Oral sodium hyaluronate relieves knee discomfort: A 12­week double­blinded, placebo­controlled study.

Sodium hyaluronate (SH) is a high molecular-weight polysaccharide composed of repeating polymeric disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine. SH is present in every connective tissue and organ, with synovial fluid having the highest concentration of SH in the body. The effectiveness of oral SH on gonarthrosis is known; although, its influence on the knees of healthy individuals is not. However, as severe diseases may require surgery, it is better to take care of healthy knees before the onset of gonarthrosis. Therefore, the present study investigated the functionality of SH on the knee of healthy individuals. The present study was a randomized double-blind, placebo-controlled trial in which healthy adults (mean age: Placebo group, 61.50±1.59; SH group, 58.50±1.81), rated as grade ≤1 based on the Kellgren-Lawrence classification, were administered 111 mg/day SH for 12 weeks. The evaluation of visual analog scales were performed to assess the discomfort in the knees of the participants and were conducted at baseline, and then 6 and 12 weeks after the start of SH ingestion. Additionally, a locomotive syndrome risk test quantifying the mobility of the participants, a one-leg standing time with eyes open test evaluating the strength of the leg muscle as well as the ability to balance by measuring the time to stand on one leg and a blood test (interleukin-10, aspartate aminotransferase, alanine transaminase, γ-glutamyl transferase, lactate dehydrogenase, creatine kinase and C-reactive protein) were performed at baseline and then 12 weeks after the start of SH ingestion. A significant suppression of knee symptoms were demonstrated in the SH group compared with the placebo group in terms of the total visual analog scale scores for pain, stiffness and discomfort for the 31 healthy adult subjects. Significant suppression of symptoms was also demonstrated in the placebo group in terms of discomfort in the knees when descending stairs and pain in the knees after walking for a longer distance or duration than normal. No significant differences between the two groups were demonstrated in the locomotive syndrome risk test, one-leg standing time with eyes open test and the blood test. The results of the present study suggest the possibility that oral SH may help to maintain a healthy condition of the knees. The study protocol was registered with the University Hospital Medical Information Network Clinical Trial Registry in advance (registration no. UMIN000045980, November 4, 2021).

Isolation of type I collagen homotrimer from human placenta with LC-MS monitoring of the α1(I)/α2(I) chain ratio.

The general molecular form of type I collagen is heterotrimer consisting of two α1(I) chains and one α2(I) chain. However, α111(I) homotrimer is rarely observed in vivo, especially in pathological tissues such as cancer. Here we utilized a previously developed LC-MS method that can accurately and sensitively quantitate α1(I) and α2(I) chains to distinguish type I collagen homotrimer from human placenta. By monitoring with the LC-MS method, the α1(I)/α2(I) chain ratio was found to be high in the supernatant of salt precipitation with >2.8 M NaCl at neutral pH. Type I collagen homotrimer was successfully isolated using optimized sequential salt fractionation and confirmed to show previously reported features of the homotrimer, including high thermal stability and overmodification. These data clearly indicate that placental tissue contains α111(I) homotrimer. Our LC-MS method can sensitively detect the rare form of type I collagen and can help understand its physiological and pathological significance.

Effects of intravaginal administration of prostaglandin F2α on luteolysis and subsequent estrus in Shiba goats (Capra hircus).

This study examined the effects of intravaginal administration of prostaglandin F2α (PGF2α ) on luteolysis and subsequent estrus in cycling goats. Goats with functional corpus lutea received one of five treatments: 2 mg of PG intramuscularly (IM2 × 1; n = 6), 2 mg of PGF2α intravaginally (IVG2 × 1; n = 7), 4 mg of PGF2α intravaginally (IVG4 × 1; n = 7), and 1 or 2 mg of PGF2α intravaginally 8 h apart (IVG1 × 2 group; n = 6 and IVG2 × 2; n = 8). Blood samples were collected at 24-h intervals from 0 to 7 days after PGF2α administration. Estrus was checked twice daily during the experiment. The proportion of goats with complete luteolysis (reduction of progesterone concentrations to <1 ng/mL until 48 h after treatment) in the IVG2 × 1 group (28.6%) was significantly lower than in the other groups (IM2 × 1; 100%, IVG4 × 1; 57.1%, IVG1 × 2; 87.5%, IVG2 × 2; 100%, respectively). For goats completing luteolysis, there was no significant difference in the onset and duration of estrus among the groups. These results suggest that intravaginal administration of PGF2α can be applied as an alternative to intramuscular administration.

