[The 499th case: Roux-en-Y gastric bypass, limb weakness, and ostealgia].

A 36-year-old woman was admitted to the Peking Union Medical College Hospital with a history of fractures for 2 years, limb weakness for 1 year, and ostealgia for 2 months. The patient's examination identified iron deficiency anemia, significantly decreased serum calcium and 25-hydroxyvitamin D3 levels, and increased alkaline phosphatase and parathyroid hormone levels. Imaging showed several typical signs of osteomalacia. Considering the history of Roux-en-Y gastric bypass surgery, the diagnosis was considered to be osteomalacia caused by a postoperative nutritional absorption disorder. The patient was supplemented with calcitriol, calcium, and vitamin D and gradually returned to normal physical activity. The bone metabolism indicators and bone density were significantly improved.

[Chaihu Guizhi Decoction plus or minus formula combined with capecitabine inhibits IL-6/STAT3 signaling to suppress triple-negative breast cancer xenografts in nude mice].

OBJECTIVE: To investigate the effect of Chaihu Guizhi Decoction (CHGZD) combined with capecitabine on growth and apoptosis of subcutaneous triple-negative breast cancer xenografts in nude mice and explore the possible mechanism. METHODS: Nude mouse models bearing subcutaneous triple-negative breast cancer xenografts were randomized into 6 groups (n=10) for treatment with distilled water (model group), low (10.62 g/kg), medium (21.23 g/kg) and high (42.46 g/kg) doses of CHGZD, capecitabine (0.2 mg/kg), or the combination of CHGZD (42.46 g/kg) and capecitabine (0.2 mg/k) once daily for 21 consecutive days. The general condition of mice was observed, and after 21-day treatments, the tumors were dissected for measurement of tumor volume and weight and histopathological examination with HE staining. Serum IL-6 levels of the mice were determined with enzyme-linked immunosorbent assay (ELISA), and the expression levels of IL-6, STAT3, p-STAT3, Bax, Bcl-2 and cyclin D1 in the tumor tissues were detected using real-time PCR and Western blotting. RESULTS: Compared with those in the model group, the tumor-bearing mice receiving treatments with CHGZD showed significantly increased food intake with good general condition, sensitive responses, increased body weight, and lower tumor mass (P < 0.01). Compared with capecitabine treatment alone, treatment with CHGZD alone at the medium and high doses and the combined treatment all resulted in significantly higher tumor inhibition rates (P < 0.01), induced obvious tumor tissue degeneration and reduced the tumor cell density. Treatments with CHGZD, both alone and in combination with capecitabine, significantly decreased serum IL-6 level, lowered the mRNA expression levels of IL-6 and STAT3, the protein expressions of IL-6, STAT3 and P-STAT3 (P < 0.05), and the mRNA and protein expressions of Bcl-2 and cyclin D1 (P < 0.05), and increased the mRNA and protein expressions of Bax in the tumor tissues (P < 0.05). CONCLUSION: CHGZD combined with capecitabine can significantly inhibit tumor growth in nude mice bearing triple-negative breast cancer xenografts, the mechanism of which may involve the inhibition of IL-6/STAT3 signaling pathway and regulation of Bax, Bcl-2 and cyclin D1 expressions to suppress tumor cell proliferation and differentiation and induce cell apoptosis.

The efficacy and safety of different doses of calcitriol combined with neutral phosphate in X-linked hypophosphatemia: a prospective study.

