestrant cholestyramine. CONCLUSIONS: These results suggest that gastroparesis induced by atropine or dopamine worsens NSAID-induced gastric antral ulcers by increasing duodenogastric bile reflux via activation of 5-HT3 and dopamine D2 receptors.

Effects of Alfaxalone on the Induction and Maintenance of Total Intravenous Anesthesia in Gentoo Penguins (Pygoscelis papua).

Systemic anesthesia in penguins is often achieved using inhalation anesthetic agents alone, and information on injectable drugs for systemic anesthesia is limited. General anesthesia with a minimal effect on circulatory dynamics is necessary to perform noninvasive examinations and treatments in animals, including penguins. In this study, alfaxalone (ALFX), an injectable anesthetic agent, was examined to establish the optimal anesthetic method for gentoo penguins (Pygoscelis papua). Alfaxalone was administered intravenously through the metatarsal vein, and anesthesia was maintained by a constant rate infusion (CRI). A biological monitor was used to record numerous clinical indices, and the anesthetic depth was evaluated every 5 minutes during anesthesia; the CRI was adjusted until the optimal anesthetic depth was obtained. Anesthesia depth was assessed, and the CRI rate was adjusted. The CRI was stopped, and the time until recovery was recorded. Blood samples were collected to analyze plasma concentrations of ALFX. The mean total dose of ALFX required for anesthetic induction was 9 ± 1.9 mg/kg, the intubation time was 126 ± 21 seconds, and the maintenance infusion rate of ALFX was 0.3 ± 0.08 mg/kg/min. The time from discontinuation of anesthesia to extubation was 42 ± 23 minutes, and the time to recovery was 90 ± 33 minutes. Significant changes in the heart rate and blood pressure were not observed during the anesthetic events. The plasma concentration of ALFX under stable anesthesia was 6734 ± 4386 ng/mL (range, 3315-14 326 ng/mL). Although anesthesia using ALFX tended to result in a prolonged time to recovery in gentoo penguins, rapid induction of anesthesia and stable hemodynamics during anesthetic maintenance were achieved. Therefore, ALFX may be considered a suitable anesthetic method for noninvasive examinations and treatments in penguins.

A seroepidemiological study across age groups before and after the 2010-2011 mumps epidemic in Japan.

In Japan, large-scale mumps epidemics recur every 4-6 years because of low vaccination coverage. This study aimed to describe the seroprevalence of mumps in the Japanese population and identify the age groups most affected. The prevalence of anti-mumps antibodies was evaluated based on 1000 serum samples obtained from the Japanese National Serum Reference Bank. These samples consisted of 50 sera for each of 10 different age groups, collected during 2007-2008 (pre-epidemic period) and 2012-2013 (post-epidemic period). Seropositivity was lowest in the 6-11 months subgroup (3% and 0% in pre- and post-epidemic periods, respectively) and highest in the 10-14 years group (66% and 72% in pre- and post-epidemic periods, respectively). A comparison of anti-mumps antibody prevalence throughout the two periods considered revealed a large rise in seropositivity among the 2004-2008 birth cohort, using that of the 1-4 years group as representative in the pre-epidemic period (from 22% in pre- to 58% in post-epidemic periods; p = 0.0002). These results indicate that most people likely gain antibodies to the mumps virus during their childhood, especially during the first epidemic that they experience after their second year of life. Therefore, children should be vaccinated against mumps soon after their first birthday for effective prevention.

Histological Features of the Nasal Passage in Juvenile Japanese White Rabbits.

Rabbits are sometimes used for intranasal toxicology studies. We investigated the postnatal development of the nasal passage in juvenile Japanese white rabbits from just after birth to 6-week-old to provide information for conducting intranasal toxicological evaluation using juvenile animals. On postnatal day (PND) 1, the nasal passage consisted of the septum with mostly cartilaginous nasal wall and turbinates. The lining squamous, transitional, respiratory, and olfactory epithelia were already distributed similar to adults and were still underdeveloped. The nasal passage gradually expanded with age, as did the nasal wall, including the turbinates formed by endochondral ossification. The maxilloturbinate elongated, during which it branched complexly. The respiratory epithelium takes the form of columnar epithelium together with a reduction in goblet cells. In addition, the olfactory epithelium had clear cytoplasm in the ethmoturbinate, the olfactory nerve bundles thickened, and Bowman's gland acini increased in size and number. Other tissues, including the vomeronasal organ, nasal-associated lymphoid tissue, and nasolacrimal duct, also developed histologically with age. This investigation characterized the postnatal histological development of the nasal passage in Japanese white rabbits, providing basic knowledge regarding the histological examination and rationale for appropriate study design of intranasal toxicology studies in juvenile rabbits.