Relationship between ovarian ultrasonographic findings on the seventh post-estrus day and plasma progesterone concentration, nutritional metabolic factors, and pregnancy outcome in dairy cows.

To improve the accuracy of ultrasonographic assessment of luteal function, we investigated the relationship between ovarian ultrasonographic findings on Day 7 (Day 1 = ovulation) and plasma progesterone (P4) concentration, nutritional metabolic factors, and pregnancy outcome. A total of 47 spontaneous estrus events were investigated in 38 lactating Holstein cows (artificial insemination, n = 31; embryo transfer, n = 16). Transrectal ultrasonography was performed on Days 0 and 7 to measure the pre-ovulatory follicle area on Day 0 and the luteal tissue area (LTA), luteal blood flow area (LBF), relative LBF (rLBF) (= LBF/LTA), and dominant follicle area (DFA) on Day 7. Blood samples were collected on Day 7 to measure plasma P4, insulin-like growth factor-I (IGF-I), insulin, and metabolites. Plasma P4 concentration was positively correlated with LTA but was not associated with LBF or rLBF. Plasma P4 concentration was positively correlated with blood glucose and IGF-I and negatively correlated with blood urea nitrogen and free fatty acid, and no significant relationship was found between the ultrasonographic findings of the corpus luteum (CL) and these blood metabolites. Pregnant cows had smaller DFA than non-pregnant cows. In conclusion, LTA measurement can help predict plasma P4 concentration, but it was difficult to detect variations in plasma P4 concentration in relation to changes in energy status by evaluating the CL ultrasonographically. A combined assessment of CL and first-wave dominant follicle may be important in evaluating fertility.

Late-onset, first-ever involuntary movement after successful surgical revascularization for pediatric moyamoya disease - Report of two cases.

Background: A small number of children with Moyamoya disease develop involuntary movements as an initial presentation at the onset, which usually resolves after effective surgical revascularization. However, involuntary movements that did not occur at the onset first occur after surgery in very rare cases. In this report, we describe two pediatric cases that developed involuntary movements during the stable postoperative period after successful surgical revascularization. Case Description: A 10-year-old boy developed an ischemic stroke and successfully underwent combined bypass surgery. However, he developed chorea six months later. Another 8-year-old boy developed a transient ischemic attack and successfully underwent combined bypass surgery. However, he developed chorea three years later. In both cases, temporary use of haloperidol was quite effective in resolving the symptoms, and involuntary movements did not recur without any medication during follow-up periods of up to 10 years. Conclusion: Postoperative first-ever involuntary movement is very rare in pediatric moyamoya disease, and the underlying mechanisms are still unclear, but a temporary, reversible imbalance of excitatory and inhibitory circuits in the basal ganglia may trigger the occurrence of these rare symptoms. Careful follow-up would be mandatory.

No adverse effect of confirmation of ovulation by rectal palpation and ultrasonography after artificial insemination on formation, development, and function of the corpus luteum and conception rate in cows.