The present study was the first prospective cohort evaluated the efficacy and safety of different doses of calcitriol in XLH children. The results suggested that a dose of 40 ng/kg/day calcitriol, compared with 20 ng/kg/day, was more effective in relieving the rickets, with similar safety outcomes. Further investigations were expected to set more dose groups. INTRODUCTION: Dose recommended for calcitriol in X-linked hypophosphatemia (XLH) varies in different studies. Therefore, we aimed to compare the efficacy as well as the safety of 20 ng/kg/d and 40 ng/kg/d calcitriol in Chinese XLH pediatrics population. METHODS: A 2-year, randomized, open-label, prospective study recruited 68 XLH children, which were randomized to receive either 40 ng/kg/day or 20 ng/kg/day calcitriol. Efficacy endpoints were the total Thacher ricket severity score (RSS) change from baseline to month 12 and 24, the difference in serum TALP level, fasting serum phosphate level, body height Z-score, and frequency of dental abscess. Safety assessments were done using renal ultrasound nephrocalcinosis grades (0-4), fasting serum and 24 h urine calcium level, and the occurrence of hyperparathyroidism. RESULTS: The decrease in the total RSS from baseline was more significant in the high-dose group at 12 (difference 0.87, p = 0.049) and 24 month (difference 1.23, p = 0.011). The serum TALP level was significantly lower in the high-dose group at 6 months. Pi level, height Z-score change, frequency of dental abscess and ratio of de novo nephrocalcinosis were comparable. A lower incidence of secondary hyperparathyroidism was seen in the high-dose group (p < 0.0001). CONCLUSION: For the first time in this prospective cohort, 40 ng/kg/d calcitriol was shown to be the more effective therapy in XLH children than the 20 ng/kg/d. Moreover, 40 ng/kg/d calcitriol was not associated with increasing adverse events. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT 03,820,518.

Safety and efficacy of common vitamin D supplementation in primary hyperparathyroidism and coexistent vitamin D deficiency and insufficiency: a systematic review and meta-analysis.

PURPOSE: Primary hyperparathyroidism (PHPT) is characterized by excessive secretion of parathyroid hormone (PTH). Vitamin D deficiency can stimulate parathyroid secretion. However, whether to correct vitamin D deficiency in patients with PHPT is controversial. We aimed to evaluate the safety and efficacy of vitamin D replacement in patients with PHPT. METHODS: We searched PubMed, Cochrane Library, and Embase. The relevant data were extracted from the included documents. The methodological items for non-randomized studies score entries were used for evaluation of quality. Review Manager 5.3 and Stata 12.0 were used for statistical analysis. RESULTS: A total of 11 articles were included with a total of 388 patients. The serum calcium mean difference (MD) was - 0.06 mg/dL [95% confidence interval (95% CI) - 0.16, 0.04]. Subgroup analysis showed that serum calcium levels did not change if the intervention time exceeded 1 month. The 24-h urinary calcium MD was 36.78 mg/day (95% CI - 37.15, 110.71), which indicated that there was no significant effect of vitamin D supplementation on 24-h urinary calcium levels. The MD of PTH was - 16.01 pg/mL (95% CI - 28.79, - 3.24). Subgroup analysis according to the intervention time showed that vitamin D intervention for more than 1 month significantly reduced PTH levels. The ALP MD was - 10.81 U/L (95% CI - 13.98, - 7.63), which indicated Vitamin D supplementation reduced its level. The MD of 25-hydroxyvitamin D was 22.09 µg/L (95% CI 15.01, 29.17), and no source of heterogeneity was found. CONCLUSION: Vitamin D supplementation in patients with PHPT and vitamin D deficiency significantly reduces PTH and ALP levels without causing hypercalcemia and hypercalciuria.

Imperatorin ameliorates learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling in prenatally-stressed female offspring.

Prenatal stress (PS) can lead to impaired spatial learning and memory in offspring. Imperatorin (IMP) is a naturally occurring furanocoumarin with many pharmacological properties. However, the effects of IMP on cognitive impairment induced by PS and the underlying molecular mechanisms remain unclear. We investigated the protective effect of IMP treatment after PS on learning and memory deficits in female offspring at postnatal 60 days. After treating prenatally-stressed offspring with IMP (15 and 30 mg/kg) for 28 days, we found that IMP increased body weight and ameliorated spatial learning and memory and working memory deficits in female offspring rats. Meanwhile, hippocampal Glu and serum corticosterone levels in prenatally-stressed offspring were significantly decreased after IMP administration. Additionally, IMP treatment significantly increased BDNF, TrkB, CaMKII, and CREB mRNA expression in the hippocampus of offspring rats. Furthermore, PS-mediated induction of RKIP protein and mRNA expression and glucocorticoid receptor protein expression in the hippocampus of offspring rats were significantly decreased by IMP treatment, and the protein expression of BDNF and TrkB and relative levels of p-EKR/ERK, p-CaMKIIα/CaMKIIα, and p-CREB/CREB were remarkably increased after IMP treatment. Taken together, IMP can ameliorate PS-induced learning and memory deficits through BDNF/TrkB and ERK/CaMKIIα/CREB signaling pathway and hypothalamic-pituitary-adrenal axis.