[Important Points at Interpretation ofNongenotoxic-Carcinogenicity Induced by Pesticidesin Rodent Bioassays].

Assessment of carcinogenicity is important for human health at dietary risk assessment of pesticide residues. This article indicated important points on interpretation of carcinogenicity in toxicological evaluation of pesticide residues based on principles of risk analysis in foods by CODEX to be a guide for risk assessors. This guidance was referred from the guidance on carcinogenicity evaluation by international and/or national organizations, and the interpretations of Food Safety Commissions of Japan (FSCJ) published in their risk assessment reports. We focused on carcinogenicity obtained from routine carcinogenicity bioassays in rodents. The guidance includes the purpose and usefulness of the bioassay studies, consideration points to be carcinogenicity and influencing factors to carcinogenicity in the test to judge carcinogenic hazard at hazard identification. Considering on human relevance as carcinogenic hazard also was proposed using practical case examples. Next, a carcinogenic hazard is evaluated on dose-response relationship to judge points of departure on carcinogenicity. At the end of this article, we challenged our recommendation on future assessment of carcinogenicity to progress from hazard to risk.

Plasma Globotriaosylsphingosine and α-Galactosidase A Activity as a Combined Screening Biomarker for Fabry Disease in a Large Japanese Cohort.

Fabry disease is an X-linked disorder of α-galactosidase A (GLA) deficiency. Our previous interim analysis (1 July 2014 to 31 December 2015) revealed plasma globotriaosylsphingosine as a promising primary screening biomarker for Fabry disease probands. Herein, we report the final results, including patients enrolled from 1 January to 31 December 2016 for evaluating the potential of plasma globotriaosylsphingosine and GLA activity as a combined screening marker. We screened 5691 patients (3439 males) referred from 237 Japanese specialty clinics based on clinical findings suggestive of Fabry disease using plasma globotriaosylsphingosine and GLA activity as primary screening markers, and GLA variant status as a secondary screening marker. Of the 14 males who tested positive in the globotriaosylsphingosine screen (≥2.0 ng/mL), 11 with low GLA activity (<4.0 nmol/h/mL) displayed GLA variants (four classic, seven late-onset) and one with normal GLA activity and no pathogenic variant displayed lamellar bodies in affected organs, indicating late-onset biopsy-proven Fabry disease. Of the 19 females who tested positive in the globotriaosylsphingosine screen, eight with low GLA activity displayed GLA variants (six classic, two late-onset) and five with normal GLA activity displayed a GLA variant (one classic) and no pathogenic variant (four late-onset biopsy-proven). The combination of plasma globotriaosylsphingosine and GLA activity can be a primary screening biomarker for classic, late-onset, and late-onset biopsy-proven Fabry disease probands.

Characterization of deoxyribonucleoside transport mediated by concentrative nucleoside transporters.

Human concentrative nucleoside transporters (CNTs) are responsible for cellular uptake of ribonucleosides; however, although it is important to better characterize CNT-subtype specificity to understand the systemic disposition of deoxyribonucleosides (dNs) and their analogs, the involvement of CNTs in transporting dNs is not fully understood. In this study, using COS-7 cells that transiently expressed CNT1, CNT2, or CNT3, we investigated if CNTs could transport not only ribonucleosides but also dNs, i.e., 2'-deoxyadenosine (dAdo), 2'-deoxyguanosine (dGuo), and 2'-deoxycytidine (dCyd). The cellular uptake study demonstrated that dAdo and dGuo were taken up by CNT2 but not by CNT1. Although dCyd was taken up by CNT1, no significant uptake was detected in COS-7 cells expressing CNT2. Similarly, these dNs were transported by CNT3. The apparent Km values of their uptake were as follows: CNT1, Km ＝ 141 µM for dCyd; CNT2, Km ＝ 62.4 µM and 54.9 µM for dAdo and dGuo, respectively; CNT3, Km ＝ 14.7 µM and 34.4 µM for dGuo and dCyd, respectively. These results demonstrate that CNTs contribute not only to ribonucleoside transport but also to the transport of dNs. Moreover, our data indicated that CNT1 and CNT2 selectively transported pyrimidine and purine dNs, respectively, and CNT3 was shown to transport both pyrimidine and purine dNs.