The effect of confirmation of ovulation by rectal palpation and ultrasonography after artificial insemination (AI) on the development of the corpus luteum (CL) and conception rate was investigated in cows. A total of 90 clinically healthy Holstein-Friesian dairy cows were examined in this study. After AI, the cows were divided into three groups (30 cows per group). In Group I, ovulation was confirmed by rectal palpation at 24 h after AI. In Group II, ovulation was confirmed using transrectal ultrasonography 24 h after AI. In Group III, ovulation was not confirmed after AI. Day 0 was defined as the day when ovulation was confirmed in Groups I and II, and as the day after AI was performed in group III. Transrectal ultrasonography was performed on days 3, 5, 7, and 14 to measure the CL diameter, tissue area, and CL blood flow area, and the ratio of CL blood flow area to CL tissue area was calculated. On the day of CL measurement, blood samples were collected to determine the plasma concentrations of progesterone (P4) and estradiol-17ß (E2). Pregnancy was diagnosed at 28 and 60 days after AI. A high conception rate of approximately 80% was achieved in Groups I and II, in which confirmation of ovulation was conducted. There were no differences in the diameter, tissue area, or blood flow area of the CL between the three groups. These results indicate that the confirmation of ovulation by rectal palpation and transrectal ultrasonography did not affect the formation and function of the CL or conception rate.

Changes in the C-reactive protein and 13,14-dihydro-15-keto-prostaglandin F2α concentrations of uterine lavage samples after the administration of povidone-iodine in cows.

Changes in the C-reactive protein (CRP) and 13,14-dihydro-15-keto-prostaglandin F2α (PGFM) concentrations of uterine lavage fluid were examined in cows given an intrauterine povidone-iodine (PI) infusion. The mean polymorphonuclear leukocyte (PMN) ratios (the ratio of PMN to total cells) and CRP concentration of uterine lavage fluid on the day after the treatment were significantly (P<0.05) greater in the PI infusion group (PMN: 53.0 ± 32.7%, CRP: 50.2 ± 32.3 ng/mL) than in the non-treatment control group (PMN: 7.9 ± 21.9%, CRP: 17.2 ± 5.9 ng/mL), whereas there was no significant difference in the mean PGFM concentration between the two groups. The present findings suggest that the uterine CRP level is a useful biomarker of local uterine inflammation in cows.

Predictors of non-response to successive waves of surveys in the Japan Environment and Children's Study during the 3-year postpartum period: a longitudinal cohort study.

OBJECTIVES: We examined changes in factors related to non-response to successive waves of the nationwide birth cohort study, the Japan Environment and Children's Study (JECS), during the first 3 years after childbirth. DESIGN: Longitudinal cohort study. SETTING: As the baseline survey, mothers completed self-administered questionnaires distributed by hand during pregnancy or 1 month after delivery. The self-administered questionnaires that we used in this study were then distributed by mail every 6 months until the children were 3 years old, for a total of six times. PARTICIPANTS: Of 103 060 mothers who consented to participate in the JECS during pregnancy, 88 489 mothers were included in the study after excluding those with multiple births, miscarriages or stillbirths and those who withdrew from the study within 3 years after providing informed consent. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected at the baseline survey on participants' socioeconomic status, medical history, health status, health-related behaviours and their children's health conditions and living situations. The strength of the impact of related factors and the prediction of response status were examined and compared using binominal logistic regression analysis. RESULTS: For all six follow-up questionnaire surveys, higher maternal age was strongly associated with providing a response. Factors that were strongly associated with mothers not providing a response were smoking after childbirth and having more children. The concordance rate of response status based on the presented model was about 70%, suggesting that the response status for the first 3 years after birth can be predicted from the information collected in the baseline survey. CONCLUSION: By identifying predictors of non-response from information obtained in baseline surveys, researchers may be able to reduce non-response to successive survey waves by issuing reminders, reviewing data collection methods and providing appropriate financial and/or non-financial incentives.

Provision of educational events and subsequent questionnaire response rates in a large-scale birth cohort study from Japan.