[Association of α-actinin-3 gene polymorphism and muscle strength of postmenopausal women].

Objective: To explore the association between α-actinin-3 (ACTN3) polymorphism and muscle strength in postmenopausal women. Methods: Five hundred and ninety-eight postmenopausal women with an average of (62.9±7.0) years old in Dongcheng District of Beijing were included. The ACTN3 polymorphism including rs540874, rs618838 and rs2229456 were genotyped by Sequenom Mass Array to explore their associations with muscle strength. One hundred and sixty-three of them were trained with regular Tai chi movement while 271 were administered with elemental calcium 600 mg/d combined with Vitamin D 800 U/d or calcitriol 0.25 µg/d for 2 years. Association between changes of muscle strength and ACTN3 polymorphism were analyzed. Results: The rs540874 genotypes were found to be significantly associated with chair stand test[GG (9.02±3.85) s vs GA (9.27±4.14) s vs AA (9.68±5.00) s, P=0.015]. Right grip strength in women with G allele were likely to be higher compared with A allele, but it was not statistically significant (P=0.056). Multiple linear regression showed that the chair stand test of AA genotype was statistically longer than that of GG and GA genotype (ß=2.639, 95% CI: 1.632-4.646, P=0.010). The associations between rs618838, rs2229456 genotypes and muscle strength of both lower and upper limbs were not significant (all P>0.05). In addition, muscle strength of lower limbs of patients with rs540874 genotyped with G allele, rs618838 genotyped with C allele and rs2229456 genotyped with A allele increased significantly after enhanced exercise and vitamin D supplementation (all P<0.05). Conclusions: The rs540874 polymorphism of ACTN3 gene was associated with the muscle function of lower limb in postmenopausal women. The improvement of muscle strength after intervention were possibly correlated with rs540874, rs618838 and rs2229456 polymorphisms.

Volatile Oil from Amomi Fructus Attenuates 5-Fluorouracil-Induced Intestinal Mucositis.

Amomi Fructus has been used to treat digestive diseases in the context of traditional Chinese medicine, so we evaluated the effects of a volatile oil from Amomum villosum (VOA) on intestinal mucositis induced by 5-fluorouracil (5-FU). We measured the effect of VOA and its main active constituent, bornyl acetate (BA), on body weight, food intake, diarrhea, inflammatory cytokines, the mucosal barrier, and gut microbiota. VOA and BA significantly increased the rats' body weight, relieved diarrhea, and reversed histopathological changes in the gut and inflammation. VOA significantly inhibited apoptosis and alleviated the endoenteritis by downregulating p38 MAPK and caspase-3 expression. VOA and BA strengthened the intestinal mucosal barrier by increasing zonula occludin-1 and occludin expression. VOA and BA reduced the amount of pathogenic bacteria and increased the abundance of probiotics. Thus, VOA prevented the development and progression of intestinal mucositis after chemotherapy.

[Clinical characteristics of adult-onset primary hypoparathyroidism: a retrospective analysis of 200 cases].

Objective: To study the clinical characteristics of primary hypoparathyroidism in adults. Methods: The clinical data of 200 cases with adult-onset primary hypoparathyroidism in Peking Union Medical College Hospital during December 1987 to December 2015 were collected and analyzed retrospectively. Among them, 128 cases were followed up for a median period of 3 years. Results: The major manifestations at their first visits were tetany and numbness in the distal extremities(81.5%, 163/200 and 62.0%, 124/200). Thirty-two percent of the cases (62 cases) had history of seizures, and 60.9%(98/161) and 74.4%(96/129) of them were with intracerebral calcifications and cataracts, respectively.Most of subjects(155/200)had more than one year delay in diagnosis. Hypercalciuria occurred in 67.2%(86/128) of the cases during the follow-up. No significant differences in the clinical characteristics and biochemical markers between the hypercalciuria subjects and the non-hypercalciuria subjects. Renal nephrocalcinosis or stones were found in 6.5%(5/77) of the cases, and kidney function decreased in 6.6%(6/91) of the patients. Kidney function was negatively associated with age and duration of disease. Conclusions: The predominant manifestations of primary hypoparathyroidism in adults included tetany and numbness in the distal extremities and seizures. It is often misdiagnosed. Calcium supplement combined with vitamin D or its metabolites effectively relieve clinical symptoms and signs. The serum and urinary calcium levels should be monitored frequently to reduce renal complications.

Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1beta.

OBJECTIVE: To provide a more complete picture of the effect of interleukin-1 beta (IL-1beta) on adult human articular chondrocyte gene expression, in contrast to the candidate gene approach. DESIGN: Chondrocytes from human knee cartilage were cultured in medium containing IL-1beta. Changes in gene expression were analyzed by microarray and reverse transcriptase-polymerase chain reaction analysis. The ability of transforming growth factor beta-1 (TGF-beta1), fibroblast growth factor (FGF)-18, and bone morphogenetic protein 2 (BMP-2) to alter the effects of IL-1beta was analyzed. Computational analysis of the promoter regions of differentially expressed genes for transcription factor binding motifs was performed. RESULTS: IL-1beta-treated human chondrocytes showed significant increases in the expression of granulocyte colony stimulating factor-3, endothelial leukocyte adhesion molecule 1 and leukemia inhibitory factor as well as for a large group of chemokines that include CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL8, CCL2, CCL3, CCL4, CCL5, CCL8, CCL20, CCL3L1, CX3CL1 and the cytokine IL-6. As expected, the mRNA for matrix metalloproteinase (MMP)-13 and BMP-2 also increased while mRNA for the matrix genes COL2A1 and aggrecan was down-regulated. A subset of chemokines increased rapidly at very low levels of IL-1beta. The phenotype induced by IL-1beta was partially reversed by TGF-beta1, but not by BMP-2. In the presence of IL-1beta, FGF-18 increased expression of ADAMTS-4, aggrecan, BMP-2, COL2A1, CCL3, CCL4, CCL20, CXCL1, CXCL3, CXCL6, IL-1beta, IL-6, and IL-8 and decreased ADAMTS-5, MMP-13, CCL2, and CCL8. Computational analysis revealed a high likelihood that the most up-regulated chemokines are regulated by the transcription factors myocyte enhancer binding factor-3 (MEF-3), CCAAT/enhancer binding protein (C/EBP) and nuclear factor-kappa B (NF-kappaB). CONCLUSION: IL-1beta has a diverse effect on gene expression profile in human chondrocytes affecting matrix genes as well as chemokines and cytokines. TGF-beta1 has the ability to antagonize some of the phenotype induced by IL-1beta.

[Effects of alfacalcidol on osteoporosis in ovariectomized rats].

OBJECTIVE: To investigate the effects of alfacalcidol on osteoporosis in rats induced by ovariectomy (OVX). METHODS: Fifty-three virgin female Wistar rats of six months old were divided into 6 groups: (1) rats in baseline group (base) were sacrificed what 6 months before OVX, and those in the other 5 groups were either bilaterally OVX or sham-operated (sham) as follows: (2) Sham; (3) OVX baseline (OVXb); (4) OVX end (OVXe); (5) OVX + 17beta-estradiol 20 microgram/kg.(-1) SC. (O + E); and (6) OVX + alfacalcidol 0.1 microgram/kg.(-1) oral (O + VD). Rats in OVXb group were sacrificed 6 weeks after OVX and the others were sacrificed 14 weeks after surgery. Alfacalcidol (TEVA, Israel) was fed orally at 6 weeks after OVX and lasted for 8 weeks. Urine and serum samples were collected before sacrifice to determine the bone turnover markers. The right tibia was processed undecalcified for histomorphometric analysis, and the right femur was prepared for pQCT scanning and bone biomechanical measurement with indentation test. RESULTS: Treatment of OVX rats with alfacalcidol (O + VD) increased tibial cancellous bone volume in histomorphometric analysis (12.0% +/- 1.1% vs 5.8% +/- 1.3%, P < 0.01). pQCT scanning showed that trabecular BMC and BMD were sharply elevated in O + VD group compared with OVXe group, increased 109.2% and 133.1% respectively (P < 0.01). In consistency with these changes in mechanical competency of cancellous bone in distal femur, maximal load was enhanced in O + VD group compared with OVXe group (21.3% +/- 4.0% N vs 7.9% +/- 1.9% N, P < 0.05). All these changes in O + VD group were similar to those in 17beta-estradiol treatment group (O + E). Serum calcium concentration increased in O + VD group. Histomorphometric and biochemical indices of bone resorption reduced in O + VD group. CONCLUSION: Alfacalcidol effectively prevent bone loss in OVX rats and restore partly the trabecula, with evidenced increasing density, contents as well as maximal loads of cancellous bone, and reduce bone resorption.

