Increased Serum Alkaline Phosphatase Research Articles

Toxicological significance of increased serum alkaline phosphatase activity in dog studies of pesticides: Analysis of toxicological data evaluated in Japan

Increased serum alkaline phosphatase (ALP) activity is an indicator of hepatobiliary damage in humans and experimental animals. Practically, increased ALP accompanied by no other hepatotoxic changes is often encountered in toxicity studies of pesticides in dogs. Here, we analyzed the toxicological significance of increased ALP in response to 206 pesticides evaluated by the Food Safety Commission of Japan as toxicological evaluation reports in their risk assessment process. Our analysis indicated that increased ALP was more frequent in dogs (108/206) than in rats (36/206). In 87 of 108 pesticides, increased ALP was observed with hepatotoxicity in dogs. However, increased ALP had no specific relationship with certain types of hepatotoxicity and was not a sensitive marker of hepatotoxicity. Approximately 50% of 87 pesticides showing hepatotoxicity also induced liver hypertrophy. No hepatotoxic changes were seen with the remaining 21 pesticides, other than increases in liver weight and/or liver hypertrophy. Most of these 21 pesticides were phenobarbital-like liver metabolism enzyme inducers in rodents. These results suggested that increased ALP was not an indicator of hepatotoxicity in dogs if hepatotoxic findings were absent. This analysis provided a new interpretation of the toxicological significance of ALP in dogs and could contribute to toxicological evaluation of pesticides.

Effects of resveratrol supplementation on bone biomarkers: a systematic review and meta-analysis.

The current study presents a comprehensive systematic review and meta-analysis of randomized controlled trials (RCTs) on resveratrol and bone health biomarkers. PubMed, Scopus, and Web of Science (until September 2018) were searched to identify the potential RCTs with information on resveratrol supplementation and bone metabolism biomarkers. Mean differences (MD) were analyzed using a random-effects model. Pooling six RCTs (eight treatment arms with 264 subjects) together identified no significant reduction of serum Ca, osteocalcin, C-terminal telopeptide of type I collagen, and procollagen I N-terminal propeptide values after resveratrol supplementation over placebo treatment. However, a significant increase in serum alkaline phosphatase (ALP) (MD: 5.69mg/mL, 95% CI: 3.58-7.80, I2 =95.7%, P < 0.001) and bone alkaline phosphatase (BAP) (MD: 10.57mmHg, 95% CI: 5.36-15.78, I2 =99.2%, P < 0.001) values was observed after resveratrol treatment relative to placebo. The findings of this study indicate that resveratrol supplementation increased some key bone biomarkers, such as ALP and BAP. Further precise clinical trials of the effects of resveratrol supplementation on bone health should be conducted.

Effects of Chlorella vulgaris polysaccharides accumulation on growth characteristics of Trachemys scripta elegans

The present study investigated the effects of the accumulated polysaccharides in Chlorella vulgaris microalgae on the growth characteristics of Trachemys scripta elegans. Sodium alginate was used to prepare immobilized C. vulgaris, and the antioxidant effects of the accumulated polysaccharides in it were determined using Caenorhabditis elegans as a model. We determined the specific growth rates of T. s. elegans (10 in each group) and their levels of non-specific immune-related indexes (including alkaline phosphatase; total superoxide dismutase; catalase; malondialdehyde). Under optimal culturing conditions, the accumulated polysaccharide content in C. vulgaris reached 32.7% (dry weight). Polysaccharides from C. vulgaris significantly improved the hydrogen peroxide-induced oxidative stress resistance and resulted in the enhancement of stress resistance-related antioxidant enzymes, including total superoxide dismutase and catalase (p < 0.05). The accumulated polysaccharides in C. vulgaris were heteropolysaccharides comprising rhamnose, ribose, arabinose, xylose, 2−deoxy−D−glucose, mannose, glucose, galactose, and glucosamine with a molar ratio of 0.26: 0.62: 0.21: 0.10: 0.08: 0.18: 1.00: 0.42: 0.17. Compared with the control group with common feeds, suspended and immobilized C. vulgaris with higher accumulated polysaccharide levels had a positive effect on the specific growth rate of the T. s. elegans (p < 0.05). Further, the suspended and immobilized C. vulgaris with higher accumulated polysaccharide levels significantly increased serum alkaline phosphatase, total superoxide dismutase and catalase activity (p < 0.05) and decreased serum malondialdehyde levels of T. s. elegans (p < 0.05).