OBJECTIVES: We examined whether providing educational events for participants in a birth cohort study would increase the response rates of study questionnaires. DESIGN: Birth cohort study. SETTING: Questionnaires were distributed and returned by post twice in 1 year. We developed and implemented two educational sessions; a Baby Food lecture for mothers with children around 8 months old (analysis 1) and a Eurythmic session for mothers with children around 1 year and 8 months old (analysis 2). Mothers with children over the target ages were not invited (not-invited group). The invited participants were divided into three groups: those who did not apply to attend (not-applied group), those who applied but did not attend (applied group), and those who applied and attended (attended group). PARTICIPANTS: The participants were 5379 mother-child pairs registered with the Toyama Regional Center of the Japan Environment and Children's Study (JECS). OUTCOME MEASURE: The outcome measure was return of the JECS questionnaire for 1 year old sent out after the Baby Food lecture and the JECS questionnaire for 2 years old sent out after the Eurythmic session. The questionnaires were returned to us by post. RESULTS: The response rate for the attended group of the Baby Food lecture was 99.7%, and the odds ratio (OR) was significantly higher for this group than for the not-invited group (crude OR 24.54; 95% confidence interval (CI) 3.42 to 176.13; analysis 1). After the exclusion of participants who had previously attended the Baby Food lecture, the response rate for the attended group of the Eurythmic session was 97.8%, and the OR was significantly higher for this group than for the not-invited group (adjusted OR 5.66; 95% CI 1.93 to 16.54; analysis 2). CONCLUSION: Providing educational events that are appropriate to the age and needs of the participants may increase questionnaire response rates in birth cohort studies. TRIAL REGISTRATION NUMBER: UMIN 000030786.

Changes in the ovary and the peripheral concentrations of sex hormones after the aspiration of follicular fluid from the spontaneous follicular cysts of dairy cows.

The aim of the present study was to clarify the ovarian and hormonal dynamics after the aspiration of follicular fluid in cows with follicular cysts. Follicular fluid was aspirated from the follicular cysts and follicles that were fated to become cystic follicles and other coexisting normal follicles, respectively, in lactating cows (n = 3). After the aspiration procedure, new follicles developed and reached a diameter of 25 mm without ovulation within 13-19 days. The plasma concentrations of inhibin decreased and follicle-stimulating hormone increased rapidly after the aspiration procedure, and subsequently increased and decreased, respectively, as a new follicle grew. No luteal structures developed after the aspiration procedure, and the animals' plasma progesterone levels remained low. The present study indicates that the cystic follicles are never luteinized by the aspiration of follicular fluid, and consequently, new follicular cysts are observed to repeatedly develop.

Association between maternal smoking history and congenital anomalies in children: Results from the Japan Environment and Children's Study.

We investigated the relationship between maternal smoking history and congenital anomalies in children. Drawing on data from the Japan Environment and Children's Study collected between January 2011 and March 2014, the smoking habits of pregnant women were categorized as "never smoked," "quit before pregnancy, "quit after pregnancy," and "full smoking." Of the 91 626 participants examined, a total of 2199 (2.4%) infants were born with any congenital anomalies. Logistic regression analysis was used to determine the odds ratio for congenital anomalies in each group based on maternal smoking history. No significant difference was seen between the full-smoking and never smoked groups in the odds ratios for congenital anomalies of the nervous system; the eyes, ears, face, and neck; the cardiovascular system; or the musculoskeletal system. However, in the full-smoking group, the odds ratios for trisomy (adjusted odds ratio, 2.14; 95% confidence interval, 1.15-3.97) and any congenital anomalies (adjusted odds ratio, 1.35; 95% confidence interval, 1.09-1.67) were significantly higher compared with the never smoked group. Our results indicate that continuing to smoke during pregnancy is associated with increased risk of trisomy and any congenital anomalies in the general Japanese population.

Predominant tubulointerstitial lupus nephritis with preceding pernicious anemia.