Early changes of pulmonary arterial hemodynamics in patients with systemic sclerosis: flow pattern, WSS, and OSI analysis with 4D flow MRI.

OBJECTIVES: To study the pulmonary artery (PA) hemodynamics in patients with systemic sclerosis (SSc) using 4D flow MRI (4D-flow). METHODS: Twenty-three patients with SSc (M/F: 2/21, 57 ± 15 years, 3 manifest PA hypertension (PAH) by right heart catheterization) and 10 control subjects (M/F: 1/9, 55 ± 17 years) underwent 4D-flow for the in vivo measurement of 3D blood flow velocities in the PA. Data analysis included area-averaged flow quantification at the main PA, 3D wall shear stress (WSS), oscillatory shear index (OSI) calculation along the PA surface, and Reynolds number. The composite outcome of all-cause death and major adverse cardiac events was also investigated. RESULTS: The maximum PA flow at the systole did not differ, but the minimum flow at the diastole was significantly greater in patients with SSc compared with that in control subjects (7.7 ± 16.0 ml/s vs. ­ 13.0 ± 17.3 ml/s, p < 0.01). The maximum WSS at the peak systole was significantly lower and OSI was significantly greater in patients with SSc compared with those in control subjects (maximum WSS: 1.04 ± 0.20 Pa vs. 1.33 ± 0.34 Pa, p < 0.01, OSI: 0.139 ± 0.031 vs. 0.101 ± 0.037, p < 0.01). The cumulative event-free rate for the composite event was significantly lower in patients with minimum flow in main PA ≤ 9.22 ml/s (p = 0.012) and in patients with Reynolds number ≤ 2560 (p < 0.001). CONCLUSIONS: 4D-flow has the potential to detect changes of PA hemodynamics noninvasively and predict the outcome in patients with SSc at the stage before manifest PAH. KEY POINTS: • The WSS at the peak systolic phase was significantly lower (p < 0.05), whereas OSI was greater (p < 0.01) in patients with SSc without manifest PAH than in controls. • The hemodynamic change detected by 4D-flow may help patient management even at the stage before manifest PAH in SSc. • The minimum PA flow and Reynolds number by 4D-flow will serve as a predictive marker for SSc.

Histological Features of Postnatal Development of the Eye in White Rabbits.

Rabbits are frequently used in studies assessing the toxicity of ophthalmic drugs; however, the postnatal histological changes that occur in the rabbit eye have not been fully described. To characterize postnatal ocular development in white rabbits, a histological investigation of the eyes and eyelids was sequentially performed between postnatal days (PNDs) 1 and 42. The eyes opened during PNDs10 to 12. Significant changes prior to eyelid opening included the proliferation of uveal and optic nerve cells, regression of the lenticular vasculature, and thinning of the retina with a decreasing number of retinal cells. After eyelid opening, several significant changes occurred in the anterior segment, including thickening of the cornea and the development of lacrimation-related tissues in the eyelid and conjunctiva. Additionally, the differentiation of retinal layer-derived cells and optic nerve thickening occurred. The lens size continued to increase throughout the postnatal period. The histological structure of the eyes and eyelids was nearly mature by PNDs28 to 42. This study characterizes the postnatal changes in the histological features of the eyes in juvenile white rabbits, providing fundamental knowledge on the appropriate design of histological studies of the eyes in juvenile rabbits, particularly ophthalmic drug evaluations.

Proteinous pancreatic lipase inhibitor is responsible for the antiobesity effect of young barley (Hordeum vulgare L.) leaf extract.

Young barley leaves (Hordeum vulgare L.) have various health effects and are employed as an ingredient in the production of health-promoting foods. Promoting antiobesity is one such health effect; however, the mechanism and bioactive compounds are unclear. In this research, young barley leaf extract (YB) was demonstrated to possess pancreatic lipase inhibitory activity. The addition of YB to a high-fat diet in mice increased fecal lipid content, indicating reduced absorption of lipids as the mechanism underlying antiobesity effect. The investigation of bioactive compounds in YB resulted in the identification of fructose-bisphosphate aldolase as a proteinous lipase inhibitor. Maximum inhibition of the protein was 45%, but inhibition was displayed at a concentration as low as 16 ng/mL, which is a characteristic inhibition compared with other reported proteinous lipase inhibitors.