Serum alkaline phosphatase and γ-glutamyl transferase in acute pyelonephritis.

BackgroundElevated serum alkaline phosphatase (AP) and γ-glutamyl transferase (γ-GT) are commonly observed in patients with acute pyelonephritis. The goal of this study was to examine the clinical significance of elevated serum AP and γ-GT levels and to explore the mechanisms underlying these changes.MethodsWe examined serum AP and γ-GT levels in 438 patients with acute pyelonephritis. Urine AP/creatinine (Cr), urine γ-GT/Cr, fractional excretion of AP, and fractional excretion of γ-GT (FEγ-GT) were evaluated in patients with elevated and normal serum levels. AP isoenzymes were also examined.ResultsWe identified 77 patients (17.6%) with elevated serum AP and 134 patients (30.6%) with elevated serum γ-GT. Among them, both enzymes were elevated in 64 patients (14.6%). Older age, longer hospital stay, elevated baseline serum Cr, and complicated pyelonephritis were associated with increases in serum AP and γ-GT. Multivariate analysis showed that high serum AP levels were significantly correlated with renal impairment (odds ratio, 2.13; 95% confidence interval, 1.08–4.19; P = 0.029). FEγ-GT was significantly lower in patients with elevated serum enzyme levels. The liver fraction for AP isoenzyme profile did not increase in patients with elevated serum AP.ConclusionOur results demonstrated that elevated serum AP and γ-GT levels are associated with complicated pyelonephritis and renal impairment. Lower FEγ-GT levels in patients with elevated serum enzymes may be the result of decreased urinary excretion of these enzymes.

Parameters influencing the pharmacokinetics/pharmacodynamics of piperacillin/tazobactam in patients with febrile neutropenia and haematological malignancy: a prospective study.

To assess population pharmacokinetics (PK) and pharmacodynamics (PD) of both piperacillin and tazobactam in neutropenia patients and examine dosage requirements related to the MIC distribution for Gram-negative bacteria involved in bloodstream infections (BSIs). We conducted a prospective study including adult haematological malignancy patients with febrile neutropenia receiving piperacillin/tazobactam as short (30 min) or prolonged (4 h) intravenous infusions. Concentration data were analysed using a population approach. Dosing simulations with the final model investigated factors influencing the PK/PD of piperacillin/tazobactam quantified by fT>MIC or PTA for piperacillin and tazobactam, respectively. In parallel, the local MIC distribution of β-lactams was documented for Gram-negative bacteria involved in BSIs. Over 10 months, 31 patients were enrolled, with 11 (35.5%) short and 20 (64.5%) prolonged infusion regimens. A one-compartment model adequately described the data for both drugs. Prolonged infusion, increased serum alkaline phosphatase (ALP) values and renal function impairment were associated with increased piperacillin fT>MIC. For patients with normal or augmented renal CL, dosing regimens q8h or q6h with 30 min of infusion were insufficient to achieve acceptable PTA for piperacillin/tazobactam at the median MIC value of 8 mg/L. Prolonged infusion of large doses was associated with the best PTA for both piperacillin and tazobactam. In a population of haematological malignancy patients with neutropenia, renal function and ALP influenced the PK of piperacillin/tazobactam. Prolonged intravenous infusion would optimize the PK of piperacillin/tazobactam, especially in the case of augmented renal CL and/or low-range bacterial susceptibility.