Predominant tubulointerstitial nephritis with negligible glomerular lesions is a rare form of lupus nephritis. Although tubulointerstitial changes occur in two-thirds of patients with lupus nephritis, these lesions were mostly accompanied by glomerulonephritis. Predominant tubulointerstitial lupus nephritis has been reported to be only 13 cases in the literature as far as we surveyed. Here, we present a case of a 72-year-old male who had pancytopenia associated with pernicious anemia and later developed a mild proteinuria and renal insufficiency. Although urinary tubulointerstitial markers increased, serological screening tests for tubulointerstitial nephritis were all negative. Three months later, the patient was diagnosed as systemic lupus erythematosus, based on polyarthritis, positive antinuclear antibody, immunological disorder and hematological disorder. Renal biopsy revealed severe infiltration of mononuclear cells in the interstitium with minimal abnormalities in glomeruli. Positive IgG and C1q staining with immunofluorescence antibody method in the tubular basement membrane and dense deposits in the same region with electron microscopy confirmed a diagnosis of predominant tubulointerstitial lupus nephritis. Since the patient's renal function declined rapidly, treatment with intravenous 500 mg methyl prednisolone followed by 40 mg/day of oral prednisolone was initiated. The patient's renal function improved and became stable even after tapering of prednisolone. Although lupus nephritis is generally accompanied by multiple symptoms such as fever, malaise, arthralgia, rashes, this case showed only pernicious anemia and tubulointerstitial nephritis initially.

Intravaginal administration of estradiol benzoate capsule for estrus synchronization in goats.

Estrus synchronization requires multiple treatments of hormonal drugs, requiring considerable time and cost. The aim of the present study was to develop an estrus synchronization protocol using intravaginal administration of estradiol benzoate (EB) capsules in goats. Two types of capsules were prepared: an EB capsule that melted immediately after administration and a sustained-release (SR) EB capsule that dissolved slowly and reached a peak after 24 h. Goats with functional corpus lutea were intramuscularly treated with prostaglandin F2α (PG). At 24 h after PG administration, goats were administered 1 mg of EB solution intramuscularly (PG + 24IM; n = 6) or 1 mg of EB capsule intravaginally (PG + 24EB; n = 6). The SR EB capsule was administered intravaginally at the time of PG administration (PG + SR; n = 6). The control group (n = 6) received only PG. All groups showed estrus within 72 h after PG administration. The onset of estrus did not differ significantly between the PG + 24IM and PG + SR groups but was earlier than in the control group. Estradiol concentration in the PG + SR group peaked at 11.5 ± 6.1 h after EB and PG administration. Peak estradiol concentrations were not significantly different between the PG + 24IM and PG + SR groups (78.0 ± 25.8 and 64.0 ± 38.1 pg/ml, respectively), and were higher than the PG + 24EB and control groups (27.3 ± 8.8 and 14.6 ± 6.1 pg/ml, respectively). These results suggest that intravaginal administration of an EB capsule with a sustained-drug release base is applicable for estrus synchronization, as an alternative to intramuscular administration.

Association of blood cadmium levels in pregnant women with infant birth size and small for gestational age infants: The Japan Environment and Children's study.

BACKGROUND: There is growing evidence of an association between cadmium (Cd) and unfavorable birth outcomes. The effect of Cd exposure on anthropometric measures at birth or small for gestational age (SGA) infants in a large, nationwide Japanese cohort remains to be clarified. OBJECTIVES: To analyze the association between maternal blood Cd levels at different sampling times and sex-dependent infant birth size, weight, body length, chest, and head circumferences, in addition to SGA. METHODS: Data of 17,584 pregnant women in the Japan Environment and Children's Study were analyzed for anthropometric measurements. For SGA determination, 13,969 cases of vaginal delivery were analyzed after excluding infants born by cesarean section. Maternal blood Cd levels were categorized into quartiles (Q1-Q4), and the Q1 was used as a reference. Multiple linear regression analysis was performed for anthropometric measurements, and multiple logistic regression analysis was used to investigate the association of maternal blood Cd levels with the risk of SGA. RESULTS: Birth weight tended to decrease according to the increase in quartiles of blood Cd levels (15.63 g decrease [95% confidence level (CI): -33.26, 2.01] for Q4). The overall analysis revealed no decreases in body length and head and chest circumference, but subgroup analysis revealed that chest circumference tended to decrease according to the increase in quartiles in the female sex/third-trimester stratification (0.16 cm decrease [95% CI: -0.32, 0.00] for Q4). SGA risk was also higher and paralleled the increase in blood Cd levels associated with the female sex/third-trimester group (Odds Ratio 1.90 [95% CI: 1.23, 2.94] for Q4). CONCLUSION: Our results provide further evidence of sex-specific health risks associated with Cd exposure in early life in a large Japanese pregnancy cohort.