Linear stapler anastomosis for esophagogastrostomy in laparoscopic proximal gastrectomy reduce reflux esophagitis.

PURPOSE: There are various reconstruction methods for Laparoscopic proximal gastrectomy (LPG), such as esophagogastrostomy (EG), double-tract reconstruction, and jejunal interposition. We have performed EG using a circular stapler (OrVil) from 2013 and using a linear stapler from 2017. The aim of this retrospective study was to clarify which stapler is better for EG for LPG. METHODS: The data of 84 patients who underwent EG for LPG between January 2013 and September 2019 were analyzed. EG with fundoplication was done using a circular stapler (OrVil) in 45 patients (CS group) and a linear stapler in 39 patients (LS group). The patients' medical records were reviewed. Clinical symptoms were obtained by interview at each outpatient consultation. All patients underwent postoperative 1-year follow-up endoscopy. To minimize bias between the two groups, propensity scores were calculated using a logistic regression model. After propensity-score matching, 60 patients (30 in the CS group and 30 in the LS group) were studied. RESULTS: Patient characteristics, operative outcomes were similar in two groups. Anastomotic leakage occurred in one patient (3.3%) in both groups. Anastomotic stenosis occurred in five patients (16.7%) in the CS group and two patients (6.7%) in the LS group. The rate of patients with severe reflux esophagitis (grade C or D) was significantly lower in the LS group (3.4%) than in the CS group (26.7%) (p = 0.026). CONCLUSIONS: EG with a linear stapler could reduce the risk of severe reflux esophagitis, and it could be a safe and feasible anastomosis for patients after LPG.

Case analysis of kinetics investigations in toxicity studies of pesticides to identify the nonlinearity of internal exposure and the influences of nonlinearity on the toxicological interpretation of pesticide residue.

The nonlinearity of internal exposure to 8 pesticides was investigated in toxicity studies using kinetics to identify nonlinearity visually and to investigate the influence of nonlinearity on toxicological evaluation. Data were obtained from risk assessment reports published by the Food Safety Commission (FSCJ). Nonlinearity was defined using 2 indicators: the lowest visual inflection point (LVIP) and the second lowest visual inflection point (SVIP) of kinetics by drawing a linear distribution chart. The area under the curve and 24-h urine concentrations were stable parameters used to identify the LVIP/SVIP. The sampling timing affected the blood concentrations, and the LVIP/SVIP was detected for 6 pesticides using the parent compounds or their metabolites as analytes. The subproportional nonlinearity was significant for these pesticides. The LVIP/SVIP values were consistent in the same species up to a 1-year period, but the values showed species-specific differences in several compounds. In all compounds found to be nonlinear, apical outcomes were observed at the SVIP or above. The presence of nonlinearity was recognized by the FSCJ. The recognition influenced their judgment of no-observed-adverse-effect levels (NOAELs) for carcinogenicity or health-based guidance values, indicating the importance of appropriate kinetics to identify the nonlinearity for toxicological evaluation of pesticide residue.

Effects of message order and active participation on vaccine risk communication.

BACKGROUND: "Message order" and "active participation" could be effective as risk communication methods. "Anticipated regret" (AR) has also been recognized as affecting risk perception and vaccine uptake in vaccination risk communication. We aimed to evaluate the effects of message order and active participation and the interactions between these two interventions on AR for vaccination. METHODS: We conducted a 2 (message order: positive-negative or negative-positive) × 2 (message calendar: with or without planning) factorial design study among 81 study participants. The effects of message order and active participation of mothers, using a message calendar, were evaluated on mothers' decision-making regarding vaccination with Haemophilus influenzae type b vaccine and pneumococcal conjugate vaccine for their children. Participants completed questionnaires to evaluate the AR of infection if unvaccinated (anticipated regret of inaction) and of side effects if vaccinated (anticipated regret of action, ARA) twice: immediately after interventions and 1 month later. RESULTS: An interaction between message order and active participation was significant with regard to anticipated regret of inaction immediately after interventions (P = 0.01), but this effect disappeared 1 month after interventions. The message order showed no main effect with regard to ARA. However, the main effect of active participation was marginally significant with regard to ARA 1 month after intervention (P = 0.09); AR over vaccine side effects was lower when vaccination was planned than in the condition without planning. CONCLUSIONS: The effect of message order was hardly detectable in a clinical setting. However, active participation induced by planning may affect AR. Further studies are needed to evaluate the effect of active participation in decision-making for vaccination.