Effect of Oral Supplementation for Rabbits of Pomegranate seed Extract on Some Serum Biochemical Parameters in Relation to oral Inflammation, oxidative stress, and wound healing

Background: Pomegranate (punicagranatum L, Punicaceae), is an edible fruit consumed around the world. The edible part of pomegranate is rich in compounds that possess antioxidant and anti-inflammatory activities. The aim of this study is to investigate the antioxidant; anti-inflammatory and gingival wound healing effects of Punicagrantum L. seed extract oral supplementation in rabbit. Methods and Methods: Forty five male rabbits were divided into 3 groups, base line (5 rabbits) left without buccal gingival wound as( group 1),study group, 20 rabbits (group2) with buccal gingival wound treated with ethanolic extract of Punicagranatum L. seed extract and control, 20 rabbits (group 3) with buccal gingival wound only. Buccal gingival wounds were created on lower right central incisor and sutured removed after (7) days. Blood biopsies by cardiocentesis were collected at times (0, 3h, 1, 3 and 7days) for estimation of serum alkaline phosphatase activity, serum total proteins, and serum uric acid. Results: The results showed a significant increase in serum Alkaline phosphatase, total proteins and uric acid in all time intervals after buccal gingival wound, in rabbits receiving water, while their levels increased significantly only at time intervals of 3 hours and 1 day after gingival wound, in rabbits receiving pomegranate seed extraction. Conclusions: It has been concluded that oral Supplementation of pomegranate seed extract in rabbits can expedite the rate of healing of gingival wound

Evaluating the therapeutic effect of Diallyl disulfide compared to that of Alderonate on Glucocorticoids induced osteoporosis in rats: Biochemical and histomorphometric analysis

Introduction: The prevalence of Glucocorticoids (GC) use made Glucocorticoid induced osteoporosis (GIO) an important form of secondary osteoporosis. Bisphosphonates (Alderonate) are considered as pharmacological agents in prevention and treatment of GIO. Garlic containing Diallyl disulfide (DAS) has received special attention for its beneficial effects as an antioxidant. The present study attempted to evaluate the Alendronate, DAS, and the combination of Alderonate and DAS effect on bone gene expression of RANKL and OPG, serum biochemical parameters [Ca, P, alkaline phosphatase (ALP)] and histological assessment of tibia in animal model of GIO. Material and Method: Fifty pathogen albino male rats were allocated in five groups:Control group(C), Methyl prednisolone group (M), methyl prednisolone Aldenronate group (A) Methyl prednisolone Diallyl disulfide (D), Diallyl disulfide Alendronate Methyl prednisolone (AD) group.Gene expression studies, biochemical parameters, histological and morphometric studies were assessed for all animals. Results: Among the study groups, Methyl prednisolone exposure provoked decrease in OPG (0.26±0.16) increase in RANKL (3.57±.39) gene expression, decrease in serum ALP(85.38±6.3),Ca(6.41±0.89), P(1.9 ±0.35) levels and decrease in trabecular thickness (57.01±23.22).Alderonate and Dially disulfide concomitant administration was shown to increase OPG(2.84 ±0.53)and decrease in RANKL (0.63 ± 0.27) gene expression, increase serum ALP(187.75±24.93),Ca(10.330 ±.69)and P(3.16 ±0.43) levels,increase trabecular thickness(154.7±31.7)(p < 0.001). Conclusion: Diallyl disulfide can add advantage to Alderonate in treatment of glucocorticoid induced osteoprosis.

Loss of Wnt Secretion by Macrophages Promotes Hepatobiliary Injury after Administration of 3,5-Diethoxycarbonyl-1, 4-Dihydrocollidine Diet

Exposure of mice to a diet containing 3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) induces porphyrin accumulation, cholestasis, immune response, and hepatobiliary damage mimicking hepatic porphyria and sclerosing cholangitis. Although β-catenin signaling promotes hepatocyte proliferation, and macrophages are a source of Wnts, the role of macrophage-derived Wnts in modulating hepatobiliary injury/repair remains unresolved. We investigated the effect of macrophage-specific deletion of Wntless, a cargo protein critical for cellular Wnt secretion, by feeding macrophage-Wntless-knockout (Mac-KO) and wild-type littermates a DDC diet for 14 days. DDC exposure induced Wnt11 up-regulation in macrophages. Mac-KO mice on DDC showed increased serum alkaline phosphatase, aspartate aminotransferase, direct bilirubin, and histologic evidence of more cell death, inflammation, and ductular reaction. There was impaired hepatocyte proliferation evidenced by Ki-67 immunostaining, which was associated with decreased hepatocyte β-catenin activation and cyclin-D1 in Mac-KO. Mac-KO also showed increased CD45, F4/80, and neutrophil infiltration after DDC diet, along with increased expression of several proinflammatory cytokines and chemokines. Gene expression analyses of bone marrow-derived macrophages from Mac-KO mice and F4/80+ macrophages isolated from DDC-fed Mac-KO livers showed proinflammatory M1 polarization. In conclusion, this study shows that a lack of macrophage Wnt secretion leads to more DDC-induced hepatic injury due to impaired hepatocyte proliferation and increased M1 macrophages, which promotes immune-mediated cell injury.