Reproducibility of nutrient intake in a food frequency questionnaire used in a general population.

This study evaluates the reproducibility of nutrient intake in a 45-item food frequency questionnaire (FFQ). The FFQ was mailed in 1980 to persons eligible to participate in a large cohort study on diet and cancer risk; a follow-up version with 75 food items was mailed in 1988 to selected original participants. A random sample of 500 men and 500 women from the New York State general population was selected from individuals who responded to both waves of the study. The subjects' 1988 responses were compared with their original 1980 responses; Pearson's correlations ranged from 0.25 for retinol to 0.55 for vitamin C with or without supplements and vitamin E with supplements in women. Reproducibility of nutrient intake in this questionnaire indicates that brief FFQs may be a useful tool to study nutrient intake and chronic disease relationships, although they are subject to substantial measurement error and dietary change.

[Immunological observation on chyluric patients with heat-clearing and hemostatic drugs].

In order to investigate the pathogenesis and therapeutic mechanism of chyluria, an experiment with a basic Heat-clearing and hemostatic prescription was conducted in treating 30 patients of chyluria. The result, 26 cases were cured completely. The cell-mediated and humoral immunity observation showed that OKT3 and OKT4 levels were commonly low in chyluric cases, and OKT8 as higher than normal value, the OKT4/OKT8 ratio was inverted before treatment. While OKT3 and OKT4 increased commonly, and OKT8 decreased with the OKT4/OKT8 ratio adjusted after treatment. Meanwhile, humoral immunity level was also commonly low before treatment, it increased after treatment.

[Treatment of hypoparathyroidism with 1 alpha-hydroxyvitamin D3].

2 male and 17 female patients with hypoparathyroidism including 7 idiopathic, 11 surgical and 1 pseudohypoparathyroidism received 1 alpha-OHD3 at a mean daily dose of 2.7 +/- 0.7 microgram (1.5-4.0 micrograms) combining with calcium 1 g for 14 weeks. The mean age of the patients was 37 +/- 9 old years and the mean course of disease was 15 +/- 10 years. The symptoms and signs of hypocalcium disappeared in 1-3 weeks after therapy, meanwhile the serum ionized calcium (Ca++) and total calcium (TCa) increased from 0.84 +/- 0.02 to 1.03 +/- 0.01 mmol/L and from 6.90 +/- 0.22 to 8.70 +/- 0.20 mg/dl (P less than 0.001) respectively. The serum Ca++ and TCa increased to normal volume in 58% and 63% patients respectively. The concentration of serum 1,25 (OH)2 D3 elevated significantly from 19.5 +/- 1.1 to 29.1 +/- 2.4 pg/ml (P less than 0.01 n = 17). The lever of urinary hydroxyproline was no significant change. The serum phosphate reduced markedly from 5.50 +/- 0.2 to 4.80 +/- 0.2 mg/dl (P less than 0.01). The serum Ca++ and TCa changed to the primitive level when we stopped to use 1 alpha-OHD3 alone for 1-3 weeks. No significant side effects were found. It might be suggested that 1 alpha-OHD3 is effective and safe in treating hypoparathyroidism because calcium absorption in intestine is promoted by 1 alpha-OHD3.