Intra-Left Ventricular Hemodynamics Assessed with 4D Flow Magnetic Resonance Imaging in Patients with Left Ventricular Thrombus.

Left ventricular thrombus (LVT) has been identified to be crucial in patients with reduced ejection fraction (EF). Three-dimensional cine phase-contrast magnetic resonance imaging (4D flow MRI) can visualize the intra-LV vortex during diastole and quantify the maximum flow velocity (Vmax) at the apex. In this study, we investigated whether the change in the intra-LV vortex was associated with the presence of LVT in patients with cardiac disease.In total, 36 patients (63.5 ± 11.9 years, 28 men, 12/24 with/without LVT) with diffuse LV dysfunction underwent 4D flow MRI. The relative vortex area using streamline images and Vmax of blood flow toward the apex at the apical left ventricle were evaluated. The correlation between the relative vortex area and Vmax was assessed using Pearson's correlation coefficient. The ability to detect LVT was evaluated using the area under the curve (AUC) of the receiver operating characteristic.The relative vortex area was found to be smaller (27 ± 10% versus 45 ± 11%, P = 0.000026), whereas Vmax at the apical left ventricle was lower (19.1 ± 4.4 cm/second versus 27.4 ± 8.9 cm/second, P = 0.0006) in patients with LVT. Vmax at the apical left ventricle demonstrated significant correlations with the relative vortex area (r = 0.43, P = 0.01) and relative transverse length of the vortex (r = 0.45, P = 0.007). The AUC was 0.91 for the relative vortex area, whereas it was 0.80 for Vmax in the apical left ventricle.A smaller LV vortex and lower flow velocity at the LV apex were associated with LVT in patients with reduced EF.

A mouse model of short-term, diet-induced fatty liver with abnormal cardiolipin remodeling via downregulated Tafazzin gene expression.

BACKGROUND: Cardiolipin (CL) helps maintain mitochondrial structure and function. Here we investigated whether a high carbohydrate diet (HCD) fed to mice for a short period (5 days) could modulate the CL level, including that of monolysoCL (MLCL) in the liver. RESULTS: Total CL in the HCD group was 22% lower than that in the normal chow diet (NCD) group (P < 0.05). The CL72:8 level strikingly decreased by 93% (P < 0.0001), whereas total nascent CLs (CLs other than CL72:8) increased (P < 0.01) in the HCD group. The total MLCL in the HCD group increased by 2.4-fold compared with that in the NCD group (P < 0.05). Tafazzin expression in the HCD group was significantly downregulated compared with that in the NCD group (P < 0.05). A strong positive correlation between nascent CL and total MLCL (r = 0.955, P < 0.0001), and a negative correlation between MLCL and Tafazzin expression (r = -0.593, P = 0.0883) were observed. CONCLUSION: A HCD modulated the fatty acid composition of CL and MLCL via Tafazzin in the liver, which could lead to mitochondrial dysfunction. This model may be useful for elucidating the relationship between fatty liver and mitochondrial dysfunction. © 2021 Society of Chemical Industry.

Orbital malignant schwannoma and embryonal rhabdomyosarcoma in rats caused by leakage of locally injected nickel subsulfide to the orbit.

Nickel subsulfide (Ni3S2) is known to induce intraocular neoplasms when injected intravitreally into the eyes of rats. Here, we found two extraocular orbital neoplasms in two different rat strains, presumably due to the leakage of locally injected Ni3S2 to the extraocular orbital tissues. In the F344/DuCrlCrlj rat, an orbital mass arose at 30 weeks after injection, and invaded into the cranium. Histologically, the orbital mass was composed of areas arranged in parallel bundles formed by densely packed elongated or spindle-shaped cells with indistinct cytoplasmic borders, and of areas of hypocellular arrangement consisting of round cells in eosinophilic myxoid-like substances. Metastases were observed in the right submandibular and cervical lymph nodes. The neoplastic cells were immunopositive for S-100 protein and vimentin. Transmission electron microscopy revealed that the neoplastic cells had cellular processes and pericytoplasmic basal laminae. In the RccHanTM:WIST rat, an orbital mass arose at 36 weeks after injection. Histologically, the mass consisted of rhabdoid-like large round cells with proliferation of small round-to-polygonal cells, and these neoplastic cells infiltrated into the extraocular muscles. Immunohistochemically, the neoplastic cells were positive for desmin and vimentin. Transmission electron microscopy detected immature myofibrils with Z-band structures in the cytoplasm of these neoplastic cells. Consequently, the tumors were diagnosed as an orbital malignant schwannoma in an F344/DuCrlCrlj rat and an orbital embryonal rhabdomyosarcoma in a RccHanTM:WIST rat. The results of this case report suggest that leakage of Ni3S2 to the orbit caused the induction of orbital malignant schwannoma or rhabdomyosarcoma in rats.