Comorbidities of Phototherapy Used in Neonatal Jaundice in Diyala Governorate, Iraq

Phototherapy is the first most common therapeutic measure in treatment of jaundice in newborns and many cases been the only treatment required. This cross-sectional study tried to assess the comorbidities of phototherapy used in neonatal jaundice. The study conducted at Al-Batool maternity and child teaching hospital in Diyala province in Iraq, during the period August 2017 to January 2018, included 100 neonates with jaundice who were treated with phototherapy. Almost, 64% of the neonates aged less than three days, After phototherapy, there was a significant decline in each of hemoglobin, serum iron, TSB, serum calcium, serum Phosphate, serum RDW, serum MCV, WBC count and platelets count (p<0.001), and there was a significant increase in serum alkaline phosphatase (p<0.001) and urine calcium level (p=0.002). In conclusion, phototherapy had significant influence on the levels of minerals and electrolytes of the neonates, hence the change in mineralization and electrolyte status need to be managed carefully.

Serum alkaline phosphatase levels correlate with long-term mortality solely in peritoneal dialysis patients with residual renal function

Introduction: Increased serum alkaline phosphatase (ALP) is predictive of a higher mortality in patients with end-stage renal disease. However, it remains unknown whether residual renal function (RRF) influences the outcome-association of serum ALP among peritoneal dialysis (PD) patients.Methods: A total of 650 incident PD patients receiving PD catheter implantation in an institute between 1 November 2005 and 28 February 2017 were retrospectively enrolled. These patients were divided into groups with and without RRF (RRF and non-RRF groups) and those with serum ALP levels in tertiles. The Kaplan–Meier method and multivariate Cox proportional hazard models were used to analyze their outcomes based on RRF and serum ALP levels.Results: These 650 patients had a mean age of 49.4 ± 14.0 years old, their median ALP level was 74 U/L (interquartile range (IQR): 59–98). After 28-month (IQR: 14–41) follow-up, 80 patients in RRF group and 40 patients in non-RRF group died. PD patients with the highest serum ALP tertile had significant lower survival (p = .014), when compared to other patients in the RRF group. However, this relationship was not observed in patients in the non-RRF group. After multivariate adjustment, in the RRF group, patients with the highest ALP tertile had a significantly higher risk of mortality (hazard ratio (HR): 2.26, 95% confidence interval (CI): 1.06–4.82, p = .034). Each 10-U/L increase in ALP level was associated with a 4% (HR: 1.04, 95% CI: 1.00–1.08, p = .045) higher mortality risk.Conclusions: Higher serum ALP level is associated with increased mortality solely in PD patients with RRF.

Oxidant stress induction and signalling in xenografted (human breast cancer-tissues) plus estradiol treated or N-ethyl-N-nitrosourea treated female rats via altered estrogen sulfotransferase (rSULT1E1) expressions and SOD1/catalase regulations.