Intravaginal administration of progesterone using a new technique for sustained drug release in goats.

The objective of the present study was to develop and evaluate a sustained release vaginal progesterone (P4) capsule containing a mixture of mucoadhesive polymer and silicone fluid. Goats were administered a gelatin capsule containing 0.4 g of P4 mixed in silicone fluid and either a hydroxypropylmethylcellulose (HM) or polyaclil starch (PA) base. The mean plasma P4 concentrations at 2 and 12 h after administration were significantly higher in goats treated with PA capsules than in those with HM capsules. The plasma P4 concentrations in goats treated with HM capsules increased and remained above 1.0 ng/ml for 96 h after administration, whereas the plasma P4 concentrations in goats treated with PA capsules remained above 1.0 ng/ml for only 24 h after administration. In the next experiment, an HM capsule was attached to a silicone device and inserted in the vagina for 10 days. The plasma P4 concentration remained similar to that of the natural luteal phase for 9 days. These results suggest that a mixture of mucoadhesive polymer and silicone fluid has the potential to be applied clinically as a sustained release base for estrus synchronization or hormonal therapy.

Toddler Neurodevelopmental Outcomes Are Associated With School-Age IQ in Children With Single Ventricle Physiology.

To examine whether neurodevelopment at preschool age predicts IQ levels and needs for special education services in school-age children with single ventricle (SV) physiology. Thirty-five patients with SV physiology were assessed using the Bayley Scale of Infant and Toddler Development (BSID) II or III at 3 years and the Wechsler Intelligence Scale for Children-Fourth Edition (WISC) at 8 years. Whether the children were receiving special education services was also determined. Factors associated with the mental developmental index (MDI) of the BSID, the full-scale IQ (FSIQ) of the WISC, and special education services were also analyzed. The MDI and FSIQ of children with SV physiology were significantly lower than the values in healthy children (P < 0.01). The MDI at 3 years was moderately correlated with FSIQ at 8 years (P < 0.01, R2 = 0.41). Ten patients (28.6%) received special education services in their school. Children with MDI <85 were more likely than those with MDI ≥85 to require special education services at school age (53% and 10%, respectively, P < 0.01). Weight at birth and stage II were correlated with the MDI, extracorporeal circulation time at stage II was correlated with FSIQ, and age at Fontan operation was correlated with FSIQ and special education services. The toddler neurodevelopment index may predict not only IQ levels but also the need for special education services in school-age children. Children with low neurodevelopmental scores need to be followed closely for a long time.

Factors of non-responsive or lost-to-follow-up Japanese mothers during the first year post partum following the Japan Environment and Children's Study: a longitudinal cohort study.

OBJECTIVES: We examined the factors related to lost-to-follow-up of a birth cohort study during the first year after delivery. DESIGN: Longitudinal cohort study. SETTING: Questionnaires were provided by mail. Mothers answered the questionnaires about the children twice: at 6 months and 1 year. PARTICIPANTS: Of 103 062 pregnancies who consented to participate in the Japan Environment and Children's Study (JECS), 93 417 mothers were included in the study after excluding those with multiple births, miscarriages or stillbirths and those who withdrew from the study within 1 year after providing informed consent. PRIMARY AND SECONDARY OUTCOME MEASURES: Participants' socioeconomic status, medical history, health status, health-related behaviours, their children's health conditions and living situations were collected by self-administered questionnaires during pregnancy or 1 month after delivery as the baseline survey. In addition, two self-administered questionnaires were distributed 6 months and 1 year after delivery. Using the response status of the two questionnaires after delivery, participants' follow-up status was divided into four groups. The related factors were examined using logistic regression analysis. RESULTS: Factors positively correlated with lost-to-follow-up to the questionnaires were postpartum physical conditions, psychological distress during pregnancy, the child's health status at birth, the child's primary caregiver and the number of siblings of the child. Partners' active participation in JECS was associated with a lower lost-to-follow-up rate to the two questionnaires, whereas inactive participation was positively associated with a higher lost-to-follow-up rate. CONCLUSION: The response rate to the questionnaires seems to be related to the interest and understanding of participants' partners. In addition, the response rates are related to participants' physical conditions and living conditions. To decrease lost-to-follow-up rates in consecutive questionnaire surveys within a cohort study, it may be important for investigators to recognise that participants and their motivation in research can be influenced by perceptions they may have regarding the objectives of the research.