Prenatal and postnatal lead exposures and intellectual development among 12-year-old Japanese children.

BACKGROUND: Low-level lead exposure during childhood is associated with deficit in child IQ. However, the association between prenatal lead exposure and child IQ remains inconsistent. The objective of our study was to examine the association between prenatal/postnatal lead exposure and child IQ at the age of 12. METHODS: We obtained data pertaining to cord-blood and child-blood lead levels and IQ for 286 children from a prospective birth cohort study (Tohoku Study of Child Development). IQ was assessed using the Wechsler Intelligence Scale for Children-Fourth Edition. Simultaneously, the Boston Naming Test (BNT) was used to assess the children's language ability. RESULTS: The median lead level in the cord blood was 0.8 µg/dL (5th-95th percentiles, 0.4-1.4 µg/dL), and that in the blood of 12-year-old children was 0.7 µg/dL (0.4-1.1 µg/dL). IQ and BNT scores were significantly lower in boys than in girls; therefore, multiple regression analysis was conducted separately for boys and girls. Among boys, IQ was associated with child-blood lead (B = -16.362, p = 0.033) but not cord-blood lead (B = -6.844, p = 0.309). When boys were divided into four groups according to the child-blood lead levels, there was a significant decreasing trend for IQ. The score with cues of the BNT was associated with both cord-blood (B = -5.893, p = 0.025) and child-blood (B = -7.108, p = 0.022) lead concentrations in boys. Among girls, there was no significant association of the outcomes with cord-blood or child-blood lead level. CONCLUSIONS: These findings suggest that postnatal lead exposure adversely affects the intellectual ability in boys. Furthermore, the language ability is sensitive to prenatal/postnatal lead exposure in boys.

Proton Pump Inhibitors Prevent Gastric Antral Ulcers Induced by NSAIDs via Activation of Capsaicin-Sensitive Afferent Nerves in Mice.

BACKGROUND/AIMS: We examined the effects of proton pump inhibitors (PPIs) on gastric antral ulcers induced by non-steroidal anti-inflammatory drugs in re-fed mice and the role of capsaicin-sensitive afferent nerves (CSANs) in the protective effects of PPIs on the antral mucosa. METHODS: Male mice were administered indomethacin after 2 h of re-feeding of diet after a 24-h fast, and gastric lesions were examined 24 h after indomethacin dosing. The effects of PPIs (lansoprazole and omeprazole), histamine H2-receptor antagonists (H2-RAs, famotidine, ranitidine), capsaicin and misoprostol on the formation of antral ulcers induced by indomethacin were examined. Functional ablation of CSANs was caused by pretreatment of mice with a high dose of capsaicin. RESULTS: Indomethacin produced lesions selectively in the gastric antrum in re-fed conditions. Formation of antral ulcers was not affected by H2-RAs, but inhibited by PPIs, capsaicin and misoprostol. The anti-ulcer effect of lansoprazole was 30 times stronger than that of omeprazole. Antral ulcers induced by indomethacin were markedly aggravated in mice with ablated CSANs. The effects of PPIs and capsaicin on ulcer formation were inhibited by ablation of CSANs, pretreatment with a capsaicin receptor antagonist (capsazepine/ruthenium red) and an inhibitor of nitric oxide synthesis (L-NAME). However, the inhibitory effect of misoprostol was not prevented by the ablation of CSANs or drugs. CONCLUSIONS: The results suggested that CSANs play an important role in protection of the antral mucosa and that both lansoprazole and omeprazole are capable of preventing NSAID-induced antral ulcers by activating CSANs.