N-ethyl-N-nitrosourea (ENU) is highly used in rodent models of tumerogenesis/carcinogenesis. Xenografting human-cancer tissues/cells with estradiol (E2) treatment is also used to generate rodent-models of gynaecological cancers. The altered metabolic-redox environment leading to establishment of pre-tumorigenesis condition and their mechanism are less studied. Here, female Wister rats were treated with these drugs at their pre-tumerogenic dosage (one group ENU single intra-peritoneal dose of 90mg/kg b.w. and another group were implanted with human breast tumor (stage-IIIB) and fed with 2.5mg of 17β-estradiol once in a week for 4months). After 4months, animals were sacrificed; their serum and liver tissues were tested. A brief comparison was made with a rat model (regarded as positive control) of toxicity induced by mutagenic environmental pollutant arsenic (0.6ppm daily/4weeks). The increase in serum alkaline phosphatase and glutamate-pyruvate transaminase suggests the possible organ toxicity is favoured by the increase in hepatic/systemic free radicals and oxidative stress in all drug application models. But the increase in the serum E2 level as noted in the ELISA data with impairment in the hepatic estrogen sulfotransferase (SULT1E1) protein expression (immuno-blot data) were noticed with interfered hepatic free-thiols only in ENU and xenograft-E2 group compared to arsenic group. It is also evident in the in vitro result from E2/GSH/NAC added hepatic slices with altered antioxidant regulations. Moreover, impairment in hepatic SOD1, catalase and glutathiole peroxidase activities (PAGEzymographic data), especially in the ENU-treated group makes them more vulnerable to the oxidative threat in creating pre-tumerogenic microenvironment. This is evident in the result of their higher DNA-damage and histological abnormalities. The Bioinformatics study revealed an important role of rSULT1E1 in the regulations of E2 metabolism. This study is important for the exploration of the pre-tumerogenic condition by ENU and E2 by impairing SULT1E1 expression and E2 regulations via oxidant-stress signalling. The finding may help to find new therapeutic-targets to treat gynaecological-cancers more effectively.

Adrenocortical Challenge Response and Genomic Analyses in Scottish Terriers With Increased Alkaline Phosphate Activity.

Scottish terriers (ST) frequently have increased serum alkaline phosphatase (ALP) of the steroid isoform. Many of these also have high serum concentrations of adrenal sex steroids. The study's objective was to determine the cause of increased sex steroids in ST with increased ALP. Adrenal gland suppression and stimulation were compared by low dose dexamethasone (LDDS), human chorionic gonadotropin (HCG) and adrenocorticotropic hormone (ACTH) response tests. Resting plasma pituitary hormones were measured. Steroidogenesis-related mRNA expression was evaluated in six ST with increased ALP, eight dogs of other breeds with pituitary-dependent hyperadrenocorticism (HAC), and seven normal dogs. The genome-wide association of single nucleotide polymorphisms (SNP) with ALP activity was evaluated in 168 ST. ALP (reference interval 8–70 U/L) was high in all ST (1,054 U/L) and HAC (985 U/L) dogs. All HAC dogs and 2/8 ST had increased cortisol post-ACTH administration. All ST and 2/7 Normal dogs had increased sex steroids post-ACTH. ST and Normal dogs had similar post-challenge adrenal steroid profiles following LDDS and HCG. Surprisingly, mRNA of hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2) was lower in ST and Normal dogs than HAC. HSD17B2 facilities metabolism of sex steroids. A SNP region was identified on chromosome 5 in proximity to HSD17B2 that correlated with increased serum ALP. ST in this study with increased ALP had a normal pituitary-adrenal axis in relationship to glucocorticoids and luteinizing hormone. We speculate the identified SNP and HSD17B2 gene may have a role in the pathogenesis of elevated sex steroids and ALP in ST.

Increased Serum Alkaline Phosphatase in Patients with Acute Ischemic Stroke

BackgroundStroke is one of the most common causes of disability and death. Higher alkaline phosphatase (ALP) levels have been associated with poor functional outcomes and mortality in previous studies. We investigated alterations in serum ALP concentrations and functional outcomes in patients with acute ischemic stroke (AIS). MethodsPatients with first-ever AIS were recruited to participate in the study. Serum ALP levels were measured using a Cobas Integra 400 Plus automatic biochemical analyzer, and severity of stroke was evaluated using the National Institutes of Health Stroke Scale (NIHSS) score on admission. Functional outcome was measured using the modified Rankin scale 1 year after admission. ResultsSerum ALP concentration was increased in patients with AIS (81.75 ± 20.49 versus 69.93 ± 16.12 U/L, P = .000) and the optimal ALP cutoff point for diagnosing patients with AIS was 81.50 U/L, with a sensitivity of 49.5% and specificity of 78.9%. However, there was no significant correlation between ALP and NIHSS scores (r = .170, P = .085) and ALP was not significantly different between favorable and unfavorable functional outcomes (81.76 ± .60 versus 81.70 ± 20.54 U/L, P = .802). ConclusionsSerum ALP concentration, which was increased in patients with AIS, might represent a low-potency biomarker for the diagnosis of AIS. However, this was not significantly correlated with NIHSS scores or the functional outcome after 1 year.

Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia.

This study used electronic medical records to identify risk factors and establish a detection algorithm for denosumab-induced hypocalcaemia. We identified 201 patients with cancer who were initially prescribed denosumab. Hypocalcaemia was defined as an adjusted serum calcium level of ≤2.13mmol/L. A diagnosis of denosumab-induced hypocalcaemia was confirmed by two physicians after reviewing patient medical records. We evaluated patient characteristics as potential screening factors. Moreover, a retrospective cohort study was conducted to identify risk factors for denosumab-induced hypocalcaemia. Odds ratios (ORs) were estimated using logistic regression analysis. We analysed 164 patients with a low risk of hypocalcaemia. Among these, 29 (17.7%) patients were suspected to have denosumab-induced hypocalcaemia. The times to onset of definitive hypocalcaemia were shorter among these patients than among patients with non-denosumab-induced hypocalcaemia. Based on receiver operating characteristic curve analysis, we used time to onset of hypocalcaemia of ≤90days as a second screening factor. The positive predictive value of this factor was 87.5%. In the retrospective cohort study, a significant difference was observed among patients with serum alkaline phosphatase (ALP) levels of >5.95μkat/L before initial prescription (P<0.01). Patients with higher serum ALP levels had a 6.63 times higher risk of developing hypocalcaemia than those without increased serum ALP levels (OR: 6.63, 95% confidence interval [CI]: 1.79-29.31). The same results were observed in a sensitivity analysis using another database. We developed a detection algorithm for denosumab-induced hypocalcaemia based on calcium levels and time to onset of hypocalcaemia. We also identified elevated ALP levels as a risk factor for hypocalcaemia. Clinicians should carefully monitor initial serum calcium levels and screen for signs of hypocalcaemia in patients receiving denosumab who demonstrate elevated serum ALP levels.

Metformin Alleviates the Bone Loss Induced by Ketogenic Diet: An In Vivo Study in Mice.

Metformin (Met), an anti-diabetes drug, has also shown therapeutic effects for ovariectomy-induced (OVX) osteoporosis. However, similar effects against bone loss induced by a ketogenic diet (KD) have not been tested. This study was aimed to evaluate the microarchitectures and biomechanics of KD-induced osteoporosis with and without administration of Met, and compare the effect of Met on bone loss induced by KD with OVX. Forty female C57BL/6J mice were randomly divided into Sham, OVX, OVX + Met (100mg/kg/day), KD (3:1 ratio of fat to carbohydrate and protein), and KD + Met (100mg/kg/day) groups. After 12 weeks, the bone mass and biomechanics were measured in distal cancellous bone and in mid-shaft cortical bone of the femur. The activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), together with immunohistochemistry staining of osteocalcin (OCN) and TRAP, were evaluated. Both OVX and KDinduced significant bone loss and compromised biomechanical properties in the cancellous bone, but no effect was found in cortical bone. The administration of Met increased the cancellous bone volume fraction (BV/TV) from 3.78 to 5.23% following the OVX and from 4.04 to 6.33% following the KD, it also enhanced the compressive stiffness from 47 to 160N/mm following the OVX and from 35 to 340N/mm with the KD. Met effectively increased serum ALP in the KD group while decreased serum TRAP in the OVX group, but up-regulated expression of OCN and down-regulated expression of TRAP in both OVX and KD groups. The present study demonstrated that Met effectively attenuated the cancellous bone loss induced by KD and maintained the biomechanical properties of long bones, providing evidence for Met as a treatment of by KD-induced osteoporosis in teenage skeleton.