The efficacy of a newly developed neurokinin 3 receptor agonist B21-750 on luteinizing hormone secretion in cycling goats.

This study aimed to investigate the efficacy of a newly developed NK3 receptor agonist (B21-750) on the secretion of luteinizing hormone (LH) in association with ovarian steroid hormones during the follicular phase (FP, n = 5) and luteal phase (LP, n = 5) of Shiba goats. The FP group was treated with both prostaglandin F2α and progesterone-controlled internal drug release (CIDR) inserts for 10 d, and B21-750 (200 nmol) was injected 12 h after removing the CIDR. Meanwhile, the LP group received B21-750 injections on a day during the mid-luteal phase. LH secretion increased at 1 h after B21-750 injection in both groups. The percent changes in the area under the curve of LH was higher during the hour after injection than during the hour before injection in both groups. Thus, this study demonstrated that B21-750 induces rapid LH secretion for a short period during both the follicular and luteal phases.

Concomitant Treatment with Etanercept and Tacrolimus Synergistically Attenuates Arthritis Progression via Inhibition of Matrix Metalloproteinase-3 Production and Osteoclastogenesis in Human TNF-α Transgenic Mice.

In the present study, we investigated the effects and mechanisms of action of a combined treatment with etanercept, a soluble tumor necrosis factor receptor (p75) Fc fusion protein, and tacrolimus, a calcineurin inhibitor on the progression of arthritis in human tumor necrosis factor-α (TNF-α) transgenic (hTNF-Tg) mice. Single-drug treatments with etanercept and tacrolimus attenuated the clinical signs but not the radiographic changes associated with the development of arthritis in mice. On the contrary, combined treatment significantly suppressed the radiographic progression and also improved the clinical signs. The combined treatment exhibited synergistic effects of the two drugs in reducing the serum matrix metalloproteinase-3 level and the number of peripheral CD11bhigh osteoclast precursor cells. Moreover, tacrolimus inhibited the cytokine-induced osteoclast differentiation in synergy with etanercept in an in vitro assay. Interestingly, tacrolimus did not inhibit the production of antidrug antibodies (ADAs) against etanercept in the hTNF-Tg mice. This result implies that the synergistic effects of etanercept and tacrolimus are not due to secondary effects derived from the suppression of ADA production by tacrolimus but are due to their primary effects. These findings suggest that concomitant treatment with etanercept and tacrolimus may be one of preferable treatment options to control disease activities for patients with rheumatoid arthritis, especially for those with bone resorption.

Endometrial adenocarcinoma with choriocarcinomatous differentiation in the uterus of a goat.

An 11-year-old female goat had invasive and metastatic endometrial adenocarcinoma in the uterus. There was a notable proliferation of endometrial epithelial cells in a tubular growth pattern, with a desmoplastic response. The endometrial epithelial tumor cells metastasized to the kidney, liver and lung. In contrast to the primary and metastatic tumor cells, pleomorphic tumor cells with a choriocarcinoma-like growth pattern infiltrated the mesometrium. Cell proliferation activity was high in both types of tumor cells. Both types of tumor cells expressed cytokeratins AE1/AE3, 7 and CAM5.2; choriocarcinomatous cells also had positive immunoreactions to human chorionic gonadotropin, human placental alkaline phosphatase and α-inhibin. The present case was diagnosed as endometrial adenocarcinoma with choriocarcinomatous differentiation.