Double intratibial injection of human tonsil-derived mesenchymal stromal cells recovers postmenopausal osteoporotic bone mass

Background and aimsOsteoporosis, which is a disease characterized by weakening of the bone, affects a large portion of the senior population. The current therapeutic options for osteoporosis have side effects, and there is no effective treatment for severe osteoporosis. Thus, we urgently need new treatment strategies, such as topical therapies and/or safe and effective stem cell therapies. MethodsWe investigated the therapeutic potential of directly injecting human tonsil-derived mesenchymal stem cells (TMSC) into the right proximal tibias of ovariectomized postmenopausal osteoporosis model mice. Injections were given once (1×) or twice (2×) during the 3-month experimental period. At the end of the experiment, micro-computed tomographic images revealed some improvement in the proximal tibias and more significant improvement in the femoral heads of treated mice. ResultsOsteogenic effect was qualitatively and quantitatively more pronounced in TMSC/2×-treated mice. Furthermore, TMSC/2× mice exhibited significant recovery of the serum osteocalcin level, which is pathologically elevated in osteoporosis, and increased serum alkaline phosphatase, which indicates bone formation. TMSC therapy was generally well tolerated and caused no apparent toxicity in the experimental mice. Moreover, TMSC therapy reduced visceral fat. ConclusionOur results demonstrate that double injection of TMSC directly into the proximal tibia triggers recovery of osteoporosis, and thus could be a potential therapeutic approach for severe bone loss.

Protocatechuic acid mitigates adriamycin-induced reproductive toxicities and hepatocellular damage in rats

Adriamycin (ADR) is an anticancer drug that has a wide report of toxicity in various organs including testes and liver. This has brought limitation to its use in chemotherapy. Protocatechuic acid (PCA) is a phenolic acid present in several foods of plant origins. The aim of this study is to assess the possible action of PCA in ADR-induced reproductive and hepatic toxicities in rats. Thirty adult male rats of about 160–180 g in weight were separated into five groups: group 1 was given normal saline and served as control group, group 2 was administered 20 mg/kg of ADR intraperitoneally, groups 3 and 4 were administered ADR and separate doses of PCA (10 and 20 mg/kg body weight) respectively, while the group 5 rats received only 20 mg/kg of PCA. Pre-treatment with PCA significantly improved sperm motility, sperm count, and viability in ADR-induced rats. Furthermore, elevated levels of testes and liver malondialdehyde were significantly reduced in rats treated with PCA. Also, the increased serum alkaline phosphatase, aspartate transaminase, total cholesterol, triglyceride total protein, and albumin levels in ADR-induced rats were brought near the control value by PCA treatment. Conversely, reduction in the levels of testes and liver glutathione as well as the serum high-density lipoprotein (HDL) cholesterol level in ADR group was significantly raised in PCA-treated rats. Therefore, PCA may represent a natural and promising compound for mitigating against oxidative stress-mediated toxicities.

Association between increased serum alkaline phosphatase and the coronary slow flow phenomenon

BackgroundDespite marked advances in our understanding of the pathophysiology of the coronary slow flow phenomenon (CSFP), the exact mechanism remains unclear. Previous studies have suggested that CSFP might be associated with generalized atherosclerosis, endothelial dysfunction, and low-grade chronic inflammation. High serum alkaline phosphatase (ALP) levels are associated with vascular calcification, atherosclerotic disease, and an increased risk of cardiovascular events. However, the relationship between ALP and CSFP is unclear.MethodsWe investigated 64 patients with angiographically proven CSFP and 50 with normal coronary flow. Serum ALP levels were measured in all studied individuals.ResultsSerum ALP levels in patients with CSFP were significantly higher than those in the control group (70.5 ± 17.1 vs. 61.9 ± 16.1 U/L, P = 0.007). A positive association was observed (r = 0.42, P = 0.032) between serum ALP levels and the mean thrombolysis in myocardial infarction frame count (mTFC). Regression analysis showed a high serum ALP level was the only independent predictor of the mTFC (β = 0.309, P < 0.001). Moreover, our study showed that a serum ALP level > 67.5 U/L was a predictor of CSFP (sensitivity = 83.3%, specificity = 84.1%).ConclusionsPatients with CSFP show high serum ALP levels, which may be associated with the pathogenesis of CSFP. A high serum ALP level is a predictor of CSFP. Future studies are needed to clarify the role of ALP in patients with CSFP.

The Effect of Maternal Supplementation of Zinc, Selenium, and Cobalt as Slow-Release Ruminal Bolus in Late Pregnancy on Some Blood Metabolites and Performance of Ewes and Their Lambs.

The aim of this study was to determine the effect of the supplementation of a slow-release bolus of zinc (Zn), selenium (Se), and cobalt (Co) at late gestation (6week prepartum) on performance and some blood metabolites of Mehraban ewes and their lambs until weaning. Seventy pregnant ewes, 6weeks prior to expected lambing, were randomly divided into two groups (35 heads each) including (1) control group and (2) slow-release bolus group. Blood samples of ewes were obtained on day 10 prepartum and 45 and 90days postpartum, and milk samples were collected on day 45. Blood samples of lambs were collected on days 10, 45, and 90. Body weight at birth and weaning and average daily gain were higher and percentage of mortality and white muscle disease rate were lower in lambs whose mothers were given a bolus (P < 0.05). Slow-release bolus administration increased serum alkaline phosphatase and whole blood glutathione peroxidase activity, plasma concentrations of Zn, Se, and vitamin B12 in ewes and their lambs (P < 0.05). In addition, serum creatine phosphokinase activity of lambs whose mothers were given bolus was lower (P < 0.05). Serum concentration of T3 in bolus given ewes and their lambs was higher (P < 0.05) and serum T4 concentration was lower (P < 0.05). Zinc, Se, and vitamin B12 concentrations in milk were significantly higher in treated ewes (P < 0.05). Obtained results showed that maternal supplementation of zinc, selenium, and cobalt as slow-release ruminal bolus in late pregnancy improved some mineral status of ewes and their lambs until weaning and led to higher body weights of lambs at weaning.

Factors influencing survival among patients with HER2-positive metastatic breast cancer treated with trastuzumab.

We have limited capability to predict survival among patients treated for metastatic HER2-positive breast cancer. Further research is warranted to identify significant prognostic and predictive factors. We identified all HER2-positive metastatic breast cancer patients receiving trastuzumab at the Sunnybrook Odette Cancer Centre (SOCC) from 1999 to 2013 through the Cancer Care Ontario (CCO) Registry (n=256) and selected patients with available pathology reports (n=154). A retrospective review was completed documenting clinical, pathologic, and laboratory characteristics at the time of first trastuzumab therapy and survival outcomes. Cox proportional hazards regression models were used to identify prognostic factors for overall survival (OS) (primary endpoint) and failure-free survival (FFS), adjusted for the known prognostic factors of the presence of CNS metastases and the presence of≥2 distant metastatic sites. A multivariable model identified older age [hazard ratio (HR) 1.18/decade, 95% confidence interval (CI) 1.02-1.37)], increased platelet-to-lymphocyte ratio (PLR) (HR 1.75/log-unit, 95% CI 1.25-2.46), increased serum alkaline phosphatase (ALP) (HR 1.87/log-unit, 95% CI 1.41-2.49), and ER positivity (HR 0.63, 95% CI 0.42-0.96) as significant prognostic factors for OS after adjusting for the presence of CNS metastasis (HR 3.19, 95% CI 1.59-6.38) and the presence of≥2 distant metastatic sites (HR 2.10, 95% CI 1.19-3.70). PLR (HR 1.54/log-unit, 95% CI 1.12-2.12) was the only prognostic factor associated with FFS after adjusting for CNS and≥2 distant metastatic sites. Older age, increased PLR, and ALP were identified as poor prognostic factors and ER positivity as a favorable prognostic factor for OS after adjusting for the presence of CNS metastasis and the presence of number of≥2 distant metastatic sites. Increased PLR was a poor prognostic factor for both OS and FFS, and warrants further investigation into its prognostic ability amongst patients with HER2-positive metastatic breast cancer.